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[ CAS No. 4637-24-5 ]

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Product Details of [ 4637-24-5 ]

CAS No. :4637-24-5 MDL No. :MFCD00008482
Formula : C5H13NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :ZSXGLVDWWRXATF-UHFFFAOYSA-N
M.W :119.16 Pubchem ID :78373
Synonyms :

Calculated chemistry of [ 4637-24-5 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 31.22
TPSA : 21.7 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) : -6.86 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.63
Log Po/w (XLOGP3) : 0.23
Log Po/w (WLOGP) : 0.12
Log Po/w (MLOGP) : 0.16
Log Po/w (SILICOS-IT) : -0.6
Consensus Log Po/w : 0.31

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.53
Solubility : 35.5 mg/ml ; 0.298 mol/l
Class : Very soluble
Log S (Ali) : -0.25
Solubility : 67.7 mg/ml ; 0.568 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.24
Solubility : 67.8 mg/ml ; 0.569 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.41

Safety of [ 4637-24-5 ]

Signal Word:Danger Class:3
Precautionary Statements:P210-P261-P280-P305+P351+P338 UN#:3271
Hazard Statements:H225-H302+H312+H332-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 4637-24-5 ]

* 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 [ 4637-24-5 ]
  • Downstream synthetic route of [ 4637-24-5 ]

[ 4637-24-5 ] Synthesis Path-Upstream   1~84

  • 1
  • [ 61535-21-5 ]
  • [ 4637-24-5 ]
  • [ 20289-27-4 ]
Reference: [1] Angewandte Chemie, International Edition, 2009, vol. 48, # 41, p. 7600 - 7603
  • 2
  • [ 18699-87-1 ]
  • [ 4637-24-5 ]
  • [ 3430-10-2 ]
  • [ 272-49-1 ]
Reference: [1] Organic Letters, 2009, vol. 11, # 6, p. 1357 - 1360
  • 3
  • [ 446-10-6 ]
  • [ 4637-24-5 ]
  • [ 399-51-9 ]
YieldReaction ConditionsOperation in experiment
5.7%
Stage #1: With pyrrolidine In DMF (N,N-dimethyl-formamide) at 20 - 115℃;
Stage #2: With hydrogen In methanol at 50℃;
Example S40; Preparation of 6-fluoro-1H-indole-7-carboxylic acid; A solution of 70.3 g of 4-fluoro-1-methyl-2-nitro-benzene (453 mmol) in 330 ml DMF was treated at rt with 87.5 ml of N,N-dimethylformamide dimethylacetal (DMFDMA, 589 mmol) and 50 ml of pyrrolidine (544 mmol) and then heated in an oil bath at 115° C. under argon. The dark red solution was then cooled down to rt, and poured into 1500 ml brine, extracted twice with diethylether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 106 g residue. About half of this residue (51.5 g) were dissolved in 800 ml methanol, treated with 12.5 g 10percent Pd/C and hydrogenated at 50° C. After removal of the catalyst by filtration, the residue was purified by silicagel chromatography (800 g silicagel, heptane/EtOAc 9:1) leading to 3.5 g of 6-fluoro-1H-indole as a light green solid (5.7percent).
Reference: [1] European Journal of Organic Chemistry, 2006, # 13, p. 2956 - 2969
[2] Patent: US2006/30613, 2006, A1, . Location in patent: Page/Page column 28
  • 4
  • [ 123-75-1 ]
  • [ 89-59-8 ]
  • [ 4637-24-5 ]
  • [ 17422-33-2 ]
Reference: [1] Patent: US5502071, 1996, A,
  • 5
  • [ 89-59-8 ]
  • [ 4637-24-5 ]
  • [ 17422-33-2 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 9, p. 4672 - 4675
[2] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 6
  • [ 127693-25-8 ]
  • [ 4637-24-5 ]
  • [ 1074-86-8 ]
  • [ 127693-05-4 ]
Reference: [1] Archiv der Pharmazie, 1990, vol. 323, # 3, p. 145 - 155
  • 7
  • [ 603-83-8 ]
  • [ 4637-24-5 ]
  • [ 5192-23-4 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 9, p. 4672 - 4675
  • 8
  • [ 13036-57-2 ]
  • [ 4637-24-5 ]
  • [ 14001-60-6 ]
  • [ 99357-40-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 2, p. 465 - 474
  • 9
  • [ 4472-44-0 ]
  • [ 4637-24-5 ]
  • [ 14001-61-7 ]
  • [ 13012-25-4 ]
  • [ 179009-28-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 2, p. 465 - 474
  • 10
  • [ 102871-92-1 ]
  • [ 4637-24-5 ]
  • [ 37865-86-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3942 - 3946
  • 11
  • [ 4637-24-5 ]
  • [ 1885-29-6 ]
  • [ 15018-66-3 ]
Reference: [1] Patent: KR2016/21163, 2016, A, . Location in patent: Paragraph 0680; 0682
  • 12
  • [ 58539-65-4 ]
  • [ 4637-24-5 ]
  • [ 23616-31-1 ]
YieldReaction ConditionsOperation in experiment
32%
Stage #1: at 50℃; for 2 h;
Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 2.5 h;
[0621] A mixture of XI-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,N-dimethylformamide dimethyl acetal was heated at 50° C. for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,N-dimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80° C. for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5° C. overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=7.0. After storage at 0-5° C. for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give XI-3 (3 g, 32percent yield). 1H NMR (DMSO-d6, 300 MHz): δ 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J=7.6 Hz, 1H).
32%
Stage #1: at 50℃; for 2 h;
Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 2.5 h;
A mixture of X-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,Ndimethylformamide dimethyl acetal was heated at 50°C for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,Ndimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80°C for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5°C overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=-7.0. After storage at 0-5°C for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give X-3 (3 g, 32percent yield). ‘H NMR (DMSO-d6, 300 MHz): ö 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J =7.6 Hz, 1H).
Reference: [1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1311 - 1317
[2] Patent: US2014/94456, 2014, A1, . Location in patent: Paragraph 0619; 0621
[3] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0367
  • 13
  • [ 504-29-0 ]
  • [ 4637-24-5 ]
  • [ 598-31-2 ]
  • [ 29096-64-8 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: for 23 h; Reflux
Stage #2: at 20℃; for 24 h;
2-Aminopyridine (1.88 g, 20 mmol) in 1,1-dimethoxyN,N-dimethylmethanamine (3.82 g, 32 mmol) was refluxed for 23 h and then evaporated. The resulting residue was dissolved in EtOH (35 mL), 1-bromoacetone (3.12 g, 22.75 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated and the residue was purified by column chromatography (eluent: dichloromethane/methanol = 40:1) to afford 12s as a pale yellow solid (2.06 g, 64percent). Mp: 95-96 °C (Lit.Mp [20] 98-99 °C). 1H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3H), 7.08 (t, J = 6.80 Hz, 1H), 7.50 (t, J = 8.00 Hz, 1H), 7.76 (d, J = 9.00 Hz, 1H), 8.34 (s, 1H), 9.65 (d, J = 6.84 Hz, 1H).
12%
Stage #1: at 90℃; for 3 h;
Stage #2: at 20℃; for 4 h;
A solution of intermediate 1 (20 g, 0.21 mol) and DMF-DMA (38 g, 0.32 mol) was stirred at 90° C. for 3 hrs. The mixture was concentrated in vacuum, the residue was dissolved in EtOH (200 ml), 1-bromopropan-2-one (32 g, 0.23 mol) was added dropwise, and the mixture was stirred at room temperature for 4 hrs. The solvent was concentrated in vacuum and purified by flash column chromatography to give intermediate 23 (4.1 g, 12percent) as a yellow solid. (0384) 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.649.66 (m, 1H), 8.35 (s, 1H), 7.76 (d, 1H, J=8.8 Hz), 7.487.52 (m, 1H), 7.077.11 (m, 1H), 2.62 (s, 3H)
Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 381 - 391
[2] Patent: US2018/214458, 2018, A1, . Location in patent: Paragraph 0382-0395
  • 14
  • [ 121-14-2 ]
  • [ 4637-24-5 ]
  • [ 4769-96-4 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 9, p. 4672 - 4675
  • 15
  • [ 15128-52-6 ]
  • [ 4637-24-5 ]
  • [ 27387-31-1 ]
YieldReaction ConditionsOperation in experiment
71% for 1 h; Reflux A mixture of 2,3-Dihydro-1H-carbazol-4(9H)-one (1.0 mmol)and DMF-DMA (10 mmol) in DMF (5.0 mL) was refluxed for 1.0 h.The reaction mixture was cooled and extracted with ethyl acetate(2 25 mL). The organic layer was separated and washed with brine solution. The organic layer was dried over anhydrous Na2SO4.The solvent was removed under reduced pressure and the solidobtained was recrystallized from ethanol.White needles, yield 71percent, m.p. 188–90 C. IR (cm1) 1695(CO), 1H NMR (400 MHz, CDCl3) d 2.24–2.27 (t, 2H, CH2,J = 6.28 Hz), 2.56–2.59 (t, 2H, CH2, J = 6.0 Hz), 2.91–2.94 (t, 2H,CH2, J = 6.21 Hz), 3.70 (s, 3H, NCH3), 7.27–7.30 (m, 3H, Ph), 8.24–8.26 (m, 1H, Ph). Anal. Calc. for C13H13NO: C, 78.36; H, 6.58, N,7.03percent. Found: C, 78.29; H, 6.49; N, 6.92percent.
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53B, # 12, p. 1606 - 1610
[2] Journal of Molecular Structure, 2014, vol. 1080, p. 137 - 144
[3] Russian Chemical Bulletin, 2005, vol. 54, # 8, p. 1887 - 1891
  • 16
  • [ 22424-58-4 ]
  • [ 4637-24-5 ]
  • [ 1215-59-4 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 14, p. 2919 - 2922
[2] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 17
  • [ 4637-24-5 ]
  • [ 26892-90-0 ]
YieldReaction ConditionsOperation in experiment
71% at 120℃; for 4 h; Ethyl 3- (2-aminophenyl) -3-oxopropionate (20.7 g, 0.1 mol) was dissolved in 100 mL of N, N-dimethylformamide,N, N-dimethylformamide dimethyl acetal (24.0 g, 0.2 mol) was added thereto, and the reaction was carried out at 120 ° C for 4 hours.The reaction solution was cooled to 20 ° C and the solvent was concentrated under reduced pressure. The residue was added to 200 g of ice water and stirred for 2 h.Ethanol and water volume (30mLx2 times), 50 drying, with 160mL ethyl acetate and petroleum ether equal volume mixedWas purified by recrystallization to obtain 15.4 g of ethyl 4-hydroxyquinoline-3-carboxylate in 71percent yield as an off-white solid.
Reference: [1] Patent: CN106187887, 2016, A, . Location in patent: Paragraph 0015; 0063; 0064; 0065; 0046; 0047
  • 18
  • [ 5372-81-6 ]
  • [ 4637-24-5 ]
  • [ 313535-84-1 ]
Reference: [1] Patent: US6348474, 2002, B1, . Location in patent: Page column 83
  • 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
  • [ 124-41-4 ]
  • [ 68-12-2 ]
  • [ 4637-24-5 ]
YieldReaction ConditionsOperation in experiment
85.4%
Stage #1: at 20 - 70℃; for 4 h;
Stage #2: at 25℃; for 2 h;
A process for the synthesis of N, N-dimethylformamide dimethylacetal comprising the steps of:(1) N, N-dimethylformamide was heated to 70 ° C, incubated with dimethyl sulfate, and reacted at the end of the dropwise addition for 4 hours to obtain an imine complex,Cooled to room temperature, and the molar ratio of N, N-dimethylformamide and dimethyl sulfate is 1: 1;(2) the solid sodium methoxide added to 200 solvent oil, ultrasonic dispersion, adjust the temperature to 25 ,Insulation, dropping imine complex, after the end of the reaction for 2h, filtration, the filtrate under normal pressure fractionation,A fraction of 105-108 ° C was collected to give N, N-dimethylformamide dimethyl acetal in a yield of 75.3percentPurity of 97percent; where the molar ratio of sodium methoxide to imine complex is 1: The synthesis method of N, N-dimethylformamide dimethyl acetal of Example 6 was the same as in Example 2 except that the organic solvent of this example was a mixed solvent oil: D40 solvent oil, D60 solvent oil, 260 (Volume ratio: 2: 1: 1) to give N, N-dimethylformamide dimethylacetal as a yield of 85.4percent and a purity of 97percent.
Reference: [1] Patent: CN106083611, 2016, A, . Location in patent: Paragraph 0034-0037; 0048-0049
  • 21
  • [ 1196967-42-6 ]
  • [ 1196967-61-9 ]
  • [ 4637-24-5 ]
Reference: [1] Angewandte Chemie, International Edition, 2009, vol. 48, # 41, p. 7600 - 7603
  • 22
  • [ 21511-55-7 ]
  • [ 4637-24-5 ]
YieldReaction ConditionsOperation in experiment
59% at 0 - 20℃; for 20 h; Inert atmosphere Separately, 440 g of anhydrous methanol and 111 g (2.05 mol) of sodium methoxide are added to a 1-liter three-necked flask under a nitrogen atmosphere and cooled to 0 to 5 ° C. 400.4 g (2.01 mol) of the immune complex was dropped for 3 hours while maintaining the temperature at 5 DEG C or lower, and the mixture was stirred at room temperature for 20 hours. The methanol was removed by distillation under atmospheric pressure and distilled under vacuum to obtain 141.3 g (yield 59percent) of colorless liquid dimethylformamide dimethylacetal.
Reference: [1] Patent: KR2016/120009, 2016, A, . Location in patent: Paragraph 0053
  • 23
  • [ 68-12-2 ]
  • [ 77-78-1 ]
  • [ 4637-24-5 ]
Reference: [1] Journal of Organometallic Chemistry, 1989, vol. 373, p. 1 - 10
[2] Journal of applied chemistry of the USSR, 1985, vol. 58, # 4 pt 1, p. 701 - 706
[3] Patent: WO2004/24727, 2004, A2, . Location in patent: Page 14
  • 24
  • [ 124-41-4 ]
  • [ 21511-55-7 ]
  • [ 4637-24-5 ]
Reference: [1] Patent: CN108516962, 2018, A, . Location in patent: Paragraph 0036; 0037; 0038
  • 25
  • [ 1192-62-7 ]
  • [ 4637-24-5 ]
  • [ 109482-86-2 ]
Reference: [1] Patent: US4374988, 1983, A,
  • 26
  • [ 350-03-8 ]
  • [ 55314-16-4 ]
  • [ 4637-24-5 ]
Reference: [1] Patent: US4374988, 1983, A,
  • 27
  • [ 68-12-2 ]
  • [ 154147-42-9 ]
  • [ 4637-24-5 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8084 - 8089
  • 28
  • [ 124-41-4 ]
  • [ 1071-38-1 ]
  • [ 1186-70-5 ]
  • [ 5762-56-1 ]
  • [ 4637-24-5 ]
Reference: [1] Advanced Synthesis and Catalysis, 2004, vol. 346, # 9-10, p. 1081 - 1086
  • 29
  • [ 67-66-3 ]
  • [ 124-41-4 ]
  • [ 4637-24-5 ]
  • [ 149-73-5 ]
Reference: [1] Tetrahedron, 1997, vol. 53, # 46, p. 15827 - 15832
  • 30
  • [ 67-66-3 ]
  • [ 124-41-4 ]
  • [ 68-12-2 ]
  • [ 4637-24-5 ]
  • [ 149-73-5 ]
Reference: [1] Tetrahedron, 1997, vol. 53, # 46, p. 15827 - 15832
  • 31
  • [ 67-66-3 ]
  • [ 124-41-4 ]
  • [ 68-12-2 ]
  • [ 201230-82-2 ]
  • [ 4637-24-5 ]
  • [ 149-73-5 ]
Reference: [1] Tetrahedron, 1997, vol. 53, # 46, p. 15827 - 15832
  • 32
  • [ 527-73-1 ]
  • [ 4637-24-5 ]
  • [ 1671-82-5 ]
YieldReaction ConditionsOperation in experiment
93.5% at 80℃; for 2 h; To 2-nitro-(1H)-imidazole (2.0 g, 17.7 mmol)N,N-dimethylformamide dimethyl acetal (8.4 g, 70.7 mmol) was added dropwise to a solution of DMF (10 ml).The reaction was carried out at 80 ° C for 2 h. Add water (30ml) and ethyl acetate (25ml),The mixture was extracted with ethyl acetate (25×2 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The crude product was separated by column chromatography (eluent: dichloromethane: anhydrous methanol = 30:1).A pale yellow solid (2.1 g, 93.5percent) was obtained.The product purity is 99.7percent (mass fraction)
Reference: [1] Patent: CN108503583, 2018, A, . Location in patent: Paragraph 0051-0053; 0059; 0060
  • 33
  • [ 4637-24-5 ]
  • [ 105-56-6 ]
  • [ 1260243-04-6 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With acetic acid In N,N-dimethyl-formamide at 25℃; for 1 h;
Stage #2: With hydrazine hydrate In N,N-dimethyl-formamide at 50℃; for 2 h;
To a solution of 25 g of ethyl cyanoacetate (1, 0.221 mol)in 25 cm3 dimethylformamide was added 37.5 cm3 glacialacetic acid (0.077 mol) followed by 47.40 g of N,N-dimethylformamidedimethyl acetal (0.397 mol) dropwise at room temperature and stirred for 1 h. To the resultant pale yellow color solution was added 25 cm3 hydrazine hydrate (0.42 mol) drop wise at 0°C and the reaction medium was stirred for 2 h 50 °C. After completion of the reaction, the reaction medium was diluted with 2.5 dm3 of water and extracted with 2 9 700 cm3 of ethyl acetate. The combined organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure to obtain the crude product as pale brown liquid. The crude product was further purified by column chromatography over silicagel, eluted with chloroform/methanol (95:5, v/v) to afford the compound 2 as a white solid (29 g, 85 percent). M.p.: 106.7–108.9 °C; TLC: Rf = 0.22 (CHCl3–MeOH 8:2); IR (ATR):v = 3193 (–NH), 2972 (=C–H), 1662 (ester –C=O), 1551(–C–C), 1496 (ester –C–O), 1337 (C–N) cm-1; 1H NMR(400 MHz, CDCl3): d = 1.23 (3H, t, J = 8 Hz, CH3), 4.15(2H, q, J = 8 Hz, OCH2CH3), 5.98 (2H, bs, ArNH2), 7.45(1H, bs, ArH), 12.04 (1H, bs, pyrazole NH) ppm; 13C NMR(100 MHz, DMSO-d6): d = 14.9, 59.1, 94.0, 139.9, 151.8,164.2 ppm; LC–MS: m/z = 156.7 [M+H]+.
70% at 20℃; for 2.5 h; Inert atmosphere To a solution of ethylcyanoacetate (3) (25 g, 221.0 mmol)in dimethylformamide (25 mL) and acetic acid(37.5 mL), dimethyl formamide dimethyl acetal(47.40 g, 397.8 mmol) was added drop wise at roomtemperature under nitrogen atmosphere over a period of30 min. The reaction medium was stirred at room temperaturefor 2 h. The reaction mixture was cooled to 0 °Cand hydrazine hydrate (80percent, 25 mL) was added drop wiseto it over a period of 45 min and then heated to 50 °C for2 h. Completion of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture wasdiluted with ice cold water (1L) and then extracted to ethylacetate (2 × 250 mL). The combined ethyl acetate layerwas dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The crude materialobtained was purified by column chromatography oversilica gel, eluted with 2–5percent methanol in chloroform to getthe product (4) as off-white solid (24 g, 70percent). MP:106.7–108.9 °C. IR (ATR, cm−1) υ: 1125.41 (C–O),1337.61 (C–N), 1496.40 (C–C), 1615.86 (N–H bend),1662.37 (ester C=O), 2972.92 (C–H), 3193.79(N–H stretch). 1H NMR (DMSO-d6, 400 MHz) δ (ppm):1.23 (3H, t, J = 7.2 Hz, ester–CH3), 4.16 (2H, q, J = 6.9Hz, ester–CH2), 5.99 (2H, bs, pyrazole–NH2), 7.47 (1H,bs, pyrazole–CH), 11.84 (1H, bs, pyrazole–NH). 13CNMR (DMSO-d6, 100 MHz) δ (ppm): 14.92 (ester–CH3),59.10 (ester–CH2), 94.00 (pyrazole–C-3), 139.93(pyrazole–C-4), 151.86 (pyrazole–C-5), 164.27 (carbonylfrom ester). LC-MS (ESI, m/z): 153.7 (M-H) and 156.7(M+H).
Reference: [1] Monatshefte fur Chemie, 2016, vol. 147, # 12, p. 2221 - 2234
[2] Medicinal Chemistry Research, 2017, vol. 26, # 4, p. 714 - 744
[3] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 3, p. 1904 - 1924
[4] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 1, p. 214 - 225
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  • [ 4637-24-5 ]
  • [ 105-45-3 ]
  • [ 23170-45-8 ]
Reference: [1] Patent: WO2016/81918, 2016, A1, . Location in patent: Paragraph 00292
[2] Patent: WO2017/205684, 2017, A1, . Location in patent: Paragraph 00706
  • 35
  • [ 4637-24-5 ]
  • [ 105-34-0 ]
  • [ 29097-00-5 ]
Reference: [1] Monatshefte fur Chemie, 2017, vol. 148, # 10, p. 1767 - 1780
  • 36
  • [ 4637-24-5 ]
  • [ 75-65-0 ]
  • [ 36805-97-7 ]
Reference: [1] Synthetic Communications, 1985, vol. 15, # 8, p. 723 - 726
  • 37
  • [ 4637-24-5 ]
  • [ 98-86-2 ]
  • [ 1201-93-0 ]
YieldReaction ConditionsOperation in experiment
97% at 140℃; for 12 h; In a 100 mL dry round bottom flask, acetophenone 1.08 g (9 mmol) of N,N-Dimethylformamide dimethyl acetal 3.9 mL (30 mmol) and 30 mL of xylene were added as a solvent. The mixture was refluxed at 140 ° C for 12 hours. After the TLC detection reaction was completed, the heating was stopped, the solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography to give a pale yellow solid N,N-(dimethylamino)-1-phenyl enaminoketones 1.48 g (97percent yield).
92% Reflux 2-1 1: Preparation of 3-dimethylamino-1- Yield: 92percent. Appearance: yellow solid. phenylprop-2-en-1-one (Protocol SA and 1H NMR: 2.93-3.14 (m, 6H); 5.73 (d, 1H, PC) J = 12.4 Hz); 7.38-7.49 (m, 3H); 7.82 (d, 1H, J = 12.4 Hz); 7.89 (d, 2H, J = 7.9 Hz).; Protocol SA:The appropriate ketone (acetophenone for Ex. 2-1; 4-trifluoroacetophenone for Ex. 2-2; 2-phenylacetophenone for Ex. 2-3; 2-acetylfuran for Ex. 2-5; para-acetylbiphenyl for Example 2-6; 3-trifluoromethylacetophenone 2.7) is dissolved in dimethyl acetal of N,N-dimethylformamide (1.2 to 1.5 eq.). The reaction mixture is stirred under reflux. The estimated reaction time varies between 24 and 48 hours. Satisfactory results were obtained in 24 hours.
83% at 115℃; for 20 h; To a 100 mL round bottom flask, was added acetophenone (1.0 g, 0.0083 mol) followed by NN-dimethylformamide dimethyl acetal (1.48 g, 0.012 mol). The reaction mixture was stirred at 115 °C for 20 h. The reaction mixture was cooled to room temperature and ether was added to get the solid. The solid was collected by filtration to get the title compound [1.2 g, 83 percent]. JH NMR (300 MHz, CDC13): δ 7.89-7.86 (m, 2H), 7.80 (d, = 12.3 Hz, 1H), 7.44-7.39 (m, 3H), 5.72 (d, = 12.6 Hz, 1H), 3.11 (s, 3H), 2.91 (s, 3H); LC-MS: 176.0 [M+H]+.
82% at 150℃; for 20 h; Inert atmosphere A mixture of acetophenone 1 (5.0 g, 41.66 mmol) and DMF-DMA (17.71 mL, 49.9 mmol) in DMF (10 mL) was heated to 150 0C under N2 atmosphere. After stirring for 2Oh at 150 0C, the reaction mixture was concentrated in vacuo. The resulting residue was triturated with diethyl ether, filtered and dried under high vacuum to obtain compound 2 (6 g, 82percent) as a yellow solid. TLC Rf = 0.5 (CHCl3 - MeOH, 7:3); 1H NMR (CDCl3) δ 7.88 (dd, J= 7.8, 1.5 Hz, 2H), 7.8 (d, J= 12.3 Hz, IH), 7.42 (m, 3H), 5.71 (d, J= 12.3 Hz, IH), 3.1 (s, 6H); MS (ES) mlz 176 (M + H)+.
82% at 150℃; for 20 h; Inert atmosphere General procedure: A mixture of acetophenone 7a-7d (41.66 mmol) and DMF-DMA (49.9 mmol) in DMF (10 mL) was heated to 150 oC under N2 atmosphere. After being stirred for 20h at this temperature, the reaction mixture was concentrated in vacuo and the residue obtained was triturated with diethyl ether, filtered and dried under high vacuum to obtain compound 2a-2d (70-85percent) as a yellow solid.
81% for 14 h; Reflux General procedure: To a mixture of acetone 14b (5.8 g, 100 mmol), inxylene (200 mL), was added dimethylformamide dimethylacetal (DMF-DMA, 11.9 g, 100 mmol)and the reaction refluxed for 15 h (monitored by TLC). The xylene was distilled off and the resultingsolid residue was purified by column chromatography using PE and EtOAc (6:1) as eluent to afford4-(dimethylamino)but-3-en-2-one 15b (4.3 g, 38percent) as a yellow oil.
62% for 21 h; Reflux 5 g of acetophenone, 15 g of N, N-dimethylformamide dimethylacetal, and 60 ml of xylene were refluxed overnight (21 hours), a little raw material was not reacted and the reaction was stopped.
The reaction solution was cooled and concentrated to remove xylene.
150 ml of petroleum ether was added to the residue, and a solid precipitated under stirring, followed by filtration to obtain 4.5 g of 3-dimethylamino-1-phenyl-prop-2-en-1-one as a yellow solid, 62percent.

Reference: [1] RSC Advances, 2017, vol. 7, # 45, p. 28483 - 28488
[2] Patent: CN108383763, 2018, A, . Location in patent: Paragraph 0044; 0046
[3] Patent: US2011/195993, 2011, A1, . Location in patent: Page/Page column 10; 14
[4] Journal of Organic Chemistry, 1980, vol. 45, # 24, p. 4857 - 4860
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 4, p. 1214 - 1217
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[7] Patent: WO2014/125426, 2014, A1, . Location in patent: Page/Page column 54; 55
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5609 - 5613
[9] Patent: WO2010/129049, 2010, A1, . Location in patent: Page/Page column 114; 118
[10] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4528 - 4532
[11] Chemical Communications, 2016, vol. 52, # 83, p. 12306 - 12309
[12] Molecules, 2017, vol. 22, # 12,
[13] Patent: WO2006/123648, 2006, A1, . Location in patent: Page/Page column 20
[14] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1707 - 1710
[15] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 8, p. 2742 - 2750
[16] Patent: EP3287456, 2018, A1, . Location in patent: Paragraph 0175
[17] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 837 - 843
[18] Journal of the Chinese Chemical Society, 2003, vol. 50, # 2, p. 283 - 296
[19] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 3055 - 3057
[20] Journal of the American Chemical Society, 2010, vol. 132, # 44, p. 15531 - 15533
[21] Journal of the Indian Chemical Society, 2010, vol. 87, # 6, p. 739 - 742
[22] ACS Combinatorial Science, 2011, vol. 13, # 4, p. 427 - 435
[23] Synthetic Communications, 2012, vol. 42, # 10, p. 1521 - 1531
[24] Tetrahedron, 2012, vol. 68, # 25, p. 5046 - 5052
[25] Organic Letters, 2012, vol. 14, # 15, p. 3920 - 3923
[26] Tetrahedron Letters, 2013, vol. 54, # 21, p. 2612 - 2614
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[28] Medicinal Chemistry Research, 2015, vol. 24, # 6, p. 2742 - 2755
[29] Synthetic Communications, 2015, vol. 45, # 16, p. 1902 - 1911
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[31] Synthetic Communications, 2015, vol. 45, # 23, p. 2683 - 2690
[32] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1749 - 1756
[33] New Journal of Chemistry, 2016, vol. 40, # 5, p. 4705 - 4709
[34] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 9966 - 9970
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[37] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 1 - 12
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[39] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 545 - 551
[40] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 307 - 317
[41] Patent: WO2018/142365, 2018, A1, . Location in patent: Page/Page column 66
[42] Bioorganic Chemistry, 2019, vol. 83, p. 549 - 558
[43] Chemical Communications, 2018, vol. 54, # 99, p. 13953 - 13956
  • 38
  • [ 23056-33-9 ]
  • [ 4637-24-5 ]
  • [ 17288-53-8 ]
  • [ 131084-55-4 ]
Reference: [1] Patent: WO2013/181075, 2013, A1, . Location in patent: Page/Page column 14; 15
  • 39
  • [ 6635-90-1 ]
  • [ 4637-24-5 ]
  • [ 17288-53-8 ]
Reference: [1] Patent: WO2016/114816, 2016, A1, . Location in patent: Paragraph 0283
  • 40
  • [ 446-10-6 ]
  • [ 4637-24-5 ]
  • [ 2923-96-8 ]
Reference: [1] Patent: WO2006/59164, 2006, A2, . Location in patent: Page/Page column 29
  • 41
  • [ 769-10-8 ]
  • [ 4637-24-5 ]
  • [ 1644-82-2 ]
YieldReaction ConditionsOperation in experiment
23%
Stage #1: at 135℃; for 12 h;
Stage #2: With sodium periodate In water; N,N-dimethyl-formamide at 20℃; for 3 h;
A mixture of l-fluoro-2-methyl-3-nitrobenzene and Λ/,Λ/-dimethylformamide dimethyl acetal (2.75 eq.) was heated to 135°C for 12 h. The reaction mixture was cooled to RT and added dropwise to a solution Of NaIO4 (2.75 eq.) in water/DMF (1 :1, 1.1 M). After the addition is finished, the reaction mixture was stirred at RT for 3 h. Then, it was filtered, and the solid was washed with toluene. The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layer was washed with water and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave a crude that was purified by flash chromatography on silica using a gradient of EtO Ac/Petroleum ether (1 :30) to afford (23percent) the title compound. MS (ES+) C7H4FNO3 required: 169, found: 170 (M+H)+.
Reference: [1] Patent: WO2010/13037, 2010, A1, . Location in patent: Page/Page column 62
  • 42
  • [ 55289-35-5 ]
  • [ 4637-24-5 ]
  • [ 20357-21-5 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: at 135℃; for 16 h;
Stage #2: With sodium periodate In water; N,N-dimethyl-formamide at 0 - 20℃; for 22 h;
Example 35; This example describes the synthesis of Aldehyde 10: To a stirred solution of 9 (4.94 g, 22.3 mmol) and DMF (22.3 mL) was added DMF'DMA (8.18 g, 9.59 mL, 68.6 mmol). After heating at 135°C for 16 h, the dark red solution was cooled to 0°C and added to a rapidly stirred solution OfNaIO4 (14.7 g, 68.6 mmol) in H2O (46 mL) and DMF (23 mL) at 0°C. The reaction flask was washed with DMF (23 mL) at 0°C and added to NaIO4 mixture. The reaction was stirred at O0C for 4 h then allowed to warm to rt. After an additional 18 h, the orange solution was filtered over a pad of celite-.(R). and rinsed with EtOAc (200 mL) to remove precipitate. The filtrate was then washed with H2O (3 x 150 mL) and sat. aq. NaCl (3 x 150 mL). The dried extract (MgSO4) was concentrated in vacuo and purified by chromatography over silica gel, eluting with 40percent EtOAc / Hexanes to give the known aldehyde 10 (3.44 g, 14.8 mmol, 67percent). 1H NMR (400 MHz, CDCl3) δ 10.3 (s, IH), 8.04 (dd, J= 1.0, 8.2 Hz, IH), 7.95 (dd, J= 1.0, 8.0 Hz, IH), 7.55 (t, J= 8.0 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 188.6, 148.4, 138.6, 132.9, 132.4, 123.4, 121.9.
Reference: [1] Patent: WO2008/156656, 2008, A2, . Location in patent: Page/Page column 58; 66; 120
  • 43
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  • [ 13512-31-7 ]
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Reference: [1] Journal of Natural Products, 1998, vol. 61, # 8, p. 1043 - 1045
  • 45
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  • [ 4637-24-5 ]
  • [ 119448-87-2 ]
Reference: [1] Zeitschrift fuer Naturforschung, B: Chemical Sciences, 1991, vol. 46, # 8, p. 1110 - 1112
[2] Zeitschrift fuer Naturforschung, B: Chemical Sciences, 1991, vol. 46, # 8, p. 1110 - 1112
[3] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 7, p. 1715 - 1720
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  • [ 111573-59-2 ]
Reference: [1] Chinese Journal of Catalysis, 2016, vol. 37, # 9, p. 1446 - 1450
  • 47
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  • [ 143722-29-6 ]
Reference: [1] Patent: US2005/90672, 2005, A1, . Location in patent: Page/Page column 3
[2] Patent: EP1548009, 2005, A2, . Location in patent: Page/Page column 5
  • 48
  • [ 1779-49-3 ]
  • [ 4637-24-5 ]
  • [ 79-22-1 ]
  • [ 147118-35-2 ]
Reference: [1] Patent: WO2014/195965, 2014, A2, . Location in patent: Page/Page column 10; 11
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  • [ 4637-24-5 ]
  • [ 52177-08-9 ]
  • [ 396091-50-2 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 50
  • [ 41252-97-5 ]
  • [ 4637-24-5 ]
  • [ 115666-47-2 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 110℃; for 4 h;
Stage #2: With hydrogenchloride; titanium(III) chloride In water; N,N-dimethyl-formamide at 0℃; for 3 h;
6-Iodoindole (4): Starting material 3 (5.00 g, 19.0 mmol, 1.0 equiv) was dissolved in DMF (50 mL). DMFDMA (3.05 mL, 22.8 mmol, 1.2 equiv) was added, followed by pyrrolidine (1.90 mL, 23.1 mmol, 1.2 equiv). The mixture was heated to 110 °C for 4 h until complete consumption of starting material as monitored by TLC, and allowed to cool to rt. DMF (100 mL) and 4 M aqueous NH4OAc buffer (83 mL, 17.5 equiv) were added and the solution was cooled with an ice bath. An aqueous solution of 20percent TiCl3 in 3percent HCl (73.3 mL, 114.06 mmol, 6.0 equiv) was added via a dropping funnel. The reaction mixture was stirred for 3 h followed by extraction with TBME (3 × 100 mL). The organic phase was washed with 2 M NaOH (100 mL), H2O (100 mL) and dried with MgSO4. After evaporation of the solvent the raw material was prepurified by short column chromatography [PE/EA (15:1)] to be sublimated in HV at 110–115 °C to give the product as a slightly yellowish solid (2.83 g, 11.6 mmol, 61percent). TLC [PE/EA (10:1)]: Rf = 0.25. Mp.: 103-105 °C. 1H NMR (400 MHz, CDCl3): = 8.10 (sbr, 1H, NH), 7.75 (dd, 1H, J = 2.0 Hz, J = 1.0 Hz, 4-H), 7.40-7.39 (m, 2H, 5-H and 7-H), 7.13 (dd, 1H, J = 3.2 Hz, J = 2.5 Hz, 2-H), 6.52 (ddd, 1H, J = 3.1 Hz, J = 2.0 Hz, J = 0.9 Hz, 3-H). 13C NMR (100 MHz, CDCl3): = 137.1 (1C, C-7a), 128.7 (1C, C-7), 127.2 (1C, C-3a), 124.5 (1C, C-2), 122.4 (1C, C-5), 120.0 (1C, C-4), 102.9 (1C, C-3), 85.8 (1C, C-6). IR (ATR): = 3888 (w), 3410 (s), 3094 (w), 3073 (w), 2925 (w), 1884 (w), 1726 (w), 1624 (w), 1597 (w), 1563 (w), 1493 (w), 1449 (m), 1392 (m), 1331 (m), 1309 (m), 1270 (w), 1232 (w), 1199 (w), 1090 (m), 1059 (w), 1043 (w), 998 (m), 944 (w), 878 (m), 858 (m), 802 (s), 759 (m), 727 (s), 651 (w), 607 (m), 586 (m), 565 (w). UV-Vis (MeOH): max (lg ) = 202 (4.32), 227 (4.62), 279 (3.86), 285 (3.86). MS (EI, 70 eV): m/z (percent) = 243 [M]+ (100), 116 [M–I]+ (56), 89 (26), 63 (12)
Reference: [1] Organic Letters, 2017, vol. 19, # 23, p. 6296 - 6299
[2] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 1700 - 1706
  • 51
  • [ 1192-62-7 ]
  • [ 4637-24-5 ]
  • [ 17168-45-5 ]
YieldReaction ConditionsOperation in experiment
97% at 100℃; for 9 h; A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100°C for 9 hours. After cooling as it was, the reaction mixture was concentrated. To the residue were added diethyl ether and hexane. The resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97percent) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J= 12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J = 0.8, 3.4 Hz), 7.68 (1H, d, J = 12.6 Hz), 7.79 (1H, dd, J = 0.8, 2.0 Hz).
97% at 100℃; for 9 h; Reference Example 5
3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one
A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for 9 hours.
After cooling as it was, the reaction solution was concentrated.
Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97percent) as a brown solid.
1H NMR (400 MHz, DMSO-d6) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J=12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J=0.8, 3.4 Hz), 7.68 (1H, d, J=12.6 Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz).
Reference: [1] Patent: EP1439175, 2004, A1, . Location in patent: Page 45-46
[2] Patent: US2004/6082, 2004, A1, . Location in patent: Page/Page column 22
[3] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1707 - 1710
[4] Organic Process Research and Development, 2008, vol. 12, # 3, p. 490 - 495
[5] Journal of the Korean Chemical Society, 2011, vol. 55, # 2, p. 243 - 250
[6] Asian Journal of Chemistry, 2012, vol. 24, # 4, p. 1837 - 1843
[7] Journal of the Chinese Chemical Society, 2003, vol. 50, # 2, p. 283 - 296
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 21, p. 6282 - 6285
[9] Synthetic Communications, 2012, vol. 42, # 10, p. 1521 - 1531
[10] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1581 - 1588
[11] Journal of Heterocyclic Chemistry, 2014, vol. 51, # SUPPL. 1, p. E384-E388
[12] Research on Chemical Intermediates, 2015, vol. 41, # 6, p. 3759 - 3765
[13] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 936 - 942
[14] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 545 - 551
[15] Bioorganic Chemistry, 2019, vol. 83, p. 549 - 558
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Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 7, p. 1853 - 1863
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Reference: [1] Patent: EP1382603, 2004, A1, . Location in patent: Page 42; 43
[2] Journal of Organometallic Chemistry, 2010, vol. 695, # 14, p. 1753 - 1760
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Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 10, p. 1598 - 1612
  • 56
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Reference: [1] RSC Advances, 2014, vol. 4, # 9, p. 4672 - 4675
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 10, p. 1598 - 1612
  • 57
  • [ 6342-56-9 ]
  • [ 50-01-1 ]
  • [ 4637-24-5 ]
  • [ 165807-05-6 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: at 110℃; for 15 h;
Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 110℃; for 36 h;
Pyruvic aldehyde dimethyl acetal (10 g, 84 mmol) and N, N’-dimethyl formamide dimethyl diacetal (10 g, 84 mmol) in DMF (30 ml) were heated in a round bottom flask at 110 °C for 15 h. Guanidine hydrochloride (12 g, 127 mmol) and NaOH (6.7 g, 169 mmol) in water were then added to the reaction mixture. The mixture was refluxed for further 36 h. The reaction mass was then cooled and filtered. The product was recrystallized from hot ethyl acetate to yield white crystalline solid 2 (10 g, 70percent).
36%
Stage #1: at 100℃; for 16 h;
Stage #2: With sodium hydroxide In water at 20℃; for 48 h;
Procedure H: Intermediate 8 (1-8) - 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal.; [0093] A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) pyruvric aldehyde dimethyl acetal was heated at 100 0C for 16 h. Methanol was removed in vacuo to afford a brown oil. A solution of 1.8 g (45 mmol, 1.1 eq.) of sodium hydroxide in 5 mL of water was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of water. The resulting solution was added to the above described oil. The resulting mixture was stirred at room temperature for 48 h. The mixture was filtered to provide 2.5 g (15 <n="38"/>mmol, 36percent) of 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (1-8).
50% With sodium hydroxide In water a)
2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal
Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h.
Methanol was removed in vacuo to afford an oil.
A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl (43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil.
The resulting mixture was stirred at 23° for 48 h.
Filtration afforded 25 g (50percent) of the title compound.
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 28, p. 3715 - 3717
[2] Patent: EP1227092, 2002, A2, . Location in patent: Page 25
[3] Patent: EP1229035, 2002, A1, . Location in patent: Page 25
[4] Patent: EP1227091, 2002, A2, . Location in patent: Page 25
[5] Patent: WO2007/104053, 2007, A2, . Location in patent: Page/Page column 36-37
[6] Patent: US5593992, 1997, A,
[7] Patent: US5670527, 1997, A,
  • 58
  • [ 50-01-1 ]
  • [ 4637-24-5 ]
  • [ 165807-05-6 ]
YieldReaction ConditionsOperation in experiment
50% With sodium hydroxide In water a
2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal
Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyrrhic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h.
Methanol was removed in vacuo to afford an oil.
A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl(43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil.
The resulting mixture was stirred at 23° for 48 h.
Filtration afforded 25 g (50percent) of the title compound.
Reference: [1] Patent: US5593991, 1997, A,
  • 59
  • [ 6342-56-9 ]
  • [ 7732-18-5 ]
  • [ 4637-24-5 ]
  • [ 180869-36-7 ]
YieldReaction ConditionsOperation in experiment
93% With sodium methylate; thiourea; methyl iodide In methanol a
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C.
After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C.
After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic).
After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL).
The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
93% With sodium methylate; thiourea; methyl iodide In methanol a)
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C.
After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C.
After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic).
After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3 X 100 mL).
The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
93% With sodium methylate; thiourea; methyl iodide In methanol a)
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C.
After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C.
After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic).
After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL).
The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
93% With sodium methylate; thiourea; methyl iodide In methanol a
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask.
After heating at 100° C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C.
After 18 h, the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic).
After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL).
The organics were combined, dried (Na2 SO4) and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.

Reference: [1] Patent: US5593991, 1997, A,
[2] Patent: US5593992, 1997, A,
[3] Patent: US5670527, 1997, A,
[4] Patent: US5739143, 1998, A,
[5] Patent: US5658903, 1997, A,
  • 60
  • [ 6342-56-9 ]
  • [ 4637-24-5 ]
  • [ 74-88-4 ]
  • [ 180869-36-7 ]
YieldReaction ConditionsOperation in experiment
82% With sodium methylate; thiourea In methanol a
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mnL, 459 mmol) were stirred together at 100° C. for 18 h.
The mixture was cooled.
Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h.
After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp.
After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82percent yield).
1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
82% With sodium methylate; thiourea In methanol a
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvic aldehyde dimethyl acetal (60 milliliter (hereinafter "mL"), 459 millimole (hereinafter "mmol")) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100° C. for 18 hours (hereinafter "h").
The mixture was cooled.
Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h.
After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp.
After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4), and concentration to yield the title compound as a brown oil (75.5 gram (hereinafter "g"), 82percent yield).
1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
82% With sodium methylate; thiourea In methanol a
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100° C. for 18 h.
The mixture was cooled.
Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h.
After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp.
After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82percent yield).
1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).
Reference: [1] Patent: US5977103, 1999, A,
[2] Patent: US6046208, 2000, A,
[3] Patent: US5756499, 1998, A,
  • 61
  • [ 6342-56-9 ]
  • [ 4637-24-5 ]
  • [ 180869-36-7 ]
YieldReaction ConditionsOperation in experiment
93% With sodium methylate; thiourea; methyl iodide In methanol; water a)
2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal
Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask.
After heating at 100° C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C.
After 18 h, the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic).
After 3 h, the solution was diluted with 250 mL of H2O and extracted with EtOAc (3*100 mL).
The organics were combined, dried (Na2SO4) and concentrated to give the title compound (26.8 g, 93percent) as a brown oil.
Reference: [1] Patent: US6218537, 2001, B1,
  • 62
  • [ 6342-56-9 ]
  • [ 4637-24-5 ]
  • [ 17356-08-0 ]
  • [ 74-88-4 ]
  • [ 180869-36-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[2] Patent: WO2016/7966, 2016, A2, . Location in patent: Paragraph 0024
[3] Patent: US2003/225082, 2003, A1, . Location in patent: Page 8-9
  • 63
  • [ 6342-56-9 ]
  • [ 22661-87-6 ]
  • [ 4637-24-5 ]
  • [ 180869-38-9 ]
Reference: [1] Patent: WO2007/104053, 2007, A2, . Location in patent: Page/Page column 37-38
  • 64
  • [ 4637-24-5 ]
  • [ 121-89-1 ]
  • [ 115955-48-1 ]
YieldReaction ConditionsOperation in experiment
89% at 140℃; for 12 h; In a 250 mL round bottom flask was added 16.5 g (100 mmol) of 3-nitroacetophenone, 26.5 mL of N,N-dimethylformamide dimethyl acetal (200 mmol) and 100 mL of xylene. The mixture was heated to 140°C for 12 hours. Then the reaction mixture was cooled to room temperature and the formed precipitate was filtered off, washed with petroleum ether and diethyl ether followed by purification by chromatography using ethyl acetate/cyclohexene (25/75) to afford 19.6 g of a yellow solid. Yield: 89percent. 1H NMR (200 MHz, DMSO-d6) δ 8.59 (t, 1H), 8.42 – 8.23 (m, 1H), 7.81 (d, J = 12.1 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 5.89 (d, J = 12.1 Hz, 1H), 3.17 (s, 1H), 2.95 (s, 1H). 13C NMR (50 MHz, DMSO-d6) δ 182.8, 155.2, 147.9, 141.6, 133.4, 129.8, 125.1, 121.5, 90.3, 44.7, 37.3.
79% Heating / reflux; Neat (no solvent) 3-Nitroacetophenone (5.0 g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) is heated at reflux overnight. The reaction mixture is cooled to room temperature and evaporated to remove the volatiles. The residue is slurried in ethyl ether and the suspension is filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C.
79% Heating / reflux 3-Nitroacetophenone (5.0g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and evaporated to remove the volatiles. The residue was slurried in ethyl ether and the suspension was filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C.
79% Heating / reflux 3-Nitroacetophenone (5.0g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and evaporated to remove the volatiles. The residue was slurried in ethyl ether and the suspension was filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C.
79% Heating / reflux Step 1: 3-(Dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one 3-Nitroacetophenone (5.0 g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) is heated at reflux overnight. The reaction mixture is cooled to room temperature and evaporated to remove the volatiles. The residue is slurried in ethyl ether and the suspension is filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C.
11.34 g for 21 h; Reflux 10 g of 3-nitroacetophenone (60.6 mmol, 1 equiv.), 35.63 g of N, N-dimethylformamide dimethylacetal (181 mmol, 3 equiv.), and 50 ml of xylene were refluxed overnight (21 hours), a little raw material was not reacted and the reaction was stopped.
The reaction solution was cooled and concentrated to remove xylene.
150 ml of petroleum ether was added to the residue, and a solid precipitated under stirring, followed by filtration to obtain 11.34 g of 3-dimethylamino-1-(3-nitrophenyl)-prop-2-en-1-one as a yellow solid.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 8, p. 1780 - 1783
[2] Patent: US2007/219183, 2007, A1, . Location in patent: Page/Page column 11
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2735 - 2738
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6890 - 6892
[5] Patent: US2006/63784, 2006, A1, . Location in patent: Page/Page column 43
[6] Patent: US2006/63785, 2006, A1, . Location in patent: Page/Page column 48-49
[7] Patent: US2007/219186, 2007, A1, . Location in patent: Page/Page column 22
[8] Journal of Medicinal Chemistry, 1998, vol. 41, # 15, p. 2858 - 2871
[9] Patent: WO2009/90548, 2009, A2, . Location in patent: Page/Page column 38-39
[10] Patent: EP3287456, 2018, A1, . Location in patent: Paragraph 0154
  • 65
  • [ 74420-15-8 ]
  • [ 4637-24-5 ]
  • [ 281192-91-4 ]
Reference: [1] Synlett, 2013, vol. 24, # 5, p. 570 - 574
  • 66
  • [ 4637-24-5 ]
  • [ 149457-03-4 ]
  • [ 123663-49-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 1, p. 131 - 139
  • 67
  • [ 367-21-5 ]
  • [ 4637-24-5 ]
  • [ 162012-67-1 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With acetic acid In toluene at 105℃; for 2 h;
Stage #2: at 125℃; for 3 h;
Compound 2-amino-4-fluoro-5-nitrobenzonitrile (7.2 g, 40 mmol) was dissolved into toluene (70 mL), DMF-DMA (N,N-dimethylformamide dimethyl acetal, 4.7 g, 40 mmol) and acetic acid (1 mL) was added, stirring to react at 105°C for 2 h, after concentration by evaporation, acetic acid (140 mL) and 3-chloro-4-fluoroaniline (6.9 g, 48 mmol) were added, stirring toreact at 125°C for 3 h. The reaction mixture was cooled to room temperature, poured into ice-water, after the pH value was adjusted to 9 with ammonia, then ethyl acetate 40 mL was added, stirred for 1 h, filtrated, dried to deliver the product N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine (8.3 g, 62percent yield). 1H-NMR (d-DMSO, 400 MHz, δ ppm): 10.61 (br, 1 H), 9.68 (d, J = 10.8 Hz, 1 H), 8.81 (s, 1 H), 8.10-8.13 (d, J= 7.6 Hz, 1 H), 8.05-8.07 (d, J = 8 Hz, 1 H), 7.81-7.85 (m, 1 H), 7.50-7.54 (d, J = 8 Hz, 1 H).
Reference: [1] Patent: EP3181553, 2017, A1, . Location in patent: Paragraph 0129
  • 68
  • [ 4637-24-5 ]
  • [ 105-45-3 ]
  • [ 203186-56-5 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 44, p. 8609 - 8613
[2] Tetrahedron, 2004, vol. 60, # 39, p. 8633 - 8644
  • 69
  • [ 85598-13-6 ]
  • [ 4637-24-5 ]
  • [ 436091-59-7 ]
YieldReaction ConditionsOperation in experiment
44%
Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 90℃; for 18 h;
Stage #2: for 1 h; Reflux
Stage #3: With sodium carbonate In water
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitro-benzene (31 g, 0.126 mol) in DMF (150 mL) was added dimethylformamide dimethylacetal (27 mL) and pyrrolidine (10.5mL, 0.127 mol). The mixture was heated at 90°C for 18h and cooled to r.t. The mixture was diluted with water and extracted with CH2CI2. The organic phase was dried over Na2S04i filtered and concentrated. The residue was dissolved into HOAc (50 mL) and added dropwise to a solution of Fe (20.5 g, 0.37 mol) in boiling HOAc (150 mL). The mixture was refluxed for 1h and cooled to r.t., water added and the mixture was neutralised with Na2C03, and extracted with CH2CI2.The organic phase was dried over Na2S04, filtered and concentrated. The residue was purified by Prep-TLC (PE/EtOAc =5/1) to give the title compound (13 g, 44percent). H NMR CDCI3400 MHz δ: 8.41 (brs, 1 H), 7.18-7.08 (m, 2H), 6.49-6.43 (m, 2H), 3.86 (s, 3H).
44%
Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 90℃; for 18 h;
Stage #2: for 1 h; Reflux
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitro-benzene (31 g, 0.126 mol) in DMF (150 mL) was added dimethylformamide dimethylacetal (27 mL) and pyrrolidine (10.5 mL, 0.127 mol). The mixture was heated at 90° C. for 18 h and cooled to r.t. The mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was dissolved into HOAc (50 mL) and added dropwise to a solution of Fe (20.5 g, 0.37 mol) in boiling HOAc (150 mL). The mixture was refluxed for 1 h and cooled to r.t., water added and the mixture was neutralised with Na2CO3, and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EtOAc=5/1) to give the title compound (13 g, 44percent). 1H NMR CDCl3400 MHz δ: 8.41 (brs, 1H), 7.18-7.08 (m, 2H), 6.49-6.43 (m, 2H), 3.86 (s, 3H).
Reference: [1] Patent: WO2013/117522, 2013, A1, . Location in patent: Page/Page column 41-42
[2] Patent: US2015/18367, 2015, A1, . Location in patent: Paragraph 0185; 0186
  • 70
  • [ 88-15-3 ]
  • [ 96605-65-1 ]
  • [ 4637-24-5 ]
  • [ 325715-02-4 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: at 150℃; for 1 h;
Stage #2: at 150℃; for 5 h;
In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene was added,(N, N-dimethylbutyl) benzylammonium chloride (202 g, 0.5 mmol)Dimethylformamide dimethylacetal (22 g, 0.15 mmol) was added, and the mixture was stirred at 150 ° C for 1 hour.Then, 1.7 g (0.05 mmol) of hydroxylamine was added, and the reaction was stirred at 150 ° C for 5 hours.6.8 g (0.05 mmol) of aminoguanidine hydrochloride and the appropriate amount of water were added and the reaction was stirred at 150 ° C for 1 hour,12.3 g (0.05 mmol) of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] -N-methylacetamide was added,The reaction was stirred at 100 ° C for 5 hours, cooled to 10 ° C,Add 100 ml of dichloromethane to extract, dry over anhydrous magnesium sulfate, filter,The methylene chloride was evaporated to give an oil which was recrystallized from methanol to give 11 g of product as a yellow needle, yield 58percent.
Reference: [1] Patent: CN104016988, 2016, B, . Location in patent: Paragraph 0034-0035
  • 71
  • [ 4637-24-5 ]
  • [ 101385-93-7 ]
  • [ 157327-42-9 ]
YieldReaction ConditionsOperation in experiment
83% at 105℃; for 1 h; [00377] Step 1: Synthesis of tert-butyl 3-((dimethylamino)methylene)-4- oxopyrrolidine– 1-carboxylate. A suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (10 g, 54.05 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (120 mL) was stirred at 105°C for 1 h., cooled down to room temperature, the solvent was removed in vacuo and the residue was purified by chromatographic column on silicagel (DCM/MeOH = 60/1 to 20/1) to give tert-butyl 3-((di-methyl- amino)methylene)-4-oxopyrrolidine-1-carboxylate (10.78 g, 83percent yield). ESI-LCMS (m/z): 241.2[M+1]+;1HNMR (400 MHz, CDCl3) δ ppm: 7.26 (s, 1H), 4.57 (s, 2H), 3.86 (s, 2H), 3.09 (s, 6H), 1.48 (s, 9H).
46% at 100℃; for 17 h; Preparation 31
3-Dimethylaminomethylene-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours.
The dioxane was removed in vacuo.
The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered.
The solid was rinsed with hexanes (2*80 mL) and air dried.
Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46percent).
46% at 100℃; for 17 h; Preparation 31
3-Dimethylaminomethylene-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours.
The dioxane was removed in vacuo.
The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered.
The solid was rinsed with hexanes (2*80 mL) and air dried.
Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46percent).
41 g at 105℃; for 0.666667 h; The 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (40g, 216mmol) was dissolved in 300ml DMF-DMA was heated at 105 deg. C 40 minutes. The solution was cooled and evaporated under reduced pressure, hexane was added, and filtered to give an orange solid 41g, and dried, it was used for the next reaction without purification.
41 g at 105℃; for 0.666667 h; (0086) 3-oxopyrrolidine-1-tert-butyl carboxylate (40g, 216mmol) was dissolved in 300mL DMF-DMA, heated for 40 minutes at 105°C. Cooled and concentrated to dry under vacuum, treated with hexane, filtered to obtain orange solid 41g, dried, the product can be used in the reaction of the next step without purification.
4.7 g at 100℃; for 1.5 h; A solution of N-Boc-3-pyrrolidinone (CAS Number 101385-93-7; 5.0 g, 27.0 mmol) in DMF- DMA (32.17 g, 270 mmol) was heated at 100°C for 1.5 h. The resulting mixture was cooled to rt and concentrated under reduced pressure. The obtained residue was triturated with n-pentane (100 ml). The resulting solid was dried under high vacuum yielding tert-butyl 3-((dimethylamino)methylene)-4- oxopyrrolidine-l-carboxylate (4.700 g, 19.58 mmol). LCMS: Method 1, 1.556 min, MS: ES+ 241.43.

Reference: [1] Patent: WO2016/44641, 2016, A2, . Location in patent: Paragraph 00377
[2] Heterocycles, 2002, vol. 56, # 1-2, p. 257 - 264
[3] Patent: US2013/237538, 2013, A1, . Location in patent: Paragraph 0308
[4] Patent: US2013/237537, 2013, A1, . Location in patent: Paragraph 0292-0293
[5] Patent: WO2007/97931, 2007, A2, . Location in patent: Page/Page column 32
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5361 - 5366
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5767 - 5771
[8] Patent: CN105622612, 2016, A, . Location in patent: Paragraph 0126; 0127
[9] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10498 - 10519
[10] Patent: EP3144310, 2017, A1, . Location in patent: Paragraph 0085-0086
[11] Patent: WO2017/158381, 2017, A1, . Location in patent: Page/Page column 73
[12] Patent: US9951069, 2018, B1, . Location in patent: Page/Page column 14-15
  • 72
  • [ 79099-07-3 ]
  • [ 4637-24-5 ]
  • [ 157327-41-8 ]
YieldReaction ConditionsOperation in experiment
100% at 80℃; for 24 h; A mixture of N,N-dimethylformamide dimethyl acetal (18 g, 20 mL, 151 mmol) and l-(tert-butoxycarbonyl)piperidin-4-one (30 g, 151 mmol) in DMF (240 mL) was stirred at 80 °C for 24 h. The mixture was concentrated in vacuo to give the title compound as a yellow solid (38.4 g, 100percent). MS (ESI, pos. ion) m/z: 255 [M + H]+.
100% at 80℃; for 24 h; N, N-dimethylformamide dimethyl acetal (18 g, 20 mL, 151 mmol) and1- (tert-butoxycarbonyl) piperidin-4-one (30 g, 151 mmol)N, N-dimethylformamide (240 mL)The mixture was heated and stirred at 80 ° C for 24 hours.The reaction was complete and concentrated under reduced pressure to give the title compound as a yellow solid (38.4 g, 100percent).
94.4% at 95℃; for 1.5 h; S1. Add N- t-butoxycarbonyl-4-piperidone (1) (12g, 60mmol) in 250ml flask, 150ml DMF-DMA, reaction at 95 1.5h, TLC showed the reaction was complete, concentrated to give 3 - ((N, N- dimethylamino) - methylene) -N- tert-butoxycarbonyl-4-piperidone (2) (white solid, 14.4g), yield 94.4percent.
82% for 20 h; Reflux Preparation 21
t-Butyl-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate
A solution of N-Boc-4-piperidone (10 g, 50.19 mmol) and DMF-dimethylacetal (20.16 ml, 150.57 mmol) in 1,4-dioxane (100 ml) was heated at reflux for 20 hours.
The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7percent MeOH in EtOAc) to give the title compound as an orange oil which crystallized on standing (10.51 g, 82percent).
82% for 20 h; Reflux Preparation 21
t-Butyl-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate
A solution of N-Boc-4-piperidone (10 g, 50.19 mmol) and DMF-dimethylacetal (20.16 ml, 150.57 mmol) in 1,4-dioxane (100 ml) was heated at reflux for 20 hours.
The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7percent MeOH in EtOAc) to give the title compound as an orange oil which crystallized on standing (10.51 g, 82percent).
76% at 80℃; for 18 h; Inert atmosphere Step 1DMF dimethyl acetal (5.82 mL, 0.044 mol) was added to a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (8.73 g, 0.044 mol) in DMF (80 mL) and the reaction mixture was heated to 80 °C under N2 for 18 h. After cooling, the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and H20. The organic layer was washed with H20 and saturated brine, then dried over MgS04 and evaporated to afford tert- butyl 3-((dimethylamino)methylene)-4-oxopiperidine-l-carboxylate (8.44 g, 76percent).
63.8% for 1.5 h; Reflux N-tert-butoxycarbonyl-4-piperidone (58, 5.8 g, 31.4 mmol) wasdissolved in N,N-dimethylformamide dimethyl acetal (45.0 mL),and the solution was heated under reflux for 1.5 h and concentrated.The residue was triturated with hexane, filtered, andwashed with hexane to give 59 as a yellow powder (5.1 g, 63.8percent):mp 135e136 C; To a solution of 59 (5.0 g, 20.8 mmol) in EtOH(200.0 mL) were added guanidine carbonate (15.0 g, 84.0 mmol)and sodium acetate (13.7 g, 167.0 mmol), and the solution washeated under reflux for 48 h. The reaction mixturewas filtered, andthe insoluble material was extracted with CHCl3 and washed withwater. The organic layer was dried over anhydrous MgSO4 andevaporated. The resultant solid was triturated with 2-propanol,filtered, and washed with 2-propanol and Et2O to give a colorlesspowder. It was dissolved in TFA (50.0 mL) at 0 C, and the solutionwas stirred at room temperature for 1 h and concentrated. Theresidue was dissolved in 2-propanol and treated with concentrated HCl (4.0 mL). The precipitated solidwas filtered andwashed with 2-propanol and Et2O to give 60a (4.2 g, 81.6percent) as a colorless powder: Mp 258e260 C; Compound 57g was obtained from 60a in thesame way as 57f.
60% for 15 h; Reflux A solution of N-t-Butoxycarbonyl-4-piperidone (10.0 g, 50.19 mmol) and N,N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in 1,4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8percent MeOH in EtOAc) to obtain the title compound as an orange oil which crystallized on standing (7.64 g, 60percent).
40% for 6 h; Reflux Stage 1: tert-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate
A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100.38 mmol, 1.0 eq.) and N,N-dimethylformamide dimethylacetal (80 ml) was refluxed for 6 hours.
After monitoring by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM (300 ml), washed with water (200 ml) and sat. NaCl solution (200 ml), dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, 2.5percent MeOH in DCM). Yield: 40percent (10.2 g, 40.16 mmol)

Reference: [1] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0308
[2] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0905; 0906; 0907
[3] Patent: CN105669672, 2016, A, . Location in patent: Paragraph 0027; 0031; 0032
[4] Patent: US2013/237538, 2013, A1, . Location in patent: Paragraph 0252
[5] Patent: US2013/237537, 2013, A1, . Location in patent: Paragraph 0236-0237
[6] Patent: US6169093, 2001, A,
[7] Patent: WO2011/103196, 2011, A1, . Location in patent: Page/Page column 82-83
[8] Heterocycles, 2002, vol. 56, # 1-2, p. 257 - 264
[9] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 399 - 412
[10] Patent: US9296747, 2016, B1, . Location in patent: Page/Page column 22-23
[11] Patent: US2012/71461, 2012, A1, . Location in patent: Page/Page column 136
[12] Patent: WO2005/105759, 2005, A1, . Location in patent: Page/Page column 81
[13] Patent: EP1806347, 2007, A1, . Location in patent: Page/Page column 17
[14] Patent: WO2007/146122, 2007, A2, . Location in patent: Page/Page column 44
[15] Patent: US2004/147561, 2004, A1, . Location in patent: Page 44
[16] Patent: EP1803710, 2007, A1, . Location in patent: Page/Page column 17
[17] Patent: WO2012/85167, 2012, A1, . Location in patent: Page/Page column 51
[18] Patent: WO2014/113191, 2014, A1, . Location in patent: Paragraph 0157; 0158
[19] Patent: WO2016/164200, 2016, A1, . Location in patent: Page/Page column 24
[20] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10498 - 10519
[21] Patent: WO2016/177655, 2016, A1, . Location in patent: Page/Page column 175; 200
[22] Patent: WO2018/83106, 2018, A1, . Location in patent: Page/Page column 20; 21
  • 73
  • [ 1005737-41-6 ]
  • [ 4637-24-5 ]
  • [ 52200-22-3 ]
Reference: [1] Heterocycles, 2008, vol. 75, # 1, p. 145 - 156
  • 74
  • [ 75-97-8 ]
  • [ 4637-24-5 ]
  • [ 17356-08-0 ]
  • [ 74-88-4 ]
  • [ 496863-48-0 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: at 100℃; for 48 h;
Stage #2: With sodium methylate In methanol for 118 h; Heating / reflux
1) 4-Acetyl-2-methylthiopyrimidine A mixture of 3, 3-dimethylbutan-2-one (25.15 g) and N, N-dimethylformamide dimethylacetal (126 mL) was stirred at an external temperature of 100°C for 48 hours. After air cooling, the low boiling point components generated during the reaction were evaporated under reduced pressure, and methanol (400 mL), thiourea (28.92 g) and sodium methoxide (15.39 g) were added to the residue thus obtained. The mixture was heated to reflux for 118 hours. After air cooling, sodium methoxide (10.26 g) was added to the reaction solution, methyl iodide (17.8 mL) was added dropwise to the mixture over 5 minutes under ice cooling, and the mixture was stirred for 5 hours. Water and ethyl acetate were added to a residue obtained by evaporating the reaction solvent under reduced pressure, and the mixture was partitioned. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and an aqueous 3 N hydrochloric acid solution (400 mL) was added to the residue thus obtained and stirred for 15 hours at room temperature. Ethyl acetate was added to the reaction solution and the mixture was partitioned, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 4-acetyl-2-methylthiopyrimidine (26.34 g, 82percent) as a solid. 1H-NMR(400MHz, CDCl3)δ: 2.63(3H, s), 2.70(3H, s), 7.51(1H, d, J=4.9Hz), 8.74(1H, d, J=4.9Hz). ESI-MSm/z: 169(M+H)+.
Reference: [1] Patent: EP1785418, 2007, A1, . Location in patent: Page/Page column 39
  • 75
  • [ 24078-21-5 ]
  • [ 4637-24-5 ]
  • [ 201932-92-5 ]
Reference: [1] Patent: WO2007/87129, 2007, A2, . Location in patent: Page/Page column 67
  • 76
  • [ 4637-24-5 ]
  • [ 224185-19-7 ]
  • [ 259860-08-7 ]
YieldReaction ConditionsOperation in experiment
16% With hydrazine hydrate In tetrahydrofuran; methanol; N,N-dimethyl-formamide 6-Bromo-5-fluoroindole
N,N-Dimethylformamide dimethylacetal (8.5 mL, 60 mmol) was added in one portion to a stirred solution of 3-bromo-4-fluoro-6-methylnitrobenzene (11.8 g, 50 mmol) in N,N-dimethylformamide (30 mL) at room temperature under Ar.
The mixture was heated to 120° C., stirred for 16 h then concentrated in vacuo to leave a crude oil.
The oil was crystallized [methanol-dichloromethane (4:1)] to give a purple solid (4.5 g).
The solid was dissolved in methanol/tetrahydrofuran (1:1; 30 mL) and Raney Nickel.(R). (1 g) was added.
The mixture was cooled to 0° C. and hydrazine hydrate (0.8 mL, 16 mmol) was added in one portion.
The mixture was stirred at 0° C. for 90 min then a further aliquot of hydrazine hydrate (0.8 mL) was added.
The mixture was stirred at 0° C. for 30 min then filtered through celite.(R). and the filter cake was washed with tetrahydrofuran.
The filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (4:1)] to give the product (1.7 g, 16percent) as an off-white solid: IR νmax (nujol)/cm-1 3395, 2925, 2855, 1570, 1469, 1451, 1408, 1314, 1145, 1105, 865, 763 and 502; NMR δH (400 MHz, CDCl3) 7.85 (1H, br. s), 7.55 (1H, d, J 5.5 Hz), 7.34 (1H, d, J 9 Hz), 7.23 (1H, t, J 2.8 Hz), 6.49-6.51 (1H, m).
Reference: [1] Patent: US6380238, 2002, B1,
  • 77
  • [ 4637-24-5 ]
  • [ 187834-88-4 ]
  • [ 280110-69-2 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: at 50℃; for 4 h;
Stage #2: With toluene-4-sulfonic acid In toluene at 100℃; for 18 h;
To a solution of 9.0 g of 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 9703986 A1 19970206) (37 mmoles, 1 eq.) in 40 ml of THF, were added 8.1 ml of dimethylformamide dimethyl acetal (55.4 mmoles, 1.5 eq.). The reaction mixture was then stirred at 50° C. for 4 hours under nitrogen. The solvent was removed under reduced pressure, the residue dissolved in 40 ml of toluene, and 400 mg of para toluene sulfonic acid were added. The mixture was then heated at 100° C. under nitrogen for 18 hours, the volatiles were removed under reduced pressure and the residue was partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol as eluant (98:2 v/v to 95:5 v/v) to afford 8.07 g of the title compound as a white solid (81percent). 1H NMR (400 MHz, CD3OD): δ 1.42 (s, 9H), 1.70 (m, 2H), 2.05 (m, 2H), 2.50 (s, 3H), 3.00 (m, 2H), 3.15 (m, 1H), 4.05 (m, 2H); LCMS: m/z APCl+, 268 [MH]+; Found; C, 58.26percent; H, 7.96percent; N, 15.78percent; C13H21N3O3 requires C, 58.41percent, H, 7.92percent, N, 15.72percent
81%
Stage #1: at 50℃; for 4 h;
Stage #2: at 100℃; for 18 h;
To a solution of ferf-butyl 4-(hydrazinocarbonyl)-1-piperidinecarboxylate (see WO 00/39125, preparation 27) (9.0 g, 37 mmol), in tetrahydrofuran (40 ml), was added dimethylformamide dimethyl acetal (8.1 ml, 55.4 mmol). The reaction mixture was stirred at 500C for 4 hours, under nitrogen. The solvent was then removed under reduced pressure, the residue was dissolved in toluene (40 ml), and para-toluenesulfonic acid (400 mg, 2.1 mmol) was added. The reaction mixture was heated at 1000C, under nitrogen, for 18 hours, after which time the cooled reaction EPO <DP n="48"/>mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (200 ml) and an aqueous solution of sodium bicarbonate (150 ml). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol as eluant (98:2 v/v to 95:5 v/v) to yield the title compound (8.07 g, 81percent) as a white solid.1H NMR (400MHz1 CD3OD): δ 1.42 (s, 9H), 1.70 (m, 2H), 2.05 (m, 2H1), 2.50 (s, 3H), 3.00 (m, 2H), 3.15 (m, 1 H), 4.05 (m, 2H); LCMS: m/z APCI+ 268 [MH]+
Reference: [1] Patent: US2005/154024, 2005, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2006/114706, 2006, A1, . Location in patent: Page/Page column 46-47
  • 78
  • [ 885519-07-3 ]
  • [ 4637-24-5 ]
  • [ 393553-57-6 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 122 - 125
  • 79
  • [ 22726-00-7 ]
  • [ 4637-24-5 ]
  • [ 342617-08-7 ]
Reference: [1] Patent: CN102516115, 2016, B, . Location in patent: Paragraph 0409; 0410
  • 80
  • [ 3132-99-8 ]
  • [ 4637-24-5 ]
  • [ 342617-08-7 ]
Reference: [1] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 165
  • 81
  • [ 141-97-9 ]
  • [ 4637-24-5 ]
  • [ 203186-58-7 ]
YieldReaction ConditionsOperation in experiment
3.6 g at 60℃; for 3 h; To a solution of ethyl acetoacetate (2.6 g, 20 mmol) in ethanol (10 mL) was added N,N-Dimethylformamide dimethyl acetal (2.5 g, 21 mmol). The mixture was allowed to stir at 60 °C for 3 h, then cooled to room temperature and concentrated to give a crude product (3.6 g, 97percent), which was used without further purification.
Reference: [1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 5, p. 1038 - 1043
[2] Patent: WO2017/151786, 2017, A1, . Location in patent: Paragraph 00230
  • 82
  • [ 23056-33-9 ]
  • [ 4637-24-5 ]
  • [ 17288-53-8 ]
  • [ 131084-55-4 ]
Reference: [1] Patent: WO2013/181075, 2013, A1, . Location in patent: Page/Page column 14; 15
  • 83
  • [ 1265234-00-1 ]
  • [ 4637-24-5 ]
  • [ 1265231-91-1 ]
Reference: [1] Patent: EP2471786, 2012, A1, . Location in patent: Page/Page column 115-116
  • 84
  • [ 697739-03-0 ]
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  • [ 1082040-43-4 ]
Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904
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