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[ CAS No. 56651-60-6 ] {[proInfo.proName]}

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Chemical Structure| 56651-60-6
Chemical Structure| 56651-60-6
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Product Details of [ 56651-60-6 ]

CAS No. :56651-60-6 MDL No. :MFCD00673064
Formula : C9H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :QRBHVARIMDDOOV-UHFFFAOYSA-N
M.W : 163.17 Pubchem ID :187910
Synonyms :

Safety of [ 56651-60-6 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P280-P305+P351+P338-P342+P311 UN#:2206
Hazard Statements:H302-H312-H315-H319-H332-H334-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 56651-60-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 56651-60-6 ]

[ 56651-60-6 ] Synthesis Path-Downstream   1~97

  • 1
  • [ 138457-70-2 ]
  • [ 56651-60-6 ]
  • [ 179559-93-4 ]
YieldReaction ConditionsOperation in experiment
69% With triethylamine In tetrahydrofuran at 50℃; for 1h;
  • 2
  • [ 32315-10-9 ]
  • [ 2393-23-9 ]
  • [ 56651-60-6 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane General procedure C: preparation of N-alkyl-3-oxobenzo[d]isothiazole-2(3H)-carboxamide analogues 6a-w General procedure: To a solution of triphosgene (2.96 g, 10 mmol) in DCM (20 ml) was added dropwise to primary amine 4 (10 mmol) in DCM (20 ml) followed by the dropwise addition of triethylamine (3 ml) in DCM (10 ml). The solvent was removed on a rotary evaporator. The resulting residue was dissolved in DCM (20 ml), and 1,2-benzisothiazol-3-one (1.51 g, 10 mmol) in THF (20 ml) was added. After the mixture was refluxed for 30 min, the solvent was removed on a rotary evaporator. The residue was dissolved in acetone (30 ml) and mixed with water (30 ml). The precipitate was collected on a funnel by vacuum filtration and washed with water-acetone (1:1,4 × 5 ml) to afford the final compound.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -80℃;
With sodium hydrogencarbonate In dichloromethane; water at 0℃; for 2.5h; 1.) Synthesis of the urea derivatives General Procedure: The amine (0.80 mmol) was added to a stirred mixture of 5 ml saturated sodium bicarbonate solution (NaHCO3) and 5 ml dichloromethane (DCM) at 0 °C. Afterwards triphosgene (0.28 mmol) was added slowly. After 2.5 h at 0 °C 10 ml of DCM were added and the organic layer separated from the aqueous phase. The aqueous phase was washed twice with 10 ml of DCM. The combined organic layers were washed with ammonium chloride (NH4Cl) and brine and later dried over sodium sulfate, filtered and concentrated to approximately 0.5 ml.
In toluene for 4h; Reflux;
In toluene Reflux; 4.2.2 General procedure for the preparation of α-amino acid ureas (3a-3l) General procedure: A solution of triphosgene (0.15 g, 0.5 mmol) in toluene was dropwise added the amine (1 mmol) at room temperature. After the addition was completed, the reaction suspension was refluxed for 6 h, then toluene was evaporated, and the residue was taken up by CH2Cl2, then added to a solution of the α-amino acid methyl ester hydrochlorides (1.2mmol) with triethylamine (0.17 ml, 1.2 mmol) in CH2Cl2 dropwise at 0 °C. After the addition was completed, the reaction solution was stirred at room temperature for hours. Then CH2Cl2 evaporated, the residue was taken up with ethyl acetate and washed with brine. After being dried with MgSO4 and condensed, α-amino acid ureas (3a-3l) were obtained without further purification.
With triethylamine In dichloromethane at 20℃; for 0.25h;
With triethylamine In dichloromethane at 0℃; for 3h; Inert atmosphere; Reflux;
With triethylamine In dichloromethane at 25℃; for 14h; C-1.1 Step 1 : To a solution of triphosgene (29.6 g) in CH2CI2 (200 mL) was added a solution of p- methoxybenzylamine (13.7 g) in CH2CI2 (200 mL), followed by the dropwise addition of Et3N (30 mL) in CH2CI2 (100 mL). The resulting mixture was stirred at 25°C for 14 h. Water (500 mL) was added and the reaction mixture was extracted with CH2CI2 (3 χ 200 mL). The organic layers were combined, washed with sat. NH4CI (600 mL), brine (600 mL), dried over Na2S04, filtered, and concentrated to afford 1-(isocyanatomethyl)-4-methoxy-benzene (17 g, crude) as yellow oil. 1H NMR (CDCI3, 400 MHz) δ 7.26 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 4.45 (s, 2H), 3.85 (s, 3H).
In toluene for 4h; Reflux; 16.1 Preparation of Compound 16: Step 1, benzylamine (5 mmol, 700 mg) and toluene (10 mL) were added to a 100 mL round bottom flask, and triphosgene (5 mmol, 1.5 g) was added under stirring, and the reaction was refluxed for 4 hours. The solvent was removed by concentration, then dichloromethane (5 mL) was evaporated.
With triethylamine In dichloromethane at 25℃; for 14h; 2.a.1 Step 1: To a solution of triphosgene (29.6 g) in CH2Cl2 (200 mL) was added a solution of p-meth- oxybenzylamine (13.7 g) in CH2Cl2 (200 mL), followed by the dropwise addition of Et3N (30 mL) in CH2Cl2 (100 mL). The resulting mixture was stirred at 25°C for 14 h. Water (500 mL) was added and the reaction mixture was extracted with CH2Cl2 (3 × 200 mL). The organic layers were com- bined, washed with sat. NH4Cl (600 mL), brine (600 mL), dried over Na2SO4, filtered, and concen- trated to afford 1-(isocyanatomethyl)-4-methoxy-benzene (17 g, crude) as yellow oil.1H NMR (CDCl3, 400 MHz) δ 7.26 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 4.45 (s, 2H), 3.85 (s, 3H).
Stage #1: bis(trichloromethyl) carbonate; 4-methoxy-benzylamine In dichloromethane Stage #2: With triethylamine In dichloromethane 3.1.6. General Procedure for the Synthesis of the Target Urea Derivatives General procedure: Triphosgene (0.20 g, 0.67 mmol) was dissolved in 10 mL DCM, a solution of substitutedaniline or benzylamine (2 mmol) in 10 mL DCM was slowly dropped in during stirring.There were solids that gradually precipitated out. Then a solution of TEA (0.4 g, 4 mmol) inDCM (10 mL) was slowly dropped into the mixture, the solids gradually dissolved, and thesolution of substituted isocyanate 7 was obtained. The solution of 5 or 6 (2 mmol) in 10 mLDCM was added. After the reaction was completed, the mixture was washed by waterand brine and dried by Na2SO4. After DCM was distilled off under reduced pressure, themixture was purified by silica gel chromatography (DCM:EA = 5:1, v/v) to afford 8a-8iand silica gel chromatography (DCM:MeOH = 20:1, v/v) to afford 9a-9g.

Reference: [1]Liu, Dazhi; Tian, Zhen; Yan, Zhihui; Wu, Lixin; Ma, Yan; Wang, Quan; Liu, Wei; Zhou, Honggang; Yang, Cheng [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 2960 - 2967]
[2]Hirota, Kosaku; Kazaoka, Kazunori; Niimoto, Itaru; Sajiki, Hironao [Organic and Biomolecular Chemistry, 2003, vol. 1, # 8, p. 1354 - 1365]
[3]Monte, Fabio Lo; Kramer, Thomas; Boländer, Alexander; Plotkin, Batya; Eldar-Finkelman, Hagit; Fuertes, Ana; Dominguez, Juan; Schmidt, Boris [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5610 - 5615]
[4]Su, Li; Cao, Jiangying; Jia, Yuping; Zhang, Xiaonan; Fang, Hao; Xu, Wenfang [ACS Medicinal Chemistry Letters, 2012, vol. 3, # 12, p. 959 - 964]
[5]Chen, Yu; Su, Li; Yang, Xinying; Pan, Wenyan; Fang, Hao [Tetrahedron, 2015, vol. 71, # 49, p. 9234 - 9239]
[6]Ueno, Sohei; Nakazaki, Atsuo; Nishikawa, Toshio [Organic Letters, 2016, vol. 18, # 24, p. 6368 - 6371]
[7]Giacomini, Daria; Martelli, Giulia; Piccichè, Miriam; Calaresu, Enrico; Cocuzza, Clementina Elvezia; Musumeci, Rosario [ChemMedChem, 2017, vol. 12, # 18, p. 1525 - 1533]
[8]Current Patent Assignee: BASF SE - WO2017/167832, 2017, A1 Location in patent: Page/Page column 67
[9]Current Patent Assignee: CHENGDU LIANCHUANG RONGCHENG MEDICINE TECH - CN108409614, 2018, A Location in patent: Paragraph 0196-0199
[10]Current Patent Assignee: BASF SE - WO2018/206479, 2018, A1 Location in patent: Page/Page column 65
[11]Hou, Shicheng; Liang, Shishao; Zhang, Chao; Han, Yingmei; Liang, Jianhui; Hu, Hongyu; Zhang, Xingeng; Hu, Chun; Liu, Xiaoping; Zhang, Hong [Molecules, 2021, vol. 26, # 12]
  • 3
  • [ 65185-56-0 ]
  • [ 56651-60-6 ]
  • 3-benzyl-1-(4-methoxy-benzyl)-3,4-dihydro-1<i>H</i>-quinazolin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In toluene at 100℃; for 20h;
  • 4
  • [ 56651-60-6 ]
  • 1,2-bis-(2-prop-2-ynyloxy-ethoxy)-benzene [ No CAS ]
  • 19-(4-methoxybenzyl)-3,6,13,16-tetraoxa-19-aza-tricyclo[16.2.2.07,12]docosa-1(21),7(12),8,10,18(22)-pentaen-20-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In 1,2-dimethoxyethane at 85℃;
  • 5
  • [ 2393-23-9 ]
  • [ 56651-60-6 ]
  • [ 93731-94-3 ]
YieldReaction ConditionsOperation in experiment
for 5h;
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 6
  • [ 50919-07-8 ]
  • [ 56651-60-6 ]
  • 1-(4-Methoxy-benzyl)-3-[(S)-1-(3-methoxy-phenyl)-ethyl]-urea [ No CAS ]
  • 7
  • [ 854028-10-7 ]
  • [ 56651-60-6 ]
  • (Z)-3-(4-methoxy-benzyliminomethyleneamino)-but-2-enoic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% In toluene at 80℃;
67% In toluene at 80℃; for 4h;
  • 8
  • [ 854028-09-4 ]
  • [ 56651-60-6 ]
  • (E)-3-(4-methoxy-benzyliminomethyleneamino)-but-2-enoic acid benzyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% In toluene at 80℃; for 4h;
  • 9
  • [ 81777-30-2 ]
  • [ 56651-60-6 ]
  • 3-(4-methoxy-benzyliminomethyleneamino)-but-2-enoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% In toluene at 80℃; for 4h;
71% In toluene at 80℃; for 4h;
  • 10
  • [ 39139-87-2 ]
  • [ 105-13-5 ]
  • [ 56651-60-6 ]
YieldReaction ConditionsOperation in experiment
97% With triphenylphosphine; 2,3-dicyano-5,6-dichloro-p-benzoquinone In acetonitrile at 20℃;
  • 11
  • [ 40785-55-5 ]
  • [ 56651-60-6 ]
  • [ 663619-18-9 ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: (2-hydroxyphenyl)-glyoxylic acid ethyl ester; 4-methoxybenzyl isocyanate With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; for 2h; Stage #2: With formic acid at 20 - 60℃; for 21h;
  • 12
  • [ 663619-17-8 ]
  • [ 56651-60-6 ]
  • 4-hydroxy-2-oxo-3,4-dihydro-2<i>H</i>-naphtho[2,1-<i>e</i>][1,3]oxazine-4-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (1-hydroxy-[2]naphthyl)-glyoxylic acid ethyl ester; 4-methoxybenzyl isocyanate With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; Stage #2: With formic acid at 20 - 60℃;
  • 13
  • [ 56651-60-6 ]
  • [ 663619-13-4 ]
  • 4-hydroxy-6-methyl-2-oxo-3,4-dihydro-2<i>H</i>-benzo[<i>e</i>][1,3]oxazine-4-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-methoxybenzyl isocyanate; ethyl 2-(2-hydroxy-5-methylphenyl)-2-oxoacetate With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; Stage #2: With formic acid at 20 - 60℃;
  • 14
  • [ 56651-60-6 ]
  • [ 663619-15-6 ]
  • 6-fluoro-4-hydroxy-2-oxo-3,4-dihydro-2<i>H</i>-benzo[<i>e</i>][1,3]oxazine-4-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-methoxybenzyl isocyanate; (5-fluoro-2-hydroxy-phenyl)-oxo-acetic acid ethyl ester With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; Stage #2: With formic acid at 20 - 60℃;
  • 15
  • [ 56651-60-6 ]
  • ethyl 2-(2-hydroxy-5-methoxyphenyl)-2-oxoacetate [ No CAS ]
  • 4-hydroxy-6-methoxy-2-oxo-3,4-dihydro-2<i>H</i>-benzo[<i>e</i>][1,3]oxazine-4-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-methoxybenzyl isocyanate; ethyl 2-(2-hydroxy-5-methoxyphenyl)-2-oxoacetate With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; Stage #2: With formic acid at 20 - 60℃;
  • 16
  • [ 56651-60-6 ]
  • [ 663619-16-7 ]
  • 4-hydroxy-7-methoxy-2-oxo-3,4-dihydro-2<i>H</i>-benzo[<i>e</i>][1,3]oxazine-4-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-methoxybenzyl isocyanate; ethyl 2-(4-methoxy-2-hydroxyphenyl)-2-oxoethanoate With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; Stage #2: With formic acid at 20 - 60℃;
  • 17
  • [ 56118-48-0 ]
  • [ 56651-60-6 ]
  • 1-(4-methoxybenzyl)-4-methyl-3-pentylidenepiperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; 1,3-bis-(diphenylphosphino)propane In dichloromethane at 20℃; for 25h;
  • 18
  • [ 359878-18-5 ]
  • [ 56651-60-6 ]
  • [ 359880-64-1 ]
YieldReaction ConditionsOperation in experiment
50% In dichloromethane for 16h; 126 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxybenzylisocyanate (196 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40° C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 192 mg (50%) 47AKU-44. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+ =382.3 (UV/MS(%)= 100/94). 1H- NMR (400 MHz, CDCl3): δ 7.10 (4H5 m); 6.98 (2H5 m); 6.76 (2H5 m); 4.58 (IH5 1); 4.45 (IH5 m); 4.33 (2H5 s); 4.25 (2H5 d); 3.76 (3H5 s); 2.97 (2H5 m); 2.34 (3H, s); 2.32 (3H, s); 2.24 (2H5 m); 1.78 (4H, m). 13C-NMR (CDCl3): δ 158.9, 158.5, 137.3, 135.2, 131.8, 129.8, 128.8, 126.2, 114.1, 55.5, 55.4, 51.7, 45.8, 45.7, 44.5, 29.7, 21.2.
  • 19
  • [ 56651-60-6 ]
  • [ 359880-78-7 ]
YieldReaction ConditionsOperation in experiment
23% In dichloromethane for 20h; 132 47AKU-5-2 (404 mg, 1.6 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxybenzylisocyanate (326 mg, 2.0 mmol) in 5 ml dichloromethane was added. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (45° C). Crude product was purified three times by flash chromatography (0-20% methanol in dichloromethane and 0-30% methanol in ethylacetate) giving 155 mg (23%) 58AKU-3. HCl-salt was prepared from 2M HCl/diethylether in dichlorom ethane/heptane. TLC (10% methanol in dichloromethane): Rf =0.3. HPLC-MS (Method A): M+ =424.2 (UV/MS(%)=92/83). 1H-NMR (400 MHz, CDCl3): δ 7.10 (4H, m); 6.99 (2H5 m); 6.76 (2H, m); 4.53 (IH, m); 4.35 (3H, s); 4.26 (2H5 d); 3.77 (3H5 s); 3.09 (2H, m); 2.32 (3H3 s); 2.22 (2H, m); 1.81-1.54 (4H5 m); 1.06 (9H, s). 13C-NMR (CDCl3): δ 158.9, 158.6, 137.1. 135.6 131.9, 129.7, 128.8, 126.2, 114.0, 62.6, 55.5, 53.0, 45.9, 45.7, 44.5, 31.0, 26.3, 21.2.
  • 20
  • [ 947522-96-5 ]
  • [ 56651-60-6 ]
  • 1-(4-methoxybenzyl)-3-[2-(methylene-4H-benzo[d][1,3]oxazine-2-yl)phenyl]urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% In toluene Heating;
88% In toluene at 20℃; Inert atmosphere; Reflux;
  • 21
  • C32H32NPO3 [ No CAS ]
  • [ 56651-60-6 ]
  • 6-benzyloxy-3-(4-methoxy-benzyliminomethyleneamino)-hex-2-enoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% In toluene at 80℃; for 4h;
  • 22
  • [ 71989-31-6 ]
  • [ 98-09-9 ]
  • [ 56651-60-6 ]
  • [ 188970-92-5 ]
  • C23H28N4O7S [ No CAS ]
  • 23
  • [ 947403-75-0 ]
  • [ 56651-60-6 ]
  • C13H22N2O4NCOC6H4CH2CH3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In toluene at 80℃; for 12h;
  • 24
  • [ 871032-54-1 ]
  • [ 56651-60-6 ]
  • N-[(4-methoxyphenyl)methyl]-4-[3-[[[6-methyl-4'-(trifluoro-methoxy)[1,1'-biphenyl]-2-yl]carbonyl]amino]phenoxy]-1-piperidinecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: 6-methyl-N-[3-(4-piperidinyloxy)phenyl]-4'-(trifluoromethoxy)-[1,1'-biphenyl]-2-carboxamide; 4-methoxybenzyl isocyanate In dichloromethane for 8h; Stage #2: In dichloromethane at 20℃; T5 N-[3-(Piperidin-4-yloxy)phenyl]-6-methyl-4'-trifluoromethoxybiphenyl-2-car- boxamide (94.1 mg; 0.2 mmol) is dissolved in 5 ml of dichloromethane, and 4- methoxybenzyl isocyanate (1.1 eq. ; 31.4 ml) is added. The reaction medium is stirred for 8 hours and Trisamine polystyrene resin (0.3 eq. ; 0.6 mmol) is then added. Stirring is continued at room temperature overnight. After filtration, the fil- trate is evaporated and the crude product is purified by flash chromatography on silica (elution: gradient of heptane to 100% EtOAc) to give 103.5 mg of the expected product. Yld = 82 % Mass: ES- = 632.4.
  • 25
  • [ 791071-55-1 ]
  • [ 56651-60-6 ]
  • [ 791071-56-2 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In toluene Heating / reflux; 5 A mixture of Compound O (3.35 g, 15.0 mmol) and 4-methoxybenzyl isocyanate (4.89 g, 30.0 mmol) prepared by the method described in J. Chem. Soc. Perkin Trans 1, (1995) p.2783 were added to toluene (30 mL). After to the mixture was added triethylamine (0.695 mL, 5.00 mmol), the mixture was heated under reflux for 2 overnights. After air-cooling, the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 1/1) to give ethyl 1-cylcopentyl-3-(4-methoxybenzylureido)-1H-pyrazole-4-carboxylate (Compound P: 5.79 g, 100%).
  • 26
  • [ 896467-75-7 ]
  • [ 56651-60-6 ]
  • [ 896467-77-9 ]
YieldReaction ConditionsOperation in experiment
100% In tetrahydrofuran at 0℃; for 0.166667h; 26.C Paramethoxybenzylisocyanate (1.62 ml, 11.34 mmol) was added dropwise to an ice cooled solution of l-(4-methoxy-benzyl)-4-nitro-lH-pyrazole-3-carboxylic acid EPO hydrazide (3 g, 10.3 mmol) in THF (70 ml). After 10 min the reaction was allowed to warm to 250C. Et2O was then added added to the reaction mixture. The desired hydrazide urea intermediate was filtered off as a white solid (5g, 100%) (LC/MS (acidic method): Rt 2.84, [M+H]+455). A portion of this material (3 g, 6.6 mmol) was added to 2N aq. NaOH (100 ml) and heated in a microwave reactor for 15 min at 14O0C. The reaction mixture was partitioned between sat. aq. NH4Cl solution (200 ml) and EtOAc (3 x 200 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give a crude solid. This was then triturated with Et2O to give 4-(4-methoxy-benzyl)-5-[l-(4-methoxy-benzyl)-4-nitro-lH-pyrazol-3-yl]- 2,4- dihydro-[l,2,4]triazol-3-one as a pale coloured solid (1.29 g, 45%) (LC/MS (acidic method): Rt 2.82, [M+H]+437).
  • 27
  • [ 896467-55-3 ]
  • [ 56651-60-6 ]
  • C20H18F2N6O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 20℃; for 6h; 3.G A mixture of 2,6-difluoro-N-(3-hydrazinocarbonyl-lH-pyrazol-4-yl)-benzamide (888 mg) and^αra-methoxybenzylisocyanate (0.5 mL) in anhydrous THF (25 mL) was stirred under a nitrogen atmosphere at ambient temperature for 6 h. The mixture was reduced in vacuo to give the intermediate hydrazide (1.71 g) as a beige solid. A mixture of the hydrazide (1.5 g) in 2 M aqueous NaOH solution (45 mL) was heated at reflux for 4 h, allowed to cool to ambient and then poured into saturated aqueous NH4Cl (200 mL). The solid formed was collected by filtration and dried through azeotrope with toluene to give the title compound (1.19 g) as an off-white solid.
  • 28
  • [ 449798-87-2 ]
  • ammonium chloride [ No CAS ]
  • [ 56651-60-6 ]
  • [ 449800-08-2 ]
YieldReaction ConditionsOperation in experiment
45.2 mg (15%) With lithium hexamethyl-disilazane In tetrahydrofuran; ethyl acetate S.8 6-(3,4-Dichloro-benzyl)-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-c-]pyrimidine-2-carboxylic acid 4-methoxy-benzylamide SYNTHESIS EXAMPLE 8 6-(3,4-Dichloro-benzyl)-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-c-]pyrimidine-2-carboxylic acid 4-methoxy-benzylamide Lithium hexamethyldisilazane (0.9 ml, 1 M in THF, 0.9 mmol) was added to a solution of 6-(3,4-dichlorobenzyl)-thiazolo[3,2-c]pyrimidine-5,7-dione (0.200 g, 0.61 mmol) in tetrahydrofuran (10 ml), under nitrogen at -72° C. After 3 minutes, 1-isocyanatomethyl-4-methoxy-benzene (0.22 ml, 1.5 mmol) was added. The reaction was stirred 15 minutes, then aqueous ammonium chloride was added, and the reaction allowed to warm to room temperature. EtOAc (50 ml) was added to the reaction, water layer was removed, and the organic layer was, dried (Na2 SO4) and evaporated. The residue was chromatographied on silica gel eluding with CH2Cl2: EtOAc, 9:1. The isolated product was triturated with diethyl ether and dried in vacuum to give 45.2 mg (15%) of the desired compound: mp 206-207° C.; MS (APCI+), m/z (%): 493(15), 492(80), 490(100), 329(40), 326(55), 263(30), 12 (30).
  • 29
  • CH2Cl299/CH3OH [ No CAS ]
  • [ 56651-60-6 ]
  • [ 221540-53-0 ]
YieldReaction ConditionsOperation in experiment
61.3% With pyridine In ethanol S.27.a 3rd Stage: 3rd Stage: Methyl 3-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate 0.750 g (3.6 mmol) of Intermediate 1 and 7.5 ml of pyridine are introduced into a round-bottomed flask. 3.6 mmol of 4-methoxybenzyl isocyanate is added. The mixture is maintained at 100° C. overnight. Since the reaction is incomplete, 2 additions of phenethyl isocyanate, i.e. 2 equivalents, are carried out. After precipitation with H2O, filtration and purification by reslurrying in hot ethanol, the product is obtained as follows: Weight: 0.750 g, yield=61.3%, NMR: DMSO 1H δ (ppm): 3.7 (s,3H); 3.8 (s,3H); 5.0 (s,2H); 6.8-6.85 (m,2H); 7.2-7.3 (m,3H), 8.1-8.2 (m,1H); 8.5 (s,1H); 11.9 (bs,1H).
  • 30
  • [ 923562-89-4 ]
  • [ 56651-60-6 ]
  • [ 1029046-51-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester; 4-methoxybenzyl isocyanate With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 0.5h; Stage #2: With acetic acid In dichloromethane 17.1 Step 1 - Preparation of3,5-dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l- carboxylic acid; 4-methoxy-benzylamide (P-0135):[0179] 3-(3,5-dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert- butyl ester (514, 10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). 1,8- Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. 1 -Isocyanatomethyl-4-methoxy- benzene (545, 6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to the reaciton. The solv ents were removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.2 mL) and purified by reverse phase HPLC on a Phenomcnex column (50mm x 10mm ID), eluting with vuitei with 0 1 % trifluoroacctic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0135. MS (ESI) [M^HT = 390.3.
  • 31
  • [ 14527-26-5 ]
  • [ 56651-60-6 ]
  • (((4-methoxybenzyl)amino)carbonyl)carbamimidothioic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
S-methylisothiouronium sulfate (15.35 g, 55.2 mmol) was dissolved in 8:2:1 MeOH/H2O/THF (150 mL) and the mixture was treated with 3 N NaOH (18.4 mL, 55.2 mmol). The solution was then cooled to 0 C and 4-methoxybenzyl isocyanate (Cpd 5a, 9.0 g, 55.2 mmol) was added dropwise over 30 min. The reaction was stirred overnight and gradually warmed to room temperature. The mixture was then washed with saturated aqueous NH4Cl (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant residue was purified by normal phase column chromatograpy (silica gel, 20% EtOAc-100% EtOAc in heptane), to give Compound 5b.
S-methylisothiouronium sulfate (15.35g, 55.2 mmol) <n="90"/>was dissolved in 8:2:1 MeOH/ H2O/ THF (150 ml_) and the mixture was treated with 3 N NaOH (18.4 mL, 55.2 mmol). The solution was then cooled to 0 C and4-methoxybenzyl isocyanate (Cpd 5a, 9.0 g, 55.2 mmol) was added dropwise over 30 min. The reaction was stirred overnight and gradually warmed to room temperature. The mixture was then washed with saturated aqueous NH4CI (100 mL) and extracted with dichloromethane (3 x 75 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant residue was purified by normal phase column chromatograpy (silica gel, 20% EtOAc - 100% EtOAc in heptane), to give Compound 5b.
With sodium hydroxide; In tetrahydrofuran; methanol; water; at 0 - 20℃; S-methylisothiouronium sulfate (15.35 g, 55.2 mmol) was dissolved in 8:2:1 MeOH/H2O/THF (150 mL) and the mixture was treated with 3 N NaOH (18.4 mL, 55.2 mmol). The solution was then cooled to 0 C. and 4-methoxybenzyl isocyanate (Cpd 5a, 9.0 g, 55.2 mmol) was added dropwise over 30 min. The reaction was stirred overnight and gradually warmed to room temperature. The mixture was then washed with saturated aqueous NH4Cl (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant residue was purified by normal phase column chromatograpy (silica gel, 20% EtOAc-100% EtOAc in heptane), to give Compound 5b.
  • 32
  • [ 359878-47-0 ]
  • [ 56651-60-6 ]
  • [ 1134815-56-7 ]
YieldReaction ConditionsOperation in experiment
71% In dichloromethane; at 20℃; for 3h; N-(4-Fluorobenzyl)-4-amino-1-methylpiperidine (4.00 g, 18.0 mmol) was dissolved in dichloromethane (150 mL). 4-Methoxybenzyl isocyanate (3.26 g, 20.0 mmol) in dichloromethane (50 mL) was added dropwise and the mixture was stirred for 3 h at room temperature. The crude mixture was concentrated and purified by flash chromatography (0-10% methanol in dichloromethane) to give N-((4-fluorophenyl)methyl)-N-(1-methylpiperidin-4-yl)-N'-((4-methoxyphenyl)methyl)carbamide (4.91 g, 71%). This carbamide (4.91 g, 13.0 mmol) was dissolved in dry dichloromethane (50 mL). The solution was cooled to 0 C. and boron tribromide (1M in dichloromethane, 39.0 mL, 39.0 mmol) was added dropwise, and the mixture stirred for 20 h at room temperature. Water (50 mL) and n-butanol (10 mL) were added and the phases separated. The aqueous phase was extracted a second time with a mixture of dichloromethane (50 mL) and n-butanol (10 mL). The combined organic phases were evaporated and the resulting solid was purified by flash chromatography (0-20% methanol in dichloromethane) to give a semi-pure solid (3.17 g, 67%). An analytical amount (25 mg) of this material was purified by preparative HPLC to give a colorless oil (10 mg). LC-MS showed [M+H]+=372 (characteristic fragment: 223). 1H-NMR (CD3OD, 400 MHz, Free base): delta 7.25-6.62 (m, 8H), 4.46 (s, 2 mul), 4.22 (s, 2H), 4.15-4.06 (m, 1H), 2.89-2.82 (m, 2H), 2.23 (s, 3H), 2.14-2.05 (m, 2H), 1.74-1.61 (m, 4H).The collected compound was converted into its hydrochloride salt, which was obtained as a colorless solid.
  • 33
  • 5-amino-1-(4-methoxybenzyl)-4-cyanoformimidoylimidazole [ No CAS ]
  • [ 56651-60-6 ]
  • [ 1070773-13-5 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 5-amino-1-(4-methoxybenzyl)-4-cyanoformimidoylimidazole; 4-methoxybenzyl isocyanate In acetonitrile at 0 - 20℃; for 6h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 1h;
  • 34
  • 5-amino-1-(4-methoxybenzyl)-4-cyanoformimidoylimidazole [ No CAS ]
  • [ 56651-60-6 ]
  • (Z)-1-(4-methoxybenzyl)-3-((1-(4-methoxybenzyl)-5-amino-1H-imidazol-4-yl)(cyano)methylene)urea [ No CAS ]
  • [ 1070773-13-5 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile at 0 - 20℃; for 6h; Inert atmosphere;
In acetonitrile at 0 - 20℃; Inert atmosphere; 1 [0578] Synthesis of 4-(l-(4-methoxybenzyl)-5-amino-l//-imidazoI-4-yl)-1-(4-ethoxybenzyl)- 5-imino-liy-imidazol-2(5if)-oiie (9):; [0579] To a suspension of 7 (1.35 g, 5.29 mmol, 1 equiv) in dry MeCN (10 mL), 4- methoxybenzyl isocyanate was added (2.16 mL, 15.87 mmol, 3 equiv) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at rt for 6 h until starting material was disappeared (TLC). The yellow precipitate was filtered, washed with diethyl ether and dried under vacuum to afford the mixture of (Z)-1-(4-methoxybenzyl)-3-((l-(4-methoxybenzyl)-5- amino-1H-imidazol-4-yl)(cyano)methylene) urea (8) and 9 as yellow solid. Further, 2-5 drops of DBU were added to a suspension of 8 and 9 and the reaction mixture was stirred for 1 h. The deep yellow precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 9 as yellow solid (1.6 g, 75%). mp: decomposed > 215-217 °C, IR: 3195 (N-H str.), 3131 (N-H str.), 1702 (C=O ), 1643, 1513, 1249, 773 cm-1. 1H NMR (400 MHz, J6-DMSO): δ = 3.70 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 4.62 (s, 2 H, CH2), 5.11 (s, 2 H, CH2), 6.85 (d, J= 8.2 Hz, 2 H, Ar-H), 6.93 (d, J= 8.2 Hz, 2 H, Ar-H), 7.21 (d, J = 8.2 Hz, 2 H, Ar-H), 7.25 (d, J= 8.2 Hz, 2 H, Ar-H), 7.73 (s, 1 H, Imid-H), 7.90 (brs, 2 H, D2O-exchangable NH2), 9.77 (s, 1 H, D2O- exchangable NH). 13C NMR (100 MHz, J6-DMSO): δ = 41.7, 45.9, 55.6, 55.7, 114.3, 114.7, 128.2, 129.4, 129.5, 130.2, 139.5, 152.2, 157.6, 158.9, 159.5, 160.1, 167.3. HRMS (FAB) Calcd for C22H22N6O3, 418.1753 (M+); observed m/z 419.1824 (M+H)+.
  • 35
  • [ 768-60-5 ]
  • [ 56651-60-6 ]
  • [ 1174004-80-8 ]
  • [ 1174004-87-5 ]
YieldReaction ConditionsOperation in experiment
1: 79% 2: 4% With chlorobis(ethylene)rhodium(I) dimer; 4,8-bis(1,1-tert-butyl)-Ν,Ν,1,2,10,11-hexamethyldibenzo[df][1,3,2]-2-dioxaphospho-6-amine In toluene at 110℃; Inert atmosphere; regioselective reaction;
  • 36
  • [ 1004546-45-5 ]
  • [ 56651-60-6 ]
  • [ 1050677-02-5 ]
YieldReaction ConditionsOperation in experiment
92% With triethylamine In acetonitrile for 13h; Reflux; AA-15 Example AA-15; 2',3',4',9'-Tetrahydro-N,N-dimethyl-4-butyl-2'-4-methoxybenzylaminocarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine (more polar diastereoisomer)4-Methoxybenzyl isocyanate (0.75 mmol) was dissolved in abs. acetonitrile (30 ml); triethylamine (0.07 ml, 511 mg, 5 mmol) and the free base of the less polar spiroamine AA-9 (170 mg, 0.5 mmol) were added. The reaction mixture was heated for 6 h at boiling, the reaction solution becoming clear. Because no reaction was detectable by TLC, heating was carried out for a further 7 h under reflux. The mixture was concentrated. Diethyl ether was added to the solid colorless residue, and the suspension was stirred for 15 min. and then filtered out with suction. The less polar urea AA-15 was obtained in a yield of 92% (200 mg).
  • 37
  • 5-amino-1-(2-chlorobenzyl)-4-cyanoformimidoylimidazole [ No CAS ]
  • [ 56651-60-6 ]
  • [ 1261168-08-4 ]
  • [ 1220095-33-9 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile at 0 - 20℃; for 6h; Inert atmosphere; 1 [0602] 4-(l-(2-ChIorobenzvϖ-5-amino-lJg-imidazol-4-yl)-1-(4-methoxybenzvn-5-imino-lH- imitlazol-2(5//)-onc (20); [0603] To a suspension of 17 (1.0 g, 3.86 mmol, 1 equiv) in dry MeCN (10 mL), 4- methoxybenzyl isocyanate was added (0.94 mL, 5.79 mmol, 1.5 equiv) under nitrogen atmosphere. The reaction mixture was stirred 6 h until starting material was disappeared (TLC). The yellow precipitate was filtered, washed with diethyl ether and dried under vacuum to afford the mixture of 19 and 20 as a yellow solid (1.2 g). Further, 1 drop of DBU was added to a suspension of the mixture in acetonitrile, and the reaction mixture was stirred for 1 h. The deep yellow precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 20 as a yellow solid (0.8 g). IR : 3218 (N-H str.), 1702 (C=O str.), 1649 (C=N, str.), 1598, 1443, 1247 (C-O str.), 753 (C-Cl str.) cm-1. 1H NMR (400 MHz, rf6-DMSO): δ = 3.71 (s, 3 H, OCH3), 4.64 (s, 2 H, CH2), 5.27 (s, 2 H, CH2), 6.79-6.82 (m, 1 H, Ar-H), 6.86 (d, J= 8.7 Hz, 2 H, Ar-H), 7.23 (d, J= 8.7 Hz, 2 H, Ar-H), 7.31-7.39 (m, 2 H, Ar-H), 7.53-7.55 (m, 1H, Ar-H), 7.63 (s, 1 H, Imid-H), 7.99 (brs, 2 H, NH2 D2O-exchangable), 9.78 (s, 1 H, NH D2O-exchangable).
In acetonitrile at 0 - 20℃; for 6h; Inert atmosphere;
  • 38
  • [ 1246619-88-4 ]
  • [ 56651-60-6 ]
  • C21H23N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide at 40℃; for 5h; General Procedure 4To a solution of ethyl 5-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-6-carboxylate (47 mg, 200 μmol) in DMF (500 μL) was added the isocyanate (400 μmol). The mixture was then heated at 40° C. for 5 h. The reaction mixtures were then diluted with EtOAc (4 mL) and washed water (2 mL). The aqueous was then removed and the organics dried under high vacuum. The residues were dissolved in HOAc (3 mL) and the appropriate hydrazine (300 mmol) added, the resulting mixture were then heated at 80° C. for 48 hours. The solution was then concentrated in vacuo to yield the crude product. The crude product was purified by reverse phase column chromatography using a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% TFA, to yield the desired products in acceptable purities by LC/MS.
  • 39
  • [ 92594-46-2 ]
  • [ 56651-60-6 ]
  • [ 905846-27-7 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 20℃; for 48h; Combinatorial reaction / High throughput screening (HTS); 4.2. General automated procedure for the 48-membered library. Preparation of 9a-aza-homoerythromycin-9a-N-(γ-aminopropyl) urea and thiourea derivatives 7{4-36}, 7{37-49}, and 8{1-56} General procedure: Step 1. Weigh the building blocks and the amine needed for the reaction and calculate the solvent volumes to get the desired concentrations (0.1 mmol/ml-building blocks; 0.05 mmol/ml-amine). Step 2. Put the vials with the building blocks and amine on the MiniMapper.Step 3. Paste calculated volumes into the MiniMapper.Step 4. Add the solvent (CH2Cl2) to the vials containing the building blocks.Step 5. Add the solvent (CH2Cl2) to the 48-position reaction tubes of the MiniBlock synthesis module.Step 6. Add the solvent (CH2Cl2) to the vials containing the amine.Step 7. Transfer amine from the vials to the 48-position reaction tubes of the MiniBlock synthesis module.Step 8. Transfer building blocks from the vials to the 48-position reaction tubes of the MiniBlock synthesis module.Step 9. Remove reaction block from MiniMapper and place it on the MiniBlock synthesizer module and stir reactions vigorously at ambient temperature for 48 h.Step 10. Add 5 equiv of PS-trisamine to every reaction tube and stir reaction at ambient temperature for 12 h.Step 11. Drain resins and wash with CH2Cl2 (2 × 0.5 mL) into new vials.Step 12. Prepare quality control (QC); dispense aliquots (5 μL) into 48 vials and dilute each vial with acetonitrile (100 μL) and water (900 μL).Step 13. Remove solvent from bulk samples by parallel centrifugal evaporation in vacuum to afford the urea and thiourea derivatives.Note: Compounds with crude purities <86% were purified by RP-HPLC.
  • 40
  • 5-amino-1-(2-chlorobenzyl)-4-cyanoformimidoylimidazole [ No CAS ]
  • [ 56651-60-6 ]
  • [ 1220095-33-9 ]
YieldReaction ConditionsOperation in experiment
67% Stage #1: 5-amino-1-(2-chlorobenzyl)-4-cyanoformimidoylimidazole; 4-methoxybenzyl isocyanate In acetonitrile at 0 - 20℃; for 6h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene at 20℃; for 1h;
  • 41
  • [ 1064162-31-7 ]
  • [ 56651-60-6 ]
  • [ 1277150-33-0 ]
YieldReaction ConditionsOperation in experiment
78% With chlorobis(ethylene)rhodium(I) dimer; C35H36NO4P In toluene at 110℃; for 12h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
  • 42
  • [ 60293-41-6 ]
  • [ 56651-60-6 ]
  • [ 1277150-29-4 ]
YieldReaction ConditionsOperation in experiment
75% With chlorobis(ethylene)rhodium(I) dimer; C35H36NO4P In toluene at 110℃; for 12h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
  • 43
  • [ 19798-80-2 ]
  • [ 56651-60-6 ]
  • [ 1334126-79-2 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 44
  • [ 84249-14-9 ]
  • [ 56651-60-6 ]
  • [ 1334126-75-8 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 45
  • [ 1072-97-5 ]
  • [ 56651-60-6 ]
  • [ 1334126-73-6 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 46
  • [ 19798-81-3 ]
  • [ 56651-60-6 ]
  • [ 1334126-69-0 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 47
  • [ 4214-73-7 ]
  • [ 56651-60-6 ]
  • [ 1334126-89-4 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 48
  • [ 4214-76-0 ]
  • [ 56651-60-6 ]
  • [ 1334126-85-0 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 49
  • [ 121-66-4 ]
  • [ 56651-60-6 ]
  • N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 50
  • [ 348-40-3 ]
  • [ 56651-60-6 ]
  • [ 1334127-07-9 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 51
  • [ 7210-76-6 ]
  • [ 56651-60-6 ]
  • [ 1334127-01-3 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; In tetrahydrofuran; hexane; at 20℃; General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 52
  • [ 19759-66-1 ]
  • [ 56651-60-6 ]
  • [ 1334127-17-1 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; In tetrahydrofuran; hexane; at 20℃; General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 53
  • [ 2103-91-5 ]
  • [ 56651-60-6 ]
  • [ 1210115-24-4 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 54
  • [ 6285-57-0 ]
  • [ 56651-60-6 ]
  • [ 1334127-13-7 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃; 1.) Synthesis of the urea derivatives General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 55
  • [ 777-12-8 ]
  • [ 56651-60-6 ]
  • [ 1334127-11-5 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; In tetrahydrofuran; hexane; at 20℃; General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 56
  • [ 42182-27-4 ]
  • [ 56651-60-6 ]
  • [ 1334126-81-6 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; In tetrahydrofuran; hexane; at 20℃; General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
  • 57
  • [ 14667-47-1 ]
  • [ 56651-60-6 ]
  • [ 221539-63-5 ]
YieldReaction ConditionsOperation in experiment
28% With triethylamine; In acetonitrile; at 170℃; for 0.5h;Microwave irradiation; Sealed vial; A mixture of <strong>[14667-47-1]methyl 2-aminonicotinate</strong> (150 mg, 0.98 mmol), 1-isocyanatomethyl-4-methoxybenzene (160 mg, 0.98 mmol) and triethylamine (10 mg, 0.10 mmol) in acetonitrile (3 mL) was heated under microwave irradiation (30 min, 170 C). After cooling down the reaction in an ice/salt bath, a pale brown precipitate was formed. The solid was filtered, washed with diethylether and dried, affording 8 as a yellowish solid (yield 28%). Mp 251-253 C; 1H NMR (300 MHz, DMSO-d6) delta (ppm): 12.01 (s, 1H, NH), 8.66 (d, J = 6.7 Hz, 1H), 8.31 (d, J = 7.0 Hz, 1H), 7.30 (m, 1H), 7.17 (m, 1H), 6.84 (m, 1H), 4.99 (s, 2H, CH2); 13C NMR (75 MHz, DMSO-d6) delta (ppm): 160.4, 158.6, 152.2, 152.1, 148.4, 137.6, 130.9, 128.7, 121.1, 114.7, 108.2, 55,8, 46.1; ESI MS (m/z): 284 [M + H]+, purity 95% (by HPLC); Anal. C15H13N3O3 (C, H, N, O).
  • 58
  • [ 134-20-3 ]
  • [ 56651-60-6 ]
  • [ 221539-62-4 ]
YieldReaction ConditionsOperation in experiment
84% With triethylamine In 1,4-dioxane at 140℃; for 0.75h; Microwave irradiation; Sealed vial; 5.1.7. 3-(4-Methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (7) A mixture of methyl anthranilate (116 mg, 0.77 mmol), 1-isocyanatomethyl)-4-methoxybenzene (125 mg, 0.77 mmol) and triethylamine (8 mg, 0.08 mmol) in 1,4-dioxane (4 mL) was heated under microwave irradiation (45 min, 140 °C). After cooling down the reaction in an ice/salt bath, a pale yellow precipitate was formed. The solid was filtered, washed with diethylether and dried, affording 7 as a white solid (yield 84%). Mp 216.7 °C (Lit. [34] 213.8 °C); 1H NMR (300 MHz, DMSO-d6) δ (ppm): 11.48 (s, 1H, NH), 7.92 (dd, J = 7.2, 0.9 Hz, 1H, H-5), 7.65 (dt, J = 7.5, 1.6 Hz, 1H, H-7), 7.27 (d, J = 8.7 Hz, 2H, H-3'), 7.17 (t, J = 7.8 Hz, 1H, H-6), 6.85 (d, J = 7.8 Hz, 1H, H-8), 6.83 (d, J = 8.7 Hz, 2nH- H-4'), 5.00 (s, 2H, CH2), 3.69 (s, 3H, MeO); 13C NMR (75 MHz, DMSO-d6) δ (ppm): 162.1, 158.5, 154.1, 141.2, 137.5, 132.8, 128.9, 126.0, 124.6, 117.8, 116.5, 114.7, 55,7, 43.9; ESI MS (m/z): 283 [M + H]+, purity 97% (by HPLC); Anal. C16H14N2O3 (C, H, N, O).
Stage #1: 2-carbomethoxyaniline; 4-methoxybenzyl isocyanate In toluene at 0 - 20℃; Stage #2: With sodium hydroxide In toluene at 70℃; for 6h;
  • 59
  • [ 1093201-55-8 ]
  • [ 56651-60-6 ]
  • [ 1093201-54-7 ]
YieldReaction ConditionsOperation in experiment
81% With triethylamine In dichloromethane at 20℃; for 48h; 227 1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea Example 227 1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea To a suspension of 6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminium chloride (25 mol, 52 mg) (Example 228) in dry DCM (6 mL) was successively added Et3N (332 mol, 46 L) and 1-(isocyanatomethyl)-4-methoxybenzene (183 mol, 26 L). The reaction was stirred for 48 hours at room temperature then concentrated in vacuo. The residue was washed with water, dried, then purified on silica gel (20% to 100% EtOAc in hexanes) to give the desired product (64 mg, 81.0% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.296 (m, 2H), 1.371 (m, 4H), 1.791 (pentet, J=8 Hz, 2H), 2.980 (q, J=6 Hz, 2H), 3.695 (s, 3H), 4.086 (d, J=6 Hz, 2H), 4.131 (t, J=6 Hz, 2H), 5.836 (br. t, J=5 Hz, 1H), 6.141 (br. t, J=6 Hz, 1H), 6.585 (d, J=8 Hz, 1H), 6.727 (d, J=8 Hz, 1H), 6.840 (d, J=9 Hz, 2H), 7.137 (d, J=9 Hz, 2H), 7.433 (t, J=8 Hz, 1H), 7.803 (br. s, 1H), 8.321 (br. s, 1H), 10.926 (s, 1H). MS 476 (MH+).
81% With triethylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate 66 1-(6-(4-amino-2,2-dioxo-1H-benzo[e][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea Example 66 1-(6-(4-amino-2,2-dioxo-1H-benzo[e][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea To a suspension of 6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminium chloride (25 μmol, 52 mg) (Example 228) in dry DCM (6 mL) was successively added Et3N (332 μmol, 46 μL) and 1-(isocyanatomethyl)-4-methoxybenzene (183 μmol, 26 μL). The reaction was stirred for 48 hours at room temperature then concentrated in vacuo. The residue was washed with water, dried, then purified on silica gel (20% to 100% EtOAc in hexanes) to give the desired product (64 mg, 81.0% yield). NMR (400 MHz, DMSO-d6) δ 1.296 (m, 2H), 1.371 (m, 4H), 1.791 (pentet, J=8 Hz, 2H), 2.980 (q, J=6 Hz, 2H), 3.695 (s, 3H), 4.086 (d, J=6 Hz, 2H), 4.131 (t, J=6 Hz, 2H), 5.836 (br. t, J=5 Hz, 1H), 6.141 (br. t, J=6 Hz, 1H), 6.585 (d, J.=8 Hz, 1H), 6.727 (d, J=8 Hz, 1H), 6.840 (d, J=9 Hz, 2H), 7.137 (d, J=9 Hz, 2H), 7.433 (t, J=8 Hz, 1H), 7.803 (br. s, 1H), 8.321 (br. s, 1H), 10.926 (s, 1H). MS 476 (MH+).
  • 60
  • [ 6343-93-7 ]
  • [ 56651-60-6 ]
  • 61
  • emetine dihydrochloride [ No CAS ]
  • [ 56651-60-6 ]
  • [ 1393924-23-6 ]
YieldReaction ConditionsOperation in experiment
75% With dmap In dichloromethane at 20℃;
  • 62
  • [ 156273-72-2 ]
  • [ 56651-60-6 ]
  • C21H20N6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile at 20℃; for 12h; Inert atmosphere; 5.2.11 1-(4-Methoxybenzyl)-4-(5-amino-1-benzyl-1H-imidazol-4-yl)-5-imino-1H-imidazol-2(5H)-one (12a) To a suspension of 11a (0.6 g, 2.67 mmol, 1.0 equiv) in 5 mL acetonitrile was added 4-methoxybenzyl isocyanate (1.30 g, 8.0 mmol, 3.0 equiv) and stirred at room temperature for 12 h. The precipitate formed was filtered, washed with diethyl ether (2 × 10 mL) and dried. This precipitate was suspended in 5 mL acetonitrile. DBU (2 drops) was added to it and stirred for 3 h. The resulting precipitate was filtered, washed with diethyl ether and dried to give 12a (yield = 0.45 g, 43.5%)
  • 63
  • [ 1421053-56-6 ]
  • [ 56651-60-6 ]
  • C16H18N6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile at 20℃; for 12h; Inert atmosphere; 5.2.11 1-(4-Methoxybenzyl)-4-(5-amino-1-benzyl-1H-imidazol-4-yl)-5-imino-1H-imidazol-2(5H)-one (12a) General procedure: To a suspension of 11a (0.6 g, 2.67 mmol, 1.0 equiv) in 5 mL acetonitrile was added 4-methoxybenzyl isocyanate (1.30 g, 8.0 mmol, 3.0 equiv) and stirred at room temperature for 12 h. The precipitate formed was filtered, washed with diethyl ether (2 × 10 mL) and dried. This precipitate was suspended in 5 mL acetonitrile. DBU (2 drops) was added to it and stirred for 3 h. The resulting precipitate was filtered, washed with diethyl ether and dried to give 12a (yield = 0.45 g, 43.5%)
  • 64
  • [ 1421053-57-7 ]
  • [ 56651-60-6 ]
  • C21H19FN6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile at 20℃; for 12h; Inert atmosphere; 5.2.11 1-(4-Methoxybenzyl)-4-(5-amino-1-benzyl-1H-imidazol-4-yl)-5-imino-1H-imidazol-2(5H)-one (12a) General procedure: To a suspension of 11a (0.6 g, 2.67 mmol, 1.0 equiv) in 5 mL acetonitrile was added 4-methoxybenzyl isocyanate (1.30 g, 8.0 mmol, 3.0 equiv) and stirred at room temperature for 12 h. The precipitate formed was filtered, washed with diethyl ether (2 × 10 mL) and dried. This precipitate was suspended in 5 mL acetonitrile. DBU (2 drops) was added to it and stirred for 3 h. The resulting precipitate was filtered, washed with diethyl ether and dried to give 12a (yield = 0.45 g, 43.5%)
  • 65
  • [ 116911-32-1 ]
  • [ 56651-60-6 ]
  • [ 1446141-49-6 ]
  • (R)-5-benzyl-N,3-bis(4-methoxybenzyl)-2,4-dioxoimidazolidine-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With triphenylphosphine In acetonitrile at 20℃; for 3h;
  • 66
  • [ 173601-46-2 ]
  • [ 56651-60-6 ]
  • [ 1446141-56-5 ]
YieldReaction ConditionsOperation in experiment
89% With triphenylphosphine In acetonitrile at 20℃; for 3h;
  • 67
  • [ 637-81-0 ]
  • [ 56651-60-6 ]
  • [ 1446141-57-6 ]
YieldReaction ConditionsOperation in experiment
85% With triphenylphosphine In acetonitrile at 20℃; for 3h;
  • 68
  • [ 1433193-94-2 ]
  • [ 56651-60-6 ]
  • [ 1433193-96-4 ]
YieldReaction ConditionsOperation in experiment
71% With dmap at 40℃; for 24h; 11 5.11
1-{2-[1-Benzyl-5-(2-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3-(4-methoxybenzyl)urea (21b) To a solution of diaryllactam 20 (93.0 mg, 239 μmol) in 1 mL of CH2Cl2, were added 4-methoxybenzyl isocyanate (40.5 μL, 263 μmol) and DMAP (9.6 mg, 78.6 μmol) at ambient temperature. The reaction mixture was heated to 40 °C and stirred for 24 h. After gradual cooling to ambient temperature, the reaction mixture was directly subjected to silica gel column chromatography (hexane/AcOEt=9/1 to 5/5) to give the titled compound (94.2 mg, 71%) as colorless solids. Mp 192-193 °C; 1H NMR (CDCl3, δ); 7.79-7.65 (br, 1H), 7.31-7.06 (m, 12H), 6.82-6.78 (br, 3H), 6.65-6.55 (br, 2H), 6.35-6.16 (br, 1H), 5.58-4.62 (m, 1H), 4.24-4.19 (br, 2H), 4.01-3.98 (br, 1H), 3.76 (s, 3H), 3.62-3.59 (br, 1H), 3.24-2.91 (br, 2H), 2.38-2.27 (br, 1H). 13C NMR (CDCl3, δ) 164.8, 158.5, 155.8, 148.4, 135.9, 135.7, 135.1, 133.5, 133.0, 132.0, 131.9, 129.1, 128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.9, 127.4, 126.2, 122.5, 113.8, 113.7, 55.2, 51.0, 45.4, 43.0, 29.0 (The peaks on 1H and 13C spectra were highly broadened.); IR (ATR) 3366, 1640 cm-1; HRMS (MH+) calcd for 552.2054. Found: 552.2059.
  • 69
  • [ 34706-60-0 ]
  • [ 56651-60-6 ]
  • [ 1442458-04-9 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 0 - 20℃; Inert atmosphere; General Procedure D: Synthesis of propargylurea 1 General procedure: 1-methyl-3-phenyl-1-(3-phenylprop-2-ynyl)urea (1a). Phenylisocyante (205 mg,1.72 mmol, 1.4 equiv) was added to a solution ofN-methyl-3-phenyl-3-phenylprop-2-yn-1-amine (325 mg, 1.23 mmol, 1.0 equiv) inDCM (2.5 mL) at 0 oC under N2. The resulting solution was stirred at ambienttemperature overnight. The reaction mixture was diluted DCM and washed withdiluted aqueous HCl, saturated aqueous NaHCO3, and brine. The organic phase was dried over MgSO4,filtered, concentrated and the residue was purified through column chromatography (silica gel,Hexane/EtOAc = 8:1 to 2:1) to give the progargylurea 1a (260 mg, 80%).
  • 70
  • [ 2634-33-5 ]
  • [ 56651-60-6 ]
  • [ 1437999-95-5 ]
YieldReaction ConditionsOperation in experiment
98% In tetrahydrofuran; dichloromethane for 0.5h; Reflux; General procedure C: preparation of N-alkyl-3-oxobenzo[d]isothiazole-2(3H)-carboxamide analogues 6a-w General procedure: To a solution of triphosgene (2.96 g, 10 mmol) in DCM (20 ml) was added dropwise to primary amine 4 (10 mmol) in DCM (20 ml) followed by the dropwise addition of triethylamine (3 ml) in DCM (10 ml). The solvent was removed on a rotary evaporator. The resulting residue was dissolved in DCM (20 ml), and 1,2-benzisothiazol-3-one (1.51 g, 10 mmol) in THF (20 ml) was added. After the mixture was refluxed for 30 min, the solvent was removed on a rotary evaporator. The residue was dissolved in acetone (30 ml) and mixed with water (30 ml). The precipitate was collected on a funnel by vacuum filtration and washed with water-acetone (1:1,4 × 5 ml) to afford the final compound.
  • 71
  • [ 1092096-40-6 ]
  • [ 56651-60-6 ]
  • [ 1449694-06-7 ]
YieldReaction ConditionsOperation in experiment
94% In N,N-dimethyl-formamide at 20℃; for 1.33333h;
94% In N,N-dimethyl-formamide at 20℃; for 1.33333h; 1 To a solution of aminoalcohol SI (9 mg, 0.0403 mmol) in DMF (1 mL) was added j methoxybenzyl isocyanate (6.3 μ, 0.0443 mmol). After stirring for 80 min at room temperature, the mixture was concentrated under reduced pressure to give a sufficiently pure hydroxyurea S2 (14.1 mg, 94%) as a colorless solid. Compound S2: colorless solid; IR (KBr) v 3285, 1636 cm"1; 1H NMR (500 MHz, DMSO-i) δ 7.72 (d, 1H, J= 3.4 Hz), 7.16 (d, 2H, J= 8.6 Hz), 7.04 (dd, 1H, J= 2.3, 1.7 Hz), 6.86 (d, 2H, J= 8.6 Hz), 6.69 (dd, 1H, J= 6.3, 5.7 Hz), 6.61 (dd, 1H, J= 4.0, 1.7 Hz), 6.18 (dd, 1H, J= 3.4, 2.2 Hz), 5.93 (d, 1H, J= 8.0 Hz), 5.32 (d, 1H, J= 4.6 Hz), 4.57 (m, 1H), 4.16-4.09 (m, 2H), 3.97 (m, 1H), 3.83-3.73 (m, 2H), 3.71 (s, 3H), 2.42 (ddd, 1H, J= 14.9, 6.3, 4.0 Hz), 2.22 (ddd, 1H, J= 14.3, 7.4, 2.3 Hz); 13C NMR (125 MHz, DMSO-t) δ 158.04, 157.69, 132.49, 128.47, 123.39, 122.44, 113.63, 111.84, 109.50, 67.37, 58.60, 57.42, 55.05, 51.39, 42.41 ; MS m/z 371 (M+H+), 93 (100%); HRMS (FAB) calcd for Ci9H23N404 (M+ +): 371.1719, found: 371.1728.
  • 72
  • [ 1312356-04-9 ]
  • [ 56651-60-6 ]
  • [ 1312356-05-0 ]
YieldReaction ConditionsOperation in experiment
73% In 1,2-dichloro-ethane at 120℃; for 1.5h; Microwave irradiation; 3 Methyl 2-[(phenylmethyl)oxy]amino}-3-pyridinecarboxylate 4.1.1.3 Methyl 2-[([4-(methyloxy)phenyl]methyl}amino)carbonyl][(phenylmethyl)oxy]amino}-3-pyridinecarboxylate (8) A solution of methyl 2-[(phenylmethyl)oxy]amino}-3-pyridinecarboxylate (3.1 g, 12 mmol) and 1-(isocyanatomethyl)-4-(methyloxy)benzene (5.1 mL, 36 mmol) in 1,2-dichloroethane (24 mL) was irradiated in microwave at 120 °C. After 90 min, the reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography (0-100% ethyl acetate-hexanes) to afford the title compound (3.7 g, 73%) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.58 (dd, J = 4.88, 1.76 Hz, 1H), 8.10 (dd, J = 7.80, 1.76 Hz, 1H), 7.37-7.45 (m, 2H), 7.27-7.33 (m, 3H), 7.18-7.24 (m, 1H), 7.06 (d, J = 8.59 Hz, 2H), 6.76-6.89 (m, 2H), 4.95-5.04 (m, 2H), 4.26 (d, J = 5.85 Hz, 2H), 3.73-3.81 (m, 6H); ES + MS: m/z = 422 (M+1).
  • 73
  • [ 959617-72-2 ]
  • [ 56651-60-6 ]
  • [ 1623153-99-0 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dichloromethane at 0 - 20℃; for 12h; 4.1.13 General procedure for the synthesis of substituted 1-benzyl-3-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (44-46) General procedure: A solution of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one (11) (0.344 mmol) in dichloromethane (3 mL) was cooled to 0 °C followed by the addition of triethylamine (1.03 mmol). Corresponding substituted benzyl isocyanate (0.413 mmol) was added to the reaction mixture and was stirred in room temperature for 12 h (monitored by TLC & LCMS for completion). The reaction mixture was washed with water (3 × 5 mL) and brine (3 × 5 mL). Organic layer was dried(MgSO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane: ethyl acetate as eluent to give the corresponding substituted1-benzyl-3-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (44-46) in good yield.
  • 74
  • [ 959616-35-4 ]
  • [ 56651-60-6 ]
  • [ 1623154-07-3 ]
YieldReaction ConditionsOperation in experiment
77% With triethylamine In dichloromethane at 0 - 20℃; for 12h; 4.1.15 General procedure for the synthesis of substituted 1-benzyl-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (50-52) General procedure: A solution of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one (12) (0.33 mmol) in dichloromethane (1mL) was cooled to 0 °C followed by the addition of triethylamine (0.99 mmol). Corresponding substituted benzyl isocyanate (0.397 mmol) was added to the reaction mixture and was stirred in room temperature for 12 h (monitored by TLC & LCMS for completion). The reaction mixture was washed with water (3 × 5 mL) and brine (3 × 5 mL). Organic layer was dried(MgSO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane: ethyl acetate as eluent to give the corresponding substituted1-benzyl-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (50-52) in good yield.
  • 75
  • [ 615-43-0 ]
  • [ 56651-60-6 ]
  • C15H15IN2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane Synthesis of Urea derivatives General procedure: Phenylisocyanate derivatives (Purchased from Sigma Aldrich) (10.0 mmol, 1 eq.) was dissolved indichloromethane (25 mL). 2-iodo aniline (1.2 eq.) was added, followed by triethylamine (1.1 eq.)and the resulting solution was stirred overnight. A precipitate was formed, filtered and washed withcold dichloromethane to get pure product. Urea derivatives were obtained as a white solid andconfirmed by 1H and 13C NMR
  • 76
  • [ 1601751-76-1 ]
  • [ 56651-60-6 ]
  • 1-(4-methoxybenzyl)-3-(1-(5-nitrothiazol-2-yl)piperidin-4-yl)urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
85.9% With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 6h; 18 General procedure for the synthesis of urea/thiourea derivatives (4-25) To a solution of 1-(5-nitrothiazol-2-yl)piperidin-4-amine (1mmol) in dry dimethylformamide (3mL) was added triethylamine (2mmol) and corresponding isocyanate/isothiocyanate (1.1mmol) at 0°C. The reaction mixture was slowly warmed to rt and stirred at rt for 6h (monitored by TLC & LCMS for completion). The reaction mixture was washed with water (2mL), brine (2mL), dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was then either recrystallised from diethylether or purified by column chromatography. 4.2.4.18 1-(4-Methoxybenzyl)-3-(1-(5-nitrothiazol-2-yl)piperidin-4-yl)urea (21) The compound was synthesized according to the general procedure using 1-(5-nitrothiazol-2-yl)piperidin-4-amine (0.1 g, 0.438 mmol), triethylamine (0.089 g, 0.88 mmol), and 4-methoxybenzyl isocyanate (0.079 g, 0.482 mmol) to afford 21 (0.146 g, 85.9%) as pale yellow solid. Mp: 198-200 °C. 1H NMR (CDCl3): δH 1.36-3.80 (m, 9H), 3.86 (s, 3H), 4.16 (s, 2H), 6.98-7.21 (m, 4H), 8.38 (s, 1H). C NMR (CDCl3): δc 171.9, 159, 157.6, 147.6, 135.5, 130.6, 130.3, 113.9, 56.1, 47.6, 45.4, 42.6, 31.2. ESI-MS m/z 392.1 (M+H)+. Anal. Calcd for C17H21N5O4S: C, 52.16; H, 5.41; N, 17.89. Found: C, 52.17; H, 5.4; N, 17.87.
  • 77
  • ethyl 4-((benzyloxy)amino)pyrimidine-5-carboxylate [ No CAS ]
  • [ 56651-60-6 ]
  • 1-(benzyloxy)-3-(4-methoxybenzyl)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
274 mg With triethylamine In dichloromethane at 20℃; for 5h; Cooling with ice; 54 Reference Example 54 To a solution of ethyl 4-((benzyloxy)amino)pyrimidine-5-carboxylate (400 mg) in methylene chloride (12 mL), 4-methoxybenzyl isocyanate (439 µL) and triethylamine (428 µL) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, ethyl acetate and a 10% aqueous citric acid solution were added. An organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in ethanol, and the deposit was collected by filtration to obtain a white solid of 1-(benzyloxy)-3-(4-methoxybenzyl)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (274 mg). 1H-NMR (CDCl3) δ value: 3.79 (s, 3H), 5.16 (s, 2H), 5.28 (s, 2H), 6.82-6.88 (m, 2H), 7.36-7.41 (m, 3H), 7.45-7.50 (m, 2H), 7.57-7.62 (m, 2H), 9.18 (s, 1H), 9.29 (s, 1H).
  • 78
  • [ 1620483-47-7 ]
  • [ 56651-60-6 ]
  • C25H23ClFN3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In toluene at 90℃; for 12h; 23 Preparation 23 To a solution of the product of Preparation 2 (100 mg, 0.3 12 mmol) in toluene (1 mL) was added 1-(isocyanatomethyl)-4-methoxybenzene (0.067 mL, 0.468 mmol). The resulting mixture was heated to 90 °C for 12 h, then purified by preparative HPLC toprovide the product as a white solid. LC retention time: 3.65 mm.
  • 79
  • C27H27N3O4 [ No CAS ]
  • [ 56651-60-6 ]
  • C36H36N4O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% In toluene at 90℃; for 12h; 115 Preparation 115 To a soin of the product of Preparation 7 (30 mg, 0.063 mmol) in toluene (1 mL)was added 1-(isocyanatomethyl)-4-methoxybenzene (21.4 mg, 0.13 1 mmol). Theresulting mixture was heated at 90 °C for 12 h, then purified by preparative HPLC to provide the title compound (25 mg, 61% yield) as a white powder. MS (E+) m/z: 621.1 (M+H); LC retention time: 3.62 mm.
  • 80
  • C27H24F3N3O3 [ No CAS ]
  • [ 56651-60-6 ]
  • C36H33F3N4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% In toluene at 90℃; for 40h; 73 Preparation 73 To a solution of the product of Preparation 52 (100 mg, 0.20 1 mmol) in anhydroustoluene (4 mL) was added p-methoxybenzylisocyanate (49 mg, 0.302 mmol). Thereaction mixture was stirred at 90 °C for 40 h. Then the reaction mixture was concentrated and purified by preparative TLC using 5% methanol/chloroform as eluent to provide the product (60 mg, 45% yield) as a sticky liquid. MS (E+) m/z: 659 (M+H); LCMS retention time: 2.14 mm (Method 7).
  • 81
  • 1-(4-nitrophenyl)imidazolidin-2-imine [ No CAS ]
  • [ 56651-60-6 ]
  • C18H19N5O4 [ No CAS ]
  • 2-imino-N-[(4-methoxyphenyl)methyl]-3-(4-nitrophenyl)imidazolidine-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; dichloromethane at 20℃; for 2h; General Procedure to Obtain Compounds 4 General procedure: To a stirred mixture of 1 eq. of 1-(4-nitrophenyl)imidazolidin-2-imine (3) in dichloromethane (DCM), tetrahydrofuran (THF) or acetonitrile (ACN) there was added a solution of 1 eq. of an isocyanate in the same solvent. The mixture was stirred for 2 h at room temperature and resulting precipitate filtered reaction mixture becomes clear as soon as the isocyanate is added and then starts turning cloudy and opaque as it progresses) or the solvent was evaporated.
  • 82
  • [ 7524-50-7 ]
  • [ 56651-60-6 ]
  • C19H22N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0 - 20℃; enantioselective reaction; 4.2.2 General procedure for the preparation of α-amino acid ureas (3a-3l) General procedure: A solution of triphosgene (0.15 g, 0.5 mmol) in toluene was dropwise added the amine (1 mmol) at room temperature. After the addition was completed, the reaction suspension was refluxed for 6 h, then toluene was evaporated, and the residue was taken up by CH2Cl2, then added to a solution of the α-amino acid methyl ester hydrochlorides (1.2mmol) with triethylamine (0.17 ml, 1.2 mmol) in CH2Cl2 dropwise at 0 °C. After the addition was completed, the reaction solution was stirred at room temperature for hours. Then CH2Cl2 evaporated, the residue was taken up with ethyl acetate and washed with brine. After being dried with MgSO4 and condensed, α-amino acid ureas (3a-3l) were obtained without further purification.
  • 83
  • [ 359878-18-5 ]
  • [ 56651-60-6 ]
  • N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-methoxybenzyl)carbamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-methyl-N-(4-methylbenzyl)-piperidin-4-amine; 4-methoxybenzyl isocyanate In dichloromethane for 16h; Stage #2: With hydrogenchloride In diethyl ether; n-heptane; dichloromethane 127 Example 127 (47AKU-44) N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-′N′-(4-methoxybenzyl)-carbamide (47AKU-44) Example 127 (47AKU-44) N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-′N′-(4-methoxybenzyl)-carbamide (47AKU-44) 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxybenzylisocyanate (196 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40° C.). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 192 mg (50%) 47AKU-44. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=382.3 (UV/MS (%)=100/94). 1H-NMR (400 MHz, CDCl3): δ=7.10 (4H, m); 6.98 (2H, m); 6.76 (2H, m); 4.58 (1H, t); 4.45 (1H, m); 4.33 (2H, s); 4.25 (2H, d); 3.76 (3H, s); 2.97 (2H, m); 2.34 (3H, s); 2.32 (3H, s); 2.24 (2H, m); 1.78 (4H, m). 13C-NMR (CDCl3): δ=158.9, 158.5, 137.3, 135.2, 131.8, 129.8, 128.8, 126.2, 114.1, 55.5, 55.4, 51.7, 45.8, 45.7, 44.5, 29.7, 21.2.
  • 84
  • [ 359880-72-1 ]
  • [ 56651-60-6 ]
  • N-(4-methylbenzyl)-N-(1-tert-butylpiperidin-4-yl)-N′-(4-methoxybenzyl)carbamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-(4-methylbenzylamino)-1-tert-butylpiperidine; 4-methoxybenzyl isocyanate In dichloromethane for 20h; Stage #2: With hydrogenchloride In diethyl ether; n-heptane; dichloromethane 133 Example 133 N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N′-(4-methoxybenzyl) carbamide (58AKU-3) Example 133 N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N′-(4-methoxybenzyl) carbamide (58AKU-3) 47AKU-5-2 (404 mg, 1.6 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxybenzylisocyanate (326 mg, 2.0 mmol) in 5 ml dichloromethane was added. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (45° C.). Crude product was purified three times by flash chromatography (0-20% methanol in dichloromethane and 0-30% methanol in ethylacetate) giving 155 mg (23%) 58AKU-3. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=424.2 (UV/MS (%)=92/83). 1H-NMR (400 MHz, CDCl3): δ=7.10 (4H, m); 6.99 (2H, m); 6.76 (2H, m); 4.53 (1H, m); 4.35 (3H, s); 4.26 (2H, d); 3.77 (3H, s); 3.09 (2H, m); 2.32 (3H, s); 2.22 (2H, m); 1.81-1.54 (4H, m); 1.06 (9H, s). 13C-NMR (CDCl3): δ=158.9, 158.6, 137.1, 135.6, 131.9, 129.7, 128.8, 126.2, 114.0, 62.6, 55.5, 53.0, 45.9, 45.7, 44.5, 31.0, 26.3, 21.2.
  • 85
  • [ 1613053-70-5 ]
  • [ 56651-60-6 ]
  • 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-methoxybenzyl)piperazine-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With triethylamine In dichloromethane at 0 - 20℃; for 12h; General procedure for the synthesis of substituted N-benzyl-4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxamide (21-22) General procedure: General procedure for the synthesis of substituted N-benzyl-4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxamide (21-22) A solution of 7-methoxy-1-(2-(piperazin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one (6) (0.1 g, 0.346 mmol) (1 equiv) in dichloromethane (1 mL) was cooled to 0 °C followed by the addition of triethylamine (0.99 mmol) (3 equiv). Corresponding substituted benzyl isocyanate (0.416 mmol) (1.2 equiv) was added to the reaction mixture and was stirred in room temperature for 12 h (monitored by TLC & LCMS for completion). The reaction mixture was washed with water (3*5 mL) and brine (3*5 mL). Organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane (30%)/ethyl acetate (70%) as eluent to give the corresponding N-benzyl-4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperazine-1-carboxamide (21-22) in good yield. 4.1.9.1. 4-(2-(7-Methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-methoxybenzyl)piperazine-1-carboxamide (21). The compound was synthesized according to the general procedure using 7-methoxy-1-(2-(piperazin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one (6) (0.1 g, 0.346 mmol) (1 equiv) and 4-methoxybenzyl isocyanate (0.067 g, 0.416 mmol) (1.2 equiv) to afford 21 (0.110 g, 71%) as brown solid. Mp: 162-164 C. 1H NMR [DMSO-d6] δH 2.45-2.62 (m, 6H, N-CH2)3), 3.40 (t, J = 4 Hz, 4H,N-CH2)2), 4.01 (s, 6H, -OCH3), 4.24 (s, 2H, -CH2), 4.40 (t,J = 6.8 Hz, 2H, -CH2), 6.68 (d, J = 9.6 Hz, 1H, -C=C-H)), 7.19 (t,J = 7.8 Hz, 2H, Ar-H), 7.41 (d, J = 8 Hz, 2H, Ar-H), 7.44 (s, 1H,Ar-H), 7.79 (d, J = 9.6 Hz, 1H, -CC-H), 8.25 (d, J = 2 Hz, 1H, Ar-H), 8.46 (br, 1H, -NH). 13C NMR [DMSO-d6] δC: 162.3, 159.7,156.1, 155.6, 142.2, 136.6, 132.8, 130.7 (2C), 129.1, 125.8, 119.2, 115.2 (2C), 105.1, 55.2 (2C), 54.6 (2C), 53.5, 51.8 (2C), 50.5, 45.6. ESI-MS m/z: (Calcd for C24H29N5O4: 451.52); Found: 452.44 (M+H)+. Anal Calcd for C24H29N5O4: C, 63.84; H, 6.47; N, 15.51; Found: C, 63.95; H, 6.46; N, 15.53.
  • 86
  • [ 83506-93-8 ]
  • [ 56651-60-6 ]
  • C16H14F2N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; at 200℃; for 0.5h; 6,7-Difluoro-3-(4-methoxybenzyl)quinazoline-2,4(lH,3H)-dione was prepared similarly to 3-(4-bromobenzyl)-5,7-dimethoxyquinazoline-2,4(lH,3H)-dione in Example 1. 2-Amino- 4,5-difluorobenzoic acid (250 mg; 1.44 mmol) and dry pyridine (2.5 ml) were placed in a microwave reaction vial and 4-methoxybenzyl isocyanate (353 mg; 2.17 mmol) was slowly added. After heating in a microwave reactor at 200 C for 30 min, aqueous sodium hydroxide (5 N; 0.43 ml; 2.17 mmol) was added and the reaction mixture was heated at 140 C for 30 min. Addition of aqueous HC1 resulted in a precipitation that was filtered, washed with water, and dried to give 290 mg of crude 6,7-difluoro-3-(4- methoxybenzyl)quinazoline-2,4(lH,3H)-dione. LC-MS (ES+APCI, Neg) [M-l]: 317.0.
  • 87
  • [ 108288-16-0 ]
  • [ 56651-60-6 ]
  • C16H14ClFN2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; at 200℃; for 0.5h;Microwave irradiation; 7-Chloro-6-fluoro-3-(4-methoxybenzyl)quinazoline-2,4(lH,3H)-dione was prepared similarly to 3-(4-bromobenzyl)-5,7-dimethoxyquinazoline-2,4(lH,3H)-dione in Example 1. <strong>[108288-16-0]2-Amino-4-chloro-5-fluorobenzoic acid</strong> (250 mg; 1.32 mmol) and dry pyridine (2.5 ml) were placed in a microwave reaction vial and 4-methoxybenzyl isocyanate (323 mg; 1.98 mmol) was slowly added. After heating in a microwave reactor at 200 C for 30 min, aqueous sodium hydroxide (5 N; 0.40 ml; 1.98 mmol) was added and the reaction mixture was heated at 140 C for 30 min. Addition of aqueous HC1 resulted in a precipitation that was filtered, washed with water, and dried to give 500 mg of crude 7-chloro-6-fluoro-3-(4- methoxybenzyl)quinazoline-2,4(lH,3H)-dione. LC-MS (ES+APCI, Neg) [M-l]: 333.0.
  • 88
  • tert-butyl 2-amino-2-(cyclohex-2-en-1-yl)propanoate [ No CAS ]
  • [ 56651-60-6 ]
  • tert-butyl 2-(cyclohex-2-en-1-yl)-2-(3-(4-methoxybenzyl)ureido)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% In tetrahydrofuran at 20℃; 2.95d tert-butyl 2-(cyclohex-2-en-1-yl)-2-(3-(4-methoxybenzyl)ureido)propanoate To a 20 mL scintillation vial was added t-butyl 2-amino-2-(cyclohex-2-en-1-yl)propanoate (Example 2.95e) (640 mg, 2.84 mmol) in dry THF (5 mL). Then p-methoxybenzylisocyanate (463 mg, 2.84 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated, and the residue was purified by flash chromatography on Biotage 40 g silica column with 10%50% EtOAc/Hex gradient. The final product was obtained as a white solid (700 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 5.79 (m, 1H), 5.55 (m, 1H), 4.66 (m, 1H), 4.26 (m, =2H), 3.79 (s, 3H), 2.70 (m, 1H), 1.94 (m, 1H), 1.77 (m, 1H), 1.62 (d J=4 Hz, 3H), 1.44 (d J=4 Hz, 9H). MS 389 (MH+)
  • 89
  • [ 139110-70-6 ]
  • [ 56651-60-6 ]
  • methyl 5-acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-3,4,5-trideoxy-4-(3-(4-methoxybenzyl)ureido)-D-glycero-D-galacto-non-2-enonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With dmap In dichloromethane at 20℃; Inert atmosphere;
  • 90
  • [ 141860-78-8 ]
  • [ 56651-60-6 ]
  • 3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: ethyl 3-amino-4,4,4-trifluorocrotonate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-methoxybenzyl isocyanate In N,N-dimethyl-formamide at 0 - 25℃; for 14h; C-1.2 Step 2: To a solution of ethyl (Z)-3-amino-4,4,4-trifluoro-but-2-enoate (19 g) in DMF (500 mL) was added NaH (6 g) in portions at 0°C. The reaction mixture was then stirred at 0°C for 1 h. The mixture was then added to 1-(isocyanatomethyl)-4-methoxy-benzene (17 g) at 0°C. The resulting mixture was stirred at 0°C to 25°C for 14 h. The solvent was removed under reduced pressure and water (1 L) was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 500 mL). The organic layers were combined, washed with brine (500 mL), dried over Na2S04, filtered, and concentrated to afford crude 3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)- 1 H-pyrimidine-2,4-dione (15 g) as yellow oil. 1H NMR (MeOD, 400 MHz) δ 7.27 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 5.80 (s, 1 H), 5.02 (s, 2H) 3.70 (s, 3H).
Stage #1: ethyl 3-amino-4,4,4-trifluorocrotonate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 4-methoxybenzyl isocyanate In N,N-dimethyl-formamide at 0 - 25℃; for 14h; 2.a.2 Step 2: To a solution of ethyl (Z)-3-amino-4,4,4-trifluoro-but-2-enoate (19 g) in DMF (500 mL) was added NaH (6 g) in portions at 0°C. The reaction mixture was then stirred at 0°C for 1 h. The mix- ture was then added to 1-(isocyanatomethyl)-4-methoxy-benzene (17 g) at 0°C. The resulting mix- ture was stirred at 0°C to 25°C for 14 h. The solvent was removed under reduced pressure and wa- ter (1 L) was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 500 mL). The organic layers were combined, washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to afford crude 3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)- 1H-pyrimidine-2,4-dione (15 g) as yellow oil.1H NMR (MeOD, 400 MHz) δ 7.27 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 5.80 (s, 1H), 5.02 (s, 2H) 3.70 (s, 3H).
  • 91
  • C16H27N2O2(1+)*Cl(1-) [ No CAS ]
  • [ 56651-60-6 ]
  • C25H36N3O4(1+)*Cl(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.2 g With triethylamine In dichloromethane at 20℃; for 12h; 16.2 Step 2, in 50 ml round bottom flask is added in A (3 mmol, 940 mg), triethylamine (1 mmol, 80 mg) and methylene chloride (10 ml), at room temperature to the reaction system in the step into a top 1 in the preparation of the solution, the reaction at room temperature for 12 hours. The reaction solution concentrated under reduced pressure, the crude product by silica gel column chromatography (dichloromethane: methanol=20:1), purification to obtain the target product (compound 16) 1.20 g, yield 84%.
  • 92
  • [ 947403-75-0 ]
  • [ 74-96-4 ]
  • [ 56651-60-6 ]
  • tert-butyl 1-ethyl-3-(4-methoxybenzyl)-2,4-dioxo-1,3,4,5,7,8-hexahydropyrido[4,3-d]pyrimidine-6(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% Stage #1: 4-amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester; 4-methoxybenzyl isocyanate With N-ethyl-N,N-diisopropylamine In toluene at 80℃; for 24h; Stage #2: With sodium methylate In methanol at 20℃; for 1h; Stage #3: ethyl bromide With potassium carbonate In acetonitrile for 4h; Reflux;
  • 93
  • [ 89656-36-0 ]
  • [ 56651-60-6 ]
  • (±)-2-allyl-N-(4-methoxybenzyl)pyrrolidine-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.324 g In dichloromethane at 20℃; Inert atmosphere;
862 mg In dichloromethane at 20℃; Inert atmosphere; 2.1.3 4.2.1. General procedure 1:synthesis of urea substrates General procedure: A clean, flame-dried round bottom flask equipped with a stir bar was cooled under a stream of nitrogen and charged with N-Boc-2-allylpyrrolidine,27N-Boc-2-(2-methallyl)pyrrolidine,28 or N-Boc-2-allylpiperidine [27] (1.0 equiv) and dichloromethane (0.2M). The resulting solution was cooled to 0°C and trifluoroacetic acid (10.0 equiv) was added. The reaction mixture was stirred until judged as complete by thin layer chromatography (c.a. 4h), then diluted with water and quenched with ammonium hydroxide until pH reached 12. The organic layer was reserved, and the aqueous layer extracted with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude intermediate was then carried on to the next step without any additional purification. The crude intermediate was re-dissolved in dichloromethane (0.2M) and charged to a new clean, dry round bottom flask with a stir bar. The appropriately substituted isocyanate (1.2 equiv) was added slowly, and the resulting reaction stirred at 20°C until judged as complete by TLC (ca. 4-14h). After concentration in vacuo, the resulting residue was purified via flash column chromatography on silica gel (20-40% ethyl acetate/hexanes gradient).
  • 94
  • [ 87-69-4 ]
  • tert-butyl 4-[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate [ No CAS ]
  • [ 56651-60-6 ]
  • 1-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1-(piperidin-4-yl)urea hemitartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
130 mg Stage #1: tert-butyl 4-[(2,4-difluorophenyl)methyl]amino}piperidine-1-carboxylate; 4-methoxybenzyl isocyanate In dichloromethane Stage #2: With trifluoroacetic acid In dichloromethane for 1h; Stage #3: L-Tartaric acid In ethanol; isopropyl alcohol 126 Example 126: l-[(2,4-difluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-l- (piperidin-4-yl)urea; hemitartrate (126) tert-Butyl 4-[(2,4-difluorophenyl)methyl]amino}piperidine-l-carboxylate (300 mg, 0.873 mmol) was dissolved in dichloromethane (2 ml) and l-methoxy-4- (isocyanatomethyl)benzene (190 mg, 1.14 mmol) dissolved in dichloromethane (1 ml) was added. The mixture was evaporated and purified by column chromatography using silicon dioxide gel, eluting with 50 % ethyl acetate in petroleum ether to afford an intermediate (387 mg). This material was stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) for 1 hour, then evaporated and partitioned between diethyl ether/EtOAc and 0.5 M NaOH. The organic phase was collected, evaporated, and the residue was crystallized from diethyl ether/hexanes and gave the title compound as the free base (195 mg, 0.46 mmol, 53 % yield). This material (163 mg, 0.418 mmol) was dissolved in 2-propanol (3 ml) and L -(+)-tartaric acid (0.4 M solution in ethanol, 1.1 equiv., 0.23 mmol, 575 μ) was added dropwise which resulted in crystallization. The crystals were isolated by filtration and then recrystallized from (0981) MeOH/ethanol and gave the title compound (130 mg, 67 % yield from the free base): NMR (400 MHz, Methanol-^) δ 7.21 (q, 1H), 7.15 (d, 2H), 6.98- 6.86 (m, 2H), 6.83 (d, 2H), 4.53 (s, 2H), 4.32 (s, 1H), 4.34-4.23 (m, 1H), 4.29 (s, 2H), 3.76 (s, 3H), 3.38 (d, 2H), 2.98 (m, 2H), 1.95- 1.81 (m, 4H); LC-MS : 390.2 [M+H]+.
  • 95
  • N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine [ No CAS ]
  • [ 56651-60-6 ]
  • 3-[(2,4-difluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(1-methylpiperidin-4-yl)urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% In dichloromethane for 1h; 125 Example 125: 3-[(2,4-difluorophenyl)methyl]-l-[(4-methoxyphenyl)methyl]-3-(l- methylpiperidin-4-yl)urea (125) A solution of l-methoxy-4-(isocyanatomethyl)benzene (172 mg 1,03 mmol) in dichloromethane (1 ml) was added to N-[(2,4-difluorophenyl)methyl]-l-methylpiperidin-4- amine (intermediate 2, 200 mg, 0.79 mmol) in dichloromethane (2 ml). The mixture was stirred for 1 hour, then evaporated and the residue was purified by column chromatography using silicon dioxide gel, eluting with 0-25 % methanol in ethyl acetate to afford the title compound (192 mg, 60 % yield): NMR (400 MHz, Chloroform-;/) δ 7.25 - 7.16 (m, 1H), 7.11 (d, 2H), 6.85 - 6.73 (m, 4H), 4.55 (t, 1H), 4.40 (s, 2H), 4.32 (d, 2H), 4.32 - 4.21 (m, 1H), 3.78 (s, 3H), 2.89 (d, 2H), 2.27 (s, 3H), 2.13 - 2.03 (m, 2H), 1.74-1.61 (m, 4H); LC-MS : 403.9 [M+H]+.
  • 96
  • tert-butyl (3R)-3-[(4-fluorophenyl)methyl]amino}piperidine-1-carboxylate [ No CAS ]
  • [ 56651-60-6 ]
  • tert-butyl (3R)-3-[(4-fluorophenyl)methyl]([(4-methoxyphenyl)methyl]carbamoyl})amino}piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96.1% In dichloromethane for 20h; 103 Tert-butyl (3R)-3 - { {(4-fluorophenyl)methyl] ( { [(4-methoxyphenyl)methyl] -carbamoyl } )-amino } piperidine- 1 -carboxylatev To a solution of tert-butyl (3R)-3 - { [(4-fluorophenyl)methyl] amino } piperidine- 1- carboxylate (107 mg, 0.347 mmol) in dry dichloromethane (2.0 ml) l-(isocyanatomethyl)-4- methoxybenzene (67.9 mg, 0.4 14 mmol) in dichloromethane (1.5 ml) was added. Stirring was continued for 20 hours before the reaction was concentrated and the crude product was purified by column chromatography using silica gel, eluting with petroleum ether:ethyl acetate 1:1 to give tert-butyl (3R)-3 - { [(4-fluorophenyl)methyl] ( { [4-methoxyphenyl] -methyl } - carbamoyl)amino}piperidine-1-carboxylate (185 mg, 96.1%) as light yellow oil.
  • 97
  • [ 56651-60-6 ]
  • [ 425672-62-4 ]
  • 2-(4-{N'-[(4-methoxybenzylaminocarbonyl)hydrazino]-4-oxobutyl}phenoxy)-2-methylpropionic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% In dichloromethane at 20℃; for 2h; 4.2.1. tert-Butyl 2-(4-(4-(2-((4-methoxybenzyl)carbamoyl)hydrazineyl-2-methyl-propanoate (4a) To a solution of tert-butyl 2-(4-(4-Hydrazineyl-4-oxobutyl)phenoxy)- 2-methyl-propanoate (3) (5.15 g, 15 mmol) in anhydrous dichloromethane (100 mL) was added 4-methoxybenzyl isocyanate (3.35 g, 20 mmol) dropwise. The reaction mixture was stirred for two hours at ambient temperature, and then concentrated to give the desired acylsemicarbazide as a solid. Crystallization from warm pet ether gave white solid 6.37 g in 85% yield, mp: 131.2 °C. 1H NMR (500 MHz, CDCl3) δ 7.71 (s, 1H), 7.17 (d, 2H), 7.07(d, 1H), 6.98 (d, 2H), 6.81 (d, 2H), 6.74 (d, 2H), 5.66 (d, 1H), 4.27 (d, 2H), 3.78 (s, 3H), 2.53 (t, 2H), 2.16 (t, 2H), 1.89 (t, 2H), 1.53 (s, 6H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 174.9, 174.0, 160.2, 159.4, 155.2, 135.8, 132.1, 130.2, 129.8, 120.5, 115.9, 83.1, 80.7, 56.6, 45.5, 35.6, 34.6, 29.3, 28.0, 26.7. Anal. Calcd for C27H37N3O6: C, 64.91; H, 7.46; N, 8.41. Found: C, 64.88; H, 7.29; N, 8.53
6.37 g In dichloromethane at 20℃; for 2h; 1 2-(4-{N'-4-methoxy-benzylaminocarbonyl)-hydrazino]-4-oxo-butyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester (6a) To a solution of crude 2-[4-(3-Hydrazinocarbonyl-propyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester (5) (5.15 g, 0.015 mol) in anhydrous dichloromethane (100 mL) was added 4-methoxybenzyl isocyanate (3.35 g, 0.02 mol) dropwise. The reaction mixture was stirred for two hours at ambient temperature, and then concentrated to give the desired acylsemicarbazide as solid. Purification by pet ether gave white solid 6.37 g in 85% yield, mp: 131.2° C. 1H NMR (CDCl3) δ 7.71 (s, 1H), 7.17 (d, 2H), 7.07 (d, 1H), 6.98 (d, 2H), 6.81 (d, 2H), 6.74 (d, 2H), 5.66 (d, 1H), 4.27 (d, 2H), 3.78 (s, 3H), 2.53 (t, 2H), 2.16 (t, 2H), 1.89 (t, 2H), 1.53 (s, 6H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 174.9, 174.0, 160.2, 159.4, 155.2, 135.8, 132.1, 130.2, 129.8, 120.5, 115.9, 83.1, 80.7, 56.6, 45.5, 35.6, 34.6, 29.3, 28.0, 26.7. Anal. Calcd for C27H37N3O6: C, 64.91; H, 7.46; N, 8.41. Found: C, 64.88; H, 7.29; N, 8.53.
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