* 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.
Reference：
[1] Liebigs Annalen der Chemie, 1983, # 7, p. 1230 - 1236
[2] Journal of the Chemical Society, 1951, p. 2323,2327
[3] Journal of the Chemical Society, 1951, p. 2323,2327
Reference：
[1] Australian Journal of Chemistry, 2015, vol. 68, # 5, p. 814 - 824
[2] Patent: CN106188014, 2016, A,
9
[ 1670-14-0 ]
[ 29509-91-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 26, p. 6529 - 6540
10
[ 1774-66-9 ]
[ 1670-14-0 ]
[ 58536-46-2 ]
Yield
Reaction Conditions
Operation in experiment
61%
With sodium hydroxide In ethanol for 12 h; Heating / reflux
Nineteen grams (67 mmol) of 3-(4-bromo-phenyl)-1-phenyl-propenon obtained in the above step (1) was dissolved in 150 milliliter of ethanol. The resultant solution was mixed with 10.6 g (69 mmol) of benzamidine hydrochloride and 5.5 g (138 mmol) of sodium hydroxide, and the resultant suspension was refluxed under heating for 12 hours. After completion of the reaction, the solution was cooled down to room temperature, then, precipitated crystals were separated by filtration and washed with water and methanol, thereby obtaining 15.9 g of 4-(4-bromo-phenyl)-2,6-diphenyl-pyrimidine (yield: 61 percent).
38%
With sodium hydroxide In ethanol for 8 h; Reflux
The intermediate body 2-1 (20 g, 69.7 mmol) and benzamidine hydrochloride (10.8 g, 69.7 mmol) were added to ethanole (300 mL). Sodium hydroxide (5.6 g, 140 mmol) was further added thereto and heated to reflux at room temperature for 8 hours. A precipitated solid was separated by filtration. Then, the obtained solid was washed with hexane. A white solid intermediate body 2-2 (10.3g, a yield rate 38percent) was obtained.
38%
With sodium hydroxide In ethanol for 8 h; Reflux
General procedure: Intermediate 1 (20g, 69.7 mmol) and benzamidine hydrochloride (10.8g, 69.7 mmol) were added to ethanol (300 mL) and sodium hydroxide (5.6g, 140 mmol) was further added. The mixture was heated under reflux for 8 hours. The precipitates were separated by filtration and washed with hexane to obtain white solids (10.3g, yield 38percent). The solids were identified as Intermediate 2 by FD-MS analysis.
38%
With sodium hydroxide In ethanol for 8 h;
The intermediate 4-1 (20 g, 69.7 mmol) and benzamidine hydrochloride (10.8 g, 69.7 mmol) were added to ethanol (300 mL). Sodium hydroxide (5.6 g, 140 mmol) was further added thereto and heated to reflux at room temperature for eight hours. A precipitated solid was separated by filtration. Then, the obtained solid was washed with hexane. A white solid intermediate 4-2 (10.3 g, a yield rate 38percent) was obtained.
Reference：
[1] New Journal of Chemistry, 2015, vol. 39, # 5, p. 3639 - 3645
[2] Patent: EP1582516, 2005, A1, . Location in patent: Page/Page column 79
[3] Patent: EP2415769, 2012, A1, . Location in patent: Page/Page column 115-116
[4] Patent: EP2589596, 2013, A1, . Location in patent: Paragraph 0098
[5] Patent: US9711732, 2017, B2, . Location in patent: Page/Page column 224
[6] Chemistry - A European Journal, 2017, vol. 23, # 12, p. 2858 - 2866
11
[ 1670-14-0 ]
[ 1122-91-4 ]
[ 98-86-2 ]
[ 58536-46-2 ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: With sodium methylate In methanol; ethanol at 20℃; for 9 h; Inert atmosphere; Reflux Stage #2: With sodium hydroxide In methanol; ethanol at 70℃; for 5 h;
4-bromobenzaldehyde (18.5 g, 100 mmol), acetophenone (12.0 g, 100 mmol), 1N-sodium methoxide/methanol solution (10 ml) and ethanol (200 ml) were stirred at room temperature for 5 hours at the room temperature under an Ar gas atmosphere. Subsequently, the reactant mixture was heated and stirred for another four hours at a reflux temperature. Next, benzamidine hydrochloride (9.4 g, 60 mmol) and sodium hydroxide (8.0 g, 200 mmol) were added thereto and stirred for five hours at 70 degrees C. After the reaction, the reactant mixture was filtered to separate an extract. The extract was refined by silica-gel column chromatography (a developing solvent: dichloromethane) to provide an intermediate body X7 as a white solid. A yield of the intermediate body X7 was 11.6 g and a yield rate thereof was 30percent
With potassium hydroxide In ethanol for 3 h; Reflux
107.7 g (0.5 mol) of 4-bromoacetophenone and 50.0 ml (0.5 mol) of benz-aldehyde are initially introduced, and 815 ml of sodium hydroxide solution (2 mol/l, 1.6 mol) and 850 ml of DI water are added. The reaction mixture is stirred at 40° C. for 24 h. The precipitated solid is filtered off with suction and rinsed with DI water. The crude product obtained in this way is recrystallised from ethanol. Yield 113 g (80percent of theory). 21.8 g (0.4 mol) of KOH pellets are dissolved in 500 ml of EtOH. 38.0 g (0.2 mol) of benzamidine hydrochloride and 115.0 g (0.4 mol) of (E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one, in each case dissolved in 250 ml of ethanol, are subsequently added, and the mixture is heated under reflux for 3 h. After cooling to room temperature, the precipitated solid is filtered off with suction, washed a number of times with ethanol and dried. Yield: 76.0 g (81percent of theory).
A 150 ml three-necked flask was charged with 0.01 mol of Compound A1, 0.01 mol of Compound B1, and 30 ml of Cholinehydroxide ((hydroxyethyl)trimethylammonium hydroxide). Heat to 60 ° C, after the reaction is completed, cool to room temperature. After adding 60 ml of distilled water, suction filtration, the filter cake was rinsed twice with analytically pure ethanol, and passed through a silica gel column to obtain Intermediate C1, purity 99.10percent, yield 62.6percent.
Reference：
[1] Patent: CN108239070, 2018, A, . Location in patent: Paragraph 0044; 0047; 0048; 0060; 0063; 0064
Reference：
[1] Journal of Materials Chemistry C, 2018, vol. 6, # 37, p. 10088 - 10100
16
[ 1670-14-0 ]
[ 1122-91-4 ]
[ 23449-08-3 ]
Yield
Reaction Conditions
Operation in experiment
68%
With copper(II) acetate monohydrate; sodium carbonate In toluene at 100℃; for 24 h;
General procedure: A mixture ofaldehyde 1 (6.8 mmol), amidine hydrochloride 2 (2 g,11.4 mmol), Na2CO3 (1.21 g, 11.4 mmol, 1.0 equiv) andCu(OAc)2 (10 molpercent) was stirred in toluene (20 mL) under100 °C in air for 24 h. After completion of the reaction, themixture was cooled to room temperature. The water wasadded to the reaction system and atmospheric distillation untiltoluene was evaporated. The resulting solution was filteredand residue with hot water washed 3 times. The crude productwas purified by column chromatography on silica gel usingpetroleum ether/EtOAc (100:1) as an eluent to give the correspondingproducts 7a-7x.
Reference：
[1] Journal of Fluorescence, 2018, vol. 28, # 2, p. 707 - 723
17
[ 1670-14-0 ]
[ 1878-68-8 ]
[ 23449-08-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 18, p. 2098 - 2102
18
[ 873-75-6 ]
[ 1670-14-0 ]
[ 23449-08-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6723 - 6727
19
[ 1670-14-0 ]
[ 108-59-8 ]
[ 13566-71-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With sodium methylate In methanol at 55℃; for 2 h; Stage #2: With acetic acid In methanol; water for 0.5 h;
Benzamidine hydrochloride (26.0 gm, 0.166 moles) and dimethyl malonate (21.9 gm, 0.166 moles) were combined in dry methanol (200 mL). This mixture was stirred as 30percent sodium methoxide in methanol (89.7 gm, 0.498 moles) was added. A precipitate of sodium chloride formed and this mixture was stirred at 55°C. for 2 hours. The reaction mixture was diluted with water (500 mL) to form a clear solution. This was acidified by the addition of acetic acid (35 mL) causing a white precipitate to quickly form. After stirring for 30 minutes, the solid was isolated by filtration. The filter cake was washed, in turn with water, methanol and acetone. After drying, the 2-phenyl-4,6-dihydroxypyrimidine was obtained in a yield of 25 gm (80percent) as a white solid.
Example 113Synthesis of(6-morpholm-4-yl-2-phenyl-pyrimidin-4-yl)-(4-trifltιorσmethoxy-phenyl)- amineStep (i). Synthesis of 2-phenyl-pyrimidine-4, 6-diol Sodium ethoxide was generated in-situ by adding sodium (18.4 g, 801 mmol) to absolute ethanol (500 mL) and then benazamidine hydrochloride (50 g, 320 mmol) was added followed by diethylmalonate (48.8 mL, 320 mmol), This reaction mixture was allowed to stir at refluxing temperature for 16 hours, under nitrogen atmosphere. Then the mixture was cooled to room temperature and concentrated tinder reduced pressure. The crude white solid was dissolved in water, acidified with 2N HCl. White solid obtained was filtered off, washed with z-propanol and dried to afford the compound 2-phenyl-pyrimidine-4,6-diol (34 g, 56percent) as off white solid.; Example 174Synthesis of 2-phenyl-pyrimidine-4, 6-diol This compound was prepared by a procedure analogous to that disclosed in Example 113 (step i), using starting materials with the appropriate substitution.
145 g
With sodium ethanolate In ethanol for 4 h; Reflux; Green chemistry
General procedure: Dry hydrogen chloride (1.3 mol) was added to an ice-cooled solution of 1 mol nitrile and 1.3 mol ethanol. The solution was stirred for two days at room temperature. A solution of 25 g (1.5 mol) of ammonia in absolute ethanol was prepared and added to the formed imido acid ethyl ester solution. The reaction mixture was stirred for 5 h, the precipitated NH4Cl was filtered off, and the clear solution was stored in a closed flask. A sodium ethanolate solution was prepared with 46 g (2 mol) of sodium in1 L of ethanol. The amidine hydrochloride–ethanol solution and 160 g (1 mol) of diethyl malonate were added. A white precipitate was immediately formed and the mixture was refluxed for 4 h. The solvent was distilled off under reduced pressure, and the crude sodium salt was dissolved in 1 L of water. From the clear solution the 2-substituted 6-hydroxy-[3H]-pyrimidin-4-one was precipitated by addition of aqueous concentrated hydrochloric acid. The precipitate was isolated, washed with distilled water, and dried under vacuum at 80°C for 6 h.
Reference：
[1] Farmaco, 1997, vol. 52, # 1, p. 61 - 65
[2] Patent: WO2006/34473, 2006, A2, . Location in patent: Page/Page column 249; 292
[3] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 8, p. 2627 - 2634
[4] Patent: US6372751, 2002, B1, . Location in patent: Example Pr1
[5] Patent: US2003/162764, 2003, A1,
[6] Patent: US6372740, 2002, B1,
[7] Australian Journal of Chemistry, 2015, vol. 68, # 5, p. 814 - 824
21
[ 1670-14-0 ]
[ 92385-43-8 ]
[ 85386-14-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium In ethanol
Example 32 2-PHENYLPYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl 3-N,N-dimethylamino-2-formylacrylate (4.0 g, 23 mmol) (Arnold, Coll. Czech. Chem. Commun. 26:3051, 1961), benzamidine hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 mL) was heated at reflux for 1 h. The solution was filtered and concentrated and the residue partitioned between EtOAc and dilute HCl (10percent). The organic layer was dried (Na2 SO4), and concentrated to give ethyl 2-phenylpyrimidine-5-carboxylate (4.0 g, 75percent yield); m.p. >220° C. (dec.).
Reference：
[1] Journal of medicinal chemistry, 2000, vol. 43, # 21, p. 3995 - 4004
[2] Patent: US5811428, 1998, A,
22
[ 80370-42-9 ]
[ 1670-14-0 ]
[ 85386-14-7 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 96 - 107
23
[ 1670-14-0 ]
[ 85386-14-7 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 7, p. 2470 - 2483
24
[ 613-92-3 ]
[ 1670-14-0 ]
Yield
Reaction Conditions
Operation in experiment
94.1%
With ammonia; hydrogen In methanol at 50℃; Autoclave
Benzal oxime (272 g, 2.0 mol, 1.0 eq), methanol (500 mL) and Raney Ni (15 g) were charged into a 1 L autoclave. A small amount of liquid ammonia was charged and N2 was substituted three times. H2 was then added to maintain the autoclave Pressure 2-3MPa, temperature control 50 , the reaction until no longer hydrogen absorption, after the end of the reaction, filtration, the filtrate was concentrated to dryness, the residue was cooled to 5 , the solid precipitation, filtration, to get gray crude benzamidine hydrochloride , Then add ethanol (700mL) heated completely dissolved, then add activated carbon bleaching, refluxing 30min, filtered while hot, cooled to 0 ° C, filtered and dried at 50 ° C in vacuo to give a white solidBenzamidine hydrochloride 325 g, yield 94.1percent, HPLC purity 99.6percent.
Reference：
[1] Patent: CN107353230, 2017, A, . Location in patent: Paragraph 0023; 0025; 0026; 0027; 0030; 0031
[2] Synthetic Communications, 2011, vol. 41, # 15, p. 2195 - 2199
[3] Antimicrobial Agents and Chemotherapy, 2015, vol. 59, # 2, p. 890 - 904
25
[ 5333-86-8 ]
[ 1670-14-0 ]
Yield
Reaction Conditions
Operation in experiment
80%
With ammonium hydroxide In ethanol at 20℃; for 24 h;
The first step was to synthesize intermediate 1. To a 250mL three-necked flask were added cyanobenzene (0.5 mol)and C2H5OH (0.6 mol) with stirring. Under −10 ~ 0 °C, HCl gas was put into reaction flask until it was saturated, giving alot of white solid. Subsequently, at room temperature, 15percent NH3-C2H5OH (140 mL) solution was added into the flask and the mixture was stirred. After 24 h stirring, the mixture became to white pulp and the reaction was stopped. The mixture was filtered and the filtrate was concentrated by rotary evaporation to afford intermediate 1. Yield: 80percent. mp 82-84 °C.
Reference：
[1] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 12, p. 3743 - 3748
[2] Australian Journal of Chemistry, 2015, vol. 68, # 5, p. 814 - 824
26
[ 100-47-0 ]
[ 1670-14-0 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 45, p. 5980 - 5983
[2] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1994, # 23, p. 3507 - 3510
[3] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 3, p. 372 - 375
[4] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 12, p. 3743 - 3748
[5] European Journal of Organic Chemistry, 2014, vol. 2014, # 17, p. 3614 - 3621
[6] Australian Journal of Chemistry, 2015, vol. 68, # 5, p. 814 - 824
[7] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 29 - 43
27
[ 5873-90-5 ]
[ 1670-14-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 3, p. 372 - 375
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 17, p. 3614 - 3621
28
[ 7664-41-7 ]
[ 5333-86-8 ]
[ 1670-14-0 ]
Reference：
[1] Die Imidoaether und ihre Derivate <Berlin 1892>, S. 152,
29
[ 5333-86-8 ]
[ 1670-14-0 ]
Reference：
[1] Chemische Berichte, 1917, vol. 50, p. 234
30
[ 7732-18-5 ]
[ 79-02-7 ]
[ 124-38-9 ]
[ 1670-14-0 ]
Reference：
[1] Die Imidoaether und ihre Derivate <Berlin 1892>, S. 157,
[2] Chemische Berichte, 1889, vol. 22, p. 1610[3] Chemische Berichte, 1890, vol. 23, p. 2925
31
[ 1670-14-0 ]
[ 6630-33-7 ]
[ 77989-15-2 ]
Yield
Reaction Conditions
Operation in experiment
59%
With copper(II) acetate monohydrate; sodium carbonate In toluene at 100℃; for 24 h;
General procedure: A mixture ofaldehyde 1 (6.8 mmol), amidine hydrochloride 2 (2 g,11.4 mmol), Na2CO3 (1.21 g, 11.4 mmol, 1.0 equiv) andCu(OAc)2 (10 molpercent) was stirred in toluene (20 mL) under100 °C in air for 24 h. After completion of the reaction, themixture was cooled to room temperature. The water wasadded to the reaction system and atmospheric distillation untiltoluene was evaporated. The resulting solution was filteredand residue with hot water washed 3 times. The crude productwas purified by column chromatography on silica gel usingpetroleum ether/EtOAc (100:1) as an eluent to give the correspondingproducts 7a-7x.
Reference：
[1] Journal of Fluorescence, 2018, vol. 28, # 2, p. 707 - 723
32
[ 1670-14-0 ]
[ 1073062-59-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydroxide In ethanol for 12 h; Reflux
Compound 2-1 (0.2 g, 0.59 mmol), benzamidine hydrochloride (0.2 g, 1.3 mmol) and NaOH (0.05 g, 1.3 mmol) were added to ethanol (2 ml) and refluxed for 12 hours. Washed with water and ethanol to obtain Compound 2-2 (0.2 g, 80percent).
Reference：
[1] Patent: KR2017/79348, 2017, A, . Location in patent: Paragraph 0067; 0072-0075
33
[ 18467-14-6 ]
[ 1670-14-0 ]
[ 864377-31-1 ]
Yield
Reaction Conditions
Operation in experiment
74%
With sodium hydroxide In ethanol for 12 h; Reflux
Compound 10-1 (1.5 g, 5.9 mmol), benzamidine hydrochloride (2.0 g, 13.0 mmol) and NaOH (0.5 g, 13.0 mmol) were added to ethanol (20 ml) and refluxed for 12 hours.Washed with water and ethanol to obtain Compound 10-2 (1.7 g, 74percent).
37%
Stage #1: With sodium hydroxide In ethanol at 80℃; for 16 h; Inert atmosphere Stage #2: With sodium t-butanolate In ethanol at 80℃; for 16 h; Inert atmosphere
Subsequently, under an argon gas atmosphere, the intermediate body 5-1 (130g, 50 mmol), benzamidine hydrochloride (152g, 100 mmol), anhydrous ethanol (1 L), and sodium hydroxide (42 g) were added together in sequential order, and stirred at 80 degrees C for 16 hours. Subsequently, sodium-t-butoxide (20 g, 208 mmol) were further added and heated at 80 degrees C for 16 hours with stirring. After the reaction solution was cooled down, a solid was separated by filtration and washed with methanol to obtain an intermediate body 5-2 (67g, a yield of 37percent).
37%
Stage #1: With sodium hydroxide In ethanol at 80℃; for 16 h; Inert atmosphere Stage #2: With sodium t-butanolate In ethanol at 80℃; for 16 h;
Subsequently, under an argon gas atmosphere, the intermediate body 1C-1 (130 g, 50 mmol), benzamidine hydrochloride (152 g, 100 mmol), anhydrous ethanol (1 L), and sodium hydroxide (42 g) were added together in sequential order, and stirred at 80 degrees C. for 16 hours. Subsequently, sodium-t-butoxide (20 g, 208 mmol) were further added and heated at 80 degrees C. for 16 hours with stirring. After the reaction solution was cooled down, a solid was separated by filtration and washed with methanol to obtain an intermediate body 1H-2 (67 g, a yield of 37percent).
26.7%
Stage #1: With sodium hydroxide In ethanol for 18 h; Inert atmosphere; Reflux Stage #2: With sodium t-butanolate In ethanol for 16 h; Inert atmosphere; Reflux
Into a 1 L four-necked round bottom flask equipped with a stirrer, an Erlin condenser, a nitrogen inlet tube and a thermometer were placed 74.8 g (0.268 mol) of the benzenamine obtained in the above , 84.6 g of benzamidine hydrochloride (0.54 mol) of sodium hydroxide, 22.7 g (0.57 mol) of sodium hydroxide and 500 mL of ethanol, and the mixture was allowed to react at a reflux temperature of ethanol for 18 hours under a nitrogen stream. After cooling to room temperature, 10.8 g (0.112 mol) of sodium tert-butylate was added, and the mixture was reacted again under a nitrogen stream at the reflux temperature of ethanol for 16 hours.The resulting reaction solution was cooled to room temperature, and the precipitated crystals were suction filtered. Next, the crystals remaining in the Nutsche were thoroughly washed with ethanol and water to obtain 28.0 g of a white target compound (yield: 26.7percent).
Reference：
[1] Patent: KR2017/79348, 2017, A, . Location in patent: Paragraph 0198; 0203-0206
[2] Patent: EP2415769, 2012, A1, . Location in patent: Page/Page column 118-119
[3] Patent: US9966541, 2018, B2, . Location in patent: Page/Page column 97
[4] Patent: JP2018/90561, 2018, A, . Location in patent: Paragraph 0066
34
[ 3132-99-8 ]
[ 1670-14-0 ]
[ 864377-31-1 ]
Yield
Reaction Conditions
Operation in experiment
83%
With nickel diacetate; sodium carbonate In toluene at 110℃; for 30 h;
100mlThree mouthfulsIn the bottleM-bromobenzaldehyde(10.8mmol, 2g),Benzoquinone hydrochloride(21.6mmol, 3.8g), Na2CO3 (21.6 mmol, 2.2 g), Ni(OAc) 2 (1.08 mmol, 0.27 g),The molar ratio is charged at 1:2:2:0.1.The solvent was chosen to be 50 g of toluene.The reaction was controlled to stir at 110 ° C for 30 h.filter,Washed,Recrystallization from absolute ethanol,The obtained cake was vacuum dried to obtain a product of 3.6 g.The yield was 83percent.
68%
With copper(II) acetate monohydrate; sodium carbonate In toluene at 100℃; for 24 h;
General procedure: A mixture ofaldehyde 1 (6.8 mmol), amidine hydrochloride 2 (2 g,11.4 mmol), Na2CO3 (1.21 g, 11.4 mmol, 1.0 equiv) andCu(OAc)2 (10 molpercent) was stirred in toluene (20 mL) under100 °C in air for 24 h. After completion of the reaction, themixture was cooled to room temperature. The water wasadded to the reaction system and atmospheric distillation untiltoluene was evaporated. The resulting solution was filteredand residue with hot water washed 3 times. The crude productwas purified by column chromatography on silica gel usingpetroleum ether/EtOAc (100:1) as an eluent to give the correspondingproducts 7a-7x.
Reference：
[1] Patent: CN108264490, 2018, A, . Location in patent: Paragraph 0068; 0069; 0070; 0071
[2] Journal of Fluorescence, 2018, vol. 28, # 2, p. 707 - 723
35
[ 1711-09-7 ]
[ 1670-14-0 ]
[ 864377-31-1 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: With triethylamine In 5,5-dimethyl-1,3-cyclohexadiene at 0 - 60℃; for 3.5 h; Inert atmosphere Stage #2: With 1,1,3,3-tetramethyldisilazane In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 5 h; Inert atmosphere
Under an argon stream, benzamidine hydrochloride (470 mg, 3.0 mmol) was suspended in xylene (7.5 mL).The suspension was cooled to 0 ° C., triethylamine (420 μL, 3.0 mmol) and 3-bromobenzoyl chloride (130 μL, 1.0 mmol) were added, and the mixture was stirred at 0 ° C. for 30 minutes and further at 60 ° C. for 3 hours.After allowing to cool, 1,1,3,3-tetramethyldisilazane (520 μL, 3.0 mmol) was added to the reaction mixture, and the mixture was stirred at 150 ° C. for 5 hours.After standing to cool, the low boiling fraction was distilled off under reduced pressure from the reaction mixture, water was added to the obtained residue, and the solid was filtered off.The solid was washed with water, methanol, then hexane.The obtained solid was dried under reduced pressure to obtain the objective 2- (3-bromophenyl) -4,6-diphenyl-1,3,5-triazine as a white solid (278 mg, 72percent).
Reference：
[1] Patent: JP2018/30792, 2018, A, . Location in patent: Paragraph 0140-0141
36
[ 25023-37-4 ]
[ 1670-14-0 ]
[ 864377-28-6 ]
Yield
Reaction Conditions
Operation in experiment
58%
With potassium carbonate In ethanol; 1-ethoxyethanol at 90℃; for 24 h;
a); 5.45 g (34.8 mmol) benzamidine hydrochloride hydrate and 4.10 g (73.1 mmol) po- tassium carbonate in 50 ml ethanol are stirred at 90 °C under dry air. 20.0 g (69.7 mmol) (E)-1-(3-bromophenyl)-3-phenyl-prop-2-en-1-one in 20 ml hot ethoxy-ethanol are added slowly. After 24 h the reaction mixture is cooled to 25 °C, the product is filtered off, washed with ethanol, water and again ethanol and is used without further purification in step b) (
Stage #1: With sodium methylate In methanol; ethanol at 20℃; for 9 h; Inert atmosphere; Reflux Stage #2: With sodium hydroxide In methanol; ethanol at 70℃; for 5 h;
3-bromobenzaldehyde (18.5 g, 100 mmol), acetophenone (12.0 g, 100 mmol), 1N-sadium methoxide/methanol solution (10 ml) and ethanol (200 ml) were stirred for five hours at the room temperature under an Ar gas atmosphere. Subsequently, the reactant mixture was heated and stirred for another four hours at a reflux temperature. Next, benzamidine hydrochloride (9.4 g, 60 mmol) and sodium hydroxide (8.0 g, 200 mmol) were added thereto and stirred for five hours at 70 degrees C. After the reaction, the reactant mixture was filtered to separate an extract. The extract was refined by silica-gel column chromatography (a developing solvent: dichloromethane) to provide an intermediate body X6 as a white solid. A yield of the intermediate body X6 was 10.1 g and a yield rate thereof was 26percent.
Stage #1: With sodium hydroxide In ethanol at 20℃; for 8 h; Stage #2: With sodium hydroxide In ethanol for 8 h; Reflux
3,5-dibromobenzaldehyde (1 0.56g, 40 mmol) and acetophenone (4.81, 40 mmol) were dissolved in ethanol (80 mL), and sodium hydroxide (0.16g, 4 mmol) was added. The resulting solution was stirred at room temperature for 8 hours. Then, benzamidine hydrochloride (4.70g, 30 mmol), sodium hydroxide (1.60g, 40 mmol) and ethanol (40 mL) were added, and the resulting solution was reacted while heating under reflux for 8 hours. White powder generated was filtered off and washed with ethanol until the liquid became colorless. The powder was further washed with water and ethanol and then dried in vacuum to obtain intermediate N (5.20g, yield: 56percent).
With sodium methylate; In methanol; ethanol; at 0℃; for 4h;Heating / reflux;
Example 6 SYNTHESIS of Compound 24 [0090] This example illustrates Reaction Scheme III. 24 Preparation of IIIA : [0091] Methyl L-BENZYL-OXO-3-PIPERIDINE carboxylate HCL (11. 27G, 39. 72mmole) was added to A solution of 25percent sodium METHOXIDE (31M1, 4eq) in methanol while cooling the reaction mixture in an ice bath. Added BENZAMIDINE HC1 (6. 93g, 39. 72mmole) slowly then diluted the mixture to 200MOL with ethanol. Refluxed the reaction 4 hours. Removed ethanol under vacuum, residue was taken up in dichloromethane and water, extracted with DICHLOROMETHANE, combined dichloromethane extracts dried over sodium sulfate (ANH) and evaporated to dryness to give 4. 36G product. Ethyl acetate was added to aqueous layer to give A white solid which was washed with minimum amount of chloroform to give 3. 65g product. A second crop was obtained upon standing overnight 3. 92g. Total yield 7. 57g (61percent yield).
Example 32 2-PHENYLPYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl 3-N,N-dimethylamino-2-formylacrylate (4.0 g, 23 mmol) (Arnold, Coll. Czech. Chem. Commun. 26:3051, 1961), benzamidine hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 mL) was heated at reflux for 1 h. The solution was filtered and concentrated and the residue partitioned between EtOAc and dilute HCl (10%). The organic layer was dried (Na2 SO4), and concentrated to give ethyl 2-phenylpyrimidine-5-carboxylate (4.0 g, 75% yield); m.p. >220 C. (dec.).
5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate[ No CAS ]
[ 1670-14-0 ]
[ 18202-73-8 ]
[ 367926-41-8 ]
Yield
Reaction Conditions
Operation in experiment
In 2-methoxy-ethanol;
EXAMPLE 62 Preparation of 3-[3-(4-Hydroxy-5-oxo-2-phenyl-2-imidazolin-4-yl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil A mixture of 5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate (0.620 g, 1.50 mmol), phenyl amidine hydrochloride (0.258 g, 1.65 mmol) and 2-methoxyethanol is stirred 40 minutes at reflux, cooled to room temperature and poured into water. The resultant yellow precipitate is filtered and saved. The filtrate is extracted four times with methylene chloride; the combined organic layers are concentrated in vacuo and the residue is triturated with ether to afford a yellow solid. The yellow solids are combined and chromatographed on silica gel with methylene chloride-methanol to afford the title compound as a solid (0.110 g, 14.6%, mp 139-141 C.) which is identified by NMR spectral analysis. Using essentially the same procedure and employing tert-butyl amidine hydrochloride, the following product is obtained (mp 192 C.):
2-phenyl-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol;
Example 9 2-Phenyl-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one A solution of methyl 4-oxotetrahydropyrane-3-carboxylate (112 mg) and benzamidine hydrochloride (470 mg) in methanol (2 ml) was added with potassium carbonate (100 mg) and heated under reflux for 3 hours. The reaction mixture was cooled, then poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the above-titled product (90 mg). 1H-NMR (CDCl3) delta: 2.83 (2H, t, J=5.6Hz), 4.02(2H, t, J=5.6Hz), 4.67 (2H, s), 7.50-7.60 (3H, m), 8.08-8.12(2H, m). Mass (EI, m/z): 228(M+).
With bromine; sodium methylate; In tetrahydrofuran; methanol; N,N-dimethyl-formamide; toluene; acetonitrile;
Example 1-3 <Synthesis of 2-phenyl-4-(2,4-dichlorophenyl)-5-methylimidazole> 51.4 g (0.322 mol) of bromine was added dropwise to a solution of 63.2 g (0.311 mol) of <strong>[37885-41-9]2',4'-dichloropropiophenone</strong> in 140 g of methanol at a reaction temperature of 50 to 55C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (150 ml * 3 times). Thereafter, the toluene was distilled off under reduced pressure, giving 85.2 g (0.302 mol) of crude brown oily 2-bromo-<strong>[37885-41-9]2',4'-dichloropropiophenone</strong>. A suspension of 47.3 g (0.302 mol) of benzamidine hydrochloride, 16.3 g (0.302 mol) of sodium methylate in 250 ml of tetrahydrofuran was heated under reflux for 1 hour, and cooled to 25C. A solution of 85.2 g (0.302 mol) of the above-mentioned crude 2-bromo-<strong>[37885-41-9]2',4'-dichloropropiophenone</strong> in 160 ml of tetrahydrofuran was added dropwise in such a manner that the reaction temperature did not exceed 30C. After the addition was complete, 16.3 g (0.302 mol) of sodium methylate was added, and the resultant was heated under reflux for 1 hour. Subsequently, the reaction solution was cooled to room temperature, and insolubles were then filtered off. The filtrate was evaporated to dryness under reduced pressure, to recover a residual solid. This solid was successively washed with water and toluene and then dried, to give 50.4 g (55.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using a mixture of acetonitrile and DMF, to give colorless purified crystals. The melting point, thin layer chromatography Rf value, NMR and mass-spectral data of the obtained crystals were as follows. mp. 222-224C TLC (silica gel, acetone): Rf=0.67 NMR(d6-DMSO): delta2.19 (s, 3H), 7.2-8.1 (m, 8H)
With bromine; potassium hydrogencarbonate; In tetrahydrofuran; methanol; water; toluene; acetonitrile;
Example 1-2 <Synthesis of 2-phenyl-4-(3,4-dichlorophenyl)imidazole> 43.9 g (0.275 mol) of bromine was added dropwise to a solution of 50.5 g (0.267 mol) of 3',4'-dichloro acetophenone in 120 g of methanol at a reaction temperature of 50 to 55C. After the addition was complete, the methanol was evaporated off the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (150 ml * 3 times). Thereafter, the toluene was evaporated off under reduced pressure, giving 68.0 g (0.254 mol) of crude brown oily 2-bromo-3',4'-dichloroacetophenone. A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-3',4'-dichloroacetophenone in 110 ml of tetrahydrofuran was added dropwise over 30 minutes, under reflux with heating, into a suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride, 102.1 g (1.02 mol) of potassium bicarbonate in 400 ml of tetrahydrofuran and 100 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 45.5 g (62.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder. The melting point, thin layer chromatography Rf value, NMR and mass-spectral data of the obtained crystal were as follows. mp. 179-182C TLC (silica gel, chloroform/ethyl acetate=9/1): Rf=0.52 NMR(CD3OD): delta 7.4-8.0 (m)
Reference Example 1 5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine To a solution of <strong>[1212-53-9]methyl N-benzyloxycarbonylglycinate</strong> (1.25 g, 5.60 mmol) in toluene (12.5 ml) was added tert-butoxy bisdimethylaminomethane (1.5 ml, 7.28 mmol), and the mixture was stirred at 70°C overnight, washed with saturated brine, and concentrated under reduced pressure. To the residue were added MTBE (13.1 ml) and 1N hydrochloric acid (9.8 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. The mixture was partitioned, and the organic layer was washed with saturated brine. A solution (1.08 g) of 28percent sodium methoxide in methanol was added dropwise to the organic layer. After completion of the reaction, the mixture was concentrated under reduced pressure. Acetonitrile (18.6 ml) was added to the residue, then benzamidine hydrochloride (0.88 g) was added thereto, and the mixture was stirred overnight at 70°C. The reaction mixture was concentrated and water was added thereto, and the mixture was stirred for 1 hr. The precipitate was filtrated and dried under reduced pressure to give the title compound as crystals (1.30 g, 4.04 mmol). 1H-NMR(DMSO-d6) deltappm: 5.18(2H, s), 7.32-7.57(8H, m), 8.06-8.09(2H, m), 8.46(1H, s), 8.79(1H, s), 13.0(1H, brs); 13C-NMR(DMSO, 400MHz) delta66.1, 124.8, 127.3, 127.6, 127.9, 128.3, 128.6, 131.1, 132.1, 136.3, 150.9, 153.4, 158.8, 158.9; MS(ESI) m/z [MH]- 320.1, m.p. 217.1-218.9°C
Benzamidine hydrochloride (4.0 g, 0.25 mol) was dissolved in 64 ml of ethanol. To this 8.0 ml of a 25 wt percent solution of sodium methoxide was added. Reaction was then stirred at room temperature for 5 hrs, and filtered. Filtrate was then added to ethyl-2-cyano-4, 4-diethoxybutyrate (4.80 g, 0.21 mol). This solution was refluxed for 5 hrs.Half of solvent was removed under reduced pressure, then 80 ml of ice water was added, and the pH was adjusted to 7 with acetic acid. Material was then chilled for 6 hrs and product was isolated by vacuum filtration
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20 - 80℃; for 4h;
To a solution of <strong>[57595-23-0]methyl 4-oxotetrahydrofuran-3-carboxylate</strong> (2.60 mL, 18.0 mmol) and benzamidine hydrochloride (3.40 g, 21.7 mmol) in DMF (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.75 mL, 45.1 mmol) at room temperature. The reaction mixture was warmed to 80 C and stirred for 4 h. After cooling to room temperature, sat. NaHCO3 aqueous solution (100 mL) and H2O (100 mL) were added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/CHCl3 = 20% to 100%) to give 2-phenyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (53) (489 mg, 2.28 mmol, 13%) as a colorless amorphous solid. To a solution of 53 (485 mg, 2.26 mmol) in CH2Cl2 (20 mL) were added triethylamine (0.473 mL, 3.39 mmol), 4-dimethylaminopyridine (27.6 mg, 0.226 mmol) and trifluoromethanesulfonic anhydride (0.456 mL, 2.71 mmol). After stirring at room temperature for 15 h, sat. NaHCO3 aqueous solution was added to the reaction mixture and the mixture was extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 10%) to give the title compound (59.8 mg, 0.173 mmol, 8%) as a colorless solid. 1H NMR (CDCl 3) delta: 5.17 (2H, t, J = 2.0 Hz), 5.27 (2H, t, J = 2.0 Hz), 7.49-7.57 (3H, m), 8.41-8.44 (2H, m).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20 - 85℃; for 18h;
To a solution of methyl 3-oxotetrahydrothiophene-2-carboxylate (0.400 mL, 3.20 mmol) and benzamidine hydrochloride (495 mg, 3.16 mmol) in DMF (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.960 mL, 6.42 mmol) at room temperature. The reaction mixture was warmed to 85 C and stirred for 18 h. After cooling, 1 N HCl aqueous solution was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 30%) to give 2-phenyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (69) (96.5 mg, 0.419 mmol, 13%). 1H NMR (DMSO-d6) delta: 3.27-3.32 (2H, m), 3.35-3.39 (2H, m), 7.49-7.59 (3H, m), 8.05 (2H, d, J = 7.4 Hz). MS (ESI) m/z: 231 (M+H)+.To a solution of 69 (96.5 mg, 0.419 mmol) in CH2Cl2 (5 mL) were added triethylamine (0.180 mL, 1.29 mmol) and trifluoromethanesulfonic anhydride (0.215 mL, 1.28 mmol) at 0 C. After stirring at room temperature for 15 h, the reaction mixture was concentrated in vacuo. The resulting residue was chromatographed (EtOAc/hexane = 0% to 30%) to give (2-phenyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl) trifluoromethanesulfonate (70) (119 mg, 0.328 mmol, 78%) as a yellow solid. 1H NMR (CDCl 3) delta: 3.49-3.57 (4H, m), 7.45-7.51 (3H, m), 8.34-8.37 (2H, m).To a solution of 70 (119 mg, 0.328 mmol) in CH2Cl2 (3 mL) was added 3-chlorobenzenecarboperoxoic acid (65 wt%, 266 mg, 1.00 mmol) at room temperature. After stirring for 18 h, the reaction mixture was concentrated in vacuo. To the residue, MeOH was added and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (89.2 mg, 1.93 mmol, 69%) as a colorless solid. 1H NMR (CDCl 3) delta: 3.62-3.65 (2H, s), 3.69-3.72 (2H, m), 7.53-7.57 (2H, m), 7.61-7.65 (1H, m), 8.46-8.49 (2H, m).
General procedure: A 25 mL Schlenk tube wascharged with a magnetic stirrer and DMSO (2.0 mL). Substituted(2-bromophenyl)methylamine (1) (0.5 mmol), amidine hydrochloride (2) (1.0 mmol),CuBr (0.1 mmol, 14.2 mg), and K2CO3 (1.5 mmol, 207 mg) were added to the tube.The mixture was stirred at 80-120 oC under nitrogen atmosphere for 24 h, and thenunder air for 0.5 h. The resulting mixture was cooled to room temperature and filtered,and the solid was washed with ethyl acetate for two times (3 × 3 mL). The combinedfiltrate was concentrated by the rotary evaporator, and the residue was purified bycolumn chromatography on silica gel using petroleum ether/ ethyl acetate as eluent togive the desired target product.
4-bromobenzaldehyde (7.40g, 40 mmol) and 4-acetyl-4'-bromobiphenyl (11.01, 40 mmol) were dissolved in ethanol (80 mL), and sodium hydroxide (0.16g, 4 mmol) was added. The resulting solution was stirred at room temperature for 8 hours. Then, benzamidine hydrochloride (4.70g, 30 mmol), sodium hydroxide (1.60g, 40 mmol) and ethanol (40 mL) were added, and the resulting solution was reacted while heating under reflux for 8 hours. White powder generated was filtered off and washed with ethanol until the liquid became colorless. The powder was further washed with water and ethanol. 200 mL of ethanol was added again, and then heated under reflux for an hour, followed by filtering. The filtered matter was dried in vacuum to obtain an intended intermediate O (9.32g, yield: 86%).
With mu-diiodo-di((eta5-pentamethylcyclopentadienyl)(iodo)iridium); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 20 - 110℃; for 20h;
General procedure: [Cp*IrI2]2 (1 mol %, 0.01 mmol), xantphos (2 mol %,0.02 mmol) and dioxane (2 mL) were stirred shortly in a Schlenk tube at room temperature. Subsequently, 3-pyridinemethanol (2.0 mmol), benzamidine hydrochloride(1.0 mmol), and cesium carbonate (1.0 mmol)were added. The mixture was heated under 110C for 20 h and then cooled down to room temperature. The resulting solution was purified by column chromatography with petroleum ether-ethyl acetate(10 : 1) as an eluent to give 2,4-diphenyl-6-(pyridin-3-yl)-1,3,5-triazine (3a) as a white solid.
With potassium phosphate; copper(l) iodide; Trimethylacetic acid; In 1,2-dichloro-benzene; at 110℃; for 18h;Sealed tube;
General procedure: Anoven-dried 10mLvialwas charged with CuI (9mg, 0.05mmol),K3PO4 (318 mg, 1.5 mmol), pivalic acid (20 mg, 0.2 mmol), a 1-(2-bromophenyl)methanamine 1 (0.5 mmol), and an amidinium salt 2or an imidate salt 4 (0.5 mmol) under air. After sealing the vial, dry1,2-dichlorobenzene (3 mL) was added by syringe and the reactionmixture was stirred at 110 C (oil bath temperature) for 18 h. Aftercooling to room temperature, the vial was opened and the reactionmixturewas partitioned between CH2Cl2 (30 mL) and brine (20 mL).The aqueous phase was extracted with CH2Cl2 (220 mL). Thecombined organic layers were dried over anhydrous MgSO4 andconcentrated in vacuum. The residue was purified by flash chromatographyon silica gel to afford the desired product.
With potassium phosphate; copper(l) iodide; Trimethylacetic acid; In 1,2-dichloro-benzene; at 110℃; for 18h;Sealed tube;
General procedure: Anoven-dried 10mLvialwas charged with CuI (9mg, 0.05mmol),K3PO4 (318 mg, 1.5 mmol), pivalic acid (20 mg, 0.2 mmol), a 1-(2-bromophenyl)methanamine 1 (0.5 mmol), and an amidinium salt 2or an imidate salt 4 (0.5 mmol) under air. After sealing the vial, dry1,2-dichlorobenzene (3 mL) was added by syringe and the reactionmixture was stirred at 110 C (oil bath temperature) for 18 h. Aftercooling to room temperature, the vial was opened and the reactionmixturewas partitioned between CH2Cl2 (30 mL) and brine (20 mL).The aqueous phase was extracted with CH2Cl2 (220 mL). Thecombined organic layers were dried over anhydrous MgSO4 andconcentrated in vacuum. The residue was purified by flash chromatographyon silica gel to afford the desired product.
[0330] Under an argon gas atmosphere, the compound T2 (5.80 g, 20.4 mmol), <strong>[14401-73-1]3,5-dibromo-4-hydroxyacetophenone</strong>(5.67 g, 20.4 mmol) and sodium methoxide (110 mg, 2.04 mmol) were added to ethanol (50 mL). The obtained solutionwas stirred at the room temperature for two hours and at the reflux temperature for three hours. Subsequently, benzamidinehydrochloride (3.29 g, 21.0 mmol) and sodium hydroxide (1.63 g, 40.8 mmol) were added to the reaction solution.The obtained solution was stirred at the reflux temperature for three hours. After the completion of the reaction, a depositwas separated by filtration. Then, the obtained solid was washed with water and methanol to obtain a compound T3(7.75 g, a yield of 38%).
38%
Under an argon gas atmosphere, ethanol (50 mL) was added to the compound T2 (5.80 g, 20.4 mmol), <strong>[14401-73-1]3,5-dibromo-4-hydroxyacetophenone</strong>(5.67 g, 20.4 mmol), sodium methoxide (110 mg, 2.04 mmol). The obtained solution was stirred for two hours at the room temperature andfor three hours at a reflux temperature. Subsequently, benzamidine hydrochloride (3.29 g, 21.0 mmol) and sodium hydroxide were added andstirred for three hours at the reflux temperature. After the completion of the reaction, a precipitated substance was separated by filtration andwashed with water and methanol to obtain a compound T3 (7.75 g, a yield of 38%).
<strong>[188813-05-0]3-bromo-5-chlorobenzaldehyde</strong> (30 g, 136.7 mmol), Benzamidine Hydrochloride (42.8 g, 273.4 mmol), K3PO4 (58.0 g, 273.4 mmol) in dimethylsulfoxide (DMSO) to put the mixture 90C for 1 hour It was heated. After the reaction was complete, add water to the reaction mixture produced by the solid was filtered to obtain a solid of a pale yellow. This, tetrahydrofuran (THF) in the re-dissolved into dried MgSO4 along with 2,3-dichloro-5 ,6-dicyano-p-benzoquinone (DDQ) (37.9 g, 136.7 mmol) was stirred for 10 minutes at room temperature the insert. After the reaction was complete, the resultant solution was filtered, and then distilled under reduced pressure. Crude to the product by using Ethyl acetate in Hexane within 0 to 10% as eluent and purified by column chromatography on silica gel solid off-white (50.3 g, yield: 87%; MS: [M + H] + = 422 ) it was obtained.
4-amino-6-(5-methoxypyridin-3-yl)-2-phenylpyrimidine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
With sodium hydroxide; In ethanol; for 16h;Reflux;
A mixture ofthe product from step A (15 mg, 0.11 mmol), benzimidamide hydrochloride(17 mg, 0.11 mmol), malononitrile (11 mg, 0.17 mmol),and NaOH (4 mg, 0.10 mmol) in anhydrous EtOH (5 mL) was refluxed for 16 hrs. The mixture was cooled. The suspension was filtered and the filter cake was washed with H20 and EtOH, dried under lamp to give the title product (2 mg, 6%) as a white solid.?H NIVIR (400 IVIFIz, CDC13) 8.96 (s, 1H), 8.50 (m, 3H), 7.91 (s, 1H), 7.56 - 7.49 (m, 3H), 5.79 (s, 2H), 3.98 (s, 3H) .MS: IVJIe 304 (M+1).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;
K2CO3 (2.1 g, 15.4 mmol) was added to a mixture of benzamidine hydrochloride hydrate (1.55 g, 10.0 mmol) and 14 (1.0 g, 7.7 mmol) in DMF at ambient temperature. The solution was heated at 100 °C for 4 h. After confirming that the reaction was complete by using TLC analysis, the solution was cooled to room temperature and water (15 mL) is added. The reaction mixture was extracted with EtOAc and brine. The organic phase was dried over Na2SO4 overnight and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography to give the target product 2g. 1H NMR (600 MHz, DMSO-d6) delta 9.31 (s, 2H), 8.49-8.44 (m, 2H), 7.59 (ddd, J = 15.9, 7.7, 3.6 Hz, 3H), 4.40 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).
With copper(I) oxide; oxygen; In 1-methyl-pyrrolidin-2-one; at 80℃; for 4h;Sealed tube; Green chemistry;
Weigh 0.3 mmol of benzamidine hydrochloride (No. 1 corresponding compound, 0.0471 g) 0.4 mmol of 5-bromo-2-phenyl-1-indole(No. (16) of the corresponding compound, 0.1090 g) And 0.06 mmol cuprous oxide (0.0086 g) In a 20 mL test tube reaction tube, Plus 3mL N-methyl pyrrolidone as solvent, tube mouth closed with oxygen balloon, Stirring at 80 C for 4 hours; after completion of the reaction, The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and separated by column chromatography (column chromatography separation conditions: the stationary phase was 300-400 mesh silica powder, the mobile phase was ethyl acetate (A) and petroleum ether (3) The mobile phase change procedure (A: B) was 1: 6) to obtain 0.0930 g of the reaction product. According to the characterization data, the reaction product was 8-bromo-2,4-diphenylbenzo [1,3,5] triazolu-5-hydrogen-6-one (purity> 95%) ; The product yield is calculated, the result is 79%.
With copper(II) acetate monohydrate; sodium carbonate; In toluene; at 100.0℃; for 24.0h;
General procedure: A mixture ofaldehyde 1 (6.8 mmol), amidine hydrochloride 2 (2 g,11.4 mmol), Na2CO3 (1.21 g, 11.4 mmol, 1.0 equiv) andCu(OAc)2 (10 molpercent) was stirred in toluene (20 mL) under100 °C in air for 24 h. After completion of the reaction, themixture was cooled to room temperature. The water wasadded to the reaction system and atmospheric distillation untiltoluene was evaporated. The resulting solution was filteredand residue with hot water washed 3 times. The crude productwas purified by column chromatography on silica gel usingpetroleum ether/EtOAc (100:1) as an eluent to give the correspondingproducts 7a-7x.
With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
With potassium phosphate; In N,N-dimethyl acetamide; for 18h;Inert atmosphere; Heating;
Under nitrogen flow, <strong>[269066-75-3]2-bromo-1-naphthaldehyde</strong> (10 g, 42.54 mmol), benzimidamide hydrochloride (20 g, 127.6 mmol), and potassium phosphate (36 g, 170.2 mmol) were put into 150 mL of a dimethylacetamide (DMAc) solvent, and the resulting solution was heated and stirred for 18 hours. The reaction solution was cooled and then filtered, and then the filtered material was subjected to slurry purification using EtOH to obtain Compound 1-1-A (16 g, yield 86%).
With caesium carbonate; In acetonitrile; at 120℃; for 24h;
The reaction bottle by adding 1 b (4 mmol), two chlorofluorcarbons sodium acetate (4 mmol), cesium carbonate (8 mmol) and acetonitrile (10 ml), then in 120 °C heating reaction 24 hours. After the reaction is finished using water quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 3 b, yield is 76percent. White solid
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