* 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] Journal of the Chemical Society, 1956, p. 2455,246
2
[ 32723-67-4 ]
[ 1685-84-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2210 - 2214
3
[ 32723-67-4 ]
[ 6880-04-2 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, p. 2662
[2] Justus Liebigs Annalen der Chemie, 1907, vol. 357, p. 373
[3] Chemische Berichte, 1898, vol. 31, p. 1151
[4] Journal of Medicinal Chemistry, 2001, vol. 44, # 5, p. 749 - 762
4
[ 32723-67-4 ]
[ 7664-41-7 ]
[ 6880-04-2 ]
Reference：
[1] Journal of the Chemical Society, 1925, vol. 127, p. 24311
5
[ 15174-69-3 ]
[ 74-88-4 ]
[ 32723-67-4 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 20℃;
General procedure: To a solution of the hydroxy-methylbenzaldehyde (34 mg,0.25 mmol) in anhydrous DMF (6.0 mL), K2CO3 (35 mg,0.25 mmol) was added and the mixture was stirred at room temperaturefor 30 minutes. Then, methyl iodide (30 μL, 68 mg,0.5 mmol) was added and the reaction was stirred at room temperatureovernight. The reaction was quenched by the additionof distilled water, and the aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases weredried with MgSO4 and concentrated in vacuo. The residue waspurified by column chromatography on silica gel.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 734 - 746
6
[ 4685-47-6 ]
[ 32723-67-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With dipotassium peroxodisulfate; copper(II) sulfate In water; acetonitrile for 0.5 h; Heating / reflux
Intermediate 60 3- (4-Hydroxy-phenyl)-2, 2-dimethyl-propionic acid methyl ester Step A 2-Methyl-4-anisaldehyde; A mixture of 2, 3-dimethylanisole (50g, 0.37 mol), Cu2+ sulfate pentahydrate (90 g, 0.36 mol), and potassium peroxydisulfate (301 g, 1.11 mol) in acetonitrile/water (1 : 1, 2.6 L) is stirred vigorously and heated to reflux for 30 minutes. The reaction is cooled to rt and extracted with CH2C12 (4L) and washed with water (2L). The layers are separated, and the aqueous layer is again extracted with CH2C12. The organic layers are combined and concentrated to afford about 55 g (-100percent) product, which is taken on as is. 1H-NMR (DMSO-d6): 10.05 (s, 1H), 7.78 (m, 1H), 6.95 (m, 1H), 6. 88 (s, 1H), 3.84 (s, 3H), 2.6 (s, 3H).
Reference：
[1] Tetrahedron, 2006, vol. 62, # 51, p. 12098 - 12107
[2] Chemical Communications, 2018, vol. 54, # 46, p. 5851 - 5854
[3] Journal of Organic Chemistry, 1995, vol. 60, # 23, p. 7479 - 7490
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1955, vol. 240, p. 2241
8
[ 108-24-7 ]
[ 143085-01-2 ]
[ 32723-67-4 ]
[ 6932-93-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 11, p. 1387 - 1392
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 11, p. 1387 - 1392
9
[ 6738-23-4 ]
[ 32723-67-4 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, # 9, p. 1647 - 1652
10
[ 6738-23-4 ]
[ 32723-67-4 ]
[ 160238-89-1 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 24, p. 7953 - 7958
11
[ 74-90-8 ]
[ 578-58-5 ]
[ 32723-67-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1907, vol. 357, p. 373
[2] Chemische Berichte, 1898, vol. 31, p. 1150
[3] Journal of the Indian Chemical Society, 1963, vol. 40, # 5, p. 327 - 338
Reference：
[1] Bulletin de la Societe Chimique de France, 1937, vol. <5> 4, p. 1468,1470
14
[ 74-90-8 ]
[ 21573-35-3 ]
[ 32723-67-4 ]
[ 775332-56-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1928, vol. 460, p. 266[2] Justus Liebigs Annalen der Chemie, 1928, vol. 464, p. 309
15
[ 123-11-5 ]
[ 74-88-4 ]
[ 32723-67-4 ]
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 6, p. 1078 - 1083
16
[ 854259-51-1 ]
[ 6738-23-4 ]
[ 32723-67-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1937, vol. <5> 4, p. 1468,1470
[2] Bulletin de la Societe Chimique de France, 1937, vol. <5> 4, p. 1468,1470
With sodium hydroxide In methanol; water at 0 - 20℃; for 1h;
1
5-Ethyl-N-[-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine Step 1. A solution of 3-methyl-p-anisaldehyde (23.13 g, 154 mmol) and nitromethane (9.40 g, 154 mmol) in MeOH (260 ml) was cooled in an ice bath and treated dropwise with NaOH (162 ml of 1 N solution ; 162 mmol). The reaction mixture was stirred at rt for 1 hr. Water (50 ml) was then added and the mixture poured into 1N HCl (300 ml). The precipitate was collected and purified by flash chromatography on silica gel eluting with dichloromethane to provide methyl 21thy1-4- [ (E)-2-nitroethenyl] phenyl ether as a yellow solid (14. 61 g ; 49% yield). 1H NMR (acetone d-6) No. 7.98 (d, 1H, J= 13.6), 7.82 (d, 1H, J= 13.6), 7.62 (bS, 2H), 7.02 (d, 1H, J= 8.9), 3.8 (s, 3H), 2.28 (s,3H).
Stage #1: 3-methyl-4-anisaldehyde With sodium tetrahydroborate In ethanol
Stage #2: With water In ethanol
60.B
Step B 4-Methoxy-2-methylbenzyl alcohol; NaBH4 (14.82 g, 0.39 mol) is added to a solution of the compound from Step A (55 g, 0.37 mol) in EtOH (800 mL). The reaction is quenched with water (3L), acidified with 5N HC1, and extracted with Et20. The organics are separated and concentrated. The crude product is purified by Biotage 75L (Hexane: EtOAc, 9: 1) to afford about 17.35 g (30%). 1H-NMR (CDCl3) : 7.22 (m, 1H), 6.7 (m, 2H), 4.64 (s, 2H), 3.8 (s, 3H), 2.4 (s, 3H).
With lithium aluminium tetrahydride; diethyl ether
With sodium tetrahydroborate In methanol for 0.25h; Ambient temperature;
With sodium tetrahydroborate In ethanol for 2h;
With sodium tetrahydroborate In methanol at 25℃; for 0.333333h; Inert atmosphere;
With N-iodo-succinimide; 2,5-bis(trifluoromethyl)aniline; palladium diacetate; trifluoroacetic acid In 1,2-dichloro-ethane at 60℃; for 24h; Sealed tube;
64%
Stage #1: 3-methyl-4-anisaldehyde With n-butyllithium for 48h;
Stage #2: With iodine
Stage #3: With oxonium Further stages.;
With n-butyllithium; iodine; lithium N-methyl-N-(N',N'-dimethyl-2-aminoethyl)amide Yield given. Multistep reaction;
With n-butyllithium; iodine; lithium N-methyl-N-(N',N'-dimethyl-2-aminoethyl)amide Yield given. Multistep reaction;
With boron tribromide In dichloromethane for 21h; Ambient temperature;
70%
Stage #1: 3-methyl-4-anisaldehyde With boron tribromide In dichloromethane at 0 - 20℃; for 50h;
Stage #2: In methanol at 15℃; for 0.5h; Heating / reflux;
Stage #3: In methanol; water for 0.5h;
7
Intermediate 74-hydroxv-3-methvlbenzaldehvde To a solution of3-methyl-4-(methyloxy) benzaldehyde (150g, 1mol) inCH2CI2at 0-5 C under N2 atmosphere was added dropwiseBBr3 (1.5L, 1.5eq) in 2h. The reaction mixture was stirred at room temperature for 48h. The solvent was evaporated to give 200 mL of solution. This residue was cooled to15 C,MeOH (500 mL) was added to give a black suspension. The mixture was refluxed for 30min and concentrated. Water (600 mL) was added and stirred for 30 min. The mixture was extracted with diethyl ether (3 x 600mL). The organic layers were dried onMgS04 and treated with charcoal, concentrated and purified by chromatography (Dichloromethane andDichloromethane/Methanol 98/2) to give the title compound as a yellow solid (94.87g). Yield=70% 'H NMR (DMSO): 8 10.55 (s, 1H) ; 9.75 (s, 1H) ; 7.63 (s, 1H) ; 7.60 (dd, 1H) ; 6.94 (d, 1H) ; 2.17 (s, 3H).
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran; hexane at -78 - 0℃; for 2.25h;
4.6
4.6.2.81 (E/Z) 3-(3-Ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-methyl-phenyl)-acrylonitrile To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.7 g, 7.4 mmol) in THF (20 mL) was added a solution of n-butyllitium in hexane (2.8 mL, 2.5 N, 7.0 mmol) at -78° C. and kept for 20 min. To the mixture was added 4-methoxy-3-methyl-benzaldehyde (1.0 g, 90% pure, 6.0 mmol) at -78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2*50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl)-methanol as a solid (2.0 g, 100% crude yield).
With ammonium acetate In ethanol for 6h; Heating / reflux;
[3-METHYL-4-METHOXY CINNAMIC ACID] :
3-Methyl-4-methoxy benzaldehyde, (1.95 [ML,] 0.013 mol), malonic acid (1.35 g 0.013 mol) were combined with ammonium acetate (2.0 g, 0. [026MOL)] in dry ethanol, then refluxed under argon for 6 hours. The solid p-amino acid was collected by filtration and the filtrate was evaporated to dryness under reduced pressure. The resulting yellow solid was recrystallized first from water, then ethanol. Yield= 18%. 1H NMR, 200 MHz, (DMSO) 8 : 2.2 (s, 3H), 3.8 (s, 3H), 6.4 (d, 1H, J= 16.2 Hz), 7.0 (d, [1H, J =] 8.1 Hz), 7.5 (m, 3H).
With dipotassium peroxodisulfate; copper(II) sulfate In water; acetonitrile for 0.5h; Heating / reflux;
60.A
Intermediate 60 3- (4-Hydroxy-phenyl)-2, 2-dimethyl-propionic acid methyl ester Step A 2-Methyl-4-anisaldehyde; A mixture of 2, 3-dimethylanisole (50g, 0.37 mol), Cu2+ sulfate pentahydrate (90 g, 0.36 mol), and potassium peroxydisulfate (301 g, 1.11 mol) in acetonitrile/water (1 : 1, 2.6 L) is stirred vigorously and heated to reflux for 30 minutes. The reaction is cooled to rt and extracted with CH2C12 (4L) and washed with water (2L). The layers are separated, and the aqueous layer is again extracted with CH2C12. The organic layers are combined and concentrated to afford about 55 g (-100%) product, which is taken on as is. 1H-NMR (DMSO-d6): 10.05 (s, 1H), 7.78 (m, 1H), 6.95 (m, 1H), 6. 88 (s, 1H), 3.84 (s, 3H), 2.6 (s, 3H).
Stage #1: trimethylsilyl cyanide; 3-methyl-4-anisaldehyde With zinc(II) iodide for 3h;
Stage #2: ethanol With hydrogenchloride at -20 - 20℃; Saturated gas;
8.a
EXAMPLE 8 Preparation of 7-(4-Methoxy-3-methylphenyl)-7-(3-propoxyphenyl)-2,7-dihydro-3H-imidazo[1.5-a]imidazol-5-amine Step a) Ethyl 2-hydroxy-2-(4-methoxy-3-methylphenyl)ethanimidoate hydrochloride A mixture of 4-methoxy-3-methylbenzaldehyde (17.6 mL) and trimethylsilyl cyanide (18.7 mL) was treated with zinc iodide (0.600 g), stirred for 3 h, treated with diethyl ether and filtered through a cellite pad. The filtrate was evaporated. The resultant residue was dissolved in absolute ethanol, cooled to -20° C. and saturated with gaseous hydrogen chloride (40 g). The solution was slowly warmed up to room temperature and concentrated in vacuo. The resultant residue was triturated with diethyl ether and filtered. The filtercake was dried under vacuum to give ethyl 2-hydroxy-2-(4-methoxy-3-methylphenyl)ethanimidoate hydrochloride as a yellow solid (28.55 g), characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS Cl 8, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD.
N-(4-methoxy-3-methylbenzylidene)-4-sulfamoylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
69.i 69(i)
69(i) N-(4-Methoxy-3-methylbenzylidene)-4-sulfamoylaniline Following a procedure similar to that described in Example 1(i), but using 4-methoxy-3-methylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a yellow powder (yield 92%). Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl3) δ ppm: 8.85 & 8.31 (total: 1H, each singlet); 7.93 (1H, doublet, J=8 Hz); 7.77-7.65 (2H, multiplet); 7.26-7.23 (2H, multiplet); 6.91-6.86 (1H, multiplet); 6.71-6.88 (1H, multiplet); 4.77 & 4.14 (total:1H, each singlet); 3.92 (3H, singlet); 2.28 & 2.21 (total:3H, each singlet).
2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In methanol
19 Synthesis of 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone
EXAMPLE 19 Synthesis of 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methyl-4-methoxybenzaldehyde 1.11 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.75 g. FAB MASS; 283 (M+1) 1 H-NMR (ppm, in DMSO-d6); 2.18 (3H, s), 3.83 (3H, s), 6.68 (1H, s), 6.70 (1H, dd, J=8.5, 2.6 Hz), 7.03 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=8.2), 7.71 (1H, d, J=2.1 Hz), 7.78 (1H, dd, J=8.5, 1.8 Hz), 11.11 (1H, s)
1 EXAMPLE 1
EXAMPLE 1 Sodium ethoxide (prepared from 0.70 g of Na and 30 mL of ethanol) was added to an ice-cold mixture of diethyl p-nitrobenzylphosphonate (9.09 g, 0.033 mole) and 3-methyl-p-anisaldehyde (5.0 g, 0.033 mole) in ethanol (about 100 mL). The resulting mixture was stirred overnight. The solid product was filtered, washed with ethanol and vacuum dried to give MMONS, 3-methyl-4-methoxy-4'-nitrostilbene (4.946 g, 0.0157 mole, 47.6% yield, m.p. 109°-111° C.).
VI.A 4-Methoxy-3-methylbenzaldoxime (20)
Step A 4-Methoxy-3-methylbenzaldoxime (20) A cold solution of hydroxylamine.hydrochloride 15 g, 0.22 mol) in H2 O (50 ml) was mixed with a cold solution of NaOH (20 g, 0.5 mol) in H2 O (150 ml) and then 4-methoxy-3-methylbenzaldehyde (30 g, 0.2 mol) was added in a steady stream. After stirring at room temperature for 30 minutes, the solution was saturated with CO2. The separated solid was collected, washed with H2 O, and dried to yield 30.9 g (94%) of 20; m.p. 70°-2° C. Analysis Calculated for C9 H11 NO2 (165.19) C, 65.44; H, 6.71; N, 8.48. Found: C, 65.11; H, 6.95; 8.19.
30.9 g (94%)
With sodium hydroxide In water
VI.A Step A:
Step A: 4-Methoxy-3-methylbenzaldoxime (20) A cold solution of hydroxylamine.hydrochloride (15 g, 0.22 mol) in H2 O (50 ml) was mixed with a cold solution of NaOH (20 g, 0.5 mol) in H2 O (150 ml) and then 4-methoxy-3-methylbenzaldehyde (30 g, 0.2 mol) was added in a steady stream. After stirring at room temperature for 30 minutes, the solution was saturated with CO2. The separated solid was collected, washed with H2 O, and dried to yield 30.9 g (94%) of 20; m.p. 70°-2° C. Analysis Calculated for C9 H11 NO2 (165.19) C, 65.44; H, 6.71; N, 8.48. Found: C, 65.11; H, 6.95; 8.19.
2-[2-(4-methoxy-3-methylphenyl)ethyl]-2-methyl-1,3-dioxolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydrogenchloride; toluene-4-sulfonic acid In ethanol; ethylene glycol; benzene
1 2-[2-(4-methoxy-3-methylphenyl)ethyl]-2-methyl-1,3-dioxolane (1)
EXAMPLE 1 2-[2-(4-methoxy-3-methylphenyl)ethyl]-2-methyl-1,3-dioxolane (1) A mixture of 4-methoxy-3-methylbenzaldehyde (50 g), ethyl acetoacetate (50 ml), piperidine (3.5 ml), phenylacetic acid (1 g) and benzene (500 ml) was heated at reflux for 24 hours with constant removal of water using a Dean-Stark trap. After cooling the resulting solution was washed with dilute aqueous sodium bicarbonate solution and then water, dried (Na2 SO4) and concentrated to give a viscous, yellow oil (83.3 g). This crude product was dissolved in ethanol (2*500 ml) and hydrogenated at room temperature and pressure for 3 hours using 10% palladium on charcoal (2*5 g) as catalyst. After removal of the catalyst by filtration, a solution of 5 N hydrochloric acid (400 ml) was added and the resulting mixture heated overnight at reflux. After cooling and removal of most of the ethanol, the crude product was extracted into diethyl ether (3*250 ml) and this in turn was washed with water (2*100 ml), dried (Na2 SO4) and concentrated to afford 4-(4-methoxy-3-methylphenyl)butan-2-one (54.2 g) as a dark yellow oil. A mixture of the latter (54.2 g), ethylene glycol (180 ml), p-toluenesulphonic acid (1.7 g) and benzene (400 ml) was heated for 2 days at reflux with constant removal of water as before. The resulting solution was cooled and the benzene layer removed. The glycol layer was basified with dilute aqueous sodium bicarbonate solution and extracted with ether (2*250 ml). The combined organic layers were then washed with water, dried (Na2 SO4) and concentrated to give 2-[2-(4-methoxy-3-methylphenyl)ethyl]-2-methyl-1,3-dioxolane (63.7 g: 81% overall yield) as a dark yellow oil.
3-(4-methoxy-3-methyl)phenylhydroxymethylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium In acetone hexane; hexane
12 3-(4-Methoxy-3-methyl)phenylhydroxymethylpyridine
PREPARATION 12 3-(4-Methoxy-3-methyl)phenylhydroxymethylpyridine Refer to Chart G (analogous to the conversion of XCVIII to CI). The procedure described in Example 34 is followed using 3-bromopyridine (24.2 g, 14.7 ml, 0.15 mole), n-butyllithium (93.8 ml of a 1.6M solution in hexane, 0.15 mole), and 3-methyl-p-anisaldehyde (25.0 g of 90% purity, 22.5 g, 0.15 mole) in ether under a nitrogen atmosphere at -78° C. The reaction is allowed to warm to room temperature over a 3 hr period and the product is washed as previously described. The crude product is chromatographed over silica gel (1.5 kg) packed as a slurry in 35% acetone-hexane. The column is eluted with 40% acetone-hexane (22 fractions) and 50% acetone-hexane (to end) with 350 ml fractions collected. The product (26.26 g, 0.114 mole, 76%) is obtained in fractions 23-40 and is crystalline. Two recrystallizations from acetone-hexane give the title product as colorless crystals with a melting point of 92.5°-95° C. The IR (Nujol) spectrum reveals peaks at 3194, 1607, 1592, 1578, 1505, 1448, 1425, 1318, 1256, 1213, 1186, 1127, 1056, 1034, 1027, 825, 814, 745, 713, and 671 cm-1. The NMR (CDCl3, δ) spectrum reveals peaks at 8.47, 8.30, 7.74, 6.68-7.33, 5.72, 3.78, and 2.17. The mass spectrum reveals ions at m/e 229.1115, 212, 198, 151, 123, and 106. Anal. Calcd. for C14 H15 NO2: C, 73.34; H, 6.59; N, 6.11. The C:H:N ratio is 73.51:6.68:5.96.
8.A (A)
(A) 3-(4-Methoxy-3-methylphenyl)glutaric acid A mixture of 4-methoxy-3-methylbenzaldehyde (100 mmole), cyanoacetic acid (210 mmole) and potassium hydroxide (250 mmole) in water (500 ml) is stirred at room temperature for 20 hours. The resulting solution is acidified with concentrated hydrochloric acid (100 ml) and the mixture is refluxed for 60 hours. After cooling, it is saturated with sodium chloride and extracted with ethyl acetate to afford the title compound.
R.38 Ethyl 3-(3-Bromo-4-methoxy-5-methylphenyl)propionate
Reference Example 38 Ethyl 3-(3-Bromo-4-methoxy-5-methylphenyl)propionate To a solution of ethyl 3-(4-methoxy-3-methylphenyl)propionate (derived from 10.0 g (66.6 mmol) of 4-methoxy-3-methylbenzaldehyde) in chloroform (200 ml) was added dropwise bromine (10.6 g, 66.6 mmol). The mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water, an aqueous solution of sodium thiosulfate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane→hexane/ethyl acetate, 9:1) to give 17.0 g (yield 85%; 3 steps) of the above-titled compound as an oily product. NMR(CDCl3) δ: 1.24(3H,t,J=7.2 Hz), 2.29(3H,s), 2.57(2H,t,J=7.0 Hz), 2.84(2H,t,J=7.0 Hz), 3.78(3H,s), 4.12(2H,q,J=7.2 Hz), 6.95(1H,d,J=1.6 Hz), 7.21(1H,d,J=1.6 Hz).
8.a Step a) Preparation of Diethyl {(4-methoxy-3 methylphenyl)[(trimethylsilyl)oxy]methyl}phosphonate
Step a) Preparation of Diethyl {(4-methoxy-3 methylphenyl)[(trimethylsilyl)oxy]methyl}phosphonate Under a nitrogen atmosphere, into a cold (0° C.) solution of 3-methyl-4-methoxy-benzaldehyde (15 g, 0.1 mol) and triethylphosphite (19.1 mL, 0.1 mol) was added dropwise chlorotrimethylsilane (12.6 mL, 0.1 mol) over 10 minutes, heated at 120° C. (oil bath) for 8 hours and distilled (180° C., 10.0 mmHg). The distillate was further purified by flash chromatography on silica gel (hexanes/ethyl acetate/isopropyl alcohol, 7/2.5/0.5) to give the title phophonate compound as a white solid (16 g, 44% of yield, mp 37° C.); MS m/e (M+H)+ 361; 1H NMR (400 MHZ, DMSOd6) δ 0.1 (s, 9H), 1.18 (dt, 6H), 2.1 (s, 3H), 3.68 (s, 3H), 3.85 (m, 4H), 4.97 (d, 1H), 6.87 (m, 1H), 7.20 (m, 2H).
8-hydroxy-7-methyl-l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine[ No CAS ]
[ 62993-57-1 ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate In nitromethane; acetic acid
l 8-Hydroxy-7-methyl-l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine.
EXAMPLE l0 8-Hydroxy-7-methyl-l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine. A mixture of 4-methoxy-3-methylbenzaldehyde (33 g, 0.22 m), nitromethane (40 g, 0.65 m) and ammonium acetate (l6.6 g, 0.22 m) in acetic acid (200ml) was heated for l6 hours, concentrated in vacuo , diluted with water and filtered. The filter cake was crystallized from toluene-hexane to afford 4-methoxy-3-methyl-(2-nitroethenyl)-benzene, m.p. 76-79°.
With ethylenediamine diacetic acid In methanol at 20℃; for 24h;
153
To a solution of 4-methoxy-3-methylbenzaldehyde (1.50 g, 10.0 mmol) in methanol (3.5 ml), nitromethane (0.6 ml, 11.2 mmol) was added ethylenediamine diacetate (182 mg, 1.01 mmol), and the mixture was stirred at room temperature for 24 hours. Ethanol (5.0 ml) was added to the reaction solution, and the mixture was stirred at 0°C for 30 minutes, followed by filtration. The resulting powder was washed with cooled ethanol to give a title compound (1.04 g, 5.38 mmol, 54%) as a yellow powder. 1H-NMR (400 MHz, CDCl3) δ: 2.24 (3H, s), 3.89 (3H, s), 6.87 (1H, d, J = 8.5 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.39 (1H, dd, J = 2.2, 8.5 Hz), 7.52 (1H, d, J = 13.4 Hz), 7.96 (1H, d, J = 13.4 Hz).
Stage #1: 2-hydroxy-4,6-dimethoxyacetophenone; 3-methyl-4-anisaldehyde In ethanol at 20℃; for 0.0833333h;
Stage #2: With sodium hydroxide In ethanol at 20℃;
Stage #1: 2-(1,3-dioxolan-2-yl)ethyl(triphenyl)phosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1h;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran at 0℃; for 0.666667h;
13
(Reference example 13) 4-(3-Methyl-4-methoxyphenyl)butyric acid [2-(1,3-Dioxolan-2-yl)ethyl]triphenylphosphonium bromide (28.2 g, 63.8 mmol) was suspended in tetrahydrofuran (100 mL) and a solution of potassium t-butoxide (7.15 g, 63.8 mmol) in tetrahydrofuran (100 mL) was added thereto under nitrogen atmosphere over 30 minutes, followed by stirring of the mixture under ice-cooling for 30 minutes. A solution of 4-methoxy-3-methylbenzaldehyde (8.2 mL, 60.6 mmol) in tetrahydrofuran (100 mL) was added thereto over 20 minutes and the mixture was stirred under ice-cooling for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 15:1-10:1) to obtain a crude product (14.9 g). 10% Palladium-carbon (5.00 g, 50% moisture) was added to a solution of the obtained crude product (14.9 g) in ethanol (100 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain [1-(1,3-dioxolan-2-yl)-3-(4-methoxy-3-methylphenyl)]propane (12.8 g, yield: 85%). A 3N aqueous hydrochloric acid solution was added dropwise to a solution of the obtained [1-(1,3-dioxolan-2-yl)-3-(4-methoxy-3-methylphenyl)]propane (12.8 g, 54.0 mmol) in THF (200 mL) and the mixture was stirred for 2 hours. Water (400 mL) and ethyl acetate (300 mL) were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 4-(3-methyl-4-methoxyphenyl)butanaldehyde (8.42 g, 81%). An aqueous solution (50 mL) of sulfamic acid (7.8 g, 0.08 mol) and an aqueous solution (50 mL) of sodium chlorite (9.2 g, 0.10 mol) were added to a solution of 4-(3-methyl-4-methoxyphenyl)butanaldehyde (8.42 g, 43.8 mmol) in dioxane (100 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. Ethyl ether (200 mL) was added to the reaction mixture to separate it. After the pH of the aqueous phase was brought to 3 to 4 by 1N hydrochloric acid, ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 4-(3-methyl-4-methoxyphenyl)butyric acid (5.38 g, yield: 60%) .
With hydrogenchloride In methanol; water at 5 - 20℃; for 6h;
2
Example-2Preparation of 4-(dimethoxymethyl)-1-methoxy-2-methylbenzene {4-methoxy-3-methyl benzaldehyde dimethyl acetal}; A solution of 4-methoxy-3-methyl benzaldehyde (10 g) and trimethylorthoformate (43.77 ml) in methanol (15 ml) was cooled to 5-10° C. Concentrated HCl (0.75 ml) was added and the reaction mixture was warmed to ambient temperature. The reaction mixture was stirred for 6 hours and quenched with 5% aqueous KOH (10 ml). The reaction mixture was extracted with hexane (100 ml) and the hexane layer was washed with water (100 ml). Hexane layer was dried over sodium sulfate and concentrated below 30° C. to obtain title compound (15.8 g).MS(ES+) (m/z) 219 [M+Na]+
Stage #1: 3-methyl-4-anisaldehyde; trimethyl orthoformate In methanol; water at 5 - 20℃;
Stage #2: With potassium hydroxide In methanol; water
2
Example-2:Preparation of 4-(dimethoxymethyl)-1-methoxy-2-methylbenzene {4-methoxy-3-methyl benzaldehyde dimethyl acetal} -A solution of 4-methoxy-3-methyl benzaldehyde (10 g) and trimethylorthoformate (43.77 ml) in methanol (15 ml) was cooled to 5-10°C. Concentrated HCI (0.75 ml) was added and the reaction mixture was warmed to ambient temperature. The reaction mixture was stirred for 6 hours and quenched with 5% aqueous KOH (10 ml). The reaction mixture was extracted with hexane (100 ml) and the hexane layer was washed with water (100 ml). Hexane layer was dried over sodium sulfate and concentrated below 30°C to obtain title compound (15.8 g).MS(ES+) (m/z) 219 [M+Na]
3-benzyl-6-(4-methoxy-3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 3-methyl-4-anisaldehyde; 3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine With acetic acid In methanol; dichloromethane at 50℃; for 2h;
Stage #2: In methanol; dichloromethane at 50℃;
Stage #3: trifluoroacetic acid
119
Example 119 3-benzyl-6-(4-methoxy-3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine 3-Benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine (43 mg, 0.15 mmol) was dissolved in a 1:1 solution of dichloromethane/methanol (1.2 mL) followed by the addition of 4-methoxy-3-methylbenzaldehyde (26 mg, 0.18 mmol) dissolved in a 1:1 solution of dichloromethane/methanol (0.6 mL) followed by the addition of acetic acid (40 μL, 0.73 mmol). The reaction mixture was shaken at 50° C. for 2 hours. Then macroporous poly(styrene-co-divinylbenzene) cyanoborohydride resin (MP-CNBH3) (196 mg, 0.45 mmol, 2.25 mmol/g loading) was added and the reaction mixture was shaken overnight at 50° C. The resin was removed via filtration, and the filtrate was concentrated to dryness. Purification via HPLC afforded the title compound as the trifluoroacetic acid salt. 1H NMR (500 MHz, pyridine-d5) δ ppm 2.24 (s, 3H), 2.34-2.43 (m, 1H), 2.50 (s, 1H), 2.85-3.10 (m, 4H), 3.27-3.36 (m, 2H), 3.59-3.79 (m, 6H), 4.06-4.21 (m, 2H), 4.35 (d, J=13.12 Hz, 1H), 4.53 (d, J=13.12 Hz, 1H), 6.82 (d, J=8.24 Hz, 1H), 6.96 (d, J=7.93 Hz, 1H), 7.05 (t, J=7.17 Hz, 1H), 7.28-7.51 (m, 9H); MS (ESI+), m/z 428 (M+H)+.
92 Synthesis of N-(4-methoxy-3-methyl-benzylidene)-N'-(7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (Compound 92)
There was suspended, in 1,4-dioxane (3 mL), 5-chloro-7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine (110 mg, 0.35 mM), then hydrazine monohydrate (170 μL, 3.5 mM) was added to the suspension and the mixture was stirred for 18 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was suspended in ethanol (5 mL), then acetic acid (8.4 μL, 0.015 mM) and 3-methyl-p-anisaldehyde (47 μL, 0.32 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. After the stirring operation, the residue obtained was purified by the reversed phase HPLC and then subjected to a desalting operation to thus give the title compound (20 mg, yield: 15.2%). 1H-NMR (300 MHz, DMSO-d6); δ 2.20 (s, 3H), 3.73 (bs, 4H), 3.83 (s, 3H), 3.88 (bs, 4H), 6.36 (s, 1H), 6.73 (s, 1H), 7.00 (d, 1H, J=9.3 Hz), 7.51 (d, 1H, J=6.9 Hz), 7.91 (d, 2H, J=3 Hz), 8.01 (s, 1H), 8.66 (d, 2H, J=3 Hz), 11.1 (s, 1H); MS (ESI) m/z 444 (M+H)+.
4.2. General method for the preparation of Schiff base analogues of 4-amino-1,5-dimethyl-2-phenylpyrazol-3-one (3a-m)
General procedure: An anhydrous ethanol solution (10 mL) of 4-amino-1,5-dimethyl-2-phenylpyrazol-3-one (203 mg, 1 mmol) was added to an anhydrous ethanol solution (10 mL) of substituted benzaldehyde (1 mmol), and the mixture was refluxed at 80 °C for 4-6 h under atmospheric conditions (Scheme 1). The progress of the reaction was monitored by TLC. The precipitates formed were collected by filtration and purified by recrystallization with ethanol, and then dried in vacuo to produce the pure compound with a high yield (80-94%).
Stage #1: ethylphosphonic acid diethyl ester With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran; hexane at -78 - 25℃; for 2.25h; optical yield given as %de;
Stage #1: ethylphosphonic acid diethyl ester With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran; hexane at -78 - 25℃; for 2.25h; optical yield given as %de;
With hydrogen bromide In water for 10h; Reflux; Green chemistry;
3. Aq. HBr catalyzed synthesis of 3,3,6,6-Tetramethyl-9-aryl-3,4,5,6,7,9-hexahydro-2H-xanthene-1,8-dione (4)
General procedure: To a mixture of aldehyde (1 mmol), 5, 5-dimethyl-1, 3-cyclohexanedione (2 mmol.) and water (20 times v/w) taken in a round bottom flask, 48 % aqueous hydrobromic acid (10 mol%) was added. The reaction mixture was heated in an oil bath at reflux temperature for 10-14 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The obtained solid product filtered, washed with water twice and dried under suction to get the pure product.
methyl 2-azido-3-(4-methoxy-3-methylphenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium methylate In methanol at -15 - 4℃;
9.8 g
With sodium methylate In methanol at -10 - 4℃;
6 Compounds 181 and 182
To the mixture of 6.59 g of 3-methylanisaldehyde (44 mmol) and 12.65 g of methyl azidoacetate (110 mmol) in 60 mL of MeOH is added 20 mL of 5.4M MeONa over 30 minute at -10 degrees. After addition the mixture was stirred for additional hour at the same temperature and then transferred in cold room (4 degrees) and stirred overnight. On the morning reaction mixture was poured in 1 L mixture of ice and conc. ammonium chloride solution, stirred for 10 minutes and filtered off. The solid was washed with plenty of ice cold water and then moved at ambient temperature. After air drying for 1 hr the solid was dissolved in 50 mL of DCM, dried over magnesium sulfate and passed through short silica gel plug. Evaporation of solvent produced 9.8 g of methyl 2-azido-3-(4-methoxy-3-methylphenyl)acrylate, that was used in the next step without further purification.
In dichloromethane at 20℃; Inert atmosphere; Sealed tube; Molecular sieve;
General procedure for the synthesis of 3,4-dihydro-β-carbolines
General procedure: Tryptamine (160 mg, 1mmol) and appropriate aldehyde (1mmol) was dissolved in 10 mL of dichloromethane and was stirred in presence of 4Å mol. sieves at rt. Once TLC indicates complete consumption of the starting material, the solution was filtered through celite and the solvent evaporated to obtain the crude tetrahydro-β-carbolines 1a-n, which were used crude in the next reaction. To a solution of the resulting crude tetrahydro-β-carbolines in 10 mL of toluene was added N-bromosuccinimide (NBS) (1.1 eq.) and the resulting solution was stirred at 0 °C for 6h after which it was gradually warmed to room temperature (rt). Once TLC confirms the total consumption of the starting imine, the reaction was quenched with water. The aqueous layer was extracted twice with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulphate and was evaporated to provide the crude compound. It was purified by column chromatography using 20% ethyl acetate in hexane as eluent to afford the desired 3,4 -dihydro-β-carbolines 2a-n.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 18h;
Step 1 : Preparation of 4-methoxy-3-methylphenol4-Methoxy-3-methylbenzaldehyde (commercially available, 1 equiv.) was dissolved in DCM (0.4 M), and m-CPBA (2.4 equiv.) was added slowly. The reaction mixture was stirred at r.t. for 18 h, monitored by LCMS analysis. An excessive amount of aqueous sodium thiosulfate solution was added. After an addition of equal volume of 1 :1 2N NaOH and methanol, the mixture was stirred for 30 minutes and neutralized to pH 7-8 with 1 N HCI and aqueous NaHC03, then extracted with DCM, and concentrated. The crude was purified by ISCO (ethyl acetate/hexane, silica gel) to afford the title product.
tert-butyl 6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate[ No CAS ]
[ 76-05-1 ]
6-benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-3-methyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
Stage #1: 3-methyl-4-anisaldehyde; tert-butyl 6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate With sodium t-butanolate In tetrahydrofuran at 20℃; for 1h;
Stage #2: With hydrogenchloride In ethyl acetate at 20℃; for 1h;
Stage #3: trifluoroacetic acid
E.I 6-Benzyloxy-7-methoxy-1-[(E)-2-(4-methoxy-3-methyl-phenyl)vinyl]-1,2,3,4-tetrahydroisoquinoline
To a solution of tert-butyl 6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [118 mg (0.2 mmol)] in THF (5 ml) with 4-methoxy-3-methyl-benzaldehyde [30 mg (0.2 mmol)] was added at room temperature Na t-butoxide [58 mg (0.6 mmol)]. The reaction was stirred at room temperature for 60 min. The reaction was quenched with sat NH4Cl (10 ml), extracted with EtOAc (20 ml), dried (MgSO4) and the solvent removed. The residue was treated for 1 h with 3NHCl/EtOAc at room temperature then rotary evaporated to a brown oil which was taken up into EtOAc and washed with 2N NaOH. The organic layer was dried (MgSO4) and the solvent removed. The residue was chromatographed via reverse phase chromatography. Yield=7.2 mg (9%) as TFA salt via prep chrom. MS (m/z): 416 [M+H]
2-(4-methoxy-3-methylphenyl)-1,4,5-trimethylimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.48 g
Stage #1: 3-methyl-4-anisaldehyde; butane-2,3-dione mono-oxime; methylamine With ammonia; acetic acid In water for 4.5h; Reflux;
Stage #2: With zinc In water for 4h; Reflux;
37
Reference Production Example 37 A mixture of 4.00 g of 4-methoxy-3-methylbenzaldehyde, 2.69 g of diacetyl monoxime, an aqueous 40% methylamine solution, and 40 mL of acetic acid was stirred with heating under reflux for 4.5 hours. After allowing to stand, 6.56 g of zinc was added and the mixture was stirred with heating under reflux for 4 hours. After allowing to stand, the mixture was filtered through Cerite and the filtrate was made basic by adding ammonia water. After extraction with tert-butyl methyl ether, the organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue thus obtained was recrystallized using chloroform and hexane to obtain 1.48 g of 2-(4-methoxy-3-methylphenyl)-1,4,5-trimethylimidazole (C37A). 1H-NMR (CDCl3) δ: 2.18 (3H, s), 2.21 (3H, s), 2.25 (3H, s), 3.53 (3H, s), 3.86 (3H, s), 6.86 (1H, d, J=8.3 Hz), 7.33 (1H, dt, J=8.3, 1.1 Hz), 7.38 (1H, t, J=1.1 Hz).
1-(4-hydroxyphenyl)-3-(4-methoxy-3-methylphenyl)propenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: 3-methyl-4-anisaldehyde; 4-Hydroxyacetophenone With sodium hydroxide In methanol at 20℃; for 0.333333h;
Stage #2: In methanol at 20℃;
4.2. General procedure for the synthesis of chalcones (3a-3o)
General procedure: To the solution of (0.05 mol, 6.8 g) of 1-(4-Hydroxy-phenyl)-ethanone (1) in 30 ml of methanol on an ice bath, freshly prepared2 N methanolic NaOH solution (50 ml) was added and stirred for20 min. To this 0.05 mol of appropriate aldehyde (2a-l) was addedand the reaction mixture was stirred at room temperature for20-24 h. The reaction mixture was cooled in an ice bath andneutralized with dilute hydrochloric acid. The obtained precipitatewas separated by filtration and washed with distilled water to givethe crude product. The product (3a-o) so obtained was recrystallizedfrom 75% methanol. The purity of the products was checkedon TLC by using a mixture of ethyl acetate and hexane as mobilephase.
(5-bromo-2,3-dimethoxyphenyl)(methyl)selenium[ No CAS ]
(3,4-dimethoxy-5-(methylselanyl)phenyl)(4-methoxy-3-methylphenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: (5-bromo-2,3-dimethoxyphenyl)(methyl)selenium With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran for 12h;
With formic acid; hydroxylamine hydrochloride; sodium formate; at 100℃; for 3h;
REFERENTIAL EXAMPLE 13 A mixture comprising 10 g of 3-methyl-panisaldehyde, 5.4 g of hydroxylamine hydrochloride, 8.4 g of sodium formate, and 40 ml of formic acid was stirred at 100 C. for 3 hours. The reaction mixture was added to 400 ml of water and extracted with 300 ml of ethyl acetate. The extract was washed twice with water, then with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from an ether-n-hexane mixture to yield 10 g of 4-methoxy-3-methylbenzonitrile; m.p. 46-47 C.
Stage #1: 4-hydroxy-3-methyl-benzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃;
Preparation of methoxy-methylbenzaldehydes
General procedure: To a solution of the hydroxy-methylbenzaldehyde (34 mg,0.25 mmol) in anhydrous DMF (6.0 mL), K2CO3 (35 mg,0.25 mmol) was added and the mixture was stirred at room temperaturefor 30 minutes. Then, methyl iodide (30 μL, 68 mg,0.5 mmol) was added and the reaction was stirred at room temperatureovernight. The reaction was quenched by the additionof distilled water, and the aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases weredried with MgSO4 and concentrated in vacuo. The residue waspurified by column chromatography on silica gel.
1-methoxy-2-methyl-4-(2-methylprop-1-en-1-yl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: isopropyltriphenylphosphonium iodide With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran at 40℃; Inert atmosphere;
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; Petroleum ether at -78 - 0℃; for 0.5h;
Stage #2: 3-methyl-4-anisaldehyde In tetrahydrofuran; Petroleum ether at 20℃; for 0.5h;
With selenium; copper; potassium hydroxide In dimethyl sulfoxide at 120℃;
13
Under anhydrous and anaerobic conditions, 0.1 mmol of 2-iodo-4-methoxyaniline was added.0.12 mmol of 3-methyl 4-methoxybenzaldehyde, 0.3 mmol of selenium powder, 0.005 mmol of copper, 0.2 mmol of potassium hydroxide and 10 ml of DMSO solution,The reaction was refluxed at 120 ° C in a single-neck round bottom flask, and the reaction was monitored by TLC.Separation of pure methoxy-containing benzoselenazole compounds by column chromatographyThe reaction product was obtained by demethylation of boron tribromide (6 eq.).The product is a white solid.The yield was 30%.
With selenium; copper; potassium hydroxide; In dimethyl sulfoxide; at 120℃;
Under anhydrous and anaerobic conditions, 0.1 mmol of <strong>[153898-63-6]2-iodo 5-methoxyaniline</strong> was added.0.12 mmol of 3-methyl 4-methoxybenzaldehyde, 0.3 mmol of selenium powder, 0.005 mmol of copper, 0.2 mmol of potassium hydroxide and 10 ml of DMSO solution,The reaction was refluxed at 120 C in a single-neck round bottom flask, and the reaction was monitored by TLC.Separation of pure methoxy-containing benzoselenazole compounds by column chromatographyThe reaction product was obtained by demethylation of boron tribromide (6 eq.).The product is a white solid.The yield was 22%.
With N-Bromosuccinimide; trifluorormethanesulfonic acid; palladium diacetate; (2,2,2-trifluoroacetyl)oxysilver; 4-Nitroanthranilic acid In 1,2-dichloro-ethane at 90℃; for 8h; Sealed tube;
43%
Stage #1: 3-methyl-4-anisaldehyde With n-butyllithium; N,N',N'-trimethylenediamine In tetrahydrofuran; hexane at 0℃; for 1h;
Stage #2: With carbon tetrabromide In tetrahydrofuran; hexane at -78 - 20℃; for 1h;
With N-chloro-succinimide; 2-hydroxyl-5-nitro-3-(trifluoromethyl)pyridine; 4-trifluoromethylphenylamine; palladium diacetate; trifluoroacetic acid In 1,2-dichloro-ethane at 80℃; for 24h; Sealed tube;
2,6-dibromo-4-methoxy-3-methylbenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 27%
2: 31%
With N-Bromosuccinimide; 4-chloro-2-(trifluoromethyl)aniline; palladium diacetate In 1,2-dichloro-ethane; trifluoroacetic acid at 60℃; for 24h;
1.2 General procedure for the synthesis of 3a-3w
General procedure: Compound 1 (0.4 mol), N-bromosuccinimide (NBS) (0.48 mol, 85.4 mg), and Pd(OAc)2(10 mol%, 8.9 mg), 2-Amino-5-chlorobenzotrifluoride (20 mol%, 15.6 mg) were mixed withDCE (2.5 mL) and TFA (0.5 mL) solvent. The reaction mixture was stirred 24 h at 60 °C. Aftercompletion of the reaction, the solution was concentrated in vacuo and purified by columnchromatography on silica gel using PE/DCM/EtOAc as eluent to give the desired product.
(E)-1-(4-methoxy-3-methylphenyl)-N-(3,4,5-trimethoxyphenyl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
In ethanol for 4h; Reflux;
4.1.1 General method I: preparation of imines
General procedure: The appropriately substituted benzaldehyde (10mmol) and substituted aniline (10mmol) were heated together at reflux in ethanol (40mL) for 4h. The reaction mixture was reduced by evaporation in vacuo and the resulting solid product was recrystallised from ethanol
(E)-ethyl 4-(4-methoxy-3-methylphenyl)-2-oxobut-3-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With iodine In neat (no solvent) at 80℃; for 2h;
General procedure for the synthesis of β,γ-unsaturated-α-ketoester derivatives (3a-u)
General procedure: A mixture of aromatic aldehydes 1a-u (0.73 mmol,0.0892 mL), iodine (10 mol%, 18.5 mg), ethyl pyruvate 2(0.73 mmol, 0.0817 mL) was heated at 80 °C for 2 h. Aftercompletion of the reaction (TLC), the reaction mixture was washed with saturated sodium thiosulfate solution (5 mL)to destroy iodine, and after the addition of diethyl ether(20 mL), both aqueous and organic phases were separated.The organic layer was washed with saturated aqueous NaCland filtered over MgSO4.The filtrate was concentrated underreduced pressure. The filtrate was loaded on to silica gel columnchromatography using hexane-EtOAc (10:2 and 10:1)as eluent to obtain pure products 3a-u. Spectroscopic datafor a representative compounds are given below.
Stage #1: 3-methyl-4-anisaldehyde; prenyl bromide With ammonium chloride; zinc In tetrahydrofuran; water at 0 - 25℃;
Stage #2: With pyridinium chlorochromate In dichloromethane at 0 - 25℃; for 6h;
2. Preparation of β, γ-unsaturated hydrazones
General procedure: (1) A round bottomed flask charged with a solution of the 3-bromo-2-methylprop-1-enes (15.0 mmol, 1.5 equiv) and an aldehyde (10.0 mmol, 1.0 equiv) in a saturated aqueous solution of ammonium chloride and THF (v:v = 3:1) was cooled to 0 °C in an ice bath. The zinc powder (20.0 mmol, 2.0 equiv) was added to the solution by portion wise. After stirring additional 30 min at 0 °C, the ice bath was removed and the resulting suspension was stirred overnight. Then 1N hydrochloric acid solution (20 mL) was added at 0 °C. The THF layer was separated from the aqueous layer, which was extracted with diethyl ether (20 mL × 3). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude products were directly used in the next step without further purification. (2) The obtained residue was dissolved into CH2Cl2 (20 mL). Then, PCC (13.0 mmol, 1.3 equiv) was added to the solution in several portions at 0 °C. After the addition of PCC, the mixture was stirred vigorously at 25 °C for 6 h. The mixture was diluted with CH2Cl2 (100 mL) and passed through a silica gel column. The organic solution was dried over anhydrous MgSO4, and concentrated in vacuo. The crude ketone products were directly used in the next step without further purification.
Synthesis of 5-amino-2-(1,3-benzodioxol-5-yl)-7-substitiutedaldehyde-7H- [1, 3, 4] -thiadiazole[3,2-a]pyrimidine-6-carbonitrile
General procedure: Mixture consisting of 5-(1,3-benzodioxol-5-yl)-1,3,4-thiadiazol-2-amine (0.01 mol), propanedinitrile (0.001 mol)and corresponding aromatic or heteroaromatic aldehyde(0.01 mol) in absolute ethyl alcohol (10-12 mL) with NaOH(pellet) as catalyst was refluxed in a 25-mL round-bottomflask. After culmination of reaction which was supervisedby TLC, the contents were decanted into a Petri plate, solventwas air-dried, and the resulting product was scrappedout. Carefully, this product was washed with dilute HCl toremove the excess base via neutralization, recrystallized byethanol in order to obtain purified product in high grade. Thesynthesis of designed compounds (B1-B9) was outlined inScheme 1.
5.1. Synthesis of compounds C1-C10, D1-D10 and E1-E12
General procedure: A solution of various aromatic aldehydes A1-A10 (1.0 mmol, 1.0 eq) and 3,4,5-trimethoxyaniline (1.0 mmol, 1.0 eq) were added into EtOH (20 ml) at 80 °C for 6 h. When the reactions were complete, organic phases were collected to give crude the products C1-C10 without further purified with column chromatography. A solution of compounds C1-C10 (1.0 mmol,1.0 eq), benzoic acid (1.0 mmol, 1.0 eq) and NaBH4 (1.0 mmol, 1.0 eq) were added into DCM (20 ml) at 25 °C for 8 h. When the reactions were complete, organic phases were collected to obtain crude products and then were purified by column chromatography to obtain compounds D1-D10. A solution of compounds D1-D10 (1.0 mmol, 1.0 eq) and acyl chloride derivatives (1.0 mmol, 1.0 eq) were added into DMF (8 ml) at 25 °C for 6-8 h. Then using EA (20 ml) extracted aqueous layers for three times. Collected organic layers were washed by saturated salt water, dried over magnesium sulfate anhydrous and evaporated to get crude products. Crude products were purified by column chromatography to obtain compounds E1-E11.
Stage #1: 3-methyl-4-anisaldehyde With lithium perchlorate; 1,1,1,3,3,3-hexamethyl-disilazane at 60℃; for 1h;
Stage #2: With methanol; sodium tetrahydroborate at 0 - 20℃;
Stage #3: With hydrogenchloride In water; acetonitrile
11-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-butadiene[ No CAS ]
(5S,6S)-6-(4-methoxy-3-methylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-5,6-dihydro-2H-1,2-oxaborinin-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: bis(pinacol)diborane With (S)-((4,4’-bi-1,3-benzodioxole)-5,5’-diyl)bis(diphenylphosphine); copper(l) chloride; sodium t-butanolate In tetrahydrofuran at 20℃; for 0.0833333h; Inert atmosphere; Glovebox;
Stage #2: 3-methyl-4-anisaldehyde; 11-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-butadiene In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Glovebox; stereoselective reaction;
2-((2-chlorobenzyl)thio)-4-(4-methoxy-3-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
Stage #1: 1-bromomethyl-2-chlorobenzene; thiourea In ethanol at 85℃; for 4h; Inert atmosphere;
Stage #2: 3-methyl-4-anisaldehyde; ethyl 2-cyanoacetate With sodium hydroxide In methanol at 70℃; for 5h; Inert atmosphere;
5.11.1. General procedure a for the synthesis of A2,A22-A31
General procedure: A1-a or A1-b (34.16 mmol), different halides (31.05 mmol), and 60ml ethanol were added to a 250 ml round bottom flask and protected by nitrogen. The mixture was heated to 85 C and refluxed for 4 h. Thereaction was detected by TLC until it was completely finished. Then theround bottom flask was removed from the oil bath and cooled to roomtemperature. The mixture was stirred slowly in the ice bath for 2 h toprecipitate a large amount of white crystalline powder. The solid wasfiltered and triturated with EtOH to give the target compound as whitepowder (Y = 61.0%-84.6%). 5.11.2. General procedure B for the synthesis of 1-18,23-34A2, A27-A38 (1.0 mmol), different benzaldehydes (1.0 mmol), ethylcyanoacetate (106.51 mg, 1.0 mmol), NaOH (44.16 mg, 1. 1 mmol) and10 ml methanol were added into a 25 ml round bottom flask under nitrogenprotection and heated to 70 C for 5 h. The reaction was detectedby TLC until it was completely finished. After cooling to room temperature,the mixture was concentrated under vacuum and the residueobtained was purified by column chromatography to give the targetcompound.
57%
Stage #1: 1-bromomethyl-2-chlorobenzene; thiourea In ethanol at 85℃; for 4h; Inert atmosphere;
Stage #2: 3-methyl-4-anisaldehyde; ethyl 2-cyanoacetate With sodium hydroxide In methanol at 70℃; for 5h; Inert atmosphere;
5.11.1. General procedure a for the synthesis of A2,A22-A31
General procedure: A1-a or A1-b (34.16 mmol), different halides (31.05 mmol), and 60ml ethanol were added to a 250 ml round bottom flask and protected by nitrogen. The mixture was heated to 85 C and refluxed for 4 h. Thereaction was detected by TLC until it was completely finished. Then theround bottom flask was removed from the oil bath and cooled to roomtemperature. The mixture was stirred slowly in the ice bath for 2 h toprecipitate a large amount of white crystalline powder. The solid wasfiltered and triturated with EtOH to give the target compound as whitepowder (Y = 61.0%-84.6%). 5.11.2. General procedure B for the synthesis of 1-18,23-34A2, A27-A38 (1.0 mmol), different benzaldehydes (1.0 mmol), ethylcyanoacetate (106.51 mg, 1.0 mmol), NaOH (44.16 mg, 1. 1 mmol) and10 ml methanol were added into a 25 ml round bottom flask under nitrogenprotection and heated to 70 C for 5 h. The reaction was detectedby TLC until it was completely finished. After cooling to room temperature,the mixture was concentrated under vacuum and the residueobtained was purified by column chromatography to give the targetcompound.
2-((2-chlorobenzyl)thio)-4-(4-methoxy-3-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.35%
With sodium hydroxide In methanol at 70℃; for 5h; Inert atmosphere;
14
Intermediate (1.0 mmol), benzaldehyde compound (1.0 mmol), ethyl cyanoacetate (106.51 mg, 1.0 mmol),Sodium hydroxide (44.16 mg, 1,1 mmol) and 10 ml of methanol were added to a 25 ml round-bottomed flask, under nitrogen protection, and heated to 70 °C for 5 h. TLC detected that the reaction was complete, and after the reaction was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and a yellow powder (229 mg, 57.35%) was obtained by column chromatography.
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