* 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] Tetrahedron, 2013, vol. 69, # 42, p. 8914 - 8920
[2] Journal of Organic Chemistry, 1961, vol. 26, p. 1754 - 1758
[3] Journal of Organic Chemistry, 1964, vol. 29, p. 2372 - 2378
[4] Phytochemistry (Elsevier), 1987, vol. 26, # 5, p. 1453 - 1458
[5] Synthesis, 1999, # 5, p. 885 - 897
[6] Synthesis, 2011, # 18, p. 2935 - 2940
2
[ 67-56-1 ]
[ 93-40-3 ]
[ 15964-79-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
Reflux
Methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 To a solution of 2-(3,4-dimethoxyphenyl)acetic acid (25.0 g, 127.4 mmol) in MeOH (100 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added a catalytic amount of sulfuric acid (around 10 drops) and the mixture was stirred overnight under reflux. After cooling to RT, MeOH was removed at 40° C. under vacuum and the product was taken up in CH2Cl2 (250 mL), washed with water (5*20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 as an orange oil (25.77 g, 96percent yield). MW: 210.23; Yield: 96percent; Orange oil. Rf: 0.25 (cyclohexane:EtOAc=3:1). 1H-NMR (CDCl3, δ): 3.56 (s, 2H, CH2), 3.70 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.82-6.83 (m, 3H, 3*ArH). 13C-NMR (CDCl3, δ): 40.6, 51.9, 55.8 (2*C), 111.2, 112.4, 121.4, 126.4, 148.2, 148.9, 172.2. MS-ESI m/z (percent rel. Int.): 233.2 ([M+Na]+, 3), 151.1 (100).
93.3%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1 h; Stage #2: at 20℃; for 1 h;
To a 1 L three-necked flask was added Compound 7a (50 g, 0.255 mol), 250 ml of dichloromethane,Stir at room temperature,Carbonyldiimidazole (62 g, 0.382 mol) was added in batches and reacted for 1 h at room temperature.Add 50ml of methanol, stir for 1h,The reaction solution was poured into a separatory funnel, 200 ml of water was added for extraction, and the organic layer was collected and dried over anhydrous sodium sulfate.The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give 50 g of compound 6a in a yield of 93.3percent.
88%
at 120℃; for 0.333333 h; Microwave irradiation
General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5–2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 1, p. 85 - 90
[2] Tetrahedron, 2007, vol. 63, # 46, p. 11377 - 11385
[3] Tetrahedron, 2013, vol. 69, # 42, p. 8914 - 8920
[4] Patent: US2012/214837, 2012, A1, . Location in patent: Page/Page column 23-24
[5] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 1165 - 1167
[6] Journal of Organic Chemistry, 2009, vol. 74, # 9, p. 3491 - 3499
[7] Journal of Organic Chemistry, 1990, vol. 55, # 4, p. 1261 - 1266
[8] Patent: CN105153105, 2018, B, . Location in patent: Paragraph 0068-0070
[9] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6808 - 6815
[10] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5594 - 5598
[11] Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 10863 - 10884
[12] Synthetic Communications, 2014, vol. 44, # 16, p. 2386 - 2392
[13] Journal of the American Chemical Society, 2015, vol. 137, # 32, p. 10246 - 10253
[14] Tetrahedron Letters, 1996, vol. 37, # 8, p. 1233 - 1236
[15] Archiv der Pharmazie (Weinheim, Germany), 1933, vol. 271, p. 431,435
[16] Tetrahedron, 1992, vol. 48, # 38, p. 8285 - 8294
[17] Patent: US2007/287708, 2007, A1, . Location in patent: Page/Page column 28
[18] Patent: US2007/287738, 2007, A1, . Location in patent: Page/Page column 17
[19] Synthetic Communications, 2008, vol. 38, # 21, p. 3662 - 3671
[20] Synthesis, 2011, # 18, p. 2935 - 2940
[21] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6567 - 6572
[22] Patent: WO2012/145234, 2012, A2, . Location in patent: Page/Page column 31-32
[23] Journal of the American Chemical Society, 2013, vol. 135, # 18, p. 6774 - 6777
[24] Patent: EP2871187, 2015, A1, . Location in patent: Paragraph 0063-0064
[25] Patent: US2015/183797, 2015, A1, . Location in patent: Paragraph 0160-0162
[26] Chemistry - A European Journal, 2015, vol. 21, # 36, p. 12601 - 12605
[27] Tetrahedron Letters, 2016, vol. 57, # 8, p. 849 - 851
3
[ 93-40-3 ]
[ 15964-79-1 ]
Reference：
[1] Patent: US6630597, 2003, B1,
4
[ 15964-80-4 ]
[ 15964-79-1 ]
Reference：
[1] Patent: US2009/41669, 2009, A1,
5
[ 186581-53-3 ]
[ 93-40-3 ]
[ 15964-79-1 ]
Reference：
[1] Chemical Communications, 2009, # 13, p. 1739 - 1741
6
[ 93-40-3 ]
[ 7664-93-9 ]
[ 15964-79-1 ]
Reference：
[1] Patent: US5219848, 1993, A,
7
[ 102-32-9 ]
[ 77-78-1 ]
[ 15964-79-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2680 - 2684
Methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 To a solution of 2-(3,4-dimethoxyphenyl)acetic acid (25.0 g, 127.4 mmol) in MeOH (100 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added a catalytic amount of sulfuric acid (around 10 drops) and the mixture was stirred overnight under reflux. After cooling to RT, MeOH was removed at 40 C. under vacuum and the product was taken up in CH2Cl2 (250 mL), washed with water (5*20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 as an orange oil (25.77 g, 96% yield). MW: 210.23; Yield: 96%; Orange oil. Rf: 0.25 (cyclohexane:EtOAc=3:1). 1H-NMR (CDCl3, delta): 3.56 (s, 2H, CH2), 3.70 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.82-6.83 (m, 3H, 3*ArH). 13C-NMR (CDCl3, delta): 40.6, 51.9, 55.8 (2*C), 111.2, 112.4, 121.4, 126.4, 148.2, 148.9, 172.2. MS-ESI m/z (% rel. Int.): 233.2 ([M+Na]+, 3), 151.1 (100).
93.3%
To a 1 L three-necked flask was added Compound 7a (50 g, 0.255 mol), 250 ml of dichloromethane,Stir at room temperature,Carbonyldiimidazole (62 g, 0.382 mol) was added in batches and reacted for 1 h at room temperature.Add 50ml of methanol, stir for 1h,The reaction solution was poured into a separatory funnel, 200 ml of water was added for extraction, and the organic layer was collected and dried over anhydrous sodium sulfate.The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give 50 g of compound 6a in a yield of 93.3%.
88%
With alumina methanesulfonic acid; at 120℃; for 0.333333h;Microwave irradiation;
General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5-2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester.
Acidic conditions; Heating / reflux;
A solution of 3,4-dimethoxyphenyl acetic acid (50 mM) in MeOH (100 mL) with concentrated sulfuric acid (conc. H2SO4, 1 mL) or concentrated hydrochloric acid (conc. HCl) was heated at reflux overnight. Concentration to dryness on a rotary evaporator and high vacuum pump overnight gave the ester as an oil which was used directly in the next step.
Acidic conditions; Heating / reflux;
EXAMPLE 1; Preparation of 4-[(3-chlorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinitrile; A solution of 3,4-dimethoxyphenyl acetic acid (50 mM) in methanol (MeOH, 100 mL) with concentrated sulfuric acid (H2SO4, 1 mL) or concentrated hydrochloric acid (HCl) was heated at reflux overnight. Concentration to dryness on a rotary evaporator and high vacuum pump overnight gave 3,4-dimethoxy-phenyl)acetic acid methyl ester as an oil which was used directly in the next step.
With acetyl chloride; at 0 - 20℃;Inert atmosphere;
Methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate (2g)In a flame dried round bottom flask, 2-(3,4-dimethoxyphenyl) acetic acid (50 mmol, 1 eq.) was dissolved in MeOH (100 mL) and cooled to 0 C. Acetyl chloride (60 mmol, 1.2 eq.) was added drop wise at 0 C. The resultant reaction mixture was stirred at rt for overnight. The reaction mixture was poured in to a separation funnel having ethyl ether and saturated NH4C1 solution. Extracted twice; combined organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. The crude methyl acetate mixture was taken to next step without further purification.
Manufacturing Example 1: Preparation of Methyl 2-(3,4-dimethoxyphenyl)acetate (32) carboxylic acid (1 equivalent) and anhydrous DMF (catalytic amount) were dissolved in anhydrous CH2Cl2 (0.1 M). After lowering the temperature of the mixture to 0C, oxalic acid (3 equivalent) was added drop by drop to the mixture. After stirring the mixture at room temperature for 30 minutes, anhydrous methanol (50 equivalent) was added drop by drop, followed by stirring again for 10 minutes. Then, the mixture was treated with water. The water layer was extracted with CH2Cl2 and the organic layer was dried over MgSO4, followed by filtering. After concentrating the mixture under reduced pressure, the residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 32. 1H NMR (CDCl3, 300 MHz) delta 6.79 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.55 (s, 2H).
carboxylic acid (1 equivalent) and anhydrous DMF (catalytic amount) were dissolved in anhydrous CH2Cl2 (0.1 M). After lowering the temperature of the mixture to 0 C., oxalic acid (3 equivalent) was added drop by drop to the mixture. After stirring the mixture at room temperature for 30 minutes, anhydrous methanol (50 equivalent) was added drop by drop, followed by stirring again for 10 minutes. Then, the mixture was treated with water. The water layer was extracted with CH2Cl2 and the organic layer was dried over MgSO4, followed by filtering. After concentrating the mixture under reduced pressure, the residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 32. [0162] 1H NMR (CDCl3, 300 MHz) delta 6.79 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.55 (s, 2H)
With thionyl chloride; at 65℃;
General procedure: To a solution of the aryl acetic acid (12.0 mmol, 1.00 equiv) in methanol (60 mL) was added thionyl chloride (2.63 mL, 36.0 mmol, 3.00 equiv). The solution was heated to reflux. Upon completion (as determined by TLC analysis), the solution was concentrated in vacuo and the crude residue was used without further purification.To a flame-dried round-bottom flask with a magnetic stir bar were added the aryl acetic acid ester (12.0 mmol, 1.00 equiv), p-ABSA (3.46 g, 14.4 mmol, 1.20 equiv), and dry acetonitrile (50 mL). The solution was stirred under nitrogen and cooled to 0 C using an ice water bath. DBU (1.97 mL, 13.2 mmol, 1.10 equiv) was added by syringe rapidly in one portion, and the reaction mixture was allowed to warm to 23 C and stir overnight. Upon completion (as determined by TLC analysis) or after 24 hours, whichever came first, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexanes and ethyl acetate as eluent. The aryl diazoacetates were obtained in 23-70% yield over two steps.
With perchloric acid; In water; at 0 - 20℃; for 1.25h;Inert atmosphere;
6,7-Dimethoxy-1-methylisoquinolin-3-ol CCH 18060 To a solution of <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> SLA 28134 (23.82 g, 113.30 mmol) in acetic anhydride (57 mL) at 0 C. in a 1 L round-bottomed flask equipped with a magnetic stirrer under N2 was added perchloric acid (70% solution in water, 11.3 mL) over a period of 30 min. The reaction mixture was then allowed to warm up to RT, stirred for a further 45 min and diluted with Et2O (450 mL). The solid was then filtered and washed several times with Et2O (6*15 mL) to give after drying under vacuum a dark yellow solid (27.97 g, 74% yield). To a suspension of the above solid (11.09 g, 34.58 mmol) in H2O (60 mL) in a 500 mL 3-neck round-bottomed flask equipped with a dropping funnel and a magnetic stirrer in an ice bath was added dropwise conc. NH4OH (90 mL) and the reaction mixture was stirred at RT for 1 h, after which the solid was filtered and washed with cold water (4*15 mL). After drying under high vacuum, 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 was isolated as a yellow solid (7.53 g, 99% yield). MW: 219.24; Yield: 74%; Yellow solid; Mp ( C.): 283 (dec.). Rf: 0.2 (cyclohexane:EtOAc=2:1). 1H-NMR (DMSO d6, delta): 2.68 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 6.51 (s, 1H, ArH), 6.97 (s, 1H, ArH), 7.12 (s, 1H, ArH), 10.69 (broad s, 1H, OH). 13C-NMR (DMSO d6, delta): 20.3, 55.6, 55.7, 99.5, 103.6, 103.8, 116.2, 138.0, 147.1, 152.0, 153.3, 159.0. MS-ESI m/z (rel. int.): 220 ([M+H]+, 100).
A 1.6M solution of n-butyllithium in hexanes (4.83 mL, 7.74 mmol) was added to a stirred solution of diisopropylamine (1.18 mL, 8.40 mmol) in tetrahydrofuran (7 mL) at-78 C under nitrogen. After 15 min, a solution of Intermediate 66 (1.0 g, 4.75 mmol) in tetrahydrofuran (14 mL) was slowly added at-78 C and the solution was stirred at the same temperature for one hour. A solution of methyl iodide (0.59 mL, 9.5 mmol) in tetrahydrofuran (5 mL) was then added and the resulting mixture was stirred 30 min at - 78 C before warming to room temperature. The reaction mixture was poured into ice- water and extracted with ethyl acetate (3x50 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4) and the solvent removed under reduced pressure to give methyl 2- (3, 4-dimethoxyphenyl) propanoate as a brown oil (1.03 g, 97%). 8 (300 MHz, CDCI3) : 1.46 (d, J=7.0 Hz, 3H); 3.64 (s, 3H); 3.65 (q, J=7.0 Hz, 1 H) ; 3.88 (s, 3H); 3. 89 (s, 3H); 6.82 (s, 3H).
79%
Manufacturing Example 14: Preparation of 2-(3,4-Dimethoxyphenyl)propanal (55) LDA (18.1 mL, 36.21 mmol, 2 M in THF solution) was added drop by drop to anhydrous THF solution (5 mL) containing methyl 3',4'-dimethoxyphenyl acetate (4.76 g, 22.63 mmol) under argon atmosphere at -78C, followed by stirring for 30 minutes. Then, methyl iodide (2.82 mL, 45.26 mmol) was added thereto, followed by stirring for 1 hour. 2 N-HCl aqueous solution was added to the above reaction mixture, leading to acidization, and then the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc:n-hexane=1:4) to give 2-(3,4-dimethoxyphenyl)propanoate as a colorless oil (yield: 79%, 4.01 g). 1H NMR (CDCl3, 500 MHz) delta 6.80 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.64 (q, 1H, J=7.1 Hz), 3.63 (s, 3H), 1.46 (d, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) delta 175.7, 148.9, 148.1, 133.0, 119.5, 111.2, 110.6, 55.8, 55.8, 51.9, 44.9, 18.6.
methyl α-(9-acridinyl)-3,4-dimethoxyphenylacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaH; In N,N-dimethyl-formamide;
EXAMPLE 5 Methyl alpha-(9-acridinyl)-3,4-dimethoxyphenylacetate To a mixture of <strong>[15964-79-1]methyl 3,4-dimethoxyphenylacetate</strong> (19.7 g,.094 mol) 0.14 mole of NaH and 250 ml of dry DMF stirred at RT for 1 hour, was added 10.0 g (46.3 mmol) of 9-chloroacridine in 250 ml of DMF. The resultant mixture was stirred at RT for 18 hours, poured onto 1 l. ice/H2 O and extracted with Et2 O (1*500 ml) and CHCl3 (1*500 ml). The combined organics were washed with H2 O (3*500 ml), dried over MgSO4 and evaporated to give a quantitative yield of the crude product. The crude oily residue was triturated with Et2 O-hexane and 16.4 g (90.5%) of solid product mp 148-154 was obtained. The analytical sample was obtained by recrystallization from MeOH/H2 O; yield 14.3 g, mp 157-158. Anal. Calcd. for C24 H21 NO4 C, H, N.
With pyridine; hydrazine hydrate; In ethanol; for 10h;Reflux;
General procedure: To a mixture corresponding ester (9a-n, 5.0 mmol) and hydrazine monohydrate (15.0 mmol) in ethanol, catalytic amount of pyridine (0.5 mL) was added and refluxed for 10 h. The reaction was monitored by TLC. After the completion of the reaction, ethanol was evaporated from the mixture, water was added and extracted using ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum to get the crude mass. Finally, the products 10a-n were purified using column chromatography. (Yield 80-85%).
To a 1.0 L three-necked round-bottomed flask was added 50 mL of THF and the reaction mixture was cooled to -78 C. Butyl lithium (BuLi, 1.6 M, 14.4 mL, 23 mmol) was added dropwise keeping the temperature below -70 C. Acetonitrile (1.3 mL, 25 mmol) in 30 mL of THF was added dropwise to the flask amidst stirring and cooling. After 2 hours (h) of stirring, (3,4-dimethoxyphenyl)acetic acid methyl ester (2.3 g, 11 mmol) was added to the resulting white colloidal mixture in the flask. The reaction mixture was stirred for a further 2 h, followed by the addition of saturated ammonium chloride solution (NH4Cl, 75 mL) at -78 C. The organic layer was separated, dried with sodium sulfate (Na2SO4), filtered to remove the drying agent and evaporated to dryness to give the crude product. This crude product was purified by silica gel column chromatography, eluting with 30-70% ethyl acetate (EtOAc) in hexanes to yield 4-(3,4-dimethoxyphenyl)-3-oxo-butyronitrile in the form of a solidifying amber oil, 1.8 g (75%).
75%
To a 1.0 L three-necked round-bottomed flask was added 50 mL of THF and the reaction mixture was cooled to -78 C. Butyl lithium (1.6 M, 14.4 mL, 23 mmol) was added dropwise keeping the temperature below -70 C. Acetonitrile (1.3 mL, 25 mmol) in 30 mL of THF was added dropwise to the flask amidst stirring and cooling. After 2 hours of stirring, 3,4-dimethoxy-phenyl)acetic acid methyl ester (2.3 g, 11 mmol) was added to the resulting white colloidal mixture in the flask. The reaction mixture was stirred for a further two hours, followed by the addition of saturated ammonium chloride solution (75 mL) at -78 C. The organic layer was separated, dried with sodium sulfate, filtered to remove the drying agent and evaporated to dryness to give the crude product. This crude product was purified by silica gel column chromatography, eluding with 30-70% ethyl acetate in hexanes to yield 4-(3,4-dimethoxyphenyl)-3-oxo-butyronitrile in the form of a solidifying amber oil, 1.8 g (75%).
Example 3; Synthesis of methyl 3-(3,5-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)-3-oxopropionate:; 23.8 g of 60% NaH in mineral oil (0.59 mol) are introduced into a 1 1 round-bottomed flask and are washed in the round-bottomed flask with 2 times 60 ml of cyclohexane, and then 46.7 g of methyl 3,5-methoxybenzoate (0.238 mol) dissolved in 200 ml of THF are added. The mixture is brought to reflux and 50 g of methyl 3,4- dimethoxyphenylacetate (0.238 mol) dissolved in 120 ml of THF are added over 10 h. The mixture is maintained at reflux for 2 h and cooled to 0-50C and 37.1 g (0.61 mol) of acetic acid diluted in 120 ml of THF are added dropwise at this temperature. 300 ml of water are then added and the THF is distilled off. The mixture is brought back to ambient temperature and extracted with 400 ml of MTBE, the organic phase is then washed with 100 ml of water and the medium is concentrated to recover 92.9 g of crude methyl 3-(3,5-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)-3-oxopropionate in the form of a viscous yellow oil.NMR (CDCl3) 200 MHzProton: delta 3.75 s (3H); delta 3.80 s (6H); delta 3.95 s (3H); delta 3.98 s (3H); delta 5.5 (IH); delta 6.5-7.3 m (6H) C13: delta 52.5 (COOCH3); delta 56.46 and 56.53 (OCH3); delta 59.88 (CH); delta 99.67;106.24; 111.50; 112.02; 121.02; 125.98; 146.48; 148.72; 149.29; 159.27(arom. CH); delta 167.89 (C=O); delta 198.97 (COOCH3).
l-(4-Bromophenyl)-4-(3,4-dimethoxyphenyl)butane-l,3-dione; Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> (10 g, 47.6 mmol) in Et2O (100 ml) at O0C. A solution of 4'-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M), extracted with Et2O (3 x 100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50 %) as a tan powder.
50%
l-(4-Bromovhenyl)-4-(3,4-dimethoxyphenyl)butane-l,3-dione; Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to methyl 2-(3,4-dimethoxyphenyl) acetate (10 g, 47.6 mmol) in Et2O (100 ml) at O0C. A solution of 4'-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added <n="17"/>dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M)5 extracted with Et2O (3 x 100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50 %) as a tan powder.
50%
l-(4-Bromophenyl)-4-(3,4-dimethoxyphenyl)butane-l,3-dione; Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> (10 g, 47.6 mmol) in Et2O (100 ml) at O0C. A solution of 4'-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M), extracted with Et2O (3 x 100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50 %) as a tan powder.
50%
With hydrogenchloride; In diethyl ether;
1-(4-Bromophenyl)-4-(3,4-dimethoxyphenyl)butane-1,3-dione Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> (10 g, 47.6 mmol) in Et2O (100 ml) at 0 C. A solution of 4'-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M), extracted with Et2O (3*100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50%) as a tan powder.
50%
With sodium hydride; In diethyl ether; mineral oil; at 0℃; for 17h;Reflux;
1-(4-Bromophenyl)-4-(3,4-dimethoxyphenyl)butane-1,3-dione Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> (10 g, 47.6 mmol) in Et2O (100 ml) at 0 C. A solution of 4'-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M), extracted with Et2O (3*100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50%) as a tan powder.
With tin(IV) chloride; In chloroform; at 0 - 20℃; for 6h;
To a solution of 315 mg (1.5 mmol) of 3,4-dimethoxyphenyl methyl acetate in 5 ml of anhydrous CHCl3, add at 0 C. and under an inert atmosphere 452 mul (3 mmol) of 1-naphthoyl chloride. Add dropwise 351 mul of SnCl4. Allow to return to room temperature. [0299] After 6 hours at room temperature, evaporate to dryness. Add 10 ml of MeOH. Stir at room temperature for 30 minutes. Evaporate to dryness. Add 7 ml of iced H2O. Allow to crystallize at 0 C. for 1 hour. Filter. Wash twice with 1 ml of H2O. Yield: 37%. The product is used as is for the subsequent reactions.
Step 1 3,4-Dimethoxyphenylacetic acid (80.0 grams, 0.41 mole), methanol (350 milliliters (mL)) and 2 mL of concentrated sulfuric acid were added to a reaction flask equipped with a Dean-Stark trap condensor and magnetic stirrer. The reaction mixture was maintained at reflux temperature overnight. After removal of unreacted methanol via a rotary evaporator, the product was dissolved in ether. The ether solution was washed twice in a sodium bicarbonate solution, washed twice with water and dried over anhydrous sodium sulfate. The ether was removed on a rotary evaporator, leaving 85 grams of methyl 3,4-dimethoxyphenylacetate as a viscous oil.
With chlorosulfonic acid; In chloroform; at 0 - 20℃; for 4h;Inert atmosphere;
In a flask containing <strong>[15964-79-1]2-(3,4-dimethoxyphenyl)methyl acetate</strong> (3.7 g, 17.65 mmol),CHCb (35 ml) is added and then chlorosulfonic acid (5.28 ml, 79.4 mmol) dropwiseat 0 o C under an Ar atmosphere. The solution obtains a dark purple color and isstirred at room temperature for 4 h. The reaction is quenched by the gradual5 addition of water (35 ml) at 0 C, followed by extractions with DCM (3x35 ml), dryingthe organic layer with Na2SO4 , condensation and column chromatography with 2: 1elution solvent PSI EA. The product is collected as a white solid in 88% yield.
With caesium carbonate; dimethyl sulfate; sodium chloride; In cyclohexane; water; ethyl acetate; N,N-dimethyl-formamide;
Cesium carbonate (6.6 g, 20.2 mmol) and dimethyl sulfate (2 ml, 21 mmol) were added to a solution of methyl 4-hydroxy-3-methoxyphenylacetate 9 (2 g, 10.2 mmol) in anhydrous DMF (80 ml). The reaction mixture was heated at 90 C. for 3 hours. After cooling, water (20 ml) was added to the mixture and the product was extracted with diethyl ether (2*50 ml). The combined organic phases were washed with an aqueous solution of NaCl (20 ml), dried over MgSO4 and concentrated under reduced pressure. Chromatography on a silica gel using cyclohexane/ethyl acetate (1/1) as eluent mixture gave methyl 2-(3,4-dimethoxyphenyl)acetate 8 (1.7 g, 80%) in the form of a colorless oil. 1H NMR (CDCl3, 300 MHz) delta 6.80-6.50 (m, 3H), 3.71 (s, 3H), 3.69 (s, 3H), 3.40 (s, 2H). 13C NMR (CDCl3, 75 MHz) delta 172.2, 148.8, 148.0, 126.4, 121.3, 112.3, 111.1, 55.8, 55.7, 51.9, 40.6.
1 Synthesis of 4,5-dimethoxy-2-[(phenylacetamino)methyl]phenylacetic acid (7)
A precooled solution of acetic acid (20 ml) and sulfuric acid (730 μl, 14 mmol) was added to a mixture of N-hydroxymethylphenylacetamide 11 and methyl 2-(3,4-dimethoxyphenyl)acetate 8 (1.5 g, 7.2 mmol). The suspension was stirred for 2 hours at 0° C. then at ambient temperature for 12 hours. The reaction mixture was neutralized with a 5M sodium hydroxide solution at 0° C. The product was extracted with ethyl acetate (2*30 ml). The combined organic phases were dried over MgSO4 and concentrated to give methyl 4,5-dimethoxy-2-[(phenylacetamino)methyl]phenylacetate 6 (2 g, 78%) in the form of a colorless oil which crystallized. M.p.=118° C. 1H NMR (CDCl3, 300 MHz) δ 7.40-7.15 (m, 5H), 6.68 (s, 1H), 6.59 (s, 1H), 6.24 (br s, NH), 4.28 (d, J=5.6 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 3.51 (s, 2H), 3.47 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ 172.8, 170.8, 148.4 (2C), 135.0, 129.7 (2C), 129.2, 127.5 (2C), 124.9, 113.8, 113.2, 56.3 (2C), 52.7, 44.2, 41.7, 38.3. IR (CHCl3) 3017, 1732, 1660, 1520, 1466, 1275.
Stage #1: methyl (3,4-dimethoxyphenyl)acetate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.333333h; Inert atmosphere;
Stage #2: 4-iodobut-1-ene In tetrahydrofuran; hexane at -78 - 0℃; Inert atmosphere;
With diisobutylaluminium hydride; In diethyl ether; at -78℃; for 1h;
Manufacturing Example 13: Preparation of 2-(3,4-Dimethoxyphenyl) acetaldehyde (52) Anhydrous diethyl ether solution containing methyl 3',4'-dimethoxyphenyl acetate (1.94 g, 9.24 mmol) was stirred, during which DIBAL-H (11.1 mL, 1 M in THF solution) was added thereto drop by drop with maintaining the temperature at -78C. The mixture was stirred at the same temperature for 1 hour. Rochelle aqueous solution was carefully added thereto for 15 minutes. The mixture of the two phases was stirred vigorously at 0 C for 1 hour, which was added to water. The water layer was extracted with EtOAc (*2) and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Then, the obtained residue was purified by flash column chromatography (EtOAc:n-hexane=1:2) to give the compound 52 of Manufacturing Example 13 (yield: 68%, 1.13 g). 1H NMR (CDCl3, 300 MHz) delta 9.66 (t, 1H, J = 2.5 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.68 (m, 1H), 6.64 (d,
68%
With diisobutylaluminium hydride; In tetrahydrofuran; diethyl ether; at -78℃; for 1h;
Anhydrous diethyl ether solution containing methyl 3?,4?-dimethoxyphenyl acetate (1.94 g, 9.24 mmol) was stirred, during which DIBAL-H (11.1 mL, 1 M in THF solution) was added thereto drop by drop with maintaining the temperature at -78 C. The mixture was stirred at the same temperature for 1 hour. Rochelle aqueous solution was carefully added thereto for 15 minutes. The mixture of the two phases was stirred vigorously at 0 C. for 1 hour, which was added to water. The water layer was extracted with EtOAc (×2) and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Then, the obtained residue was purified by flash column chromatography (EtOAc:n-hexane=1:2) to give the compound 52 of Manufacturing Example 13 (yield: 68%, 1.13 g). [0214] 1H NMR (CDCl3, 300 MHz) delta 9.66 (t, 1H, J=2.5 Hz), 6.80 (d, 1H, J=8.0 Hz), 6.68 (m, 1H), 6.64 (d, 1H, J=1.8 Hz), 3.81 (s. 6H), 3.56 (d, 2H, J=2.5 Hz).
With lithium hexamethyldisilazane; In tetrahydrofuran; tert-butyl methyl ether; at -66 - 20℃; for 2.33333h;
Methyl 2-(3,4-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate CCH 34144-5 To a solution of <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> SLA 28134 (73 mg, 347 mumol) in dry THF (10 mL) at -66 C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added LiHMDS (1.0 N in TBME, 0.70 mL, 700 mumol) and the mixture was stirred for 20 min at that temperature. 3-(Chloromethyl)-5-methoxyquinoline hydrochloride CCH 34144B (84 mg, 344 mumol) was then added and the mixture was stirred for 2 h allowing the temperature to reach RT. The mixture was then quenched by carefully adding H2O (4 mL) and diluted with EtOAc (30 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (40 mL). Both organic phases were washed with brine (10 mL), then combined, dried over Na2SO4, filtered and concentrated at 40 C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) provided methyl 2-(3,4-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate 34144-5 as a pale yellow oil (46 mg, 35% yield). MW: 381.42; Yield: 35%; Pale yellow oil. 1H-NMR (CDCl3, delta): 3.20 (dd, 1H, J=7.1 & 13.9 Hz, CHH), 3.56 (dd, 1H, J=8.5 & 13.9 Hz, CHH), 3.62 (s, 3H, OCH3), 3.85 (s, 6H, 2*OCH3), 3.85-3.91 (m, 1H, CH), 3.99 (s, 3H, OCH3), 6.81-6.87 (m, 4H, 4*ArH), 7.52-7.65 (m, 2H, 2*ArH), 8.33 (s, 1H, ArH), 8.66 (d, 1H, J=2.2 Hz, ArH). 13C-NMR (CDCl3, delta): 37.3, 52.2, 52.8, 55.7, 55.9, 55.9, 104.3, 110.9, 111.3, 120.2, 120.4, 121.3, 128.8, 130.1, 130.4, 130.9, 147.8, 148.5, 149.1, 152.1, 154.9, 173.6. MS-ESI m/z (% rel. Int.): 382 ([MH]+, 100).
With perchloric acid; In water; at 0 - 20℃; for 1.25h;
1-Ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 To a solution of <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> SLA 28134 (10.01 g, 47.6 mmol) in propionic anhydride (24.0 mL, 187.2 mmol) at 0 C. in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added HClO4 (ca. 70% solution in water, 4.89 mL, 56.6 mmol) over a period of 30 min. The reaction mixture was then allowed to warm up to RT, stirred for 45 min and diluted with Et2O (450 mL). The solid was filtered and washed several times with Et2O giving 10.5 g of a brown solid. To a suspension of this solid (9.98 g, 29.8 mmol) in H2O (54 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer and cooled in an ice bath was added dropwise concentrated NH4OH (81 mL). After complete addition, the ice bath was removed and the reaction mixture was stirred at RT for 1 h, after which the solid was filtered and washed with plenty of water until neutral pH of the filtrate. The solid was dried under vacuum in presence of P2O5 to give 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 as a yellow solid (5.30 g, 48% yield). MW: 233.26; Yield: 48%; Yellow solid; Mp ( C.): 219.7 1H-NMR (CDCl3:CD3OD=1:1, delta): 1.42 (t, 3H, J=7.6 Hz, CH3), 3.11 (q, 2H, J=7.6 Hz, CH2), 3.97 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.56 (s, 1H, ArH), 6.74 (s, 1H, ArH), 6.92 (s, 1H, ArH). 13C-NMR (CDCl3:CD3OD=1:1, delta): 17.6, 28.0, 59.5, 59.7, 105.6, 106.6, 108.8, 116.4, 146.7, 152.0, 154.7, 159.3, 165.0. MS-ESI m/z (% rel. Int.): 234.1 ([MH]+, 100).
With perchloric acid; In water; at 0 - 20℃; for 2.16667h;
1-Isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 To a solution of <strong>[15964-79-1]methyl 2-(3,4-dimethoxyphenyl)acetate</strong> SLA 28134 (10.09 g, 48.0 mmol) in isobutyric anhydride (60.5 mL, 364.8 mmol) at 0 C. in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added HClO4 (ca. 70% solution in water, 4.91 mL, 56.8 mmol) over a period of 10 min. The reaction mixture was then allowed to warm up to RT, stirred for 2 h and diluted with Et2O (400 mL). The solid was filtered and washed several times with Et2O to give 16.88 g of a brown solid. The solid was then suspended in H2O (70 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer and cooled in an ice bath before dropwise addition of concentrated NH4OH (180 mL). After complete addition, the ice bath was removed and the reaction mixture was stirred overnight at RT. The mixture was then extracted with CH2Cl2 (100 mL, the organic layer was isolated and the aqueous layer was further extracted with CH2Cl2 (3*100 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum to give 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 as a yellow solid (9.69 g, 82% yield). MW: 247.29; Yield: 82%; Yellow solid; Mp ( C.): 175.0 1H-NMR (CDCl3, delta): 1.52 (d, 6H, J=6.9 Hz, 2*CH3), 3.63-3.70 (m, 1H, CH), 3.93 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.57 (s, 1H, ArH), 6.60 (s, 1H, ArH), 6.94 (s, 1H, ArH), OH not seen. 13C-NMR (CDCl3, delta): 21.1 (2*C), 29.4, 55.8, 56.0, 101.8, 102.8, 104.8, 111.8, 142.0, 147.5, 154.5, 154.8, 161.2. MS-ESI m/z (% rel. Int.): 248 ([MH]+, 100).
6,7-Dimethoxy-1-methoxymethyl-isoquinolin-3-ol SMA 44012 A mixture of methoxyacetic acid (21.9 g, 242.67 mmol) and acetic anhydride (24.80 g, 242.67 mmol) in a 250 mL round-bottomed flask equipped with a magnetic stirrer and a distillation assembly was heated with stirring for 2 h at 100 C. and then distilled under reduced pressure. Methoxyacetic anhydride (13.5 g, 34% yield) was collected at 108 C. at around 20 mb. To a solution of methyl 2-(3,4-dimethoxy-phenyl)acetate SLA 28134 (3.36 g, 15.98 mmol) in methoxyacetic anhydride SMA 44010 (10.19 g, 62.85 mmol) at 0 C. in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise HClO4 (ca. 70% solution in water, 1.64 mL, 18.98 mmol). The mixture was then stirred for 45 min at RT then diluted with Et2O (151 mL). The organic solution was removed to give a viscous residue that was suspended in H2O (30 mL) at 5 C. before dropwise addition of a conc. NH4OH solution (38 mL). After complete addition, the mixture was stirred overnight at RT and extracted with CH2Cl2 (50 mL) then with CH2Cl2:MeOH=95:5 (100 mL). The organic phase was combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated at 40 C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) gave 6,7-dimethoxy-1-methoxymethyl-isoquinolin-3-ol SMA 44012 as a yellow solid (96 mg, 2% yield). MW: 249.27; Yield: 2%; Yellow Solid. Mp ( C.): 214.1 (dec.) Rf (free base)=0.2 (CH2Cl2:MeOH=95:5). 1H NMR (CDCl3:CD3OD=2:1, delta): 3.57 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.88 (s, 2H, CH2), 6.65 (s, 1H, ArH), 6.74 (s, 1H, ArH), 6.87 (s, 1H, ArH). 13C-NMR (CDCl3:CD3OD=2:1, delta): 57.4, 57.6, 60.5, 70.3, 102.3, 104.2, 107.9, 114.5, 143.9, 145.2, 150.0, 156.9, 161.8. MS-ESI m/z (% rel. Int.): 250 ([MH]+, 100).
methyl 2-(4-trifluoromethylphenyl)-2-diazoacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-acetamidobenzenesulfonyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃;Inert atmosphere;
The resultant methyl acetate was dissolved in acetonitrile and /?-acetamidobenzene sulfonyl azide (/?-ABSA)(60 mmol, 1.2 eq.) was added. The reaction mixture was cooled to 0 C and l,8-Diazabicycloundec-7-ene (DBU) (120 mmol, 2 eq.) was added drop wise at 0 C. The reaction mixture was stirred at rt for overnight. Reaction mixture was quenched with saturated aqueous NH4C1 solution, extracted twice with diethyl ether (2X100 mL); combined organic layers were washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 9: 1 hexane/Et20 as eluant to isolate 11.12 g (94 % yield) of yellow crystalline solid. 1H NMR (400 MHz, CDCI3) delta 3.86 (s, 3 H) 3.88 (s, 3 H) 3.90 (s, 3 H) 6.87 - 6.90 (m, 1 H) 7.19 (d, J=1.17 Hz, 1 H) 7.26 (s, 1 H).
With 4-acetamidobenzenesulfonyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃; for 24.3333h;Inert atmosphere;
General procedure: The methyl arylacetate (1 equiv.) and p-ABSA (1.3 equiv.) were dissolved in acetonitrile and cooled to 0 C using an ice bath under an argon atmosphere. 1,8-Diazabicycloundec-7-ene (DBU, 1.3 equiv.) was then added to the stirring mixture over the course of 5 minutes. After the addition of the DBU, the reaction mixture continued to stir at 0 C for an additional 15 minutes. Once this allotted time had passed, the ice bath was removed and the reaction mixture was stirred for 24 hours at room temperature. The resulting orange solution was quenched with saturated NH4Cl and the aqueous layer was extracted with diethyl ether (3x). The organic layer was then washed with deionized H2O to remove any residual salts. The combined organic layers were dried over MgSO4 and filtered. The organic layer was then concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (10:1 Hexanes:EtOAc).
With 4-acetamidobenzenesulfonyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 23℃;Inert atmosphere;
General procedure: To a solution of the aryl acetic acid (12.0 mmol, 1.00 equiv) in methanol (60 mL) was added thionyl chloride (2.63 mL, 36.0 mmol, 3.00 equiv). The solution was heated to reflux. Upon completion (as determined by TLC analysis), the solution was concentrated in vacuo and the crude residue was used without further purification.To a flame-dried round-bottom flask with a magnetic stir bar were added the aryl acetic acid ester (12.0 mmol, 1.00 equiv), p-ABSA (3.46 g, 14.4 mmol, 1.20 equiv), and dry acetonitrile (50 mL). The solution was stirred under nitrogen and cooled to 0 C using an ice water bath. DBU (1.97 mL, 13.2 mmol, 1.10 equiv) was added by syringe rapidly in one portion, and the reaction mixture was allowed to warm to 23 C and stir overnight. Upon completion (as determined by TLC analysis) or after 24 hours, whichever came first, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexanes and ethyl acetate as eluent. The aryl diazoacetates were obtained in 23-70% yield over two steps.
With sodium methylate; In dimethyl sulfoxide; at 20℃; for 24h;
Manufacturing Example 2: Preparation of Methyl 2-(3,4-dimethoxyphenyl)-3-(4-methoxybenzyloxy)propanoate (33) The compound 32 (500 mg, 2.38 mmol) prepared in Manufacturing Example 1 and paraformaldehyde paraformaldehyde (76 mg, 2.50 mmol) were dissolved in anhydrous DMSO (5.0 mL), which was then treated with sodium methoxide (6.8 mg, 0.12 mmol). The mixture was stirred at room temperature for 24 hours, which was poured into ice water (10 mL), followed by stirring. The mixture was neutralized with 2 N-HCl solution, which was poured into water, followed by extraction with EtOAc (*3). The organic layer was washed with saturated brine once and dried over MgSO4, followed by filtering and concentrating under reduced pressure. Then, the residue was purified by silica gel resolution chromatography (EtOAc:n-hexane=1:1) to give the aldol product as a yellow solid (yield: 58%, 331 mg). 1H NMR (CDCl3, 300 MHz) delta6.74 (m, 3H), 4.05 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73 (m, 2H), 3.65 (s, 3H).
With N-Bromosuccinimide; In tetrahydrofuran; at -78℃; for 0.5h;
Manufacturing Example 6: Preparation of methyl 2-(2-bromo-4,5-dimethoxyphenyl)acetate (38) N-bromosuccinimide (449 mg, 2.50 mmol) was added to anhydrous THF (12.0 mL) solution containing the compound 32 (500 mg, 2.38 mmol) prepared in Manufacturing Example 1. The reaction mixture was stirred at -78C for 30 minutes. After raising the reaction temperature to room temperature, the mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 38 of Manufacturing Example 6 as a light-yellow solid (yield: 96%, 660 mg). 1H NMR (CDCl3, 300 MHz) delta 6.96 (s, 1H), 6.72 (s, 1H), 3.79 (s, 6H), 3.66 (s, 2H), 3.65 (s, 3H).
96%
With N-Bromosuccinimide; In tetrahydrofuran; at -78℃; for 0.5h;
N-bromosuccinimide (449 mg, 2.50 mmol) was added to anhydrous THF (12.0 mL) solution containing the compound 32 (500 mg, 2.38 mmol) prepared in Manufacturing Example 1. The reaction mixture was stirred at -78 C. for 30 minutes. After raising the reaction temperature to room temperature, the mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 38 of Manufacturing Example 6 as a light-yellow solid (yield: 96%, 660 mg). [0185] 1H NMR (CDCl3, 300 MHz) delta 6.96 (s, 1H), 6.72 (s, 1H), 3.79 (s, 6H), 3.66 (s, 2H), 3.65 (s, 3H).
Multi-step reaction with 2 steps
1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C
1.2: 1 h / -78 °C
2.1: diisobutylaluminium hydride / tetrahydrofuran / 1 h / -78 °C
Multi-step reaction with 2 steps
1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere
1.2: 1 h / -78 °C / Inert atmosphere
2.1: diisobutylaluminium hydride / tetrahydrofuran / 1 h / -78 °C
Multi-step reaction with 3 steps
1.1: diisobutylaluminium hydride / tetrahydrofuran; diethyl ether / 1 h / -78 °C
2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere
2.2: 1 h
3.1: diisobutylaluminium hydride / tetrahydrofuran / 1 h / -78 °C
Multi-step reaction with 3 steps
1.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C
1.2: 1 h / -78 °C
2.1: diisobutylaluminium hydride / tetrahydrofuran / 2 h / -78 °C
3.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 0.5 h / -78 °C
3.2: 1 h / -30 - 0 °C
methyl 2-formyl-2-(3,4-dimethoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With sodium methylate; In dimethyl sulfoxide; at 20℃; for 24h;
The compound 32 (500 mg, 2.38 mmol) prepared in Manufacturing Example 1 and paraformaldehyde paraformaldehyde (76 mg, 2.50 mmol) were dissolved in anhydrous DMSO (5.0 mL), which was then treated with sodium methoxide (6.8 mg, 0.12 mmol). The mixture was stirred at room temperature for 24 hours, which was poured into ice water (10 mL), followed by stirring. The mixture was neutralized with 2 N-HCl solution, which was poured into water, followed by extraction with EtOAc (×3). The organic layer was washed with saturated brine once and dried over MgSO4, followed by filtering and concentrating under reduced pressure. Then, the residue was purified by silica gel resolution chromatography (EtOAc:n-hexane=1:1) to give the aldol product as a yellow solid (yield: 58%, 331 mg). [0165] 1H NMR (CDCl3, 300 MHz) delta6.74 (m, 3H), 4.05 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73 (m, 2H), 3.65 (s, 3H).
methyl 3-Cyano-2-(3,4-dimethoxyphenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of LDA (30 mmol) in dry THF (90 mL) at -78 C was added dropwise asolution of methyl phenylacetate (3.8 g, 25 mmol) in dry THF (10 mL) and the mixture wasstirred at this temperature for 20 min. Then to this mixture was introduced a solution ofBrCH2CN (1.8 mL, 27.5 mmol) in dry THF (10 mL) and the mixture was stirred at -78 C.After completion of the reaction (30 min), the mixture was quenched by addition of satd aqNH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried(Na2SO4), and concd. The crude product was purified by silica gel column chromatography(eluted with hexane / AcOEt = 1 : 1) to give the desired product (4.7 g, 100%) as a paleyellow solid.
With potassium carbonate; In tetrahydrofuran; at 40℃; for 2h;
To a 250 mL three-necked flask, compound 6a (10 g, 0.048 mol) and 80 mL of tetrahydrofuran were added.Paraformaldehyde (15 g, 0.48 mol), potassium carbonate (20 g, 0.144 mol) were successively added, and reacted at 40 C. for 2 h.After the reaction was completed, the reaction solution was poured into a separatory funnel, 100 ml of water was added, and the mixture was extracted with 150 ml of tetrahydrofuran.The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give 9.6 g of compound 5a.Yield 90.0%.
5-amino-1-(2-hydroxyethyl)-1H-imidazole-4-carboxamide[ No CAS ]
2-(3,4-dimethoxybenzyl)-9-(2-hydroxyethyl)-1,9-dihydropurin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium methylate; In methanol;Reflux;
General procedure: 1.4mmol of 5-amino-1-substituted-4-carboxamide-1H-imidazole (1) was dissolved in 10mL of absolute methanol. Then 5.6mmol of the appropriate ester isadded into this solution. This mixture was added in 10mL ofmethoxide-methanol solution prepared from sodium (0.15 g, 6.3mmol) and 10mL of absolute methanol. The mixture was refluxed for 15-20 h. After cooling, the solvent was evaporated off and the residue was taken into ethyl acetate. The organic phase was dried over Na2SO4 and evaporated. And the residue was purified via silica gel chromatography(eluent: the mixture of ethyl acetate and methanol) to obtainthe pure product (2a-2q).
5-amino-1-(3-phenylpropyl)-1H-imidazole-4-carboxamide[ No CAS ]
2-(3,4-dimethoxyphenyl)-9-(3-phenylpropyl)-1,9-dihydropurin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With sodium methylate; In methanol;Reflux;
General procedure: 1.4mmol of 5-amino-1-substituted-4-carboxamide-1H-imidazole (1) was dissolved in 10mL of absolute methanol. Then 5.6mmol of the appropriate ester isadded into this solution. This mixture was added in 10mL ofmethoxide-methanol solution prepared from sodium (0.15 g, 6.3mmol) and 10mL of absolute methanol. The mixture was refluxed for 15-20 h. After cooling, the solvent was evaporated off and the residue was taken into ethyl acetate. The organic phase was dried over Na2SO4 and evaporated. And the residue was purified via silica gel chromatography(eluent: the mixture of ethyl acetate and methanol) to obtainthe pure product (2a-2q).
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