* 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：
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[2] Tetrahedron, 1985, vol. 41, # 14, p. 2933 - 2938
[3] Chemistry - A European Journal, 2007, vol. 13, # 27, p. 7780 - 7784
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4026 - 4029
[5] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 3, p. 918 - 920
[6] Journal of the American Chemical Society, 1957, vol. 79, p. 3114,3117
[7] Tetrahedron Letters, 1983, vol. 24, # 6, p. 621 - 622
[8] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1619 - 1624
[9] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 2, p. 372 - 375
[10] Patent: US5541343, 1996, A,
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5586 - 5590
[12] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
2
[ 4521-28-2 ]
[ 7021-11-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
for 12 h; Reflux
11. Synthesis of (R)-4-(4-(hydroxyamino)-4-oxobutyl)phenyl-3-(5-(benzyloxy) pyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound 11); [Show Image] (i) Synthesis of 4-(4-hydroxyphenyl)butanoic acid 4-(4-Methoxyphenyl)butanoic acid (0.97 g, 5 mmol) was mixed with HBr (50 mL) and acetic acid galacial (80 mL). The mixture was refluxed for 12h (monitored by TLC), poured into ice, stirred for 1h, and then extracted with DCM. The solvent was evaporated in vacuo to give the title compound (0.83 g, 92percent). NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.72(m, 2H, CH2), 2.16(t, 2H, CH2, J = 7.4Hz), 2.45(t, 2H, CH2, J= 7.6Hz), 6.65(d, 2H, Ar-H, J= 8.3Hz), 6.95(d, 2H, Ar-H, J= 8.3Hz).
92%
for 12 h; Reflux
(i) Synthesis of 4-(4-hydroxyphenyl)butanoic acid4-(4-Methoxyphenyl)butanoic acid (0.97 g, 5 mmol) was mixed with HBr (50 mL) and acetic acid galacial (80 mL). The mixture was refluxed for 12 h (monitored by TLC), poured into ice, stirred for 1 h, and then extracted with DCM. The solvent was evaporated in vacuo to give the title compound (0.83 g, 92percent). NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.72 (m, 2H, CH2), 2.16 (t, 2H, CH2, J=7.4 Hz), 2.45 (t, 2H, CH2, J=7.6 Hz), 6.65 (d, 2H, Ar-H, J=8.3 Hz), 6.95 (d, 2H, Ar-H, J=8.3 Hz).
83%
With hydrogen bromide In water for 6 h; Reflux
(MM-1-31) A 50 mL round bottom flask equipped with reflux condenser was charged with 4- (4-methoxyphenyl) butanoic acid (5.00 g, 25.7 mmol). Aqueous HBr (48percent solution, approx 6 mL) was added. A tygon line was fed from the top of the condenser to the rear of the fume hood, to allow for complete exhaust of the HBr. The reaction mixture was ' heated to reflux for 6 hours. After cooling to about 50 °C, the mixture was poured into chilled H20 (45 mL) , causing immediate precipitation of the product as white solid needles. After 1 hour at 0 °C, the mixture was vacuum filtered and the needles collected, affording 3.86 g (83percent) of the phenolic product. 1H NMR (300 MHz, Acetone-d6) δ 10.48 (s, 1H) , 8.07 (s, 1H) , 7.07 - 6.99 (m, 2H) , 6.79 - 6.71 (m, 2H) , 2.60 - 2.50 (m, 2H) , 2.29 (t, J = 7.4 Hz, 2H) , 1.92 - 1.77 (m, 2H) .
Reference：
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[4] Patent: EP2388247, 2011, A2, . Location in patent: Page/Page column 12
[5] Patent: US2011/288133, 2011, A1, . Location in patent: Page/Page column 10
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[7] Journal of Medicinal Chemistry, 1996, vol. 39, # 26, p. 5215 - 5227
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[12] Journal of the American Chemical Society, 1948, vol. 70, p. 3177
[13] Journal of the American Chemical Society, 1948, vol. 70, p. 1759,1761
[14] Journal of the American Chemical Society, 1947, vol. 69, p. 3018,3021
[15] Journal of Organic Chemistry, 1956, vol. 21, p. 929
[16] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 7, p. 1601 - 1604
[17] Patent: US6340691, 2002, B1, . Location in patent: Page column 39
[18] Patent: WO2009/80722, 2009, A2, . Location in patent: Page/Page column 20
[19] Patent: EP1147080, 2004, B1, . Location in patent: Page 26
[20] Patent: EP2151236, 2010, A1, . Location in patent: Page/Page column 29-30
[21] Patent: US2010/130506, 2010, A1, . Location in patent: Page/Page column 89
[22] Patent: WO2010/70076, 2010, A1, . Location in patent: Page/Page column 75
[23] Patent: US2011/98311, 2011, A1,
[24] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 2211
3
[ 3153-44-4 ]
[ 4521-28-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen; acetic acid In tetrahydrofuran for 9 h;
Step G After 4-(4-methoxyphenyl)-4-oxobutanoic acid (40 g) was added to (not completely dissolved in) a mixed solvent of acetic acid (100 ml) and THF (100 ml), 10percent palladium-carbon (50percent-wet) (4 g) was added thereto and the resulting mixture was stirred for 9 hours under a hydrogen atmosphere (0.4 MPa). The catalyst was removed by filtration through Celite and toluene was added to the residue. The solvent was distilled off under reduced pressure to obtain 4-(4-methoxyphenyl)butanoic acid quantitatively. 1H-NMR (CDCl3) δ 1.89(m,2H), 2.32(t,J=7.3Hz,2H), 2.58(t,J=7.4Hz,2H), 3.73(s,3H), 6.78-6.82(m,2H), 7.03-7.08(m,2H), 10.96(brs, 1H).
51%
With hydrogenchloride; mercury dichloride; zinc In water at 20℃; for 3.66667 h; Heating / reflux
A 500 mL round bottom flask equipped with a magnetic stirrer bar and an inert atmosphere (nitrogen gas) was charged with 5.25 mL (48.3 mmol) of anisole, 4.83 g (48.3 mmol) of succinic anhydride, 125 mL 1,1,2,2-tetrachloroethane and 125 mL of nitrobenzene. The reaction vessel was cooled with an external ice bath and stirred for 30 minutes. Aluminum trichloride (14.2 g, 106.4 mmol) was added to the pale yellow solution, which then turned to a dark reddish brown color. The ice bath was removed, and the reaction was allowed to stir at room temperature for 36 hours. Reaction was again cooled with an external ice bath. Prepared acidic solution by pouring IN hydrogen chloride solution into a 100 mL beaker filled with ice. This solution was added to the reaction mixture carefully, drop-wise at first until reaction became clear with white precipitate. After that point a 10 mL portion was carefully added to test for reactivity, and then the remained of the ice/acid mixture was added. A second 100 mL of ice/acid mixture was added, the external ice bath removed and the pale emulsion was stirred for 2 hours. A white precipitate was collected form the emulsion by suction filtration. This solid was dissolved in 300 mL of 0.3 M sodium hydroxide, washed with 10OmL of ethyl <n="27"/>acetate, and acidified to ~pH 1 with 1 M hydrochloric acid. The white precipitate that was collected upon vacuum filtration was washed with 3 X 100 mL de-ionized water, dried and reserved for use in next procedure.To a 50 mL rounded bottom flask was added 4.77 g (86.1 mmol) of cut zinc. To this was added a solution of 0.22 g (0.81 mmol) of mercury(II)chloride and 0.2 mL concentrated hydrochloric acid (37percent) in 4 mL of water. The mixture was allowed to stir at room temperature for 10 minutes. The liquid was decanted off and immediately replaced with a fresh solution of 10 mL concentrated hydrochloric acid (37percent) in 2 mL of water. 3.00 g (14.4 mmol) of 4-(4-methoxyphenyl)-4-oxobutyric acid was added to the zinc mixture followed by an additional 10 mL of concentrated hydrochloric acid (37percent) and 2 mL water. The reaction was heated to reflux for three hours, with an additional 0.4 mL of concentrated hydrochloric acid (37percent) being added every thirty minutes. The reaction was cool to room temperature and allowed to mix overnight. 10 mL of diethyl ether was added to the reaction mixture and stirred for thirty minutes. The liquid was decanted away from the solid into a 125 mL separatory funnel and the solid residue was rinsed with 20 mL of ether which was also decanted into the separatory funnel. The aqueous layer was separated and extracted an additional two times with 30 mL diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and solvent removed under reduced pressure. The residue solid was dissolved in -250 mL of 0.3M sodium hydroxide solution and washed with 25 mL of ethyl acetate. The aqueous solution was acidified with -200 mL IN hydrochloric acid solution and allowed to rest overnight. The product (1.42 g, 51percent) was isolated as a white solid, mp 57-58°C. Combustion analysis: Found: C 67.87, H 7.33percent; CnH14O3 requires C: 68.02, H: 7.27 percent IH NMR (d6-DMSO): δ 12.0, s, IH (COOH); δ 7.2 d, 2H (aryl H's); δ 6.8, d, 2H, (arylH's); δ 3.7, s, 3H (OMe H's); δ 2.5, t, 2H (CH2 α to aryl group); δ 2.2, t, 2H (CH2 α to COOH), δ 1.75, p, 2H (middle CH2).
Reference：
[1] Patent: EP1726587, 2006, A1, . Location in patent: Page/Page column 33
[2] Chemistry of Natural Compounds, 2003, vol. 39, # 4, p. 404 - 406
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1998, vol. 37, # 3, p. 281 - 284
[4] Research on Chemical Intermediates, 2017, vol. 43, # 10, p. 5933 - 5942
[5] Journal of Organic Chemistry, 1990, vol. 55, # 11, p. 3537 - 3543
[6] Chemistry - A European Journal, 2007, vol. 13, # 27, p. 7780 - 7784
[7] Journal of the Indian Chemical Society, 2002, vol. 79, # 11, p. 906 - 907
[8] RSC Advances, 2017, vol. 7, # 8, p. 4763 - 4775
[9] Journal of Medicinal Chemistry, 1996, vol. 39, # 8, p. 1664 - 1675
[10] Synthetic Communications, 2001, vol. 31, # 10, p. 1467 - 1475
[11] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 2, p. 372 - 375
[12] Patent: WO2008/112368, 2008, A2, . Location in patent: Page/Page column 25-26
[13] RSC Advances, 2016, vol. 6, # 85, p. 81763 - 81766
[14] Journal of the Chemical Society, 1934, p. 1950
[15] Journal of the Indian Chemical Society, 1939, vol. 16, p. 35,42
[16] Justus Liebigs Annalen der Chemie, 1943, vol. 554, p. 23,37
[17] Journal of the American Chemical Society, 1949, vol. 71, p. 1036
[18] Journal of the American Chemical Society, 1936, vol. 58, p. 1438,1439[19] Org. Reactions, 1942, vol. 1, p. 155,167
[20] Chemische Berichte, 1923, vol. 56, p. 630
[21] Organic Syntheses, 1937, vol. 17, p. 97[22] Organic Syntheses, 1943, vol. Coll. Vol. II, p. 500
[23] Journal of the American Chemical Society, 1968, vol. 90, p. 4924 - 4929
[24] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 614 - 622
[25] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4140 - 4142
[26] Synthetic Communications, 2004, vol. 34, # 7, p. 1247 - 1258
[27] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5586 - 5590
[28] Patent: WO2012/46253, 2012, A2, . Location in patent: Page/Page column 24; 33
[29] Advanced Synthesis and Catalysis, 2018, vol. 360, # 15, p. 2894 - 2899
[30] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 460
4
[ 20637-08-5 ]
[ 4521-28-2 ]
Reference：
[1] Synlett, 2004, # 13, p. 2391 - 2393
[2] New Journal of Chemistry, 2011, vol. 35, # 2, p. 292 - 298
With sulfur; indium(III) chloride; phenylsilane In 1,2-dichloro-benzene for 24 h; Inert atmosphere; Sealed tube
General procedure: To a screw-capped tube were successively added InCl3 (5.5 mg, 0.025 mmol), o-dichlorobenzene (0.5 mL), the appropriate lactone (0.50 mmol), S8 (17.6 mg, 0.550 mmol) or Se (43.4 mg, 0.550 mmol), and PhSiH3 (36.1 mg, 0.333 mmol). After the tube was sealed with a cap that contained a PTFE septum, the mixture was heated for 24 h at 120 °C for thiolactones and at 120 °C for selenolactones. After the reaction, the mixture was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc) to afford either the desired thiolactone or selenolactone derivative.
With hydrogen bromide; acetic acid; for 12h;Reflux;
11. Synthesis of (R)-4-(4-(hydroxyamino)-4-oxobutyl)phenyl-3-(5-(benzyloxy) pyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound 11); [Show Image] (i) Synthesis of 4-(4-hydroxyphenyl)butanoic acid 4-(4-Methoxyphenyl)butanoic acid (0.97 g, 5 mmol) was mixed with HBr (50 mL) and acetic acid galacial (80 mL). The mixture was refluxed for 12h (monitored by TLC), poured into ice, stirred for 1h, and then extracted with DCM. The solvent was evaporated in vacuo to give the title compound (0.83 g, 92%). NMR (400 MHz in CDCl3, Bruker AVANCE-400): delta 1.72(m, 2H, CH2), 2.16(t, 2H, CH2, J = 7.4Hz), 2.45(t, 2H, CH2, J= 7.6Hz), 6.65(d, 2H, Ar-H, J= 8.3Hz), 6.95(d, 2H, Ar-H, J= 8.3Hz).
92%
With water; hydrogen bromide; acetic acid; for 12h;Reflux;
(i) Synthesis of 4-(4-hydroxyphenyl)butanoic acid4-(4-Methoxyphenyl)butanoic acid (0.97 g, 5 mmol) was mixed with HBr (50 mL) and acetic acid galacial (80 mL). The mixture was refluxed for 12 h (monitored by TLC), poured into ice, stirred for 1 h, and then extracted with DCM. The solvent was evaporated in vacuo to give the title compound (0.83 g, 92%). NMR (400 MHz in CDCl3, Bruker AVANCE-400): delta 1.72 (m, 2H, CH2), 2.16 (t, 2H, CH2, J=7.4 Hz), 2.45 (t, 2H, CH2, J=7.6 Hz), 6.65 (d, 2H, Ar-H, J=8.3 Hz), 6.95 (d, 2H, Ar-H, J=8.3 Hz).
83%
With hydrogen bromide; In water; for 6h;Reflux;
(MM-1-31) A 50 mL round bottom flask equipped with reflux condenser was charged with 4- (4-methoxyphenyl) butanoic acid (5.00 g, 25.7 mmol). Aqueous HBr (48% solution, approx 6 mL) was added. A tygon line was fed from the top of the condenser to the rear of the fume hood, to allow for complete exhaust of the HBr. The reaction mixture was ' heated to reflux for 6 hours. After cooling to about 50 C, the mixture was poured into chilled H20 (45 mL) , causing immediate precipitation of the product as white solid needles. After 1 hour at 0 C, the mixture was vacuum filtered and the needles collected, affording 3.86 g (83%) of the phenolic product. 1H NMR (300 MHz, Acetone-d6) delta 10.48 (s, 1H) , 8.07 (s, 1H) , 7.07 - 6.99 (m, 2H) , 6.79 - 6.71 (m, 2H) , 2.60 - 2.50 (m, 2H) , 2.29 (t, J = 7.4 Hz, 2H) , 1.92 - 1.77 (m, 2H) .
With hydrogen bromide; In water; for 2h;Reflux;
Synthesis of IntermediatesR1 = Phenyl. Methyl 2-{2-(4-[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5- phenylpentanoate (Intermediate A).a) 4-(4-Hydroxyphenyl)butanoic acidA suspension of 4-(4-methoxyphenyl)butanoic acid (2.0 g, 9.603 mmol) in HBr (20 ml_, 48% aqueous solution) was refluxed for 2 h. The reaction mixture was allowed to reach room temperature (hereinafter abbreviated as "r.t."), poured into H2O (150 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 1.81 g of 4- (4-hydroxyphenyl)butanoic acid (white solid). The crude residue was submitted to next step without purification.
With boron tribromide; In dichloromethane; at 0 - 20℃; for 2h;
To a solution of 1.00g (5.15 mmol) of 4-(4-methoxyphenyl)butyric acid in 100 mL of dichloromethane at 0C was added 15.5 mL (15.5 mmol) of boron tribromide and the reaction was then allowed to warm to room temperature and stirred for 2h. The reaction mixture was then poured into 200 mL of saturated sodium bicarbonate solution and the organic layer was separated. The aqueous layer was acidified with concentrated HCl solution and then extracted with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide 0.696g of impure 4-(4-hydroxyphenyl)butyric acid.
With water; hydrogen bromide; acetic acid; for 6h;Reflux;
Example 1; Preparation of 4-{4-[2-(2-butylpyridinylamino)ethoxy]phenyl}butanoic acid (5, NCG20); [Show Image] Step 1: Preparation of 4-(4-hydroxyphenyl)butanoic acid (1) ; [Show Image] 4-(4-methoxyphenyl)butanoic acid (5.0 g) was dissolved in 48% hydrobromic acid (50 mL) and acetic acid (80 mL), then the solution was refluxed by heating for 6 hours. Ethyl acetate (300 mL) is added into the reaction solution, then organic layer was washed with water (100 mL) and saturated sodium chloride solution (50 mL), dried on anhydrous sodium sulfate, filtered and vacuum concentrated, then washed with n-hexane to give the above-identified compound (4.6 g, yield 99%). 1H-NMR (CDCl3, 500 MHz, delta; ppm) 7.04 (2H, d, J = 8.6 Hz), 6.75 (2H, d, J = 8.6 Hz), 2.60 (2H, t, J = 8.0 Hz), 2.36 (2H, t, J = 7.3 Hz), 1.92 (2H, quintet, J = 7.6 Hz).
With hydrogen bromide; In acetic acid; at 150℃;
Step 1 4-(4-Methoxyphenyl)butyric acid (25 g, 129 mmol) is dissolved in 48% HBr (125 ml) and AcOH (125 ml). The resultant solution is heated at 150 C. overnight. The resultant mixture is concentrated in vacuo and the residue taken up in EtOAc (500 ml). This solution is washed with water (500 ml), dried (MgSO4) and concentrated to give 4-(4-Hydroxy-phenyl)-butyric acid as a tan solid; 1H NMR (d6-DMSO): 1.72 (2H, tt, J=7.4 and 7.8 Hz), 2.18 (2H, t, J=7.4 Hz), 2.45 (2H, t, J=7.8 Hz), 6.66 (2H, dd, J=1.98 and 9.3 Hz), 6.96 (2H, dd, J=2.8 and 9.3 Hz), 9.12 (1H, s), 12.0 (1H, s).
With water; hydrogen bromide; for 2h;Reflux;
Example 1 : Synthesis of Intermediates A and B.; Synthesis of Intermediate A: Methyl 2-{2-(4-[(trifluoromethyl)sulfonyl] oxy}phenyl)ethyl}-5-phenylpentanoate.; 4-(4-Hydroxyphenyl)butanoic acid.; A suspension of 4-(4-methoxyphenyl) butanoic acid (2.0 g, 9.603 mmol) in HBr (20 ml_, 48% aqueous solution) was refluxed for 2 h. The reaction mixture was allowed to reach r.t., poured into H2O (150 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 1.81 g of 4-(4-hydroxyphenyl)butanoic acid (white solid). The crude residue was submitted to the next step without purification.
With acetic acid; In hydrogen bromide; ethyl acetate;
Step 1 4-(4-Methoxyphenyl)butyric acid (25 g, 129 mmol) is dissolved in 48% HBr (125 ml) and AcOH (125 ml). The resultant solution is heated at 150 C. overnight. The resultant mixture is concentrated in vacuo and the residue taken up in EtOAc (500 ml). This solution is washed with water (500 ml), dried (MgSO4) and concentrated to give 4-(4-Hydroxy-phenyl)-butyric acid as a tan solid; 1H NMR (d6-DMSO): 1.72 (2H, tt, J=7.4 and 7.8 Hz), 2.18 (2H, t, J=7.4 Hz), 2.45 (2H, t, J=7.8 Hz), 6.66 (2H, dd, J=1.98 and 9.3 Hz), 6.96 (2H, dd, J=2.8 and 9.3 Hz), 9.12 (1H, s), 12.0 (1H, s).
With hydrogen bromide; acetic acid; at 150℃;
4-(4-Methoxyphenyl)butyric acid (25 g, 129 mmol) is dissolved in 48% HBr (125 ml) and AcOH (125 ml). The resultant solution is heated at 150 C. overnight. The resultant mixture is concentrated in vacuo and the residue taken up in EtOAc (500 ml). This solution is washed with water (500 ml), dried (MgSO4) and concentrated to give 4-(4-Hydroxy-phenyl)-butyric acid as a tan solid; 1H NMR (d6-DMSO): 1.72 (2H, tt, J=7.4 and 7.8 Hz), 2.18 (2H, t, J=7.4 Hz), 2.45 (2H, t, J=7.8 Hz), 6.66 (2H, dd, J=1.98 and 9.3 Hz), 6.96 (2H, dd, J=2.8 and 9.3 Hz), 9.12 (1H, s), 12.0 (1H, s).
With Eaton?s reagent; In dichloromethane; toluene; at 20℃;
To 4-(4-methoxyphenyl)butanoic acid (285 g) toluen (285 mL) and dichloromethane (2,425 L) is added and cooled to 15C. Slowly Eaton's reagent (1 ,54 L; Eaton's reagent being: 9,1 wt% P2O5 in methanesulfonic acid) is added, and colour is changed to dark yellowish brown.Reaction mixture is then heated to room temperature and monitored with HPLC. When reaction is completed it is quenched in mixture of ie f-butyl methyl ether (3,04 L) and water (3,04 L) cooled at 2C. Organic phase was separeted and washed with saturated water solution of sodium bicarbonate (3,04 L). Solvent is evaporated and further crystallization in 80% ethanol afforded 7-methoxy-1 -tetralone as yellow crystals (267g, yield 91 %).
With hydrogen; acetic acid;palladium 10% on activated carbon; In tetrahydrofuran; under 3000.3 Torr; for 9h;
Step G After 4-(4-methoxyphenyl)-4-oxobutanoic acid (40 g) was added to (not completely dissolved in) a mixed solvent of acetic acid (100 ml) and THF (100 ml), 10% palladium-carbon (50%-wet) (4 g) was added thereto and the resulting mixture was stirred for 9 hours under a hydrogen atmosphere (0.4 MPa). The catalyst was removed by filtration through Celite and toluene was added to the residue. The solvent was distilled off under reduced pressure to obtain 4-(4-methoxyphenyl)butanoic acid quantitatively. 1H-NMR (CDCl3) delta 1.89(m,2H), 2.32(t,J=7.3Hz,2H), 2.58(t,J=7.4Hz,2H), 3.73(s,3H), 6.78-6.82(m,2H), 7.03-7.08(m,2H), 10.96(brs, 1H).
94%
With palladium 10% on activated carbon; hydrogen; acetic acid; In tetrahydrofuran; at 30℃; under 3750.38 Torr;
4-(4-methoxyphenyl)-4-oxobutanoic acid (650 g), tetrahydrofuran (2,6 L), acetic acid (2,6L) and 10 % Pd/C (13 g) is charged in 10L hydrogenator. Reaction mixture is stirred at 30 C and 5 bar H2. Reaction is monitored with HPLC and after completion, reaction mixture is filtered. Further toluene (3,13 L) is added, extracted with water (3,13 L) and solvent is evaporated. Product is obtained as white solid (570 g, yield 94 %)
51%
With hydrogenchloride; mercury dichloride; zinc; In water; at 20℃; for 3.66667h;Heating / reflux;
A 500 mL round bottom flask equipped with a magnetic stirrer bar and an inert atmosphere (nitrogen gas) was charged with 5.25 mL (48.3 mmol) of anisole, 4.83 g (48.3 mmol) of succinic anhydride, 125 mL 1,1,2,2-tetrachloroethane and 125 mL of nitrobenzene. The reaction vessel was cooled with an external ice bath and stirred for 30 minutes. Aluminum trichloride (14.2 g, 106.4 mmol) was added to the pale yellow solution, which then turned to a dark reddish brown color. The ice bath was removed, and the reaction was allowed to stir at room temperature for 36 hours. Reaction was again cooled with an external ice bath. Prepared acidic solution by pouring IN hydrogen chloride solution into a 100 mL beaker filled with ice. This solution was added to the reaction mixture carefully, drop-wise at first until reaction became clear with white precipitate. After that point a 10 mL portion was carefully added to test for reactivity, and then the remained of the ice/acid mixture was added. A second 100 mL of ice/acid mixture was added, the external ice bath removed and the pale emulsion was stirred for 2 hours. A white precipitate was collected form the emulsion by suction filtration. This solid was dissolved in 300 mL of 0.3 M sodium hydroxide, washed with 10OmL of ethyl <n="27"/>acetate, and acidified to ~pH 1 with 1 M hydrochloric acid. The white precipitate that was collected upon vacuum filtration was washed with 3 X 100 mL de-ionized water, dried and reserved for use in next procedure.To a 50 mL rounded bottom flask was added 4.77 g (86.1 mmol) of cut zinc. To this was added a solution of 0.22 g (0.81 mmol) of mercury(II)chloride and 0.2 mL concentrated hydrochloric acid (37%) in 4 mL of water. The mixture was allowed to stir at room temperature for 10 minutes. The liquid was decanted off and immediately replaced with a fresh solution of 10 mL concentrated hydrochloric acid (37%) in 2 mL of water. 3.00 g (14.4 mmol) of 4-(4-methoxyphenyl)-4-oxobutyric acid was added to the zinc mixture followed by an additional 10 mL of concentrated hydrochloric acid (37%) and 2 mL water. The reaction was heated to reflux for three hours, with an additional 0.4 mL of concentrated hydrochloric acid (37%) being added every thirty minutes. The reaction was cool to room temperature and allowed to mix overnight. 10 mL of diethyl ether was added to the reaction mixture and stirred for thirty minutes. The liquid was decanted away from the solid into a 125 mL separatory funnel and the solid residue was rinsed with 20 mL of ether which was also decanted into the separatory funnel. The aqueous layer was separated and extracted an additional two times with 30 mL diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and solvent removed under reduced pressure. The residue solid was dissolved in -250 mL of 0.3M sodium hydroxide solution and washed with 25 mL of ethyl acetate. The aqueous solution was acidified with -200 mL IN hydrochloric acid solution and allowed to rest overnight. The product (1.42 g, 51%) was isolated as a white solid, mp 57-58C. Combustion analysis: Found: C 67.87, H 7.33%; CnH14O3 requires C: 68.02, H: 7.27 % IH NMR (d6-DMSO): delta 12.0, s, IH (COOH); delta 7.2 d, 2H (aryl H's); delta 6.8, d, 2H, (arylH's); delta 3.7, s, 3H (OMe H's); delta 2.5, t, 2H (CH2 alpha to aryl group); delta 2.2, t, 2H (CH2 alpha to COOH), delta 1.75, p, 2H (middle CH2).
With triethylsilane; at 40 - 45℃; for 4h;
A mixture of 4-(4-methoxyphenyl)-4-oxobutanoic acid compound of formula- 11 (15 g) and triethylsilane (41.46 g) was heated to 40-45C and then stirred for 4 hours at 40-45C. After completion of the reaction, the reaction mixture was cooled to 25-30C and added water followed by ethylacetate. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethylacetate. Both the organic layers were combined and washed with 10% sodium chloride solution. Distilled off the solvent completely from organic layer and co-distilled with pet.ether.The reaction mixture was cooled to 25-30C and pet.ether was added and further cooled to 0-5C. Filtered the solid, washed with pet.ether and then dried to get the title compound. Yield: 9 grams.
A mixture of 4- (4-methoxyphenyl) butyric acid (5.0 g, 25.8 mmol) and H2SO4 (concentrated, cat. amount) in MeOH (30 ml) was refluxed for 3 hr. The mixture was concentrated to remove excess MeOH. The residue was diluted with EtOAc (30 ml) and washed with H20 (20 ml), Sat. NaHCO3 (2 x 15 ml), Ha0 (20 ml), and brine (30 ml) respectively. The organic layer was then dried (MgS04), filtered. The filtrate was concentrated in vacuo to provide methyl 4- (4-methoxyphenyl) butyrate (5.3 g, 100%). 'H NMR (CDC13, 300 MHz) 6 1.89 (p, J = 6.6 Hz, 2H), 2. 30 (t, J = 7.2 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 3.64 (s, 3H), 3.76 (s, 3H), 6. 80 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H).
97%
With sulfuric acid; at 20℃; for 16h;
To a solution of 4(4-Methoxyphenyl)-butyric acid (1) (10 g, 0.051 mol) in methanol (200 mL) was added concentrated sulfuric acid (1 mL) and the reaction mixture stirred at room temperature for 16 h. After concentration to remove methanol, the oil was dissolved in ethyl acetate (120 mL), washed with Na2CO3 (3*70 mL), water (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated to give the methyl ester as an oil (10.34 g) in 97% yield. 1H NMR (CDCl3) delta 7.12 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 2.62 (t, 2H), 2.59 (t, 2H), 1.96 (t, 2H); 13C NMR (CDCl3) delta 173.9, 157.2, 133.3, 129.8, 128.7, 114.1, 113.1, 56.5, 53.6, 34.1, 33.2, 26.6.
To a solution of <strong>[4521-28-2]4-(4-methoxyphenyl)butyric acid</strong> (19) (1.0 g, 5.1 mmol) in THF (20 mL) was added 4-methylmorpholine (572 mg, 5.7 mmol) at 0 C under nitrogen atmosphere. To this solution, iso-butylchloroformate (842 mg, 6.2 mmol) was added dropwise over 5 minutes. After stirring for 30 min at 0 C, a 7M solution of ammonia in methanol (1.45 mL, 10.3 mmol) was added. The reaction was stirred overnight. To the reaction mixture, ethyl acetate (150 mL) was added and extracted with water and brine solution. The organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The crude product was crystallized from ethyl acetate and hexane to afford 4-(4-methoxyphenyl)butanamide (20) as a white solid (920 mg, 93%). 1H NMR (400 MHz, CDC13) delta 1.94-1.98 (m, 2H), 2.23 (t, J= 7.7 Hz, 2H), 2.64 (t, J= 7.7 Hz, 2H), 3.81 (s, 3H), 6.85 (d, J= 8.7 Hz, 2H), 7.12 (d, J= 8.7 Hz, 2H); Mass (m/z) 194 (M+H).
With thionyl chloride; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Preparation 103 4-(4-Methoxyphenyl)-butyramide 4-(4-Methoxyphenyl)-butyric acid (Aldrich Chemical Co.) (2g, 10.4 mmol) was dissolved in 50 ml DCM and thionyl chloride (1.85g, 15.5 mmol) added dropwise with stirring. After the addition was complete, the mixture was then refluxed for 4 h. The solvent was removed in vacuo, more was added and then evaporated off and this cycle of addition/evaporation continued until all the thionyl chloride had been removed from the crude mixture. This mixture was dissolved in 20 ml DCM and added dropwise to a stirred solution of 0.88NH3 at 0 C. After the addition was complete, the whole was stirred for 4 h, the organic layer separated, dried (Na2CO3) and evaporated to give the title product as a white solid of the amide (1.5 g), which was used with no further purification.
Step A: Preparation of Methyl 4-(4-methoxyphenyl)-butyrate To a solution of 4-(4-methoxyphenyl)-butyric acid (25.1 g, 0.129 mol) in methanol (130 mL), was added sulfuric acid (concentrated, 1.0 mL) dropwise and it was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated, washed with brine (3*200 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil (26.8 g, 99%). Mass (MH+)=209.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere;
General procedure: To a suspension of EDC*HCl (0.46 g, 2.4 mmol, 1.2 equiv.) and NMM (0.81 mL, 8 mmol, 4 equiv.) in DMF (10 mL) at rt were added successively HOBt (0.33 g, 2.4 mmol, 1.2 equiv.), appropriate carboxylic acid (1.2 mmol, 1.2 equiv.) and the free base of 2-benzofuranoylpiperazine hydrochloride (5*HCl, 0.46 g, 2 mmol, 1 equiv.). The reaction mixture was stirred at rt for 20 h and then diluted with H2O (50 mL) and then extracted with CHCl3:MeOH (9:1 v/v, 3 × 50 mL). The combined organic fractions were then washed with aqueous sodium hydroxide (1 M, 100 mL), dried (Na2SO4) and concentrated under reduced pressure to give a crude residue, which was triturated with cold EtOAc (ca. 10 mL).
2-(4-(4-methoxyphenyl)butanoyl)benzo[d]isothiazol-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
General procedure: The acid 4 (5 mmol), EDC (1.2 g, 6.26 mmol), HOBt (0.9 g,5.88 mmol), NMM (1.2 mL, 10.74 mmol), and dichloromethane (10 mL) were mixed at ice-bath and stirred at 0 C for half an hour. 1,2-Benzisothiazol-3-one 1 (800 mg, 5.3 mmol) was added to NMM (1.6 mL, 14.32 mmol) in 10 mL of dichloromethane at 0 Ct hen the above mixture was added and stirred at room temperature overnight. After stirring overnight, the mixture was diluted with CH2Cl2, and then successively through washed with water, 5% KHSO4 solution, saturated NaHCO3 solution, and brine, the extract was dried with anhydrous Na2SO4 and evaporated under vacuum. The product was isolated by column chromatography (petroleum ether/CH2Cl2, 10:1) to yield the final compound. 4.2.29 2-(4-(4-Methoxyphenyl)butanoyl)benzo[d]isothiazol-3(2H)-one (33) Compound 33 was prepared through <strong>[4521-28-2]4-(4-methoxyphenyl)butyric acid</strong>, obtained a white solid in 86% yield. Mp 139.5-140.8 C. 1H NMR (400 MHz, DMSO-d6) delta 7.94 (t, J = 8.0 Hz, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H), 3.09 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 1.97-1.88 (m, 2H). 13C NMR (101 MHz, DMSO-d6) delta 173.3, 163.5, 157.9, 141.4, 135.0, 133.8, 129.7, 127.4, 126.6, 125.8, 122.5, 114.2, 55.4, 36.6, 33.9, 26.0. IR (KBr, cm-1): 1684. HRMS-ESI (m/z) calcd for C18H17NO3S [M+H+] 328.1007, found 328.1018.
N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine[ No CAS ]
[ 204777-78-6 ]
[ 137076-54-1 ]
Fmoc-D-arginine[ No CAS ]
[ 204251-33-2 ]
C113H167N25O28[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7.9%
Stage #1: Fmoc-Lys(ivDde)-OH
Stage #2: With N-Acetylimidazole In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #3: N-(fluoren-9-ylmethoxycarbonyl)glycine; 4-(4-Methoxyphenyl)butyric acid; Fmoc-L-Lys(iPr,Boc)-OH; N-Fmoc L-Phe; Fmoc-Glu(OtBu)-OH; Fmoc-Tyr(tBu)-OH; N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine; Fmoc-Lys(ivDde)-OH; 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-10-acetic acid; Fmoc-D-arginine; γ-allyl (2R)-N-(fluoren-9-ylmethoxycarbonyl)glutamate Further stages;
Synthesis of BL23
Fmoc-Rink Amide ProTide resin (CEM, 0.25 mmol, 0.58 mmol/g) was deprotected with 20% v/v piperidine in DMF for 1 min at 90°C twice. Fmoc-Lys(ivDde)-OH was then coupled to the resin. The resin was then capped using 1-acetylimidazole in DM F (0.1 w/v) at room temperature for 30 minutes. Fmoc-Lys(iPr,Boc)-OH, Fmoc-D-Glu(OAII)-OH, Fmoc-Gly-OH (coupled twice), Fmoc-2Nal-OH (coupled twice), Fmoc-D-Arg-OH (coupled twice for 4 mins each), Fmoc-Lys(iPr,Boc)-OH, Fmoc- Tyr(tBu)-OH, and Fmoc-Phe-OH (coupled twice) were sequentially coupled to the peptidyl resin. At a 0.1 mmol scale, the -OAllyl protecting group on D-Glu was removed using Pd(PPh3)4 (25 mg)/Phenylsilane (600 mL) in DCM (5 mL) (2 x 5 min at 35°C). The AT-Fmoc on Phe was then removed, and cyclization was performed using DIC/HOBt in DMF (3 c 10 min at 90°C). Following cyclization, the ivDde protecting group was removed by 2% v/v hydrazine in DMF (5 x 5 min at RT). From the synthesis of BL02, following the removal of the ivDde group, the resin (0.025 mmol) was coupled with Glu(OtBu), Lys(ivDde) and Glu(OtBu) sequentially. Afterwards, the chelator DOTA tri-f-butyl ester (4 equiv.) in DMF was coupled to the terminal amine with HATU/DIEA (4/8 equiv.) for 18 hours at room temperature. The ivDde protecting group was removed by 2% v/v hydrazine in DMF (5 x 5 min at RT). From the synthesis of BL19, following the coupling of Fmoc-Gly-OH, the Fmoc group was removed and 4-(4-methoxyphenyl)butyric acid (4 equiv.) was coupled using HATU and DIEA (4 and 8 equiv.) for 10 minutes at 50 °C with two cycles. The peptide was deprotected and cleaved for 3.5 h at 35°C and the crude peptide mixture was worked up as previously described. The reaction mixture was purified by HPLC using the preparative column eluted with 20-40% acetonitrile in water with 0.1% TFA for 0-15 min at a flow rate of 30 mL/min. The retention time was 7.0 min, and the yield of the peptide was 7.9%. ESI-MS: calculated [M+3H]3+ for BL23 C113H170N25O28 775.4221 ; found [M+3H]3+ 775.4712.
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