* 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.
With sodium carbonate In dichloromethane at 20℃; Cooling with ice
General procedure: Syntheses of G(2–4) and P(2–4): General experimental procedure is as follows: Glycine or L-phenyl alanine derivative (as HCl salt) (10 mmol) and Na2CO3 (2.1 g, 20 mmol) were dissolved in anhydrous dichloromethane (50 mL) and cooled in an ice bath before tosyl chloride (1.9 g, 10 mmol) was added. The resultant reaction mixture was stirred overnight at room temperature. After the reaction, more solvent was added and the residue was washed sequentially with 0.1 M HCl, saturated NaHCO3 and brine. Organic portion was dried with Na2SO4 and concentrated in vacuo to give crude product. The product was purified by column chromatography on silica with hexane and EtOAc (1:1). Compound G2: Yield 78percent as white solid. 1H NMR (400 MHz,CDCl3): δ 7.74 (d, J= 8.3 Hz, 2H, ArH), 7.31 (d, J= 8.3 Hz, 2H, ArH), 5.04 (t, J= 5.1 Hz, 1H, –NH–), 3.78 (d, J= 5.1 Hz, 2H, –CH2–), 3.64 (s, 3H, –OCH3), 2.42 (s, 3H, –CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 169.4, 144.0, 136.3, 129.9, 127.4, 52.7, 44.2, 21.7 ppm. Anal.Calcd. [C10H13NO4S]: C, 49.37; H, 5.39; N, 5.76; S, 13.18. Found:C, 50.63; H, 5.09; N, 5.36; S, 12.87.
Reference：
[1] Organic Letters, 2005, vol. 7, # 25, p. 5717 - 5719
[2] ChemMedChem, 2011, vol. 6, # 8, p. 1459 - 1470
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 18, p. 7190 - 7200
[4] Tetrahedron, 2008, vol. 64, # 52, p. 11884 - 11895
[5] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 9, p. 982 - 986
[6] Chemical Biology and Drug Design, 2011, vol. 77, # 3, p. 189 - 198
[7] Journal of Organic Chemistry USSR (English Translation), 1989, vol. 25, # 6.2, p. 1162 - 1167[8] Zhurnal Organicheskoi Khimii, 1989, vol. 25, # 6, p. 1292 - 1298
[9] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 23, p. 7353 - 7358
[10] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1972, p. 627 - 633
[11] Tetrahedron, 1989, vol. 45, # 6, p. 1691 - 1702
[12] Journal of the American Chemical Society, [13] Journal of the American Chemical Society, 2009, vol. 131, p. 3832 - 3833
[14] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2162 - 2167
3
[ 67-56-1 ]
[ 1080-44-0 ]
[ 2645-02-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 3 h;
To a solution of (toluene-4-sulfonylamino)-acetic acid (2 g, 8.72 mmol) in methanol (60 mL), cone. H2SO4 (1.5 mL) was added. The mixture was stirred at room temperature for 3h then the solvent was removed under reduced pressure. The crude was dissolved in DCM (20 mL) and the organic phase was washed with H2O (1x20 mL), 5percent Na2CO3 (aq) (1x20 mL) and brine (1x20 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude (toluene-4-sulfonylamino)-acetic acid methyl ester was used in the next step without further purification. Yield: 98percent; LCMS (RT): 3.47 min (Method A); MS (ES+) gave m/z: 244.03 (MH+).
Reference：
[1] Patent: WO2006/123257, 2006, A2, . Location in patent: Page/Page column 77
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 7, p. 1671 - 1676
[3] Chemische Berichte, 1956, vol. 89, p. 1674,1679
[4] Journal of the American Chemical Society, 1956, vol. 78, p. 3841,3842
[5] Justus Liebigs Annalen der Chemie, 1961, vol. 640, p. 136 - 139
4
[ 21978-63-2 ]
[ 616-34-2 ]
[ 2645-02-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2 h;
General procedure: In an oven dried 25 mL R.B. flask equipped with magnetic stir bar, was loaded with TsOBt (289 mg, 1 mmol) in DCM (1 mL) followed by DIPEA (1 equiv.) was added. Then amine (1 equiv.) was added followed by 1 mL of DCM for amines and 1.5 mL of 1:3 DMF: DCM mixture for amino acid esters. The progress of the reaction was checked by TLC. After completion of the reaction, the reaction mixture was diluted with 10 mL of DCM and organic layer was washed with 5percent HCl (3.x.10 mL), 5percent NaHCO3 (3.x.10 mL), and saturated NaCl solution (2.x.10 mL) and dried over anhydrous CaCl2. Then it is dried in vaccuo and purified by column chromatography.
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 52, p. 7132 - 7134
[2] European Journal of Organic Chemistry, 2013, # 13, p. 2627 - 2633
11
[ 67-56-1 ]
[ 63366-76-7 ]
[ 2645-02-5 ]
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1980, vol. 9, p. 209 - 220
12
[ 941-55-9 ]
[ 616-34-2 ]
[ 2645-02-5 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2681 - 2691
13
[ 1738-68-7 ]
[ 2645-02-5 ]
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1980, vol. 9, p. 209 - 220
14
[ 79-20-9 ]
[ 1080-44-0 ]
[ 2645-02-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1961, vol. 640, p. 142 - 144
15
[ 1455091-04-9 ]
[ 2645-02-5 ]
[ 1455091-10-7 ]
Yield
Reaction Conditions
Operation in experiment
72.5%
Stage #1: With sodium methylate; potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 50℃; for 1 h; Inert atmosphere Stage #2: With sodium methylate In methanol; N,N-dimethyl-formamide at 20℃; for 0.5 h;
Methyl 2-(chloromethyl)-4-phenoxybenzoate (0.68 g, 2.46 mmol),N-p-toluenesulfonylglycine methyl ester (0.7 g, 2.88 mmol), potassium carbonate (0.68 g, 4.923 mmol), potassium iodide (0.16 g, 0.96 mmol), DMF was added to the reaction flask, replaced with nitrogen, and heated to 50 ° C. After reacting for 1 hour, 2 mL of methanolic sodium methoxide solution was added to room temperature and stirred for 30 min. After the reaction was completed by thin layer chromatography, 40 mL of purified water was added to the reaction mixture, and glacial acetic acid was added dropwise with stirring to adjust pH=7, suction filtration, and the filter cake was added with acetone. 4 mL was stirred for 2 hours, and suction filtered to give the title compound 2d (525 mg, 72.5percent).
Reference：
[1] Patent: CN108341777, 2018, A, . Location in patent: Paragraph 0199; 0200; 0205; 0206
[2] Patent: WO2014/14834, 2014, A1, . Location in patent: Paragraph 0236
With sodium carbonate; In dichloromethane; at 20℃;Cooling with ice;
General procedure: Syntheses of G(2-4) and P(2-4): General experimental procedure is as follows: Glycine or L-phenyl alanine derivative (as HCl salt) (10 mmol) and Na2CO3 (2.1 g, 20 mmol) were dissolved in anhydrous dichloromethane (50 mL) and cooled in an ice bath before tosyl chloride (1.9 g, 10 mmol) was added. The resultant reaction mixture was stirred overnight at room temperature. After the reaction, more solvent was added and the residue was washed sequentially with 0.1 M HCl, saturated NaHCO3 and brine. Organic portion was dried with Na2SO4 and concentrated in vacuo to give crude product. The product was purified by column chromatography on silica with hexane and EtOAc (1:1). Compound G2: Yield 78% as white solid. 1H NMR (400 MHz,CDCl3): delta 7.74 (d, J= 8.3 Hz, 2H, ArH), 7.31 (d, J= 8.3 Hz, 2H, ArH), 5.04 (t, J= 5.1 Hz, 1H, -NH-), 3.78 (d, J= 5.1 Hz, 2H, -CH2-), 3.64 (s, 3H, -OCH3), 2.42 (s, 3H, -CH3) ppm. 13C NMR (100 MHz, CDCl3): delta 169.4, 144.0, 136.3, 129.9, 127.4, 52.7, 44.2, 21.7 ppm. Anal.Calcd. [C10H13NO4S]: C, 49.37; H, 5.39; N, 5.76; S, 13.18. Found:C, 50.63; H, 5.09; N, 5.36; S, 12.87.
After subjecting the above Compound 5 (59.0 g, 195 mmol) to Mitsunobu reaction with N-tosylglycine methyl ester according to the method described in Document (WO02/30930), ring-closure was caused with 1M sodium methoxide, to give 3-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine -7-carboxylic acid methyl ester 6(50.3 g) in 83 % yield. NMR (CDCl3) d: 4.13 (3H, s), 4.23 (2H, s), 7.02-7.08 (2H, m), 7.17-7.23 (2H, m), 7.97 (1H, m), 8.77 (1H, s), 9.08 (1H, d, J = 2.1 Hz), 11.77 (1H, s).
Example AF Ethyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate The title compound was prepared using a procedure adapted from Bioorg. Med. Chem. 2003, 11, 1451. A solution of methyl N-[(4-methylphenyl)sulfonyl]glycinate (55.2 g, 0.23 mol), potassium carbonate (31.5 g, 0.23 mol) and potassium iodide (1.85 g, 0.011 mol) in acetone (600 mL) was stirred at 60 C. for 30 minutes. To this mixture was added ethyl 2-(bromomethyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (75 g, 0.2 mol), and the reaction was stirred at 60 C. for 16 hours. The reaction was allowed to cool, filtered, and the solids washed with acetone (100 mL). The solvent was removed in vacuo and the resulting residue was dissolved in methylene chloride (500 mL). The organic layer was washed with water (3×250 mL) and dried over sodium sulfate. The solvents were removed in vacuo and ethyl acetate (150 ml) was added to the resulting residue. A seed crystal obtained from a previous reaction, the product of which had been purified by flash chromatography on silica gel (eluting with 20% to 50% ethyl acetate in heptanes) was added and the title compound was isolated as a colorless solid that was washed with diethyl ether and dried (70.3 g, 65%). A second crop of the title compound was isolated from the filtrate by allowing it to stand at room temperature.
With sodium hydride; In N,N-dimethyl-formamide; at -20 - 0℃; for 2h;Cooling with iso-propanol/dry ice;Product distribution / selectivity;
Example AE Ethyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate Ethyl 2-(bromomethyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (30.0 g, 80.6 mM) and tosyl-glycine (19.6 g, 80.6 mM) were dissolved in DMF (220 mL). Sodium hydride (6.45 g, 161 mM, 60% in mineral oil which was washed by hexanes 3 times) was added dropwise at -20 C. (Isopropanol and dry ice bath) by pipette. The reaction mixture was stirred for 2 hours at a temperature of from about -20 C. to about 0 C. Saturated ammonium chloride was then added to the reaction mixture and the mixture was extracted 2 times with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, concentrated. The concentrated mixture was allowed to stand uncovered at room temperature overnight to afford the title compound as crystals that were washed with cold hexanes and dried in vacuo overnight to afford 56 g of the title compound. The mother liquor was further purified by flash column (5% to 60% EtOAc/hexanes) to provide an additional 14.7 g of the title compound.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃;
To a solution of 3-methyl-2-methylene-butyraldehyde (850 mg, 8.72 mmol) and (toluene-4-sulfonylamino)-acetic acid methyl ester (2.09 g, 8.59 mmol) in THF (60 mL), DBU (2.90 mL, 19.18 mmol) was added. The mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure and the crude was dissolved in diethyl ether (50 mL). The organic layer was washed with IN HCl (1x50 mL), 5% NaHCO3 (aq) (1x50 mL) and H2O (1x50 mL), then it was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude 3- hydroxy-4-isopropyl- 1 -(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was used in the next step without further purification. EPO <DP n="79"/>Yield: 99%; LCMS (RT): 3.94 min (Method A); MS (ES+) gave m/z: 341.00 (MH+).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 18h;Heating / reflux;
c. 2-{ [Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino] -methyl}-6-phenoxy- benzoic acid methyl ester[0230] Amixture of 2-methyl-6-phenoxy-benzoic acid methyl ester (8.9 mmol, 2.15 g), N- bromosuccinimide (9.1 mmol, 1.64 g), benzoyl peroxide (0.44 mmol, 110 mg), and CCl4 (35 mL) was refluxed with stirring for 6 h. After cooling to ambient temperature the mixture was <n="62"/>filtered and the filtrate was concentrated in vacuo to give a yellowish oil (3.01 g). The oil (3.00 g) was dissolved in dry DMF (8 mL). NaI (2.42 g), K2CO3 (2.21 g), and (toluene-4- sulfonylamino)-acetic acid methyl ester (2.04 g) were added and the mixture was stirred at ambient temperature for 18 h before water was added with stirring. The aqueous phase was then decanted from the oily precipitate formed. The oil was dissolved in ethyl acetate (70 mL) and the solution was washed with concentrated aqueous NaHCO3 solution before it was dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (3.87 g). The crude product was used in the next step without further purification; MS-(+)-ion: M+23 = 506.0.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;
b. 3-Iodo-2-[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-benzoic acid methyl ester[0236] A mixture of 3-iodo-2-methyl-benzoic acid methyl ester (75 mmol, 20.7 g), N- bromosuccinimide (76.6 mmol, 13.8 g), benzoyl peroxide (890 mg), and CCl4 (300 mL) was refluxed with stirring for 15 h. After cooling to ambient temperature the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a tan oil. The oil (26.3 g) was dissolved in dry DMF (75 mL). NaI (22.4 g), K2CO3 (20.5 g), and (toluene-4- sulfonylamino)-acetic acid methyl ester (19 g) were added and the mixture was stirred at ambient temperature for 24 h before it was poured into water (900 mL). The mixture was extracted with ethyl acetate (2x250 mL). The combined organic phases were washed with a solution of sodium meta-bisulfte (20 g) in water (300 mL) and water (2x300 mL) before they were dried over MgSO4 and concentrated in vacuo to give the title compound as a dark gum (38.1 g). The crude product was used in the next step without further purification; MS-(+)-ion: M+23 = 539.9.
b. 4-Renzyl-2-[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}- benzoic acid, methyl ester[0250] Amixture of 5-benzyl-3H-isobenzofuran-l-one (6 rnmol, 1.35 g), boric acid (0.18 mmol, 11 mg), triphenylphosphine oxide (0.18 mmol, 51 mg), and thionyl chloride (7.8 mmol, 0.59 mL) was rcfluxcd in an oil bath (bath temperature 130 to 140 C) for 18 h with stirring. Subsequently, methanol (6 mL) was added and the mixture was stirred for 15 min before it was concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL). The solution was washed with saturated aqueous NaHCO3 solution (2x20 mL), dried over MgSO4 and was concentrated in vacuo to give a yellowish oil (1.51 g). The oil (906 mg) was dissolved in anhydrous DMF (5 mL). NaT (1.0 g), K2Ctheta3 (912 mg), and (toluene-4-sulfonylamino)-acetic acid methyl ester (803 mg) were added and the mixture was stirred at ambient temperature for 15 h before it was poured into water (50 mL). Traces of iodine were removed by adding a small amount of sodium meta-bisulfite before extracting the mixture with ethyl acetate (1x50 mL). The organic phase was then washed with water (1x50 mL), dried over MgSO4 and concentrated in vacuo to give the crude title compound as a dark gum (1.58 g) that was used in the next step without further purification; MS-(+)-ion: M+l = 481.8.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 4h;
d. 2-{rMethoxycarbonylmethyl-(toluene-4-sulfonyl)-aminol-methyl}-3-phenoxy- benzoic acid ethyl ester[0193] A mixture of 2-bromomethyl-3-phenoxy-benzoic acid ethyl ester (6.83 g, 0.02 mol), (toluene-4-sulfonylamino)-acetic acid methyl ester (4.97 g, 0.02 mol), sodium iodide (4.59 g, 0.03 mol), potassium carbonate (4.24 g, 0.03 mol), and anhydrous dimethylformamide (50 mL) was stirred at room temperature for 4 h before it was diluted with water and extracted with ethyl acetate. The organic layer was separated and washed with water and brine. Then it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.10 g): MS: (+) m/z 497.8 (M+l).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;
c. 3-(4-Fluoro-phenoxy)-2-[methoxycarbonylmethyl-(toluene-4-suIfonyl)-amino]- methyl}-benzoic acid ethyl ester[0200] A mixture of 2-bromometh.yl-3-(4-fluoro-phenoxy)-benzoic acid ethyl ester (3.37 g, 9.57 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (2.33 g, 9.57 mmol), sodium iodide (2.15 g, 14.36 mmol) and potassium carbonate (1.98 g, 14.36 mmol) in anhydrous dimethylformamide (22 mL) was stirred at room temperature for 24 h before it was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexane to give the title compound as a yellow oil (2.67 g): MS: (+) m/z 538.13 (M+Na1).
Step 3: Ethyl 4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2-oxoethyl)[(4- methylphenyl)sulfonyl)amino}methyl)-1 H-pyrrole-3-carboxylate; To a stirring solution of methyl N-[(4-methylphenyl)sulfonyllglycinate (51.75g, 0.213mol, prepared by the method of: Ginzel, K. D.; Brungs, P. ; Steckhan, E. Tetrahedron 1989,45, 1691- 1701) in anhydrous DMF (0.5L) was added NaH (60% in oil, 8.59g, 0.215mol) in one portion. The mixture was allowed to stir for 30 minutes (warms and returns to room temperature) at which time a solution ethyl 4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate (105.92g, 0.213mol) in anhydrous DMF (0.5L) was added over 1 hour. The mixture was allowed to stir at room temperature for 16 hours, then the DMF was removed in vacuo (approx 2 Torr, 40C water bath) and the oily residue was dissolved in dichloromethane (0.75L), the solution was washed with saturated aq. NH4CI (0.5L), brine (0.5L), and dried (Na2S04). Filtration and concentration in vacuo provided the crude alkylated material as a viscous reddish oil. The crude material was heated in the presence of MeOH (0.75L) until the MeOH was boiling, then dichloromethane was added slowly until solution was achieved. The red solution was cooled to room temperature (see off-white crystals) and the crystallization was completed by cooling in a refrigerator (4C) for 16 hours. The ivory solid was isolated by filtration, the solid was rinsed with diethyl ether: hexanes (0.5L, 10: 90 v/v) and the solid was dried in a vacuum oven (approx. 20 Torr, 50C) overnight to furnish ethyl 4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2- oxoethyi)[(4-methy.pheny') sulfonyl]amino}methyl)-1/-/-pyrrole-3-carboxylate (108.2g, 77%) as a '"lee ':10,Jli.,.(at),, line, ivory solis. TLC (rtrerc[t,16){S,nss:::::tOAc 75:25, UV-+, cerium molybdate-+ . 3u:-?'s): .(at).f Z.31, ._(at)'(at)1(at)..(at) , ;c..::3s }-(at)=3.4:;E, 3.S..- /.:No.. £::(at)::(at):3(at)i(at) S:J:2(at) '(at):J 5:£3 '-.z2 [-'-0.I%a HOAc):CH3CN - 5 minutes, ESI, + mode) : RT- 4.436 min, m/e = 680.8 (55), 681.8 (18), 682.9 (base), 683.9 (30), 684.8 (62), 686.8 (10) - M+Na; 'H-NMR (300MHz, CDCI3): 8 = 1.24 (t, J = 7.16 Hz, 3H), 2.14 (s, 3H), 3.49 (s, 3H), 3.89 (s, 2H), 4.19 (q, J = 7.16 Hz, 2H), 4.55 (s, 2H), 7.02 (d, J = 2.45 Hz, 2H), 7.04 (s, 2H), 7.28 (d, J = 8.19 Hz, 2H), 7.59 (d, J = 8.19 Hz, 2H)
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