* 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 oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Inert atmosphere
To a solution of 2, 6-dichlorobenzoic acid (0.1 g, 0.52 mmol) in DCM (5 mL) was added DMF (3.83 mg, 52.35 umol) at 0°C under N2, then oxalyl dichloride (0.20 g, 1.57 mmol) was added drop-wise at 0°C and the reaction mixture was stirred at 0 to 20°C for 2 hours. TLC (Petroleum ether: Ethyl acetate = 5:1, Rf= 0.77) showed the starting material was consumed completely. And the solvent was removed to give 2,6- dichlorobenzoyl chloride (0.11 g, 0.37 mmol, 70percent yield) which was used for next step directly. To 28g-int (65 mg, 0.17 mmol, HCl salt) and DIEA (87.3 mg, 0.68 mmol) in DCM (10 mL), was added drop-wise a solution of 2,6-dichlorobenzoyl chloride (88.43 mg, 0.42 mmol) in DCM (5 mL) at 0°C under N2. The reaction mixture was stirred at 0 - 20°C for 16 hrs after which LCMS indicated that 28h-int was present and 28g-int was consumed. The solvent was removed and the residue was purified by prep-HPLC to give pure 28h-int; LCMS (ESI+): m/z 521.3 (M+H)+, RT: 1.1 min.HPLC purification conditions: Gilson 281 semi-preparative HPLC system; Mobile phase: A: TFA/ H2O = 0.075percent v/v; B: ACN (gradient of B: 20percent at T= 0 to 40percent at T = 12 min); Column: YMC-Actus Triart C18150 x 305u; Flow rate: 20 mL/ min; Monitor wavelength: 220 & 254 nm.
Reference：
[1] Patent: WO2018/49068, 2018, A1, . Location in patent: Paragraph 0430; 0431
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 1432,1434
[3] Journal of the Chemical Society, 1903, vol. 83, p. 1213
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2843 - 2852
[5] Journal of Medicinal Chemistry, 1982, vol. 25, # 11, p. 1280 - 1286
[6] Pesticide Science, 1994, vol. 41, # 2, p. 139 - 148
[7] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 171 - 175
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 13, p. 3936 - 3940
[9] Molecules, 2010, vol. 15, # 6, p. 4267 - 4282
[10] Tetrahedron Letters, 2011, vol. 52, # 20, p. 2594 - 2596
[11] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 5, p. 3037 - 3042
[12] Journal of Medicinal Chemistry, 2013, vol. 56, # 11, p. 4521 - 4536
[13] Patent: WO2015/8234, 2015, A1, . Location in patent: Page/Page column 35
[14] Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 7021 - 7056
[15] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2544 - 2546
[16] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3263 - 3270
[17] Chemical Biology and Drug Design, 2016, p. 664 - 676
[18] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7745 - 7748
[19] Molecules, 2018, vol. 23, # 9,
2
[ 79-19-6 ]
[ 50-30-6 ]
[ 89978-31-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4292 - 4295
3
[ 118-45-6 ]
[ 2751-90-8 ]
[ 50-30-6 ]
[ 1823-59-2 ]
Reference：
[1] Patent: US5153335, 1992, A,
4
[ 50-30-6 ]
[ 55775-97-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 20 - 55℃; for 1 h;
Step a: Synthesis of 2,6-dichloro-3-nitro-benzoic acid2,6-Dichloro-benzoic acid (10g, 52 mmol) was treated with a previously stirred mixture of nitric acid (15 mL) and sulfuric acid (30 mL) at 55 °C for 30 minutes followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in ice cold water (1 L) and the solid obtained was filtered and dried to afford the product (9 gm). The filtrate was extracted with ethyl acetate (2 χ 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to dryness to yield more product (2 gm). (1 1 g, 88percent).1H NMR (400 MHz, MeOH-c/4): δ 7.98 (d, J=8.8 1 H), 7.67 (d, J=8.8 1 H).
43%
With nitric acid In sulfuric acid
(i) 2,6-dichloro-3-nitrobenzoic acid The procedure described in K. Lehmstedt and K. Schrader, Chem. Berichte 70, 1526, (1937) was used. From 28.23 g (148 mmol) of 2,6-dichlorobenzoic acid, 75 mL of sulfuric acid, 6.75 mL of fuming nitric acid in 22.5 mL of sulfuric acid at 70°-90° C. was obtained 29.48 g of crude nitrated product. Crystallization from toluene afforded 14.92 g (43percent) of 2,6-dichloro-3-nitrobenzoic acid; mp 133°-135° C.
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6597 - 6611
[2] Patent: WO2012/160464, 2012, A1, . Location in patent: Page/Page column 79
[3] Patent: US2014/155398, 2014, A1, . Location in patent: Paragraph 0474
[4] Chemische Berichte, 1987, vol. 120, p. 803 - 810
[5] Chemische Berichte, 1937, vol. 70, p. 1526,1531
[6] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 696 - 706
[7] Patent: US5294631, 1994, A,
5
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 50-30-6 ]
[ 55775-97-8 ]
Reference：
[1] Chemische Berichte, 1937, vol. 70, p. 1526,1531
With nitric acid;sulfuric acid; at 20 - 55℃; for 1h;Product distribution / selectivity;
Step a: Synthesis of 2,6-dichloro-3-nitro-benzoic acid2,6-Dichloro-benzoic acid (10g, 52 mmol) was treated with a previously stirred mixture of nitric acid (15 mL) and sulfuric acid (30 mL) at 55 C for 30 minutes followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in ice cold water (1 L) and the solid obtained was filtered and dried to afford the product (9 gm). The filtrate was extracted with ethyl acetate (2 chi 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to dryness to yield more product (2 gm). (1 1 g, 88%).1H NMR (400 MHz, MeOH-c/4): delta 7.98 (d, J=8.8 1 H), 7.67 (d, J=8.8 1 H).
88%
With sulfuric acid; nitric acid;
2,6-Dichloro-benzoic acid (10 g, 52 mmol) was treated with a previously stirred mixture of nitric acid (15 mL) and sulfuric acid (30 mL) at 55 C. for 30 minutes followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in ice cold water (1 L) and the solid obtained was filtered and dried to afford the product (9 gm). The filtrate was extracted with ethyl acetate (2*200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to dryness to yield more product (2 gm). (11 g, 88%). 1H NMR (400 MHz, MeOH-d4): delta 7.98 (d, J=8.8 1H), 7.67 (d, J=8.8 1H).
14.92 g (43%)
With nitric acid; In sulfuric acid;
(i) 2,6-dichloro-3-nitrobenzoic acid The procedure described in K. Lehmstedt and K. Schrader, Chem. Berichte 70, 1526, (1937) was used. From 28.23 g (148 mmol) of 2,6-dichlorobenzoic acid, 75 mL of sulfuric acid, 6.75 mL of fuming nitric acid in 22.5 mL of sulfuric acid at 70-90 C. was obtained 29.48 g of crude nitrated product. Crystallization from toluene afforded 14.92 g (43%) of 2,6-dichloro-3-nitrobenzoic acid; mp 133-135 C.
With 1,8-diazabicyclo[5.4.0]undec-7-ene for 24h; Heating;
98%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 160℃; for 0.4h; microwave irradiation;
97.5%
With 1,4-diaza-bicyclo[2.2.2]octane at 20 - 90℃; for 10h;
1; 1
1) 2,6-dichlorobenzoic acid (38.2g, 200mmol), dimethyl carbonate (305.6g) and triethylenediamine ( DABCO, 22.4 g, 200 mmol) was dissolved with stirring at room temperature. The temperature was raised to 90°C, and the reaction was maintained for 10 hours.2) After the reaction is completed, the heating is stopped, and the reaction is cooled to room temperature by itself. The solvent was evaporated under reduced pressure, and 152.8 g of water was added to the residual liquid, followed by vigorous stirring, followed by extraction with ethyl acetate. The ethyl acetate layer was washed successively with water, dilute hydrochloric acid (5%), saturated sodium bicarbonate and water, and the organic phase was dried and concentrated to obtain a colorless transparent oily liquid, namely methyl 2,6-dichlorobenzoate, weighing about 40 g , the yield is 97.5%, and the content is 98.680%
86%
With 1,8-diazabicyclo[5.4.0]undec-7-ene for 48h; Heating / reflux;
151
2,6-Dichlorobenzoic acid (5.00g, 26.2 mmol) was diluted in dimethylcarbonate (44 mL, 530 mmol). 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) (3.91 mL, 26.2 mmol) was added last. The reacted was refluxed for 2 days. Upon cooling, the solution was diluted with ethyl acetate and water. The aqueous layer was removed and the organic layer was washed with water, 2N HCl (2 x's), sat. NaHC03 (2 x's), and twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield 4.61g (86%) of the desired compound as a clear oil. ¹H NMR (CDC13) No.: 4.5 (s, 3H) , 7.28 - 7.38 (m, 3H) .
EXAMPLE 26 4-Chlorophthalic anhydride (30 g, 16o mmol), tetraphenyl phosphonium bromide (0.3 g, 0.7 mmol), and 2,6-dichlorobenzoic acid (0.08 g, 0.4 mmol) were heated to approximately 220 C. Potassium carbonate (7.95 g, 58 mmol) was added over 45 minutes. The reaction was sampled after addition of the potassium carbonate and showed a 28.3% conversion to 4,4'-oxydiphthalic anhydride. The reaction mixture was diluted with 1,2,4-trichlorobenzene (90 g) and filtered. The 4,4'-oxydiphthalic anhydride was allowed to crystallize and was collected, washed with 1,2,4-trichlorobenzene followed by hexane, and dried in an air circulating oven at 120 C. to give crude 4,4'-oxydiphthalic anhydride, 11.4 g.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;
Example 44; s 2,6-Dichloro-iV-[2-(4-[(2i?)-2-hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino}piperidin-l-yl)ethyl]benzamide; i) 2,6-Dichloro-iV-[2-(4-hydroxypiperidin-l-yl)ethyl]benzamideA solution of l-(2-aminoethyl)piperidm-4-ol (0.312 g), 2,6-dichlorobenzoic acid (0.826g), 0 and triethylamine (0.61 mL) in DMF (10 mL) was treated with PyBROP (1.2Ig) at ambient temperature. After stirring for 14 h the mixture was loaded onto a SCX cartridge and eluted with acetonitrile followed by methanol. The product was then eluted off with ammonia/methanol solutions to give the subtitle compound, after solvent evaporation, as a yellow oil. Yield: 0.7g s MS APCI+ 317/319/321 [M+H]+
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;
methyl 2,4,6-trimethylbenzoate (S4)
General procedure: To a 250 mL round bottom flask equipped with a stir barwere added 2,4,6-trimethylbenzoic acid (6.57 g, 40.0 mmol, 1 equiv), potassium carbonate (8.29g, 60.0 mmol, 1.5 equiv) and DMF (50 mL). Iodomethane (3.00 mL, 48.0 mmol, 1.2 equiv) wasslowly added to the reaction vessel and the resulting suspension was stirred vigorously at roomtemperature for 24 h. The reaction was poured onto 300 mL of H2O and extracted with 3 x 300mL portions of Et2O. The combined organic extracts were washed with 3 x 150 mL portions ofH2O and 2 x 150 mL portions of brine. The organic layer was dried over MgSO4, filtered, andconcentrated to dryness. The residue was purified by passing through a pad of silica eluting with1:1 EtOAc/hexanes to give methyl ester S4 (6.28 g, 35.2 mmol, 88% yield) as a pale yellow oil.Spectral data are in agreement with those previously published.4
70%
With sodium hydrogencarbonate; sodium sulfate In N,N-dimethyl-formamide at 20℃; Cooling with ice;
Step i): A mixture of 2,6-dichlororbenzoic acid (4 g; 20,94 mmol), cone. H2S04 (50 mL) and <strong>[50667-69-1]N-(hydroxymethyl)trifluoroacetamide</strong> (2,996 g; 20,94 mmol) was stirred at rt overnight. The mixture was diluted with 500 mL crushed ice and 200 mL H20, the precipitate was filtered and dried to give crude 3-(trifluoromethylcarbonylamino-methyl)-2,6-dichloro-benzoic acid.
With sulfuric acid; at 20℃;
A mixture of 2,6-dichlorobenzoic acid (4 g; 20.94 mmol), conc. H2SO4 (50 mL) and <strong>[50667-69-1]N-(hydroxymethyl)trifluoroacetamide</strong> (2.996 g; 20.94 mmol) was stirred at rt overnight. The mixture was diluted with 500 mL crushed ice and 200 mL H2O, the precipitate was filtered and dried to give crude 3-(trifluoromethylcarbonylamino-methyl)-2,6-dichloro-benzoic acid.
A mixture of <strong>[39217-08-8]2-chloropyridine-3,4-diamine</strong> (2.80 g, 19.4 mmol), 2,6-dichlorobenzoic acid (3.71 g, 19.4 mmol) and polyphosphoric acid (50 g) was heated at 190 C for 3 hours with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of saturated Na2C03. The crude product was collected by filtration, washed with water, and dried to afford a brown solid (5.4 g, 97% yield). ¾ NMR(DMSO- 6, 500 MHz): delta 13.08 (s, lH), 11.21 (s, 1H), 7.67 - 7.58 (m, 3H), 7.15 (m, 1H), 6.49 (d, J= 7.0 Hz, 1H). LCMS(ESI) m/z: 280.0 [M+H+]
97%
With polyphosphoric acid; at 190℃; for 3h;
A mixture of <strong>[39217-08-8]2-chloropyridine-3,4-diamine</strong>(2.80 g, 19.4mmol), 2,6-dichlorobenzoic acid(3.71 g, 19.4mmol)andpolyphosphoricacid (50 g) was heated at 190 Cfor 3 h with stirring. The mixture was cooled to room temperature and poured into ice/water. The resulting mixture was neutralized by addition of aq. saturated Na2CO3solution. The crude product was collected by filtration, washed with water, and dried to afford a brown solid(5.4 g, 97% yield).1H NMR(DMSO-d6, 500 MHz):delta13.08 (s, 1H), 11.21 (s, 1H), 7.67-7.58 (m, 3H),7.15 (m, 1H), 6.49 (d,J= 7.0 Hz, 1H).LCMS(ESI) m/z: 280.0 [M+H+].
A mixture of <strong>[4316-98-7]6-chloropyrimidine-4,5-diamine</strong> (3 g, 20.8 mmol), 2,6-dichlorobenzoic acid (4.33 g, 20.8 mmol) in polyphosphoric acid (PPA, 20 mL) was heated at 190 C for 4 hours. The mixture was cooled to room temperature and carefully poured into ice/water slowly, neutralized with Na2C03 to basic (pH 7-8). The resulting mixture was extracted with EtOAc (3 xlOO mL) and the organic layer was washed with brine (3 x50 mL), dried over Na2S04, and concentrated by vacuum. The residue was purified by column chromatography (EA= 100%) to afford the desired product (2 g, 34% yield). *H NMR (DMSO- , 500 MHz): delta 13.82 (s, 0.5 H), 13.56 (s, 0.5 H),12.41 (s, 0.5 H), 12.33 (s, 0.5 H),12.37 (d, J = 38 Hz, 1H),8.04 (s, 1H), 7.60 - 7.68 (m, 3H). LCMS(ESI) m/z: 281.0 [M+H+]
n-(Hydroxymethyl)trifluoroacetamide (11.23 g; 78.5 mmol) was added to a mixture of 2,6-dichlorobenzoic acid (15 g; 78.5 mmol) in conc. H2SO4 (180 mL) and it was stirred at rt overnight. The mixture was poured into 1.8 L crushed ice/H2O, the precipitate was filtered off and dried. The crude was diluted with 150 mL MeOH and 80 mL 2 M aq. NaOH solution and stirred at rt for 2 h. The solvent was removed, the residue was diluted with H2O and extracted 2× with DCM. The aq. layer was acidified with 70 mL 4 M aq. HCl solution, washed with DCM and concentrated. The residue was diluted with 400 mL EtOH, filtered and concentrated i. vac. to obtain the subtitle compound.Yield: 13.82 g (69%); MS: [m+H]+=220; HPLC: Rt=1.77 min (Method CC-4)
Stage #1: 2,6-dichlorobenzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h;
Stage #2: 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-4-amine In N,N-dimethyl-formamide at 20℃; for 16h;
16
A solution of HATU (46 mg, 0.12 mmol) in DMF (200 μΙ) was added to 2,6- dichlorobenzoic acid (22 mg, 0.1 1 mmol, Avocado) followed by DIPEA (50 μΙ, 0.286 mmol) and left to stand for 5 min at ambient temperature. A solution of 1-[(2,4- dichlorophenyl)methyl]-1 /-/-pyrazol-4-amine (Art Chem GmbH; 53 mg, 0.22 mmol) in DMF (200 μΙ) was then added and the solution left to stand for 16 h at ambient temperature. The solvent was removed using a Genevac. The sample was dissolved in 1 : 1 MeOH:DMSO (0.6 ml) and purified by MDAP on a standard C18 column (method D) using acetonitrile-water with a TFA modifier. The solvent was evaporated in vacuo using a Genevac to give the title compound (35 mg); LCMS (System 3): MH+ = 414, tRET = 1.18 min.
Stage #1: 2,6-dichlorobenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: methylamine With 4-methyl-morpholine In N,N-dimethyl-formamide at 0 - 20℃;
With tetra-N-butylammonium tribromide; In acetonitrile; at 20℃; for 24h;Irradiation;
General procedure: In a 50ml Pyrex round-bottom flask, a mixture of alcohol (1mmol), TBATB (10-20mg, 0.02-0.04mmol) in 10ml of CH3CN was exposed to blue or violet light LED irradiation at room temperature under an air atmosphere with stirring. The progress of the photocatalytic oxidation reaction was monitored by TLC on silica gel plates. The reaction mixture externally irradiated until the alcohol was completely consumed.
66.6%
With Au NCs/TiO2; oxygen; sodium hydroxide; In water; at 120℃; under 7500.75 Torr; for 6h;Autoclave; Green chemistry;
General procedure: The oxidation of alcohols was performed in an autoclave reactor equipped with a magnetic stirrer, thermocouple, automatic temperature controller and a pressure gauge. After the addition of desired amount of reactant, catalyst, water and NaOH, the autoclave was sealed. The atmosphere over the mixture was replaced with O2 for three times. Then the reactor was heated to the desired temperature with stirring. Subsequently, the pressure of O2 was charged to 1.0 MPa and kept constant during the reaction through feeding O2. When the reaction was finished, the reactor was cooled down to the ambient temperature. The reaction mixture was diluted with acetone to dissolve the products. After the catalyst was separated, the filtrate was acidified to pH of 2.0 by hydrochloric acid. The oxidation products were analyzed by gas chromatography equipped with a flame ionization detector. The isolated yield of carboxyl acid was obtained with the following procedure. The solvent of the mixture after acidification was removed through rotary evaporation. The pH of the residual was adjusted to 10.0 with NaOH (2.0 M), and then it was extracted with ethyl acetate for three times. The aqueous layer was acidified to pH 2.0 using HCl (6.0 M) and extracted with ethyl acetate. The organic layer was removed ethyl acetate through rotary evaporation to get the carboxylic acid. The carboxylic acid was dried overnight for calculation of the isolated yield.
Multi-step reaction with 2 steps
1: thionyl chloride / toluene / 3 h / Reflux
2: ammonium hydroxide / 1 h / 0 - 10 °C
Stage #1: 2,6-dichlorobenzoic acid With thionyl chloride In dichloromethane Reflux;
Stage #2: With ammonium hydroxide In dichloromethane
3 General procedure for the preparation of compounds 2
General procedure: A solution of starting material 1 (20 mmol), thionyl chloride(SOCl2) (40 mmol) and dichloromethane (30 mL) was stirred underreflux for 3 h, then the reaction mixture was concentrated underreduced pressure, the residue was added to the aqueous ammonia(20 mL) at room temperature or below. Upon reaction completion(as monitored by TLC), the reaction was terminated with water,followed by extraction with ethyl acetate (3 10 mL), dried overanhydrous sodium sulphite and then filtered to obtain a crudeproduct and recrystallized to get compounds 2.
To a mixture of 2,6-dichlorobenzoic acid and 2,6-di- chloro-3-iodobenzoic acid (molarratio is about 1:1,235mg) was added dropwise 13H3.THF (1 M, 2.3 mE, 2.3 mmol) atambient temperature. Afier addition, the resulting mixture was heated to reflux for 20 h. Methanol (10 mE) was added to quench the excess borane. Solvents and trimethyl borate by-product were evaporated under reduced pressure to dryness. The same process was repeated one more time. The residue was purified by column chromatography on silica gel (HexanesEtOAc=41) to afford a mixture of (2,6-dichlo- rophenyl)methanol and (2,6-dichloro-3-iodophenyl)metha- nol (molar ratio from 1H NMR was 1:1, total 160 mg) as light yellow oil, which was used in the next step without further purification.
2-deoxy-2-iodo-3,4,6-tri-O-benzyl-α-D-glucosyl 2,6-dichlorobenzoate[ No CAS ]
2-deoxy-2-iodo-3,4,6-tri-O-benzyl-β-D-glucosyl 2,6-dichlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 66%
2: 9%
With N-iodo-succinimide; C40H58CoN2O6(1-)*H(1+) In dichloromethane at 20℃; for 12h; Molecular sieve; Darkness; Inert atmosphere; Overall yield = 75 %; diastereoselective reaction;
3.6 General Procedure for the Synthesis of 2-Deoxy-2-Iodoglycosyl Carboxylates 6a-6e
General procedure: A 10-mL oven-dried vial was charged with catalyst Λ-1c (7.2 mg, 0.01 mmol), NIS (27.0 mg, 0.12mmol), activated 4 Å molecular sieves (100 mg), glycal 2a (41.6 mg, 0.10 mmol) and distilledCH2Cl2 (1 mL) at room temperature in the absence of light. Then the carboxylic acids as well assodium salts 5 (0.15 mmol) was added and the resulting solution was stirred vigorously under N2for 12 hours. The reaction was then quenched with NEt3 (140 μL, 1.0 mmol) and saturated aqueousNa2S2O3 (0.2 mL). The mixture was purified by flash column chromatography to give thecorresponding glycosyl carboxylates 6 as a α/β mixture.
a. Fmoc-Dap(Alloc) on Wang-ChemMatrix resin: In a round bottom flask suspend the resin in 9: 1 (V/V DCM/DMF) (15 mL/g of resin). In a separate flask dissolve 2 equivalent of the carboxylic acid in a minimum amount of DMF, which was added the same equivalent of HOBt and stir the mixture until HOBt dissolves. Then add the solution to the resin. In another separate flask dissolve 0.1 equivalent of DMAP in a minimum amount of DMF. Add 1.0 equivalent of DIC to the resin mixture and then add the DMAP solution. Agitate the mixture with a mechanical shaker for 2-3 h at room temperature. Add 2 equivalent of acetic anhydride and pyridine to the reaction flask and mix an additional 30 min at room temperature to consume the unreacted hydroxyl group on the resin. Filter the resin, wash it with DCM (x3) and dried under vacuum. [0642] b. Removal of Fmoc group: The Fmoc amino resin (3.83 mmol/g assumed) was treated with 20% 4-methylpiperidine in DMF (200 mL) for 5 min and repeated once. The resin was washed with DMF (x3), DCM (x3), and MeOH(x3) and dried under vacuum. [0643] c. Synthesis of amide: To a DCM swollen amino resin (3.83 mmol/g assumed) was added 2,6-dichloro benzoic acid (3.64 g, 19.15 mmol, 5 equiv), DIPEA (6.7 mL, 38.3 mmol, 10 equiv), and HATU (7.2 g, 18.96 mmol, 4.95 equiv) in DCM and shaken overnight. The resin was filtered and washed with DCM and DMF successively to give the resin. [0644] d. Removal of Alloc group: To a DCM swollen amino resin (3.83 mmol/g assumed) was added PdfPPhyM (89 mg, 0.077 mmol, 0.02 equiv) and Me2NH*BH3 (2.26 g, 38.3 mmol, 10 equiv) in DCM and shaken 15 min. The resin was filtered and washed with DCM, repeated two times more and dried it in vacuo.
General procedure: Complex 11 was prepared by the reaction of an acetonitrile solution of copper(II) acetate monohydrate (1mmol, 0.20g) with N-methylnicotinamide (2mmol, 0.27g) followed by addition of 2,5-dichlorobenzoic acid (2mmol, 0.38g). The reaction mixture was stirred until a blue product was precipitated (1day). The fine blue microcrystals were filtered off, washed with a small portion of water and dried at ambient temperature. The mother liquors obtained from filtration were left to crystallize. The blue crystals suitable for X-ray structure determination were separated after several days. Yield: 0.67g (85%).
Complex 5B was prepared by the reaction of an acetonitrile solution of copper(II) acetate monohydrate (1mmol, 0.20g) with N-methylnicotinamide (2mmol, 0.27g) followed by addition of 2,6-dichlorobenzoic acid (2mmol, 0.38g). The reaction mixture was stirred until a blue product was precipitated (1day). The fine blue microcrystals were filtered off, washed with a small portion of water and dried at ambient temperature. The mother liquors obtained from filtration were left to crystallize. The blue crystals suitable for X-ray structure determination were separated after several days. Yield: 0.64g (81%). Anal calc. for C28H30Cl4CuN4O10 (Mr=787.92): C 42.68, H 3.84, N 7.11. Found: C 42.30, H 3.90, N 7.17. IR (cm-1): 3414 (m), 3364 (m), 3194 (m), 3076 (w), 1648 (m), 1603 (w), 1588 (w), 1573 (s), 1562 (w), 1482 (w), 1450 (w), 1431 (m), 1415 (w), 1389 (s), 1339 (m), 1330 (w), 1264 (w), 1199 (m), 1183 (w), 1114 (w), 1086 (w), 1060 (w), 1036 (w), 1016 (w), 993 (w), 983 (w), 963 (w), 940 (w), 876 (w), 828 (w), 807 (w), 788 (m), 750 (m), 742 (m), 704 (w), 696 (m), 657 (w), 530 (w), 496 (m), 448 (w), 430 (w).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In dimethyl sulfoxide at 140℃; for 18h; Inert atmosphere;
1 Synthesis of compound (7)
2-iodobiphenyl 74.1 g (264.4 mmol), 2,6-dichlorobenzoic acid in a 1000 mL three-necked flask under a nitrogen stream. 50.0 g (261.8 mmol), 90.5 g (654.5 mmol) of potassium carbonate, 1.5 g (1.3 mmol) of tetrakis (triphenylphosphine) palladium, and 300 mL of dimethyl sulfoxide were added, and the mixture was stirred at 140 ° C. for 18 hours. After cooling to room temperature, 300 mL of toluene and 300 mL of pure water were added, the aqueous layer and the organic layer were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution. .. Then, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Silica gel column chromatography on the residue (mixed solvent of toluene and hexane (volume ratio = 1: 1) By purifying in 1)) and further concentrating under reduced pressure, the obtained residue is recrystallized (toluene / 2-propanol). A white solid of compound (7) was isolated in 54.9 g (208.9 mmol) (yield 80%).
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