* 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.
5.0mmol N-(3-hydroxypropyl) phthalimide, 5.00mmol PBr3The refluxing reaction was completed for 0.5 h, and was detected by TLC. After cooling, it was poured into ice water to precipitate a solid. The crude product was recrystallized from anhydrous ethanol to obtain white solid N-(3-bromopropyl)phthalimide (1.14 g). Mp71-73°C, yield 85.1percent.
Reference：
[1] Chemical Communications, 2003, # 2, p. 260 - 261
[2] Tetrahedron Letters, 2003, vol. 44, # 44, p. 8143 - 8147
[3] Patent: CN107540647, 2018, A, . Location in patent: Paragraph 0045-0048
2
[ 85-44-9 ]
[ 156-87-6 ]
[ 883-44-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 125℃; for 6.5 h; Inert atmosphere
3-Aminopropan-1-ol (10.0 g, 133.1 mmol) was dissolved in anhydrous toluene (100 ml). Phthalic anhydride (19.7 g, 133.1 mmol) was added and the reaction mixture was heated to 125 °C with stirring, under an atmosphere of argon for 6.5 h. After cooling to rt, the solvent was evaporated in vacuo to give phthalimide 5 (31.7 g, quantitative) as a white powder that required no further purification.
90%
With o-phthalimide-N-sulfonic acid In ethanol at 80℃; for 2 h; Green chemistry
General procedure: A mixture of phthalic anhydride (0.296 g, 2 mmol), amine (2.2 mmol), and phthalimide-N-sulfonic acid (0.091 g, 20 molpercent) in ethanol (5 ml) was stirred for 3 h at 80 °C. After completion (monitored by TLC), the insoluble catalyst was separated by filtration, washed with acetone, and dried (weight: 0.090 g, 99 percent recovered). The organic layer was concentrated under reduced pressure to give the desired product, washed with water, and recrystallized in ethanol (each product was dissolved in a minimum amountof hot ethanol and allowed to reach gradually to room temperature). In addition, some products needed extrapurification step by small column chromatography using the CH2Cl2/n-hexane solvent mixture (50:50).
87%
With triethylamine In toluene for 24 h; Reflux
Step 1To a solution of 3 -aminopropan- 1 -ol ( 1.0 g, 13.1 mmol) and isobenzofuran- 1 ,3 -dione (2.0 g,13.1 mmol) in toluene (25 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol) and the reaction was heated at reflux for 24 h. Then reaction was quenched with water and extracted with EtOAc (2 x 40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)isoindo line- 1,3- dione (1.8 g, 87percent). Observed mass (M+l): 206.1. This material was taken to the next step without further purification
80.2%
for 1 h; Reflux
0.013mol phthalic anhydride in the three-neck flask, 0.013mol propanolamine was added dropwise at room temperature, the reaction was refluxed for 1.0H, cooled and the precipitated solid was recrystallized to give a white solid N- (3- hydroxypropyl) phthalimido imine 2.14g,
79%
for 4 h; Reflux; Inert atmosphere
2-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)meth l)(methyl)amino)propyl)isoindoline-l,3-dioneStep 1. Preparation of 2-(3-hydroxypropyl)isoindoIine-l,3-dioneTo a solution of isobenzofuran-l ,3-dione (10.0 g, 135.1 mmol) in toluene (250 mL) was added 3-amino-l -propanol (10.0 g, 67.6 mmol) and the mixture was heated to reflux for 4 h under N2. The mixture was concentrated and water was added. The mixture was extracted with EA (100 mL x4). The organic phase was dried with Na2S04 and concentrated to afford 2-(3-hydroxypropyl)isoindoline-l ,3-dione (1 1.0 g, 79percent) as white solid. 1H NMR (500 MHz, CDC13): δ 7.84-7.87 (m, 2H), 7.72-7.75 (m, 2H), 3.85-3.88 (m, 2H), 3.61 -3.63 (m, 2H), 2.42 (brs, 1H), 1.86-1.9 (m, 2H) ppm. MS (ESI): m/z 206.7 [M+l]+.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 644 - 647
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 32, p. 6094 - 6104
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 16, p. 5903 - 5914
[4] Chemistry - A European Journal, 2014, vol. 20, # 44, p. 14256 - 14260
[5] Chemical Papers, 2017, vol. 71, # 11, p. 2293 - 2299
[6] Patent: WO2011/103196, 2011, A1, . Location in patent: Page/Page column 110-111
[7] Patent: CN107540647, 2018, A, . Location in patent: Paragraph 0042-0044
[8] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 245
[9] Organic Letters, 2013, vol. 15, # 4, p. 917 - 919
[10] Journal of the American Chemical Society, 2015, vol. 137, # 2, p. 807 - 819
[11] Tetrahedron, 2003, vol. 59, # 45, p. 8877 - 8888
[12] Atti della Accademia delle Scienze di Torino, Classe di Scienze Fisiche, Matematiche e Naturali, 1933, vol. 9, p. 358,362
[13] Tetrahedron Letters, 2002, vol. 43, # 27, p. 4747 - 4751
[14] Journal of Medicinal Chemistry, 2004, vol. 47, # 10, p. 2411 - 2413
[15] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
[16] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 649 - 664
3
[ 2436-29-5 ]
[ 883-44-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triphenylphosphonium ruthenium chloride; C29H30NOPRu; hydrogen; sodium carbonate In ethanol; toluene at 25℃; for 24 h; Autoclave
In a 10 ml reaction tube, adding phosphine nitrogen ligand L10a (0.35 mg, 0 . 65 μmol) with the three-phenyl phosphorus is great (0.48 mg, 0 . 50 μmol), system through the vacuum line, replace the nitrogen 3 times, and steams newly added new degassed toluene 2 ml, solution in 90 °C under stirring 3 hours, cooling to room temperature, solvent is removed under reduced pressure. At the same time in another 10 ml hydrogenation bottle, adding β - aminoketone laq (40.6 mg, 0.2 mmol) with anhydrous sodium carbonate (2.12 mg, 0 . 02 mmol), system through the vacuum line, replace the nitrogen 3 times. A syringe has been coordination of the new catalyst for steaming and new degassing of ethanol (3 ml) containing dissolved out and injected into the substrate and additive in the reaction tube, the reaction system is put in an autoclave, in 25 °C and H2(50 Bar) is stirred under the condition 24 hours, the solvent is removed under reduced pressure, taking a small amount of the mixed system is nuclear magnetic resonance to determine the conversion rate. The rest of the survivor column chromatography separation, to obtain the pure product 2 aq. The conversion is 100percent, enantiomeric excess is 92percent. 2 Aq: white solid. According to the embodiment 1 - 12 and not the result of the symmetrical field of catalytic hydrogenation of the well known common sense, can without any doubt be inferred in this embodiment of the product structure is shown in formula (II) of the structure.
With dipotassium peroxodisulfate In water at 100℃; for 0.166667 h; Microwave irradiation; Green chemistry
General procedure: Amide (1.0 mmol), amine (1.0 mmol) and K2S2O8 (1.5 mmol) were charged in microwave vial added water (2.0 mL), the reaction mixture was treated at 100°C and 100W for 10 min. After the complete conversion (by TLC) of the amine, distilled water (10 mL) was added and extracted with ethyl acetate (2 ×10 mL). The combined organic phase was dried over Na2SO4, and then concentrated using rotary vacuum evaporator. The crude product was purified by column chromatography (30percent Ethyl acetate/hexane) to get pure compound.
With t-butyl bromide In acetonitrile for 1.5 h; Reflux
General procedure: To asolution of the PMB ether (1 mmol) in acetonitrile (10 mL), t-BuBr (1.1 equiv)was added and stirred at reflux. After completion of the reaction (monitored byTLC), it was concentrated under reduced pressure and the resulting crude wasdissolved in ethyl acetate (50 mL) and washed with saturated sodiumhydrogenocarbonate (25 mL). The aqueous layer was extracted with ethylacetate (2 5 mL) and the combine organic layer was washed with brinesolution, dried (MgSO4), concentrated under reduced pressure and the residuewas purified by column chromatography (silica gel, EtOAc, cyclohexane) toafford the corresponding alcohol.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 49, p. 6823 - 6826
[2] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 9227 - 9235,9
6
[ 1074-82-4 ]
[ 627-30-5 ]
[ 883-44-3 ]
Reference：
[1] Tetrahedron Letters, 1993, vol. 34, # 24, p. 3919 - 3920
[2] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 10, p. 1649 - 1658
[3] Journal of the American Chemical Society, 1931, vol. 53, p. 2763,2767
[4] Journal of the American Chemical Society, 1988, vol. 110, p. 5779
7
[ 22509-74-6 ]
[ 156-87-6 ]
[ 883-44-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 4, p. 706 - 721
[2] Chemical & Pharmaceutical Bulletin, 1982, vol. 30, # 5, p. 1639 - 1645
8
[ 1074-82-4 ]
[ 627-18-9 ]
[ 883-44-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 1, p. 292 - 295[2] Angew. Chem., 2018, vol. 130, # 1, p. 298 - 301,4
[3] Patent: US6201016, 2001, B1,
[4] Patent: US5681966, 1997, A,
9
[ 4409-98-7 ]
[ 627-18-9 ]
[ 883-44-3 ]
Yield
Reaction Conditions
Operation in experiment
24%
With potassium carbonate In N,N-dimethyl-formamide
(e) Preparation of N-(3-hydroxypropyl)phthalimide (106). A mixture of 3-bromopropanol (4 g, 0.029 mol), potassium phthalate (8 g, 0.043 mol) and potassium carbonate (4 g, 0.029 mol) in dry DMF (50 ml) was stirred and heated at 70° C. for four hours. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (3*75 ml). The organic extract was washed with water (3*100 ml) and dried (Na2 SO4). Removal of the solvent under reduced pressure left a white solid which was extracted with benzene. The benzene extract was evaporated to a white solid and recrystallized from ethyl acetate-hexanes to give white crystals (1.27 g, 24percent).
Reference：
[1] Patent: US5681966, 1997, A,
10
[ 627-32-7 ]
[ 1074-82-4 ]
[ 883-44-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7029 - 7043
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 633,2389
[2] Chemische Berichte, 1890, vol. 23, p. 89
16
[ 883-44-3 ]
[ 2436-29-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With 2-iodoxybenzoic acid In ethyl acetate for 2 h; Reflux
Step 2. Preparation of 3-(l,3-dioxoisoindolin-2-yl)propanal A mixture of 2-(3-hydroxypropyl)isoindoline-l,3-dione (2.0 g, 8.76 mmol) and IBX (8.2 g, 29.27 mmol) in 60 mL EA was refluxed for 2 h. The mixture was filtered and filtrate was concentrated to afford 3-(l,3-dioxoisoindolin-2-yl)propanal (2.0 g , yield: 100percent) as white solid. NMR (500 MHz, CDC13): δ 9.82 (s, 2H), 7.84-7.86 (m, 2H), 7.72-7.74 (m, 2H), 4.04 (t, J = 7.0 Hz, 2H), 2.87-2.89 (m, 2H) ppm. MS (ESI): m/z 553.7 [M+l]+.
38%
With N-chloro-succinimide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; potassium carbonate In chloroform; water at 20℃; for 4.5 h;
A 50 ml round bottom flask was charged with aq. NaHCO3(0.05 M, 10 ml), aq. K2CO3(0.5 M, 10 ml) and CHCl3(5 ml). Alcohol 5 (16.02 g, 78.1 mmol) was dissolved in CHCl3(50 ml) and transferred to the reaction mixture followed by tetra-nbutylammonium chloride (4.34 g, 15.6 mmol), N-chlorosuccinimide (20.9 g, 156.1 mmol) and TEMPO (2.44 g, 15.6 mmol) and the reaction mixture was stirred vigorously at rt for 4.5 h. The phases were separated and the organic phase was washed with sulfate buffer (100 ml), NaHCO3(100 ml), and brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography (35percent EtOAc in n-heptane, v/v) gave aldehyde 9 (6.54 g, 38percent) as a white amorphous solid.
Reference：
[1] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 245-246
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 32, p. 6094 - 6104
[3] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
[4] Tetrahedron, 2002, vol. 58, # 9, p. 1719 - 1737
[5] Helvetica Chimica Acta, 2005, vol. 88, # 10, p. 2610 - 2616
[6] Journal of Organic Chemistry, 1989, vol. 54, # 22, p. 5387 - 5390
[7] Organic Letters, 2003, vol. 5, # 17, p. 3115 - 3118
[8] Green Chemistry, 2012, vol. 14, # 5, p. 1493 - 1501
[9] Journal of the American Chemical Society, 2013, vol. 135, # 24, p. 9083 - 9090
[10] Tetrahedron, 2003, vol. 59, # 45, p. 8877 - 8888
[11] Journal of Medicinal Chemistry, 1999, vol. 42, # 4, p. 706 - 721
[12] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 10, p. 2609 - 2624
[13] Journal of Organic Chemistry, 2017, vol. 82, # 24, p. 13121 - 13140
[14] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 644 - 647
[15] Journal of the American Chemical Society, 1988, vol. 110, p. 5779
[16] Tetrahedron Letters, 1993, vol. 34, # 24, p. 3919 - 3920
[17] Journal of Medicinal Chemistry, 2004, vol. 47, # 10, p. 2411 - 2413
[18] Patent: US2006/84687, 2006, A1, . Location in patent: Page/Page column 22
[19] Patent: US2005/119332, 2005, A1,
[20] Organic Letters, 2009, vol. 11, # 11, p. 2465 - 2468
[21] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 223-224
[22] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 265-266
[23] Chemistry - A European Journal, 2013, vol. 19, # 20, p. 6213 - 6216
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;
INTERMEDIATE 3; 3-(fert-Butyldimethylsilanyloxy)propylamine; To a solution of <strong>[883-44-3]N-(3-hydroxypropyl)phthalimide</strong> (5.25 g, 24.36 mmol) in DMF (20 niL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethyl- silanyloxy)propyl]isoindole-l,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimetliyl- silanyloxy)propyl]isoindole-l,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75C for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 niL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). deltaH (DMSOd6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J 1.1 Hz), 0.00 (6H, d, J 1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
With 2-iodoxybenzoic acid; In ethyl acetate; for 2h;Reflux;
Step 2. Preparation of 3-(l,3-dioxoisoindolin-2-yl)propanal A mixture of 2-(3-hydroxypropyl)isoindoline-l,3-dione (2.0 g, 8.76 mmol) and IBX (8.2 g, 29.27 mmol) in 60 mL EA was refluxed for 2 h. The mixture was filtered and filtrate was concentrated to afford 3-(l,3-dioxoisoindolin-2-yl)propanal (2.0 g , yield: 100%) as white solid. NMR (500 MHz, CDC13): delta 9.82 (s, 2H), 7.84-7.86 (m, 2H), 7.72-7.74 (m, 2H), 4.04 (t, J = 7.0 Hz, 2H), 2.87-2.89 (m, 2H) ppm. MS (ESI): m/z 553.7 [M+l]+.
38%
With N-chloro-succinimide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; potassium carbonate; In chloroform; water; at 20℃; for 4.5h;
A 50 ml round bottom flask was charged with aq. NaHCO3(0.05 M, 10 ml), aq. K2CO3(0.5 M, 10 ml) and CHCl3(5 ml). Alcohol 5 (16.02 g, 78.1 mmol) was dissolved in CHCl3(50 ml) and transferred to the reaction mixture followed by tetra-nbutylammonium chloride (4.34 g, 15.6 mmol), N-chlorosuccinimide (20.9 g, 156.1 mmol) and TEMPO (2.44 g, 15.6 mmol) and the reaction mixture was stirred vigorously at rt for 4.5 h. The phases were separated and the organic phase was washed with sulfate buffer (100 ml), NaHCO3(100 ml), and brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography (35% EtOAc in n-heptane, v/v) gave aldehyde 9 (6.54 g, 38%) as a white amorphous solid.
With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -78℃; for 0.566667h;
The reaction was carried out with oven dried glassware. DMSO (85 mul, 1.1 mmol) was added to oxalyl chloride solution (0.35 mL 2 M DCM solution with 5 mL dry DCM) at -78 C. The reaction mixture was stirred at -78 C. for 10 min. 2-(3-Hydroxy-propyl)-isoindole-1,3-dione solution (102 mg, 0.5 mmol, in 2 mL DCM) was added drop wise in 2 min. Then triethylamine (0.35 mL, 2.5 mmol) was added drop wise in 2 min. The mixture was stirred for additional 30 minutes at -78 C. and was warmed up to room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude product was purified by flash chromatography to give 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde.
With sodium bromide; sodium bicarbonate; cyfluthrin; In dichloromethane;
Example 30 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)thiophene-3-carboxylic acid; To a stirred mixture at 0 C. of <strong>[883-44-3]2-(3-hydroxy-propyl)-isoindole-1,3-dione</strong> (0.2 g, 0.97 mmol), 0.7 M sodium bromide (0.70 ml, 0.46 mmol), TEMPO (3.0 mg, 0.02 mmol) in dichloromethane (1 ml) was added dropwise a solution of bleach (2.1 ml, 4.9 mmol) and sodium hydrogen carbonate (117 mg, 1.4 mmol). The mixture was stirred at 0 C. for 2 hours after the addition was finished. The mixture was extracted with ethyl acetate (3*20 ml). The combined organic extracts were washed with 10% sodium thiosulphate (3*10 ml), brine (10 ml), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was washed with ethyl acetate (2*1 ml) affording after drying 161 mg (81%) of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde as a solid. 1H NMR (400 MHz, CDCl3) delta 9.82 (s, 1H), 7.85 (dd, 2H, J=5.6, 2.8 Hz), 7.73 (dd, 2H, J =5.6, 2.8 Hz), 4.04 (t, 2H, J=7.2 Hz), 2.89 (t, 2H, J=7.2 Hz).
With 2-iodoxybenzoic acid; In ethyl acetate; for 3h;Reflux;
Compound 330(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-((5-(tert-butyl)-lH-benzo[d]imidazol- 2-yl)amino)propyI)amino)methyl)tetrahydrofuran-3,4-diolStep 1. Preparation of 3-(l,3-dioxoisoindolin-2-yl)propanal2-(3-hydroxypropyl)isoindoline-l,3-dione (414 mg, 2.0 mmol) and IBX (1.68 g, 6 mmol) were dissolved in EA (25 mL) and the reaction mixture was heated to reflux with stirring for 3 h. And then the mixture was filtrated and rinsed with EA (15 mL x 3), the filtrate was concentrated to afford the product (crude, 412 mg, yield: 100 %) as a yellow solid which was directly used for next step without further purification.
With 2-iodoxybenzoic acid; In ethyl acetate; for 2h;Reflux;
Compound 359l-(3-((((2R^S,4R,5R)-5 6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)propyl)-3-(3-chlorophenyl)ureaStep 1. Preparation of 2-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methyl)amino)propyl)isoindoline-l,3- dioneTo a solution of 2-(3-hydroxypropyl)isoindoline-l,3-dione (1.0 g, 4.88 mmol) in EA (50 mL) was added IBX (3.4 g, 12.19 mmol). The mixture was heated to reflux for 2h. After cooling, the mixture was filtered and the filtrate was concentrated to give 3-(l,3- dioxoisoindolin-2-yl)propanal crude (not weight), which was directly used for next step.To a solution of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)-9H-purin-6-amine (1.5 g, 4.90 mmol) and 3- (l ,3-dioxoisoindolin-2-yl)propanal (from last step) in DCE (50 mL) was added NaBH(OAc)3 (1.56 g, 7.30 mmol). The reaction mixture was stirred at rt overnight then saturated NaHC03 aqueous solution (50 mL) was added. The resulting mixture was extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by SGC (DCM : MeOH = 100 : 1 to 10 : 1) to afford the title compound (1.38 g, yield: 57%) as a white solid. 1H NMR (500 MHz, MeOD): 58.30 (s, 1H), 8.23 (s, 1H), 7.85-7.79 (m, 4H), 6.17 (d, J = 2.5 Hz, 1H), 5.48 (dd, J = 2.5, 6.0 Hz, 1H), 5.03 (dd, J = 3.0, 6.5 Hz, 1H), 4.36 (t , J = 3.5 Hz, 1H), 3.67-3.65 (m, 2H), 2.94-2.89 (m, 2H), 2.62-2.60 (m, 2H), 1.82-1.79 (m, 2H), 1.60 (s, 9H), 1.39 (s, 3H) ppm; ESI-MS (m/z): 494.2 [M+l]+.
With sodium hydride; In DMF (N,N-dimethyl-formamide); for 1.5h;
To a solution of 4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid, 1,I-di-methylethyl ester (6.7 g, 19 mmol, as prepared in Example 1, Part C) in anhydrous N,N-dimethylformamide (40 ml) at ambient temperature was added <strong>[883-44-3]N-(3-hydroxypropyl)phthalimide</strong> (4 g, 19 mmol), followed immediately by NaH (700 mg, 20 mmol, 60% dispersion in mineral oil). After 1.5 hr, HPLC showed less than 1% of the starting Electrophile. The reaction mixture was quenched with water (60 ml). The cloudy mixture was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with brine (1×200 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to give a tan, viscous oil that crystallized from methanol (3.2 g, 52%). ESMS m/z=489 [M+H]+. This material was used without further purification.
2-[3-(2-Oxo-2H-1-benzopyran-4-yloxy)-propyl]-isoindole-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃;
4-hydroxycoumarin (6.17 mmol, 1.0 g), PPh3 (6.48 mmol, 1.70 g), and <strong>[883-44-3]2-(3-hydroxy-propyl)-isoindole-1,3-dione</strong> (6.48 mmol, 1.33 g) is disolved in 20 mL THF and is cooled to 0 C. DIAD (6.79 mmol, 1.33 mL) is added dropwise at 0 C. A precipitate is formed immediately and the reaction mixture thickens. The precipitate is filtered, is washed with Et2O and is dried to afford the title compound (1.62 g, 75%). 1H NMR (DMSO-d6, 300 MHz) delta 7.82 (4H, m), 7.61 (2H, m), 7.37 (1H, m), 7.21 (1H, m), 5.83 (1H, s), 4.28 (2H, t, J=5.75 Hz), 3.83 (2H, t, J=6.25 Hz), 2.19 (2H, m); MS (ESI, Pos.) calcd for C20H15NO5 m/z [M+H]=350.1, found 350.1.
N4-Boc-N1-Nbs-trans-1,4-diaminocyclohexane[ No CAS ]
[ 883-44-3 ]
N1-Boc-N4-Nbs-N4-(3-propyl-1-phthalimide)-trans-1,4-diaminocyclohexane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; toluene; benzene; at 25℃; for 18h;Under argon;
N1-Boc-N4-Nbs-N4-(3-propyl-1-phthalimide)-trans-1,4-diaminocyclohexaneA solution of 310 mg (0.78 mmol) of N4-Boc-N1-Nbstrans-1,4-diaminocyclohexane was dissolved in 20 mL of 1:3 CH2Cl2/benzene together with 254 mg (0.97 mmol) of Ph3P and 127 mg (0.62 mmol) of <strong>[883-44-3]N-(3-hydroxypropyl)phthalimide</strong>. The resulting solution was stirred at 25 C. under argon. To this solution was added 191 L (0.97 mmol) of a 40% solution of DIAD in toluene dropwise. After addition was complete, stirring was continued for an additional 18 hours. The solution was evaporated to dryness and the crude oil purified on silica gel eluting first with 8:2 Hexane/EtOAc then with 1:1 Hexane/EtOAc to give a total of 322 mg (89%) of product as a clear oil (Rf 0.35 (1:1 Hexane/EtOAc
With sulfuric acid; In dichloromethane; at -5 - 20℃;
Dissolve 2- (3-HYDROXYPROPYL) ISOINDOLE-1, 3-dione (2 g, 9.74 mmol, leq) in 40 mL of dichloromethane under N2. Add sulfuric acid (780 U. L) and cool reaction mixture to - 5C. Condense isobutylene gas to a liquid using a-78C cold finger charged with dry ice and acetone. Add approximately 20 mL of the condensed liquid to the reaction mixture and slowly warm the solution to room temperature overnight while stirring. Add saturated, aqueous sodium hydrogencarbonate to the reaction mixture and extract product into the organics. Wash separated organic layer with water and dry over magnesium sulfate to give 1.969 g (77% yield) of 2- (3-TERT-BUTOXYPROPYL) ISOINDOLE-1, 3-dione as a colorless oil.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 18h;
Resin 2.7; - To all of the resin 2.6 obtained above suspended in 30 mL of dry THF is added as solids 11.02 g (42 mmole, 3 equiv) of triphenylphosphine and 8.62 g (42 mmole, 3 equiv) of <strong>[883-44-3]N-(3-hydroxypropyl)phthalimide</strong>. The resulting suspension is agitated with a slow stream of argon through the bottom of the vessel while 8.49 g (42 mmole, 3 equiv) of diisopropylazodicarboxyate is introduced in a dropwise fashion. The resulting suspension is agitated for 18 h at 25C when the solvents are filtered and washed with CH2C12, 'PrOH, DMF, THF then CH2C12 (3 x 75 mL each). The resin is dried under vacuum overnight to give a product that is negative by the Kaiser amine test reaction.
5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)thiophene-3-carboxylic acid[ No CAS ]
[ 2436-29-5 ]
Yield
Reaction Conditions
Operation in experiment
With sodium bromide; sodium bicarbonate; cyfluthrin; In dichloromethane;
Example 30 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)thiophene-3-carboxylic acid To a stirred mixture at 0 C. of <strong>[883-44-3]2-(3-hydroxy-propyl)-isoindole-1,3-dione</strong> (0.2 g, 0.97 mmol), 0.7 M sodium bromide (0.70 ml, 0.46 mmol), TEMPO (3.0 mg, 0.02 mmol) in dichloromethane (1 ml) was added dropwise a solution of bleach (2.1 ml, 4.9 mmol) and sodium hydrogen carbonate (117 mg, 1.4 mmol). The mixture was stirred at 0 C. for 2 hours after the addition was finished. The mixture was extracted with ethyl acetate (3*20 ml). The combined organic extracts were washed with 10% sodium thiosulphate (3*10 ml), brine (10 ml), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was washed with ethyl acetate (2*1 ml) affording after drying 161 mg (81%) of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde as a solid. 1H NMR (400 MHz, CDCl3) delta9.82 (s,1H), 7.85 (dd, 2H, J=5.6, 2.8 Hz), 7.73 (dd, 2H, J=5.6, 2.8 Hz), 4.04 (t, 2H, J=7.2 Hz), 2.89 (t, 2H, J=7.2 Hz).
cis 2-(3,4,5-trimethoxyphenyl)-5-(3-phthalimidyl propoxy) tetrahydrofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With triethylamine; trifluoroacetic anhydride; In dichloromethane;
(i) Preparation of trans and cis 2-(3,4,5-trimethoxyphenyl)-5-(3-phthalimidyl propoxy) tetrahydrofuran (compounds 107, 108) Compound 105 (1.14 g, 4.49 mmol) was dissolved in 4 mL dichloromethane. Triethylamine (681.4 mg, 6.73 mmol) was added to this solution. The reaction mixture was cooled with an ice bath and trifluoroacetic anhydride (1.41 g, 6.73 mmol) was added in a dropwise manner. The reaction mixture was stirred at 0 C. for 30 minutes and then 3-phthalimidylpropanol (106) (2.4 g, 13.26 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (107: 522 mg (trans); 108: 271 mg (cis); 1:1 mixture of 107 and 108: 110 mg; total yield 46%). 1 H NMR (CDCl3): 107: 1.70 (m,1H); 1.82 (m,1H); 2.00(m,2H); 2.02(m,1H); 2.28(m,1H); 3.46(m,1H); 3.83(s,3H); 3.84(m,3H); 3.88(s,6H); 4.99(t,1H); 5.30(dd,1H); 6.56(s,2H); 7.72(m,2H); 7.85(m,2H). 108: 1.95(m,3H); 2.00(m,2H); 2.20(m,1H); 3.51(m,1H); 3.83(s,3H); 3.85(m,2H); 3.88(s,6H); 3.92(m,1H); 4.90(m,1H); 5.16(dd,1H); 6.60(s,2H); 7.72(m,2H); 7.84(m,2H).
With potassium carbonate; In N,N-dimethyl-formamide;
(k) Preparation of 3-phthalimidylpropanol (compound 106) 3-Bromopropanol (4.0 g, 28.78 mmol), potassium phthalimide (8.0 g, 43.17 mmol) and potassium carbonate (4.0 g, 28.78 mmol) were added to 20 mL DMF. The reaction mixture was stirred at 70 C. for 4 hours, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl solution and evaporated in vacuo to a solid which was crystallized in ethyl acetate (3.5 g, 67%).
With potassium carbonate; In N,N-dimethyl-formamide;
(e) Preparation of N-(3-hydroxypropyl)phthalimide (106). A mixture of 3-bromopropanol (4 g, 0.029 mol), potassium phthalate (8 g, 0.043 mol) and potassium carbonate (4 g, 0.029 mol) in dry DMF (50 ml) was stirred and heated at 70 C. for four hours. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (3*75 ml). The organic extract was washed with water (3*100 ml) and dried (Na2 SO4). Removal of the solvent under reduced pressure left a white solid which was extracted with benzene. The benzene extract was evaporated to a white solid and recrystallized from ethyl acetate-hexanes to give white crystals (1.27 g, 24%).
N-(3-(pyridin-2-yloxy)propyl)phthalimide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaH; In N,N-dimethyl-formamide;
Step 25a. N-(3-(2-pyridyloxy)propyl)phthalimide A mixture of <strong>[883-44-3]N-(3-hydroxypropyl)phthalimide</strong> (Aldrich, 8.00 g, 38.98 mmol), 2-chloropyridimide (3.68 mL, 38.98 mmol) and NaH (60% dispersion, 2.33 g, 58.47 mmol) in DMF (100 mL) was heated at 75 C. and stirred for 5 days. The reaction mixture was then diluted with CH2 Cl2, filtered, and the filtrate concentrated to give the title compound (13 g).
A N-(3-hydroxypropyl)phthalimide A solution of 18.95 g (0.25 mo.) of 3-aminopropanol and 37.0 g (0.25 mol) of phthalic anhydride in 25 ml of dry toluene was refluxed for three hours using a Dean-Stark apparatus. The mixture was cooled, concentrated in vacuo, dissolved in dichloromethane and washed with water. The evaporated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 183-184 C. (0.1 mm Hg) to give 28.18 g (55%) of a white solid; m.p. 75-77 C.; NMR: (CDCl3) delta1.9 (2H,q), 3.65 (5H,m), 7.6 (4H,s),
B. 3-phthalimidopropyl acetoacetate A solution of 22.8 g (0.111 mol) of N-3-hydroxypropyl phthalimide and 14.46 g (0.111 mol) of ethyl acetoacetate was heated at 145-150 C. for 12 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was cooled to room temperature, dissolved in dichloromethane, and washed with brine. The separated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 211-219 C. (0.125 mm Hg) to yield 17.3 g (54%) of a white solid; m.p. 67-71 C. NMR: (CDCl3) delta2.0 (2H,m), 2.2 (3H,s), 3.3 (2H,s), 3.7 (2H,t), 4.05 (2M,t), 7.62 (4H,d).
EXAMPLE 29 3-(Phthalimido)-propyl formate A mixture of 3-(phthalimido)-propanol (20.5 g) and formic acid (33 ml) was refluxed overnight and evaporated in vacuo to leave a yellow oil which crystallized from absolute ethanol to give colourless crystals with m.p. 68-70 C.
EXAMPLE 67 5-Chloro-N-((l -(2-(3-(1 ,3-dioxoisoindolin-2-yl)propoxy)-4-(2-oxopyridin- 1 (2H)- yl)phenyl)-lH-l,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (67); <n="98"/>SCHEME 6Step l :N-(3-Hydroxypropyl)phthalimide (1.68 g, 8.2 mmol) was dissolved in 20 niL anhydrous DMSO. To it was added sodium hydride (60 % in mineral oil, 0.33 g, 8.2 mmol). After stirring for 1 hr at RT, a solution of compound 3.2 (0.96 g, 4.1 mmol) in 10 mL anhydrous DMSO was added. The mixture was stirred for 1 hr in 80 0C bath. It was diluted with chloroform and washed with brine three times. The organic phase was dried, concentrated and purified using flash column to afford compound 6.1 (45 %). MS found for C22H17N3O6 (M+H)+ 420.1.
With triphenylphosphine; diethylazodicarboxylate; at 0 - 20℃;
The procedure a for preparing compound 11 was similar to that of compound 10. And the procedure b was that to a solution of <strong>[580-18-7]3-hydroxyquinoline</strong> (0.73 g, 5.0 mmol), PPh3 (1.44 g, 5.5 mmol) and N-(3-hydroxypropyl)phthalimide (1.13 g, 5.5 mmol) was added DEAD (0.96 g, 5.5 mmol) at 0 dropwise. The mixture was stirred at 0 for 1 h and allowed to warm to room temperature and stirred at room temperature overnight. The reaction was filtered, washed with EA to give compound 11 (0.78 g, 47%), as a white solid. 1H NMR (400MHz, CDCl3): delta 8.46 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.84-7.82 (m, 2H), 7.72-7.68 (m, 3H), 7.55-7.48 (m, 2H), 7.32 (s, 1H), 4.16 (t, , J=6.0 Hz, 2H), 3.97 (t, J=6.8 Hz, 2H), 2.31-2.27 (m, 2H). HR-MS (ESI): calcd for C20H16N2O3 [M+H]+ 333.1234, found: 333.1362.
[00424] To a solution of Example 70c (3.42g, 16.65mmol) in dry THF (20mL) was added NaH (721 mg, 60% in mineral oil, 18.03mmol) at 0C. The suspension was stirred for 30min. Example 70b (3.8 g, 13.86 mmol) was added dropwise over 5min, and after lOmin, the ice bath was removed. The reaction mixture was stirred at r.t. overnight. To the mixture was added water (100 mL), which was then extracted with EtOAc (150 mL*2). The organic phase was dried over Na2S04and concentrated under reduce pressure to give the crude product Example 70d (5.0 g, crude yield90%) as yellow oil.LCMS [M+l]+ = 400.1
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 60℃; for 3h;Inert atmosphere;
<strong>[50824-04-9]4-bromo-2-trifluoromethylphenol</strong> (100 mg, 0.415 mmol), N-(3-hydroxypropyl) quinone imine (85mg, 0.415mmol), Diethyl azodicarboxylate (131 muL, 0.830 mmol) and triphenylphosphine (218 mg, 0.830 mmol) were dissolved in ultra dry THF, and reacted under nitrogen for 3 hours at 60 C. Directly add silica gel to dry and mix. Separation and purification by column chromatography to obtain intermediate 44a (white solid, 73mg), The yield was 41%.
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