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Structure of 28188-41-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Organic Process Research and Development, 2002, vol. 6, # 2, p. 190 - 191
3
[ 10406-24-3 ]
[ 28188-41-2 ]
Reference：
[1] Patent: US6187945, 2001, B1,
4
[ 620-22-4 ]
[ 28188-41-2 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 2010, vol. 75, # 10, p. 1041 - 1050
[2] Journal of Organic Chemistry, 1990, vol. 55, # 3, p. 1040 - 1043
[3] Journal of Organic Chemistry, 1952, vol. 17, p. 272,284
[4] Justus Liebigs Annalen der Chemie, 1925, vol. 445, p. 232
[5] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1925, vol. <6> 2, p. 426
[6] Die Pharmazie, 1973, vol. 28, # 11, p. 724 - 729
[7] Archiv der Pharmazie, 1978, vol. 311, # 2, p. 81 - 97
[8] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1990, # 1, p. 257 - 261
[9] Journal of Organic Chemistry, 1990, vol. 55, # 3, p. 1040 - 1043
[10] Journal of the Indian Chemical Society, 1990, vol. 67, # 11, p. 909 - 911
[11] Journal of Fluorine Chemistry, 1996, vol. 77, # 1, p. 65 - 70
[12] Journal of Physical Organic Chemistry, 2000, vol. 13, # 10, p. 587 - 590
[13] Pest Management Science, 2000, vol. 56, # 10, p. 875 - 881
[14] Organic Letters, 2013, vol. 15, # 16, p. 4194 - 4197
5
[ 64407-07-4 ]
[ 28188-41-2 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1925, vol. <6> 2, p. 426
6
[ 7726-95-6 ]
[ 620-22-4 ]
[ 28188-41-2 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1925, vol. <6> 2, p. 426
7
[ 28188-41-2 ]
[ 10406-24-3 ]
Reference：
[1] Chemical Communications, 2015, vol. 51, # 39, p. 8253 - 8256
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3477 - 3482
[3] Journal of the American Chemical Society, 1991, vol. 113, # 11, p. 4208 - 4218
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[5] Patent: WO2016/7966, 2016, A2,
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 24, p. 6908 - 6910
10
[ 28188-41-2 ]
[ 52010-98-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1981, vol. 24, # 5, p. 535 - 544
11
[ 74-89-5 ]
[ 28188-41-2 ]
[ 90389-96-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 20℃; for 3 h; Inert atmosphere
Step 1: 3-[(methylamino)methyllbenzonitrileIn a 3 necked round bottom flask (250 ml), put under nitrogen atmosphere, a solution of 3- (bromomethyl)benzonitrile (5 g; 25.5 mmol; 1 eq.) in anhydrous THF (20 ml) was added dropwise into methylamine (63.76 ml; 2 M; 127.52 mmol; 5 eq.) (2M solution in THF) over 1 hour. The reaction mixture was stirred at RT for 2 hours. Some bis-benzylation was observed (7percent). The reaction mixture was filtered to remove the salt. The filtrate was evaporated under reduced pressure. The residue was taken up with DCM and evaporated again to give the title compound as a yelllow oil (3.78 g, quantitative yield). It was used in the next step without any further purification. LC/MS (Method B) 146.8 (M+H)+.
96%
at 20℃; for 24 h;
To a commercially available solution of methylamine 2M in tetrahydrofuran (200 ml, 400 mmol), 11.2 g (57.1 mmol) of 3-(bromomethyl)benzonitrile dissolved in 112 ml of <n="46"/>tetrahydrofuran were added dropwise. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The obtained residue was diluted with ethyl ether and extracted with 1 N HCI. The acidic extracts were basified with solid potassium carbonate and the basic solution extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The title compound was obtained as an oil (7.98g, 96percent).
82%
at 0 - 20℃; for 3.16 h;
To a stirred solution of methylamine(40percent in water) (200 ml_) under N2, was added 3-(bromomethyl)benzonitrile (10 g, 0.051 mol) slowly in small portions over a period of 10min at O0C. After being stirred at RT for 3h, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The obtainted crude was purified using column chromatography on silica gel (pet ether/ehyl acetate) to afford the title compound as a pale yellow liquid (6.1 g, 82percent). 1H NMR (DMSO-de, 400 MHz) δ 7.74 (s, 1 H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1 H), 3.66 (s, 2H), 2.22 (s, 3H).
82%
at 0 - 20℃; for 3.16667 h;
To a stirred solution of methylamine (40percent in water, 200 mL) under N2, was added 3- (bromomethyl)benzonitrile (10 g, 51 mmol) slowly in portions over 10 minutes at O0C. After being stirred at RT for 3 hours, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid (6.1 g, 82percent). 1H NMR (DMSOd6, 400 MHz) δ 7.74 (s, 1 H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1 H), 3.66 (s, 2H), 2.22 (s, 3H).
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; toluene at 0℃; for 2.5 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; dichloromethane; toluene for 1 h;
Synthesis of Compounds 60 and 61 Compounds 60 and 61 were synthesized from α-bromomethyl-tolunitril. To a solution of α-bromomethyl-tolunitril (15.3 mmol) in toluene (30 mL) was added DIBAL-H in THF (1.0 M, 1.4 eq.) at 0° C. within 30 minutes. After stirring at 0° C. for 2 h, the reaction mixture was poured into a mixture of 40 mL of methylene chloride and 100 mL of 10percent HCl. The resulting mixture was stirred for 1 h and the organic layer was washed with water and then brine, and the aqueous was extracted with methylene chloride twice. After dried over Na2SO4, filtered, and concentrated, the obtained semi-oily product was stored in a refrigerator to give 3-(bromomethyl)benzaldehyde as a white crystalline solid in quantitative yield. Reaction of the resulting compound with acetone in ethanol following the procedure descripted in Scheme 4 yielded Compound 61 as a light yellow crystalline solid. ESI MS m/z: 420.9 [M+H]+; 1H NMR (400 MHz, CDCl3) δ: 7.71 (d, 2H, J=16.0 Hz, H-1, 5), 7.63-7.60 (m, 2H, aromatic ring H), 7.54-7.50 (m, 2H, aromatic ring H), 7.44-7.37 (m, 4H, aromatic ring H), 7.08 (d, 2H, J=16.0 Hz, H-2, 4), 4.50 (s, 4H, -CH2Br).
93%
With diisobutylaluminium hydride In tetrahydrofuran; toluene at 0℃; for 2 h;
To a solution of 3-(bromomethyl)benzonitrile (212mg, 1.081 mmol) in 2.5mL Toluene was added dropwise 1M DIBAL-H in THF (1.5 ml, 1.5 mmol) at 0° C. After stirring at 0°C for 2 h the reaction was diluted with DCM and IN aq. HCl and stirred for 1 hour. The organic layer was washed with brine, dried over sodium sulfate, and concentrated yielding the titled compound as an orange oil. (200mg, 0.970 mmol, 93percent yield)
88%
With diisobutylaluminium hydride In toluene at -78 - 0℃; for 1.5 h;
3- (Bromomethyl) benzonitrile (1.0 g, 5.10 mmol) was dissolved in toluene (17 L), cooled to 0 C and 1.5 M DIBAL (4.08 L, 6.12 mmol) dissolved in toluene was slowly added dropwise. The reaction solution was stirred at 0 ° C for 1.5 hours, and 1N HCl solution was slowly added thereto.The reaction solution was diluted with CH2Cl2 and washed with water. The organic solvent was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-Hex / EtOAc = 9/1) to obtain the target compound 3- (bromomethyl) benzaldehyde (880 mg, 88percent).
71%
Stage #1: With diisobutylaluminium hydride In chloroform; chlorobenzene at 5℃; for 1 h; Cooling with ice Stage #2: With hydrogenchloride; water In hexane; chloroform; chlorobenzene
Step 1: 3-Bromomethyl-benzaldehyde A solution of 3-cyanobenzyl bromide (available from Aldrich; 10.1 g, 51.5 mmol) in chlorobenzene (100 mL) was cooled in an ice-water bath. A solution of diisobutylaluminum hydride in hexanes (available from Aldrich; 1 M; 65 mL, 65 mmol) was added over 25 minutes, and the reaction mixture was stirred below 5° C. for 1 h. Chloroform (100 mL) was added, followed by 10percent aqueous hydrochloric acid (dropwise). The layers were separated and the organic layer was washed with water. Each aqueous layer was back extracted with chloroform, and the organic phases were combined, dried over sodium sulfate, filtered, evaporated and purified by chromatography, eluting with 0-40percent ethyl acetate/hexanes to give pure fractions and a number of impure fractions. The impure fractions were chromatographed a second time, eluting with 0-27percent ethyl acetate/hexanes. Fractions homogeneous for the product from the two chromatographic separations were combined and concentrated. The residue was dissolved in ether and layered with hexane. The mixture was chilled overnight and the solid was filtered off, washed with hexane and dried under high vacuum at room temperature to give 3-bromomethyl-benzaldehyde (7.32 g, 71percent).
Reference：
[1] Patent: US2012/46247, 2012, A1, . Location in patent: Page/Page column 29
[2] Chemical Communications, 2014, vol. 50, # 56, p. 7424 - 7426
[3] Patent: WO2017/223086, 2017, A1, . Location in patent: Page/Page column 84
[4] Tetrahedron, 1997, vol. 53, # 20, p. 6755 - 6790
[5] Patent: KR2018/56603, 2018, A, . Location in patent: Paragraph 0363; 0365-0367
[6] Journal of the American Chemical Society, 1992, vol. 114, # 12, p. 4889 - 4898
[7] Journal of the American Chemical Society, 1991, vol. 113, # 11, p. 4208 - 4218
[8] Organic and Biomolecular Chemistry, 2010, vol. 8, # 5, p. 1181 - 1187
[9] Journal of the American Chemical Society, 1997, vol. 119, # 33, p. 7726 - 7733
[10] Patent: US2011/124686, 2011, A1, . Location in patent: Page/Page column 25
[11] Archiv der Pharmazie, 1997, vol. 330, # 8, p. 247 - 252
[12] Dalton Transactions, 2012, vol. 41, # 23, p. 7092 - 7097
13
[ 7647-01-0 ]
[ 28188-41-2 ]
[ 82072-23-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
With dibal-H In toluene
Compound 8 A 2 L round-bottom was charged with 3-(bromomethyl)-benzonitrile 7 (48.0 g) and dry toluene (480 mL). After cooling to 0° C., DIBAL-H (1.0 M in PhMe, 306 mL) was added over a 90 min period via pressure-equalizing addition funnel under N2. Once addition was complete, the reaction was allowed to stir an additional 90 min. Then 1.0 M aq HCl (1.2 L) was added carefully, and the reaction was allowed to stir for 15 min. The organic phase was collected, and the aq phase was extracted (2*250 mL Et2O). All organic extracts were combined, dried (MgSO4), filtered, and concentrated. The oily residue was purified on a 330 g normal phase silica gel column (combiflash, EtOAc/Hex 10:90 to 50:50, gradient), giving the 3-(bromomethyl)-benzaldehyde (37.14 g, 77percent yield). 1H-NMR (300 MHz, CDCl3) d: 9.98 (s, 1H), 7.86 (app. s, 1H), 7.77 (app.d, J=7.6 Hz, 1H), 7.63 (app. d, J=7.7 Hz, 1H), 7.48 (app. dd, J=7.7, 7.6 Hz, 1H), 4.51 (s, 2H). LCMS-ESI failed to provide reliable data.
Reference：
[1] Patent: US2011/150836, 2011, A1,
14
[ 1191-15-7 ]
[ 28188-41-2 ]
[ 82072-23-9 ]
Reference：
[1] Patent: US6489487, 2002, B1,
15
[ 28188-41-2 ]
[ 34231-22-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8140 - 8151
16
[ 28188-41-2 ]
[ 57213-48-6 ]
Reference：
[1] Patent: WO2004/103984, 2004, A1,
17
[ 28188-41-2 ]
[ 220364-34-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8140 - 8151
In THjfF (tetrahydrofuran); at 20℃; for 3h;Inert atmosphere;
Step 1: 3-[(methylamino)methyllbenzonitrileIn a 3 necked round bottom flask (250 ml), put under nitrogen atmosphere, a solution of 3- (bromomethyl)benzonitrile (5 g; 25.5 mmol; 1 eq.) in anhydrous THF (20 ml) was added dropwise into methylamine (63.76 ml; 2 M; 127.52 mmol; 5 eq.) (2M solution in THF) over 1 hour. The reaction mixture was stirred at RT for 2 hours. Some bis-benzylation was observed (7%). The reaction mixture was filtered to remove the salt. The filtrate was evaporated under reduced pressure. The residue was taken up with DCM and evaporated again to give the title compound as a yelllow oil (3.78 g, quantitative yield). It was used in the next step without any further purification. LC/MS (Method B) 146.8 (M+H)+.
96%
In tetrahydrofuran; at 20℃; for 24h;
To a commercially available solution of methylamine 2M in tetrahydrofuran (200 ml, 400 mmol), 11.2 g (57.1 mmol) of 3-(bromomethyl)benzonitrile dissolved in 112 ml of <n="46"/>tetrahydrofuran were added dropwise. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The obtained residue was diluted with ethyl ether and extracted with 1 N HCI. The acidic extracts were basified with solid potassium carbonate and the basic solution extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The title compound was obtained as an oil (7.98g, 96%).
82%
In water; at 0 - 20℃; for 3.16h;
To a stirred solution of methylamine(40% in water) (200 ml_) under N2, was added 3-(bromomethyl)benzonitrile (10 g, 0.051 mol) slowly in small portions over a period of 10min at O0C. After being stirred at RT for 3h, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The obtainted crude was purified using column chromatography on silica gel (pet ether/ehyl acetate) to afford the title compound as a pale yellow liquid (6.1 g, 82%). 1H NMR (DMSO-de, 400 MHz) delta 7.74 (s, 1 H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1 H), 3.66 (s, 2H), 2.22 (s, 3H).
82%
In water; at 0 - 20℃; for 3.16667h;
To a stirred solution of methylamine (40% in water, 200 mL) under N2, was added 3- (bromomethyl)benzonitrile (10 g, 51 mmol) slowly in portions over 10 minutes at O0C. After being stirred at RT for 3 hours, the reaction mixture was extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid (6.1 g, 82%). 1H NMR (DMSOd6, 400 MHz) delta 7.74 (s, 1 H), 7.63-7.68 (m, 2H), 7.48-7.52 (m, 1 H), 3.66 (s, 2H), 2.22 (s, 3H).
In methanol; for 1h;Heating / reflux;
A-BROMO-M-CYANOTOLUENE (1.0 g, 5.1 mmol) in 2M MeNH2/MeOH (25. 5 mL, 51 mmol) was refluxed for lh. After evaporating most of solvent, the resulting solid was filtered. The mother liquor was concentrated in vacuo and it was purified by chromato- GRAPHY.
Synthesis of Compounds 60 and 61 Compounds 60 and 61 were synthesized from alpha-bromomethyl-tolunitril. To a solution of alpha-bromomethyl-tolunitril (15.3 mmol) in toluene (30 mL) was added DIBAL-H in THF (1.0 M, 1.4 eq.) at 0 C. within 30 minutes. After stirring at 0 C. for 2 h, the reaction mixture was poured into a mixture of 40 mL of methylene chloride and 100 mL of 10% HCl. The resulting mixture was stirred for 1 h and the organic layer was washed with water and then brine, and the aqueous was extracted with methylene chloride twice. After dried over Na2SO4, filtered, and concentrated, the obtained semi-oily product was stored in a refrigerator to give 3-(bromomethyl)benzaldehyde as a white crystalline solid in quantitative yield. Reaction of the resulting compound with acetone in ethanol following the procedure descripted in Scheme 4 yielded Compound 61 as a light yellow crystalline solid. ESI MS m/z: 420.9 [M+H]+; 1H NMR (400 MHz, CDCl3) delta: 7.71 (d, 2H, J=16.0 Hz, H-1, 5), 7.63-7.60 (m, 2H, aromatic ring H), 7.54-7.50 (m, 2H, aromatic ring H), 7.44-7.37 (m, 4H, aromatic ring H), 7.08 (d, 2H, J=16.0 Hz, H-2, 4), 4.50 (s, 4H, -CH2Br).
93%
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at 0℃; for 2h;
To a solution of 3-(bromomethyl)benzonitrile (212mg, 1.081 mmol) in 2.5mL Toluene was added dropwise 1M DIBAL-H in THF (1.5 ml, 1.5 mmol) at 0 C. After stirring at 0C for 2 h the reaction was diluted with DCM and IN aq. HCl and stirred for 1 hour. The organic layer was washed with brine, dried over sodium sulfate, and concentrated yielding the titled compound as an orange oil. (200mg, 0.970 mmol, 93% yield)
88%
With diisobutylaluminium hydride; In toluene; at -78 - 0℃; for 1.5h;
3- (Bromomethyl) benzonitrile (1.0 g, 5.10 mmol) was dissolved in toluene (17 L), cooled to 0 C and 1.5 M DIBAL (4.08 L, 6.12 mmol) dissolved in toluene was slowly added dropwise. The reaction solution was stirred at 0 C for 1.5 hours, and 1N HCl solution was slowly added thereto.The reaction solution was diluted with CH2Cl2 and washed with water. The organic solvent was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-Hex / EtOAc = 9/1) to obtain the target compound 3- (bromomethyl) benzaldehyde (880 mg, 88%).
71%
Step 1: 3-Bromomethyl-benzaldehyde A solution of 3-cyanobenzyl bromide (available from Aldrich; 10.1 g, 51.5 mmol) in chlorobenzene (100 mL) was cooled in an ice-water bath. A solution of diisobutylaluminum hydride in hexanes (available from Aldrich; 1 M; 65 mL, 65 mmol) was added over 25 minutes, and the reaction mixture was stirred below 5 C. for 1 h. Chloroform (100 mL) was added, followed by 10% aqueous hydrochloric acid (dropwise). The layers were separated and the organic layer was washed with water. Each aqueous layer was back extracted with chloroform, and the organic phases were combined, dried over sodium sulfate, filtered, evaporated and purified by chromatography, eluting with 0-40% ethyl acetate/hexanes to give pure fractions and a number of impure fractions. The impure fractions were chromatographed a second time, eluting with 0-27% ethyl acetate/hexanes. Fractions homogeneous for the product from the two chromatographic separations were combined and concentrated. The residue was dissolved in ether and layered with hexane. The mixture was chilled overnight and the solid was filtered off, washed with hexane and dried under high vacuum at room temperature to give 3-bromomethyl-benzaldehyde (7.32 g, 71%).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
3-Bromomethyl-benzonitrile (42.9g, 219 mmol, 1 equivalent) is combined with <strong>[51779-32-9]Di-tert-butyl iminodicarboxylate</strong> (50 g, 230.13 mmol, 1.05 equivalents) and cesium carbonate (74.98g, 230.13 mmol, 1.05 equivalents) in Nu,Nu-dimethyl formamide (DMF) (230 mL). The reaction is stirred at room temperature overnight and then partitioned between diethyl ether (500 mL) and water (1L). The aqueous layer is extracted with an additional portion of diethyl ether (250 mL) and the combined ether layers are washed with brine (2x200 mL). The organic layer is then dried (MgSC>4), filtered, and reduced in vacuo to yield oil that slowly crystallized to give 2 (3-cvanophenyl)methyl1-Imidodicarbonic acid 1.3-bis(l.l-dimethylethyl) ester (72 g, 99%). MS: 333 (M+H), 355 (M+Na).1H NMR (300 MHz, CDC13): delta = 1.47 (s, 18H), 4.79 (s, 2H), 7.42 (t, 1H), 7.54-7.60 (m, 3H).
87%
With caesium carbonate; lithium iodide; In tetrahydrofuran; at 70℃; for 22h;
3-(Bromomethyl) benzonitrile (5g, 25. 5mmoles) and di-tert- BUTYLIMINODICARBOXYLATE (5.54g, 25. 5MMOLES) were dissolved in anhydrous THF (50mL) and cesium carbonate (16.62g, 25. 5mmoles) and lithium iodide (170. 5mg, 1. 275mmoles) were added. The mixture was stirred at 70 C FOR 22H and the reaction was worked up as described in Preparative Example 89, Step B above. The residue was chromatographed on a silica gel column (60x5cm) using 5% ethyl acetate in hexane as the eluant to give 3- (DI-TERT- BUTOXYCARBONYLAMINO) BENZONITRILE (7.39g, 87%): FABMS: m/z 333.2 (MH+) ; HRFABMS: m/z 333.1815 (MH+) ; Calcd. for C18H25N204 : m/z 333.1814 ; 8H (CDCI3) 1.52 (18H, S,-COOC (CH3) 3), 4. 84 (2H, s, CH2), 7.48 (1H, m, Ar-H), 7.60 (2H, m, Ar-H) and 7.65 ppm (1H, m, Ar-H); 8c (CDCI3) CH3 : 28.1, 28.1, 28.1, 28.1, 28.1, 28.1 ; CH2 : 48.4 ; CH: 129.2, 131.0, 131.0, 131.9 ; C: 83.2, 83.2, 112.5, 118.8, 140. 1, 152.5, 152.5.
1-(3-cyano-benzyl)-4-(5-nitro-pyridin-2-yl)-piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetone; for 2h;Heating / reflux;
To a stirred solution of 5-nitro-2-piperazinyl-pyridine (10.1 g) and potassium carbonate (20.29 g) in acetone (500 mL) was added portionwise 3-cyano-benzyl bromide (9.6 g) and the mixture was heated under reflux during 2 hours. The salts were removed by filtration, washed with acetone and the filtrate was evaporated to dryness. The residue was taken in CH2Cl2, and the solution washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure to leave an oil which crystallized by trituration with diisopropyl oxyde. The title compound was obtained as a yellow solid (14.4 g). [0245] m.p.: 103-105 C.
Diethyl 2-t-butoxycarbonylamino-2-(3-cyanophenyl)methyl malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.38 g (95%)
With NaOEt; In tetrahydrofuran;
To the NaOEt solution at 0 C. was added dropwise diethyl 2-t-butoxycarbonylamino malonate (4 g, 14.5 mmol). After 10 minutes, a solution of 3-bromomethylbenzonitrile (3.13 g, 15.13 mmol) in dry THF (7 mL) was added dropwise, and the solution was stirred for 2 h at 0 C. After concentration, the residue was taken up with EA, washed with the saturated NH2Cl and then brine, dried and concentrated to give 5.38 g (95%) of the title compound.
Reference Production Example 8 To a solution of 5.00 g (25.5 mmol) of 3-(bromomethyl)benzonitrile in 50 ml of dry toluene was added dropwise 37.9 ml (36 mmol) of diisobutylaluminumhydride (0.95 mol/liter of n-hexane solution) with ice-cooling under an atmosphere of nitrogen and the mixture was stirred with ice-cooling for additional 1 hour. To the reaction solution was added 80 ml of chloroform with ice-cooling and further was added 200 ml of about 10% aqueous hydrochloric acid with ice-cooling, The mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed with water, dried and concentrated. The solid residue (4.90 g) was washed with n-hexane, cooled, collected by filtration, and dried to obtain 4.27 g of crude 3-(bromomethyl)benzaldehyde as crystals.
3-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 9 Preparation of 3-(3,5-Di-t-butylphenoxymethyl)-1benzenecarbonitrile Using the method of Example 1, 20.6 g (0.10 mole) of alpha-bromo-m-tolunitrile was reacted with 3,5-di-t-butylphenol to give white crystalline 3-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile. Analysis: Calculated for C22 H27 NO: %C 82.2; %H, 8.4; %N, 4.4; Found: %C, 82.2; H, 8.5; %N, 4.1.
1-(m-cyanobenzyl)-5-aminoimidazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol; acetone;
EXAMPLE 3 Preparation of 1-(m-cyanobenzyl)-<strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong> A mixture of <strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong> (5.00 g), potassium carbonate (12.0 g), and alpha-bromo-m-tolunitrile (9.80 g) were refluxed in acetone (300 ml) for 24 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The solid residue was washed with acetone and the combined filtrates were evaporated to dryness. The residual solid was dissolved in acetone (50 ml), concentrated to a volume of 20 ml in vacuo, and diluted with diethyl ether (100 ml) to provide a gum. The solvent was decanted from the residue and deposited crystals of crude product on standing. The gum was triturated twice with acetone, and the acetone layers were combined with the above crystals, and evaporated to provide 5.9 g of a dark gum. The gum was dissolved in methanol (100 ml), filtered, added to 100 ml. E. Merck 7734 silica gel, and evaporated to dryness in vacuo. The product on silica gel was placed on top of a column of 1200 ml E. Merck 7734 silica gel and eluted with 9:1 v/v methylene chloride/methanol. After a forerun of 1.0 l, 400 ml fractions were collected and fractions 8-11 and 12-15 were combined separately and evaporated to dryness. The solid product from fractions 8-11 was triturated with a small volume of acetone and filtered. The filtrate was combined separately with the product from fractions 12-15 and evaporated to dryness. The product was recrystallized from methanol to provide 320 mg of 1-(m-cyanobenzyl)-<strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong>, m.p. 246-247 C.
EXAMPLE 23 alpha-(5-Methoxy-1-indolinyl)-m-tolunitrile An ice cold slurry of 5.89 g (42.6 mmole) of K2 CO3 and 5.3 g (35.5 mmole) of <strong>[21857-45-4]5-methoxyindoline</strong> in 55 ml of DMF was treated dropwise with a solution of 7.28 g (37.3 mmole) of alpha-bromo-m-tolunitrile in 50 ml of DMF. After stirring for 1 hour at room temperature, the reaction mixture was concentrated under high vacuum. The residue was partitioned between methylene chloride (250 ml) and water (250 ml). The organic layer was separated, washed with 5% NaOH (300 ml), brine (300 ml), dried over Na2 SO4 and concentrated under vacuum to yield 9.28 g (98.9% yield) of alpha-(5-methoxy-1-indolinyl)-m-tolunitrile.
EXAMPLE 59 2-Acetamino-N-benzyl-5-cyano-N-n-propyl-benzylamine, m.p. 109-111 C, was prepared from 2-acetamino:5-cyano-benzylbromide and N-n-propyl-benzylamine analogous to Example 8.
With potassium bromide; sulfuric acid; sodium thiosulfate; sodium nitrite; In dichloromethane; water;
Example 5 m-Cyanobenzylamine (13.2 g), potassium bromide (23.8 g), water (18 g), and methylene chloride (18 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (98% by weight) (29.4 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. Further, sodium thiosulfate was added to the mixture, and the resultant mixture was stirred at room temperature for one hour. Gas chromatographic analysis revealed that the yield of m-cyanobenzyl bromide was 57%.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80℃; for 5h;
A mixture of <strong>[612832-83-4]2-benzyloxy-5-chlorophenylboronic acid</strong> (2. 1G), 3-cyanobenzyl bromide (1.57g), sodium carbonate (1.7g) and tetrakis (triphenylphosphine) palladium (0) (0.46g) in ethylene glycol dimethyl ether (30ML) was heated at 80C for 5H. The mixture was cooled, partitioned between WATER/DIETHYLETHER, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethylacetate/isohexane, yield 0.53g. H NMR DMSO-D6 : 8 7.68-7. 24 (11H, m); 7.08 (1H, d); 5.10 (2H, s); 3.97 (2H, s)
5-benzyloxy-1-(3-cyano-benzyl)-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: 5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester With sodium hydride In DMF (N,N-dimethyl-formamide) at 20℃; for 1h;
Stage #2: m-(bromomethyl)benzonitrile at 20℃; for 1.5h;
5-benzyloxy-1-(3-cyano-benzyl)-1H-indole-2-carboxylic acid 3-cyano-benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: 5-benzyloxy-1H-indole-2-carboxylic acid With potassium carbonate In DMF (N,N-dimethyl-formamide) at 60℃; for 1h;
Stage #2: m-(bromomethyl)benzonitrile at 60℃; for 5h;
Example 12 (S)-N-[1-(3-Cyano-benzyl)-1H-pyrazol-3-yl]-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide A solution of <strong>[26621-44-3]3-nitropyrazole</strong> (prepared as in Example 5, 938 mg, 8.3 mmol) in N,N-dimethylformamide (15 mL) was treated with sodium hydride (519 mg, 60% suspension, 12.97 mmol). Effervescence was observed. The mixture was stirred for 30 min. Then, a solution of 1-bromo-3-cyano-toluene (2.14 g, 10.37 mmol) in N,N-dimethylformamide (5 mL) was added. The mixture was stirred for 24 h at room temperature. The reaction mixture was diluted with water, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 90% ethyl acetate/hexanes) to afford, 3-(3-nitro-pyrazol-1-ylmethyl)-benzonitrile (1. 17 g, 59%), as a white solid.
With triethylamine; In acetonitrile; at 0 - 20℃; for 5h;
To a solution of N-(2-methoxyethyl)-N-methylamine (3.8 g, 42.8 mmol) and TEA (4.68 ml_, 46.4 mmol) in ACN (75 ml.) under N2, was added 3-(bromomethyl)benzonitrile (7 g, 35.7 mmol) at 00C. After being stirred at RT for 5h, the reaction mass was concentrated under reduced pressure and the resulting pale yellow liquid diluted with DCM and washed water with to afford the title compound as a pale yellow liquid (6.4 g, 87%). 1H NMR (DMSO-d6, 400 MHz) delta 7.69-7.71 (m, 2H), 7.62-7.64 (m, 1 H), 7.50-7.54 (m, 1 H), 3.54 (s, 2H), 3.41-3.44 (m, 2H), 3.21 (s, 3H), 2.48-2.52 (m, 2H), 2.14 (s, 3H).
Intermediate 413-[(3-Amino-4-chloro-1H-indazol-1-yl)methyl]benzonitrile; To a suspension of ground potassium hydroxide (421 mg, 7.50 mmol) in anhydrous dimethyl sulfoxide (5 mL) at room temperature under nitrogen was added a solution of <strong>[20925-60-4]4-chloro-1H-indazol-3-amine</strong> (for a preparation see Intermediate 40) (503 mg, 3.0 mmol) in anhydrous dimethyl sulfoxide (15 mL). After 30 minutes 3-cyanobenzyl bromide (Aldrich) (735 mg, 3.75 mmol) was added in one portion. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (200 mL), forming a yellow/brown emulsion. This was extracted using chloroform (2×200 mL). The combined organic solutions were washed with water:brine (1:1) (200 mL), passed through a hydrophobic frit, and evaporated in-vacuo to yield a brown oil. The oil was applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-100% ethyl acetate in cyclohexane gradient over 80 min. Fractions 32-34 were combined and the solvent was evaporated in-vacuo to yield the title compound as an off white solid (216 mg, 25%). LCMS (System B) RT=2.51 min, ES+ve m/z 283 (M+H)+.
Compound 8 A 2 L round-bottom was charged with 3-(bromomethyl)-benzonitrile 7 (48.0 g) and dry toluene (480 mL). After cooling to 0 C., DIBAL-H (1.0 M in PhMe, 306 mL) was added over a 90 min period via pressure-equalizing addition funnel under N2. Once addition was complete, the reaction was allowed to stir an additional 90 min. Then 1.0 M aq HCl (1.2 L) was added carefully, and the reaction was allowed to stir for 15 min. The organic phase was collected, and the aq phase was extracted (2*250 mL Et2O). All organic extracts were combined, dried (MgSO4), filtered, and concentrated. The oily residue was purified on a 330 g normal phase silica gel column (combiflash, EtOAc/Hex 10:90 to 50:50, gradient), giving the 3-(bromomethyl)-benzaldehyde (37.14 g, 77% yield). 1H-NMR (300 MHz, CDCl3) d: 9.98 (s, 1H), 7.86 (app. s, 1H), 7.77 (app.d, J=7.6 Hz, 1H), 7.63 (app. d, J=7.7 Hz, 1H), 7.48 (app. dd, J=7.7, 7.6 Hz, 1H), 4.51 (s, 2H). LCMS-ESI failed to provide reliable data.
General procedure: A mixture of 44 (300 mg, 1.56 mmol), K2CO3 (372 mg, 2.34 mmol), and halogenated compound (1 equiv) in acetone (10 mL) was stirred for 0.5-3.5 h at rt. After filtering the mixture and removing the solvent in vacuo, the residue was purified by column chromatography (eluent: hexane/EtOAc 85:15) to obtain the target compounds (11-23) as white solids.
With triethylamine; In dichloromethane; at 0℃; for 5h;Reflux;
To a reaction flask equipped with a stirrer, a condenser and a thermometer was added 19.2 g of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one, which was then dispersed in 80 mL dichloromethane and cooled to 0 C. under stirring. 30.4 g of triethylamine were added to the mixture. After addition of 15.2 g of 3-cyanobenzyl bromide to the reaction system in batches, the reaction mixture was heated to reflux and continued to react for 5 h (completion of the reaction was monitored by TLC). The reaction liquid was washed with water (3×80 mL). Then the dichloromethane layer was separated, fully dried over anhydrous sodium sulfate, and filtered. The dichloromethane was evaporated off under reduced pressure to obtain 20.8 g light yellow solid product (HPLC: 96.4%). Rf=0.45 [single point, developing solvent: v (petroleum ether): v (ethyl acetate)=1:2]. MS, m/Z: 270.0 (M).
General procedure: Potassium carbonate (1-1.6 equiv) was added to a stirred solution of the phenol (1 equiv) in DMF. After 30 min the cyanobenzyl bromide (1-1.2 equiv) was added, and the mixture was stirred until completion (1-4 days). The reaction mixture was poured over ice or diluted with water. The precipitated product was filtered off and recrystallized if needed.
To a solution of 14 (0.804 g, 7.5 mmol) in dry THF (30 mL) was added n-BuLi (1.6 M solution in hexanes, 4.68 mL, 7.5 mmol), and the reaction was stirred for 30 min at 0 C. This solution (red color) was added dropwise to a solution of 3-(bromomethyl)benzonitrile (15, 1.16 g, 6.0 mmol) in THF (20 mL) at -78 C using a cannula, until the solution became pale red. The reaction mixture was allowed to stir for an additional 20 min, and then quenched with H2O (50 mL). After addition of ethyl acetate (100 mL), the organic layer was partitioned, dried with MgSO4, and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography (EtOAc/hexanes) to yield the title compound as a yellow oil (680 mg, 51%). 1H NMR (500 MHz, CDCl3) delta 8.40 (d, J = 5.0 Hz, 1H), 7.52- 7.39 (m, 3H), 7.36 (t, J = 7.6 Hz, 1H), 6.96 (dd, J = 5.1, 1.5 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 3.19- 2.94 (m, 4H), 2.30 (s, 3H); 13C NMR (126 MHz, CDCl3) delta 159.85, 149.15, 147.57, 143.05, 133.15, 132.02, 129.78, 129.12, 123.96, 122.49, 119.04, 112.24, 39.44, 35.32, 20.97; MS (ESI) m/z 222.97 [M + H]+.
Stage #1: methyl (S)-pyroglutamate With lithium hexamethyldisilazane In tetrahydrofuran at -20℃; for 1h; Inert atmosphere;
Stage #2: m-(bromomethyl)benzonitrile In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere;
General procedure: A solution of methyl pyroglutamate, 10 (2.0gm, 1eq, 13.9mmol) and THF (100ml) was taken in a three necked RBF fitted with rubber septa, N2inlet and cooled to-20°C. LiHMDS (14ml, 1.2eq, 16.7mmol) was added through a syringe to that solution and allowed to stir for 1h. Substituted benzylbromide (1.1eq) was added and stirring was continued for 4hfrom 0°C to room temperature. The reaction was quenched by addition of 1N HCl (10ml) and extracted with ethyl acetate (3×25ml). The organic layer was washed with brine (2×25ml), dried over Na2SO4and concentrated under reduced pressure to give an oily ester. The ester was then re-dissolved in methanol (10ml) and cooled to 0°C. 20% sodium carbonate solution was then added to the reaction mixture portion wise. The reaction mixture was then stirred at room temperature for 5h. Methanol was then distilled off and the reduced reaction mixture was then extracted with ether (1×25ml). The mixture was acidified with conc. HCl and extracted with ethyl acetate (3×30ml). The organic layer was dried and concentrated.
4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde[ No CAS ]
[ 28188-41-2 ]
(S)-4-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)benzylamino)-3-hydroxybutanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.1 mg
Added a solution of triethyl amine (15.33 mul, 0.110 mmol) in dimethylformamide (1000 mul) to 3-(bromomethyl)benzonitrile (21.56 mg, 0.110 mmol) and 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2-hydroxybenzaldehyde (37.6 mg, 0.1 mmol) and stirred overnight at room temperature. Added sodium triacetoxyhydroborate (63.6 mg, 0.300 mmol) and<strong>[7013-05-0](S)-4-amino-3-hydroxybutanoic acid</strong> (23.82 mg, 0.200 mmol) and stirred at room temperature for 72 hours. The crude material was purified via preparative LCMS with the following conditions: Column: XBridge C18, 19×200 mm, 5-mum particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/minutes Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.1 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LCMS injections were used to determine the final purity. LCMS Condition A: 1.7 minutes, M+1=595.3, M-1=593.2, EM=594.2. LCMS Condition M: 3.0 minutes, M+1=595.3, M-1=593.3, EM=594.2. 1H NMR (500 MHz, DMSO-d6) delta 7.95 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.65-7.60 (m, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.29-7.21 (m, 2H), 7.16 (d, J=7.3 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.80-6.73 (m, 3H), 6.68 (d, J=8.4 Hz, 1H), 5.22 (s, 2H), 5.11 (s, 2H), 4.29 (s, 4H), 3.91 (t, J=5.9 Hz, 1H), 3.84-3.69 (m, 2H), 2.62 (d, J=5.9 Hz, 2H), 2.41-2.22 (m, 2H), 2.20 (s, 3H).
α-(N,N-di(3-cyanobenzyl))amino-ε-caprolactam[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium carbonate In methanol Reflux;
6 Preparation of I-14
The added 1L three-necked flask -ε- α- amino-caprolactam hydrochloride 16.5g(0.1mol), sodium carbonate 53.0g (0.5mol) and methanol 500ml, and stirred to dissolve,was added 3-bromo-benzyl nitrile 98.1g (0.5 mol), a reflux condenser. For 48h the methanol was removed by distillation under reduced pressure, dissolved indichloromethane was added 500ml, 100ml with distilled water three times, washed oncewith saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtratewas collected, dichloromethane was distilled off under reduced pressure to give crudeproduct. The crude product from methanol / ether system recrystallized α- (N- 3-carbonitrile two benzyl)) amino-caprolactam -ε- 21.5g, 60% yield.
With potassium carbonate; In acetone; for 6h;Reflux;
General procedure: <strong>[3470-50-6]6-Hydroxy-1-tetralone</strong> (0.3 g, 1.85 mmol) was suspended in acetone (15 mL) containing K2CO3 (3.70mmol). The reaction was treated with an appropriately substituted arylalkyl bromide (2.035 mmol) and heated under reflux for 6 h. The reaction progress was monitored using silica gel TLC with ethyl acetate:petroleum ether (1:2) as mobile phase. Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by recrystallization from cyclohexane.
3-cyanobenzyl 3-([1,1'-biphenyl]-4-yl)propiolate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With caesium carbonate; silver(I) iodide In acetonitrile at 40℃; for 48h; Schlenk technique;
4.2. General procedure of Ag (I)-catalyzed carboxylation
General procedure: In a typical procedure, a 50 mL Schlenk tube was charged withalkyne 1 (1.0 mmol), benzyl halide 2 (1.1 mmol), AgI (0.02 mmol),Cs2CO3 (1.5 mmol) and anhydrous CH3CN (5 mL). CO2 (99.999%,balloon) were then introduced into the reaction mixture understirring. After stirring at 40 C for 48 h, the reaction mixture wascooled to room temperature, ltered and evaporated in vacuo. Theresulting residue was then puried by column chromatography onsilica gel (eluent: petroleum ether: ethyl acetate 20:1) to affordthe corresponding products 3aa-3aq.
3-cyanobenzyl 3-(4-chlorophenyl)propiolate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With caesium carbonate; silver(I) iodide In acetonitrile at 40℃; for 48h; Schlenk technique;
4.2. General procedure of Ag (I)-catalyzed carboxylation
General procedure: In a typical procedure, a 50 mL Schlenk tube was charged withalkyne 1 (1.0 mmol), benzyl halide 2 (1.1 mmol), AgI (0.02 mmol),Cs2CO3 (1.5 mmol) and anhydrous CH3CN (5 mL). CO2 (99.999%,balloon) were then introduced into the reaction mixture understirring. After stirring at 40 C for 48 h, the reaction mixture wascooled to room temperature, ltered and evaporated in vacuo. Theresulting residue was then puried by column chromatography onsilica gel (eluent: petroleum ether: ethyl acetate 20:1) to affordthe corresponding products 3aa-3aq.
N’’-methyl(3-cyanophenyl)-N,N-dimethylimino dicarboanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.8%
With potassium iodide; sodium hydroxide; In dichloromethane; at 20℃; for 18h;
In a 250 ml round bottom flask, 8 g (48.3 mmol) of <strong>[1115-70-4]metformin hydrochloride</strong> was added, 100 ml of methylene chloride,25% sodium hydroxide 40ml, stirring, clarification and then adding 3-cyano-benzyl bromide 9.47g (48.3mm0l), potassium iodide 3 small particles, magneticForce stirring, room temperature, a total reaction of 18 hours, after treatment. Reaction flask see solid, filter, dichloromethane 5ml washing, drying, noColor solid 6g. The solid was recrystallized from 500 ml of acetonitrile to give 2.1 g of colorless solid. The yield was 17.80%.
With sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 60h;Cooling with ice;
In a 250 ml round bottom flask, add 2 g (12 mmol) of metformin and 100 ml of anhydrous DMF, and ice bath and add 3.4 g (24 mmol) of sodium iodide to the flask. Stir the solution of 2.35 g (12 mmol) of 3-cyanobenzyl bromide DMF 20 ml and the reaction was followed by magnetic stirring thin-layer chromatography (developing solvent: dichloromethane: methanol: triethylamine = 4.3: 0.7: 3dr). Metformin hydrochloride almost finished reaction. A total of 60 hours at room temperature, after filtration, the filtrate evaporated to give an oil about 1.8g. The oily product was purified by column chromatography on 100-200 mesh silica gel (mobile phase: methylene chloride: methanol = 900: 100) to give the crude product (0.9 g). The crude product was then separated on a medium pressure column in reverse phase. Mobile phase: water / acetonitrile = 98 /2, the target pure product 0.6g. Yield 20.1%.
(S)-3-[(5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxochroman-7-yl)oxy]methylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Alkaline conditions;
General procedure: K2CO3 (172.76 mg, 1.25 mmol) and the appropriate substitutedbromine (4-10 mmol) were added, under stirring, to a solution of <strong>[520-33-2]hesperetin</strong>(604 mg, 2 mmol) in anhydrous DMF (15 mL). Another 1 mmolof K2CO3 was intermittently added to the solution to keep the pH as aweak alkaline. The mixture was reacted at room temperature for 4-6 hunder atmospheric conditions. The progress of the reaction was monitoredby TLC. The reaction mixture poured into ice cold water thenacidified by dilute hydrochloric acid and extracted with ethyl acetate,then washed three times with saturated aqueous NaCl solution. After drying with anhydrous sodium sulfate, the solution was filtered throughabsorbent cotton. The precipitate obtained by removing the solventunder reduced pressure was purified by column chromatography (SiO2)using trichloromethane/petroleum ether (1:1-5) as eluent. The purifiedprecipitate was recrystallized from dichloromethane/petroleum ether.
3-((3-nitrophenethoxy)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.41 g
A solution of <strong>[52022-77-2]2-(3-nitrophenyl)ethanol</strong> (1 .3 g, 7.78 mmol) in DMF (40 mL) was treated with sodium hydride (95%, 0.236 g, 9.33 mmol) at 0 C and the mixture stirred at 0 C for 30 min. 3- (Bromomethyl)benzonitrile (1 .525 g, 7.78 mmol) was then added and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 C, quenched with saturated aqueous NH4CI aqueous, and extracted with EtOAc (3x). The extract was dried (Na2S04), evaporated and the residue was purified by chromatography (silica gel, gradient 0 to 50% EtOAc/hexanes) to give the desired product (1 .41 g) as a pale brown oil. 1H NMR (400 MHz, CDCI3) delta ppm 3.08 (t, J = 6.46 Hz, 2H), 3.80 (t, J = 6.46 Hz, 2H), 4.58 (s, 2H), 7.42 - 7.66 (m, 6H), 8.10 - 8.20 (m, 2H).
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: m-(bromomethyl)benzonitrile With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h;
Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃;
3-(3-cyanobenzyl)thiazolidin-2-ylidenecyanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.1%
With sodium hydroxide; In water; acetonitrile; at 20℃; for 8h;
General procedure: Thiazolidin-2-ylidene-cyanamide (0.317 g, 2.50 mmol) inacetonitrile (20 mL) was dropwise added to a stirred solutionof substituted benzyl bromide (2.5 mmol) and 14 mL NaOHaqueous solution (1 M). The mixture is stirred at room temperaturefor 8-10 h. The soild was collected by filtration,washed with n-hexane and dried in vacuo.
3-((2-chloro-4-formyl-6-methoxyphenoxy)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.5%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1h;
7 [Synthesis Method 1] Compounds 1 to 17
General procedure: Substituted 4-hydroxybenzaldehyde (1 equivalent) and correspondingly substituted benzyl chloride (1 equivalent), and K2CO3 (1 equivalent) was incubated in DMF in a solvent at 80° C. for 1 hour.After cooling the reaction mixture to room temperature, extraction was performed using ethyl acetate, The extract was washed with water, NaHCO3 and brine, and then dried over MgSO4.Then, after completely removing the solvent through reduced pressure,Silica gel chromatography was performed to obtain compounds 1 to 17
3-((3-methylpyridin-2-yl)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With bis(1,1-dimethylethyl)methylphosphine tetrafluoroborate; palladium diacetate; potassium carbonate; sodium 3-methoxy-3-oxopropane-1-sulfinate In dimethyl sulfoxide at 120℃; for 18h; Inert atmosphere; Schlenk technique;
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