* 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.
A mixture of 4-cyano benzoic acid (500 g, 3.4 mol) and Raney Nickel (100 g) in methanol (5 L) was hydrogenated at a pressure of 10 kg for 16 h. The catalyst was removed by filtration, followed by the removal of the solvent under reduced pressure to afford 4-(aminomethyl)benzoic acid (430 g, 84percent) as a white solid.
Reference：
[1] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 23
[2] Journal of the Chemical Society, 1944, p. 678
[3] Patent: US4634689, 1987, A,
2
[ 53148-13-3 ]
[ 56-91-7 ]
Yield
Reaction Conditions
Operation in experiment
95.8%
Stage #1: at 20℃; for 3.5 h; Stage #2: With hydrogenchloride In water
62 g of methyl 4-hydroxyiminomethylbenzoate obtained as above, 600 g of water, 55.4 g (4.0 eq) of sodium hydroxide and 4.5 g of 5 wt percent Pd/C (wet 50percent water) were placed in a 1 L autoclave, and the reaction was carried out under conditions of a hydrogen pressure of 10 kg/cm2, room temperature, a stirring rate of 1500 rpm, and a time of 3.5 hr. After the catalyst was removed, 145.2 g of conc. hydrochloric acid was added so that the solution was neutralized to pH 7, and water was then removed to concentrate the solution.The concentrated solution was then filtered and dried, thus obtaining 4-aminomethylbenzoic acid.; These examples were performed in the same manner as in Example 5, with the exception that the amount of NaOH added was changed to 48.5 g (3.5 eq), 33.7 g (2.4 eq), and 41.6 g (3.0 eq). The different results relative to the amount of added NaOH are given in Table 2 below.
2) adding methyl 4-aminomethylbenzoate to the concentrated sulfuric acid solution,The molar ratio of sulfuric acid to 4-aminomethylalkyl benzoate is 1:1.The reaction was stirred at 50 ° C for 1.5 h, and after the reaction was completed, it was cooled to room temperature.Add water (the amount of water is 20 times the amount of methyl 4-aminomethylbenzoate), then add sodium hydroxide solution dropwise to the solution to make the solution alkaline.There is a lot of solids to precipitate, filter, wash,And dried to give a white solid aminomethylbenzoic acid.
Reference：
[1] Patent: CN108623488, 2018, A, . Location in patent: Paragraph 0037; 0039; 0053
[2] Patent: EP1724263, 2006, A1, . Location in patent: Page/Page column 24
4
[ 366-84-7 ]
[ 56-91-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 80℃; for 1 h;
2) adding ethyl 4-aminomethylbenzoate to the concentrated sulfuric acid solution,The molar ratio of sulfuric acid to 4-aminomethylalkyl benzoate is 2:1,The reaction was stirred at 80 ° C for 1 h, and after completion of the reaction, it was cooled to room temperature.Add water (the amount of water is 20 times the amount of methyl 4-aminomethylbenzoate), then add ammonia water dropwise to the solution to make the solution alkaline.There is a lot of solids to precipitate, filter, wash,Drying gave a white solid aminotoluic acid.
Reference：
[1] Patent: CN108623488, 2018, A, . Location in patent: Paragraph 0040; 0042; 0043; 0045; 0046; 0048; 0053
Reference：
[1] Chemische Berichte, 1890, vol. 23, p. 1061
11
[ 34040-64-7 ]
[ 56-91-7 ]
Reference：
[1] Patent: CN108623488, 2018, A,
12
[ 1201-90-7 ]
[ 56-91-7 ]
Reference：
[1] Patent: CN108623488, 2018, A,
13
[ 3477-93-8 ]
[ 56-91-7 ]
Reference：
[1] Journal of Organic Chemistry, 1973, vol. 38, p. 2185
14
[ 120-61-6 ]
[ 56-91-7 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
[2] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 42967-55-5 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 7377-26-6 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 1129-35-7 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
18
[ 6232-88-8 ]
[ 56-91-7 ]
Reference：
[1] Journal of the Chemical Society, 1946, p. 466
19
[ 150-13-0 ]
[ 56-91-7 ]
Reference：
[1] Journal of the Chemical Society, 1944, p. 678
20
[ 17201-43-3 ]
[ 56-91-7 ]
Reference：
[1] Journal of the Chemical Society, 1946, p. 466
21
[ 6757-31-9 ]
[ 56-91-7 ]
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Reference：
[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
22
[ 7647-01-0 ]
[ 303795-50-8 ]
[ 56-91-7 ]
Reference：
[1] Chemische Berichte, 1890, vol. 23, p. 1061
23
[ 67-56-1 ]
[ 56-91-7 ]
[ 18469-52-8 ]
Yield
Reaction Conditions
Operation in experiment
92%
for 6 h; Heating / reflux
To a solution of 4-(aminomethyl)benzoic acid (300 g, 1.98 mol) in methanol (5 L) was added thionylchloride (473 g 3.97 mol). The reaction mixture was refluxed for 6 h, followed by the removal of the solvent under reduced pressure to obtain the crude product. The crude was purified by acid-base work up to afford methyl-4-(aminomethyl)benzoate (300 g, 92percent) as a liquid.
88%
Stage #1: With hydrogenchloride In water for 7 h; Heating / reflux Stage #2: With sodium hydroxide In methanol; dichloromethane; water at 5 - 10℃;
EXAMPLE In a 1200 1 stirred vessel made of steel and enamel, 60 kg of 4-(aminomethyl)benzoic acid, 480 kg of methanol and 89 kg of 30percent hydrochloric acid are heated to boiling at reflux. After a reaction time of 7 h, the reaction mixture is cooled to 10° C. Addition of 290 kg of 4percent sodium hydroxide solution initially adjusts the pH of the reaction mixture to a pH of 6-7, before a methanol/water mixture is distilled off under reduced pressure. Subsequently, 400 kg of methylene chloride are added and the pH of the aqueous phase is adjusted to a value of 10-11 at a temperature of 5-10° C. The lower organic phase is removed. The aqueous phase is extracted once more with 265 kg of methylene chloride. The organic phases are combined and stored at 0-5° C. The content of the solution is determined by means of quantitative HPLC chromatography. The yield of methyl 4-(aminomethyl)benzoate is 88-89percent.
82%
With thionyl chloride In methanol at 0 - 60℃; for 12 h;
Intermediate VI: methyl (2E)-3-14-(AMINOMETHVLOPHENYLLACRVLATE, HYDROCHLORIDE SALT; 5 TEP A) FO/WON of methyl-(4-aminomethyl)benzoate; To a solution of (4-aminomethyl) benzoic acid (125 g, 0.83 mol) in methanol (1.5 L) was added THIONYLCHLORIDC (350 g, 3 eq. ) at 0°C with stirring and then allowed to stir at rt for overnight and finally REFLUXED at 60°C for 12 H for the completion of the reaction. The reaction mixture was concentrated and crude hydrochloric salt was neutralized using 10percent aqueous NaHCO3 solution to pH 8. The aqueous layer was concentrated and kept at 0°C overnight. The solid obtained was filtered, washed with cold water and dried under suction to give the title compound (112 g, 82percent).
79%
at 70℃; for 3.5 h;
4-aminomethyl benzoic acid (6.69 g, 44.09 mmol) was dissolved methanol (200 mL). SOCl2 (12 mL) was added via syringe. The mixture was stirred at 70°C for 3.5 h. After cooling, the reaction mixture was evaporated and the crude product was dissolved in CH2Cl2 (500 mL). The organic layer was washed with aqueous K2CO3 10percent (300 mL), dried with MgSO4, filtered and evaporated. Methyl 4-(aminomethyl)benzoate was obtained (5.78 g, 79 percent) as a white solid. [] MW: 165.19; Yield: 79 percent; White Solid; Mp (°C): 73.3.1H-NMR (CDCl3,δ): 1.53 (s, 2H, NH2), 3.94 (s, 1H, CH3), 3.96 (s, 2H, N-CH2), 7.39 (d, 2H, J = 8.4 Hz, ArH), 8.02 (d, 2H, J = 8.4 Hz, ArH).
37%
With hydrogenchloride In waterReflux
Step 1. Synthesis of methyl 4-(aminomethyl)benzoate To a solution of 4-(aminomethyl)benzoic acid (0.500 g, 3.31 mmol) in methanol (15.0 mL) was added concentrated HCl(aq) (0.8 mL). After the reaction mixture was reflux for overnight and cooled to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4(s), filtered, and concentrated to give a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (100percent ethyl acetate and 15percent MeOH in CH2Cl2) to give methyl 4-(aminomethyl)benzoate (200 mg, 37percent). 1H NMR (CDCl3, 400 MHz) δ 7.98 (d, 2H), 7.36 (d, 2H), 3.91 (s, 2H), 3.88 (s, 3H).
Reference：
[1] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 23
[2] Patent: US2007/149802, 2007, A1, . Location in patent: Page/Page column 2-3
[3] Patent: WO2005/12280, 2005, A1, . Location in patent: Page/Page column 51-52
[4] Patent: EP1541549, 2005, A1, . Location in patent: Page/Page column 25; 42
[5] European Journal of Inorganic Chemistry, 2013, # 7, p. 1149 - 1156
[6] Patent: US2017/253569, 2017, A1, . Location in patent: Paragraph 0897-0898
[7] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 5, p. 483 - 486
[8] Journal of Medicinal Chemistry, 2004, vol. 47, # 2, p. 467 - 474
[9] Patent: WO2011/28741, 2011, A1, . Location in patent: Page/Page column 228
[10] Patent: WO2011/37610, 2011, A1, . Location in patent: Page/Page column 54
[11] Journal of the American Society for Mass Spectrometry, 2018, vol. 29, # 4, p. 694 - 703
24
[ 56-91-7 ]
[ 18469-52-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
With chloro-trimethyl-silane In methanol
2-6. Synthesis of Methyl 4-(Aminomethyl)benzoate Compound of Chemical Formula 13 The mixture of 4-(aminomethyl)benzoic acid (1.0 g, 6.61 mmol) and chlorotrimethylsilane (3.35 mL, 26.44 mmol) was stirred for 30 minutes at room temperature, and anhydrous methanol (20 mL) was added thereto. The reaction mixture was stirred for 48 hours and then vacuum distilled to give methyl 4-(aminomethyl)benzoate (1.25 g, 94percent). 1H NMR (500 MHz, D2O) δ 8.02 (d, 2H, J=6.4 Hz), 7.51 (d, 2H, J=8.2 Hz), 4.20 (s, 2H), 3.88 (s, 3H).
Reference：
[1] Patent: US2014/350227, 2014, A1, . Location in patent: Page/Page column
[2] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 276 - 279[3] Angewandte Chemie, 2015, vol. 127, # 1, p. 278 - 281,4
25
[ 120-61-6 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
[2] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 42967-55-5 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 7377-26-6 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 1129-35-7 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
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[ 6757-31-9 ]
[ 56-91-7 ]
[ 18469-52-8 ]
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[1] Organic Process Research and Development, 2015, vol. 19, # 3, p. 444 - 448
30
[ 56-91-7 ]
[ 39895-56-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 13, p. 5719 - 5732
[2] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3165 - 3168
[4] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 1, p. 161 - 175
[5] Patent: EP748310, 1999, B1,
[6] Patent: US5827881, 1998, A,
[7] Angewandte Chemie - International Edition, 2010, vol. 49, # 37, p. 6633 - 6637
[8] Steroids, 2012, vol. 77, # 12, p. 1177 - 1191,15
[9] Steroids, 2012, vol. 77, # 12, p. 1177 - 1191
[10] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10460 - 10474
[11] Patent: WO2013/109859, 2013, A1, . Location in patent: Paragraph 0298
[12] RSC Advances, 2013, vol. 3, # 38, p. 17150 - 17155
[13] Patent: WO2017/100154, 2017, A1, . Location in patent: Paragraph 00120
31
[ 56-91-7 ]
[ 64-17-5 ]
[ 366-84-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 20℃; for 4.5 h; Cooling with ice; Reflux
Example 1 Preparation of p-aminomethylbenzoic acid ethyl ester In 250mL neck round bottom flask was added 7.5g (50mmol) p-aminomethylbenzoic acid. Added with 100mL anhydrous ethanol. In an ice bath, was slowly added thionyl chloride 20.8g (175mmol), after the addition was complete, stirring at room temperature after 30min, was heated at reflux for 4h. After stopping the heating, removal of the ethanol under reduced pressure to give a white solid. The solid was dissolved with 150mL ethyl acetate in an ice bath was slowly added 35percent NaOH aqueous solution to pH 7-8. Still stratification, washed three times with saturated saline aqueous layer was removed, and the organic layer, each 30mL. Dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid, 90percent yield.
Reference：
[1] Patent: CN104016942, 2016, B, . Location in patent: Paragraph 0090; 0091; 0092
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 2281,2283
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 36, p. 6023 - 6028
[4] Journal of the American Society for Mass Spectrometry, 2018, vol. 29, # 4, p. 694 - 703
32
[ 56-91-7 ]
[ 366-84-7 ]
Reference：
[1] Patent: EP976722, 2000, A1,
33
[ 56-91-7 ]
[ 366-84-7 ]
Reference：
[1] Patent: US5834468, 1998, A,
34
[ 56-91-7 ]
[ 24424-99-5 ]
[ 33233-67-9 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water for 16 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran
Stage 1 - Boc protection; 4-(Aminomethyl)benzoic acid (10.0Og, 65.36mmol) was stirred with BoC2O (28.0Og, 130.72mmoi) in H2O (10OmL) and THF (10OmL) at RT. Sat NaHCO3(aq) was added until pH ~ 6 was reached and the reaction was allowed to stir for 16h. The reaction was then carefully acidified to pH ~ 3 with 1 M HCIaq which caused a solid to precipitate out. This EPO <DP n="62"/>60 was filtered and dried to give the product as a white solid (16.1g, 97percent). m/z = 274 [M+Na]+.
97%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 16 h; Stage #2: With hydrogenchloride; water In water
Example 73; Cvclopentyl (2S)-cvclohexyl((4-r({3-r(1 E)-3-(hvdroxyamino)-3-oxoprop-1-en-1- yl1benzyl)amino)rnethvπbenzyl)amino)acetate; <n="59"/>The title compound was prepared by the following methodology:Intermediate J1Stage 4NaBH(OAc)3, DCEExample 12 ioxane Stage 1 - Preparation of 4-[(te/t-butoxycarbonyl)amino]methyl}benzoic acid; 4-(Aminomethyl)benzoic acid (10.0Og1 65.36mmol) was stirred with BoC2O (28.0Og, 130.72mmol) in H2O (10OmL) and THF (10OmL) at RT. Sat. NaHCO3 solution was added until pH ~ 6 was reached and the reaction was allowed to stir for 16h. The reaction was then carefully acidified to pH ~ 3 with 1 M HCIaq which caused a solid to precipitate out. This was filtered and dried to give the product as a white solid (16.1g, 97percent). m/z = 274 [M+Na]+.
96%
Stage #1: With sodium hydroxide In ethanol; water at 0 - 20℃; Stage #2: With citric acid In water
4-Aminomethylbenzoic acid (10.0 g, 66 mmol) was dissolved in a mixture of 10 percent aqueous NaOH (90 niL) and EtOH (250 mL). The solution was cooled to 0 0C and di-tert-butyl- dicarbonate (15.2 g, 73.0 mmol) was added slowly. The reaction mixture was stirred for 18 h at ambient temperature and TLC showed the consumption of amino acid. The ethanol was removed in vacuo and water (500 mL) was added. The aqueous layer was acidified slowly with a saturated solution of citric acid (20 mL) and the precipitate formed was filtered under suction, and dried in vacuo to afford the title compound as a white solid. No further purification was required. Yield: 16.0 g, 96 percent. 1H NMR (300 MHz, CDCl3) δ ppm 7.88 (2H, d, J 8.1 Hz), 7.45 (IH, br s), 7.33 (2H, d, J 8.1 Hz), 4.18 (2H, d), 1.30 (9H, s)
92%
Stage #1: With potassium carbonate In water at 20 - 40℃; Cooling with ice Stage #2: With citric acid In water
(1) Synthesis of 4-[(tert-butoxycarbonylamino)methyl]benzoic acid 2.00 g (13.2 mmol) of 4-(aminomethyl)benzoic acid suspended in water (20 ml) was mixed with 3.81 g (27.6 mmol) of potassium carbonate and then with 3.57 g (16.4 mmol) of di-tert-butyl bicarbonate under cooling with ice. The mixture was allowed to react at 40° C. for 2.5 hours and stirred at room temperature overnight. Then, water (7 ml) and 5.6 g of citric acid monohydrate were gradually added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (3.05 g, yield 92percent).
92%
With sodium hydroxide In 1,4-dioxane; water at 0℃; for 1 h;
4-(Aminomethyl)benzoic acid (5.0 g, 33.1 mmol) was dissolved in a mixture of dioxane (60mL), H2O (30 mL) and 1 M NaOH (40 mL). The resulting solution was cooled to 0 °C in an ice bath and di-tert-butyl dicarbonate (7.46 g, 34.2 mmol) was added. The reaction mixture was stirred for 1 h at 0 °C and a white precipitate was formed. The solvent was concentrated to 40 mL under reduced pressure and 1 M NaHSO4 solution was added to adjust the pH value to 2. The resulting suspension was extracted with EtOAc (ca. 100 mL) and the organic layer was washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure to yield 9. Colorless solid, mp 169 °C, yield 7.63 g (92 percent). C13H17NO4 (251.1). Rf = 0.18 (ethyl acetate:cyclohexane = 1:1, detection: 254 nm). 1H NMR (400 MHz, DMSO-D6): δ [ppm] = 1.39 (s, 9H, (H3C)3C), 4.19 (d, J = 6.2 Hz, 2H, NHCH2), 7.34 (d, J = 8.0 Hz, 2H, 3-HB, 5-HB), 7.46 (t, J = 6.1 Hz, 1H, NHCH2), 7.89 (d, J = 8.1 Hz, 2H, 2-HB, 6-HB), 12.84 (s, 1H, CO2H). 13C NMR (101 MHz, DMSO-D6): δ [ppm] = 28.2 (3C, (H3C)3C), 43.2 (1C, NHCH2), 77.9 (1C, (H3C)3CO), 126.9 (2C, C-3B, C-5B), 129.2 (1C, C-1B), 129.3 (2C, C-2B, C-6B), 145.3 (1C, C-4B), 155.8 (1C, OCONH), 167.2 (1C, CO2H). FT-IR: ν [cm-1] = 3352 (N-H) 3074 (C-HAr), 2982, 2932, 2886, 2839 (C-Haliph.) 2677, 2558 (CO2H), 1682 (C=O), 1612, 1578, 1504 (C=CAr), 1427 (C-Haliph. deform.), 1242 (C-Ctert-butyl), 1161 (C-O), 841 (Arout of plane). HRMS (APCI): m/z = 252.1233 (calcd. 252.1230 for C13H18NO4 [M+H]+). HPLC: tR = 17.8 min, purity 99.9 percent.
90%
Stage #1: With triethylamine In 1,4-dioxane; water for 16 h; Stage #2: With phosphoric acid In water at 0℃;
A solution of 4-aminomethylbenzoic acid (5.67 g, 37.5 mmol) triethylamine (5.20 mL, 37.5 mmol) and di-tert-butyl dicarbonate (9.5 mL, 41.2 mmol) in aqueous 1,4-dioxane (1/1) was stirred for 16 hours, reduced in volume under vacuum, cooled to 0 °C, acidified with 1M H3PO4, then extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4) and evaporated to provide the title compound (8.47 g, 90percent). MS (APCI-) m/e 250 (M- H)-.
86%
With sodium hydroxide In tetrahydrofuran; water for 12 h;
Preparation of 4-[(tert-Butoxycarbonyl)aminomethyl]benzoic acidTo a solution of commercially available 4-aminomethylbenzoic acid (10.078 g, 66.7 mmol, 1 eq.) in aqueous NaOH (5.866 g, 146.6 mmol, 2.2 eq.) in water (25 ml) and THF (tetrahydrofuran; 50 ml) was added di-te/t-butyl dicarbonate (16 g, 73.3 mmol, 1.1 eq.). After stirring for 12 h the mixture was washed with hexane (2 x 50 ml), the aqueous phase cooled to 5° C and adjusted to pH3 with aqueous saturated citric acid. The resulting white precipitate was extracted with ethyl acetate (3 x 50 ml) and the organic extracts combined and dried (MgSO4). Concentration in vacuo yielded the title carbamate as white needles (14.43 g, 86percent) from EtOAc.R, = 0.43 (SiO2 petrol: EtOAc; 1 :3); υmax (neat)/cm~1 3357 (m), 2968 (w), 2930 (w), 2884 (w), 2488 (m), 1682 (s), 1510 (m), 1409 (m), 1291 (m), 1244 (m), 1 172 (m), 944 (m), 879 (m), 783 (m); δH (DMSO-d6) 1 .39 (9 H, s, 3 x CH3), 4.18 (2 H, d, J = 6.3, CH2), 7.34 (2 H, d, J = 8.1 , H-3, 5), 7.48 (1 H, t, J = 6.1 , NH), 7.89 (2 H, d, J = 8.2, H-2, 6), 12.87 (1 H, s, br, COOH); δc (DMSO-d6) 28.2 (3 x CH3), 43.2 (CH2), 77.9 (C(CH3)3), 126.9 (CH), 129.2 (C-1 ), 129.3 (CH), 145.3 (C-4), 155.8 (C=O), carbamate), 167.2 (C=O, acid).
79%
With hydrogenchloride; sodium hydroxide In 1,4-dioxane; water
(1-1) Synthesis of 4-(N-t-Butyloxycarbonylaminomethyl)benzoic Acid: In 150 ml of a mixture of dioxane and water (2:1 by volume) was dissolved 7.6 g of 4-aminomethylbenzoic acid, and 50 ml of an aqueous 1 mol sodium hydroxide solution and 25 ml of a dioxane solution of 12.0 g of di-t-butyl dicarbonate were added dropwise to the solution over a period of 10 minutes. Then, after stirring the mixture for 2.5 hours at room temperature (about 20° to 30° C.), the reaction mixture was concentrated under reduced pressure to about 1/3 of the original volume on a water bath of external temperature of from 50° C. to 60° C. and about 40 ml of 1N hydrochloric acid was added dropwise to the reaction mixture under ice-cooling to adjust the pH thereof to from 3 to 4. Then, the reaction product was extracted three times, each time with 40 ml of ethyl acetate, the organic layer thus obtained was washed with 30 ml of purified water and 30 ml of a saturated aqueous sodium chloride solution, and after drying it with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were washed with isopropyl ether and then recrystallized from ethyl acetate to provide 9.9 g (yield 79percent) of a colorless powder of 4-(N-t-butyloxycarbonylaminomethyl)benzoic acid.
78%
With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 48 h;
Stage 1 - 4-[(ter/-butoxycarbonyl)amino]methyl}benzoic acid; To a solution of 4-aminomethyl benzoic acid (19.22 g, 126 mmol) in THF (200 mL) was added saturated sodium hydrogen carbonate solution (300 mL) and di-tert-butyl dicarbonate (42.72 g, 195.7 mmol). The mixture was stirred at room temperature for 48 hours, then poured into ethyl acetate (250 mL). The aqueous layer was washed with ethyl acetate (250 mL), then acidified with 2M HCl solution. The precipitate was collected by filtration and dried under high vacuum to yield the desired product (24.6 g, 78percent yield). LC/MS: m/z 274 [M+Na]+
78%
With sodium hydroxide In tetrahydrofuran at 20℃; for 8 h;
To a solution of compound 1 (605 mg, 4.0 mmol) in 8.8mL of 1 N NaOH, was added a solution of (Boc)2O (960 mg, 4.4 mmol)in tetrahydrofuran (THF, 2 mL). After stirring themixture at room temperature for 8 h, THF was evaporated in vacuum with theresidues being adjusted to pH 4-5 with 1 N aqueous citric acid. Then themixture was extracted with EtOAc (3 × 25 mL). The extractions were combined,washed with brine (3 × 20 mL), dried over MgSO4 and evaporated togive compound 2 (yield: 78 percent) as a white solid. 1H-NMR (MeOH-d4, 400 MHz): δ 1.41 (s, 9H), 4.34 (s, 2H,), 7.32(d, J = 7.6 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H). 13CNMR (MeOH-d4): δ 26.7, 42.6, 78.2, 125.8, 128.5, 128.8, 144.3, 157.1, 167.6. HR-MS m/z: calcd for C13H17NNaO4,274.1050 [M-Na]+, found 274.1047 [M-Na]+.
66%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane at 0 - 20℃; for 16 h; Stage #2: With hydrogenchloride In water
To a stirred solution of 4-(aminomethyl)benzoic acid (5 g, 33 mmol) in 1,4-dioxane (50 mL) and H2O (25 mL) was added NaHCO3 (8.3 g, 99.2 mmol) followed by Boc anhydride (10.8 g, 49.6 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of reaction (by TLC), the volatiles were evaporated under reduced pressure and the residue was neutralized using cold 1N HCl solution. The precipitated solid was filtered and dried under reduced pressure to afford 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid (5.5 g, 66percent) as a white solid.
60%
Stage #1: With sodium hydroxide In 1,4-dioxane for 1 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water
To a solution of 4-Aminomethyl-benzoic acid (5.0 g, 33.1 mmol) in 1,4-dioxane (60.0 mL) were added 1M sodium hydroxide (30 mL), BOC-anhydride (6.8 mL, 29.8 mmol) drop wise at ice temperature and it was stirred at same temperature over a period of 60 min. The resulting mixture acidified (PH=:5.0) with 1.5 N hydrochloric acid and extracted with ethyl acetate (3X100 mL), dried over sodium sulphate. Volatiles were evaporated under reduced pressure to obtain 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid as a colourless solid (5.0 g, 60 percent).
60%
Stage #1: With sodium hydroxide In 1,4-dioxane for 1 h; Cooling with ice Stage #2: With hydrogenchloride In 1,4-dioxane; water
To a solution of 4-Aminomethyl-benzoic acid (5.0 g, 33.1 mmol) in 1,4-dioxane (60.0 mL) were added 1M sodium hydroxide (30 mL), BOC-anhydride (6.8 mL, 29.8 mmol) drop wise at ice temperature and it was stirred at same temperature over a period of 60 min. The resulting mixture acidified (PH=5.0) with 1.5 N hydrochloric acid and extracted with ethyl acetate (3*100 mL), dried over sodium sulphate. Volatiles were evaporated under reduced pressure to obtain 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid as a colourless solid (5.0 g, 60percent).
47%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 0℃; for 1 h; Stage #2: With potassium hydrogensulfate; water In 1,4-dioxane; ethyl acetate
Example 103 TERT-BUTYL(4-[3-[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYL}-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-10(11H)-YL]CARBONYL}BENZYL)CARBAMATE Step A. 4-[(tert-Butoxycarbonyl)amino]methyl}benzoic acid; To a solution of 4-(aminomethyl)benzoic acid (5.00 g, 0.0331 mol) in dioxane (60 mL), water (30 mL), and 1 M sodium hydroxide (34 mL, 0.034 mol) at 0° C. was added di-tert-butylpyrocarbonate (7.94 g, 0.0364 mol) and the reaction mixture stirred at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo to 30 mL, ethyl acetate (80 mL) added and the mixture acidified to pH 4 by the addition of 1 M aqueous potassium hydrogen sulfate solution with vigorous stirring. The organic phase was separated, washed with water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a white solid. Recrystallization from ethyl acetate (60 mL) gave the title compound (3.94 g, 47percent) as a white crystalline solid, m.p. 165° C. MS [(-)ESI, m/z]: 250 [M-H]- Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 61.74; H, 6.51; N, 5.42.
46.5%
Stage #1: With sodium hydroxide In water; butan-1-ol at 0 - 20℃; for 3 h; Stage #2: With citric acid In water; butan-1-ol at 0℃;
Step 2; Preparation of 4-((t-butoxycarbonylamino)niethyI)benzoic acid.; To a solution of 4-aminomethylbenzoic acid (5 g, 33 mmol) in water maintained at 0 0C, was added 5percent aqueous NaOH solution (100 mL), followed by dropwise addition of Boc anhydride (15 mL, 66 mmol) in n-butanol (10 mL). Subsequently, the reaction mixture was stirred at room temperature for 3 hours. Upon completion, as monitored by TLC using DCM:MeOH (9: 1) as the eluent, the reaction mixture was poured in ice water, acidified with citric acid upto pH 4. On standing at room temperature for 10 minutes the precipitate formed was filtered, washed with water (100 mL) and dried to give the Boc protected product (6.5 g. 46.5 percent yield).
46.5%
Stage #1: With sodium hydroxide In water; butan-1-ol at 0 - 20℃; Stage #2: With citric acid In water; butan-1-olCooling with ice
To a solution of 4-aminomethylbenzoic acid (5 g, 33 mmol) in water maintained at 0° C., was added 5percent aqueous NaOH solution (100 mL), followed by dropwise addition of Boc anhydride (15 mL, 66 mmol) in n-butanol (10 mL). Subsequently, the reaction mixture was stirred at room temperature for 3 hours. Upon completion, as monitored by TLC using DCM:MeOH (9:1) as the eluent, the reaction mixture was poured in ice water, acidified with citric acid up to pH 4. On standing at room temperature for 10 minutes the precipitate formed was filtered, washed with water (100 mL) and dried to give the Boc protected product (6.5 g, 46.5percent yield).
Reference：
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[2] Patent: WO2008/40934, 2008, A1, . Location in patent: Page/Page column 57-58
[3] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 206
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 965 - 984
[5] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 4, p. 501 - 508
[6] Journal of Organic Chemistry, 1996, vol. 61, # 25, p. 8811 - 8818
[7] Patent: US2012/209005, 2012, A1, . Location in patent: Page/Page column 35
[8] European Journal of Medicinal Chemistry, 2017, vol. 129, p. 124 - 134
[9] Journal of the American Chemical Society, 2017, vol. 139, # 50, p. 18365 - 18375
[10] Journal of Medicinal Chemistry, 2001, vol. 44, # 10, p. 1491 - 1508
[11] Patent: EP1080070, 2006, B1, . Location in patent: Page/Page column 12
[12] Journal of the American Chemical Society, 2010, vol. 132, # 49, p. 17366 - 17369
[13] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3331 - 3341
[14] Patent: WO2011/23986, 2011, A1, . Location in patent: Page/Page column 29; 31
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[16] Journal of Medicinal Chemistry, 1995, vol. 38, # 19, p. 3798 - 3805
[17] Tetrahedron Letters, 2008, vol. 49, # 42, p. 6033 - 6035
[18] Organic and Biomolecular Chemistry, 2008, vol. 6, # 23, p. 4356 - 4373
[19] Patent: US5166403, 1992, A,
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[38] Patent: US6521658, 2003, B1,
[39] Patent: US5486525, 1996, A,
[40] Patent: US5656660, 1997, A,
[41] Patent: EP1273571, 2003, A1,
[42] Patent: US7169759, 2007, B1, . Location in patent: Page/Page column 11; 24-25
[43] Patent: US6680311, 2004, B1, . Location in patent: Page/Page column 151
[44] Patent: EP1181269, 2004, B1, . Location in patent: Page 21
[45] Patent: EP1389460, 2004, A1, . Location in patent: Page/Page column 44
[46] Patent: WO2004/89925, 2004, A1, . Location in patent: Page 72
[47] Patent: EP1550657, 2005, A1, . Location in patent: Page/Page column 109
[48] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
[49] Journal of the American Chemical Society, 2012, vol. 134, # 10, p. 4465 - 4468
[50] RSC Advances, 2014, vol. 4, # 76, p. 40444 - 40448
[51] Patent: WO2017/87695, 2017, A1, . Location in patent: Paragraph 00103; 00104
[52] Patent: US5231102, 1993, A,
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 21, p. 4872 - 4875
[2] European Journal of Medicinal Chemistry, 2017, vol. 129, p. 124 - 134
[3] Patent: US5585381, 1996, A,
47
[ 67-56-1 ]
[ 56-91-7 ]
[ 6232-11-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 0℃; for 24 h; Reflux
Example 1: Preparation of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-l- oxoisoindolin-2-yl) methyl)benzamideStep 1 : Preparation of methyl 4-(aminomethyl)benzoate hydrochloride4-Aminomethylbenzoic acid (2.0 g, 13 mmol) was dissolved in MeOH(5.0 mL), thionylchloride (2.9 mL, 3 equiv.) was slowly added thereto at 0 °C and fluxed for 24 hrs. The mixture thus obtained was distilled under a reduced pressure to remove the solvent and thionyl chloride, and dried under vacuum to obtain the title compound (2.7 g, 99 percent).1H NMR (300 MHz, D2O): δ 7.93 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 4.12(s, 2H), 3.79 (s, 3H).
93%
at 0 - 75℃; for 5 h;
Compound 5 (1.5 g, 10 mmol) was dissolved in 200 mL MeOH, thenacetyl chloride (2.4 g, 30 mmol) was added dropwise at 0 °C; themixed solution was refluxed at 75 °C for 5 h. The solvent wasevaporated under vacuum, the product was washed by diethylether to give compound 6, a white solid powder (1.7 g, 93percent).
Reference：
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[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 19, p. 4189 - 4206
[3] Patent: WO2010/131922, 2010, A2, . Location in patent: Page/Page column 28
[4] Organic Letters, 2017, vol. 19, # 7, p. 1768 - 1771
[5] Journal of Medicinal Chemistry, 1994, vol. 37, # 12, p. 1810 - 1822
[6] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8948 - 8952
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[9] Molecules, 2008, vol. 13, # 5, p. 1111 - 1119
[10] Journal of the American Chemical Society, 2015, vol. 137, # 5, p. 1983 - 1992
[11] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 185 - 206
[12] Journal of Organic Chemistry, 1995, vol. 60, # 21, p. 6970 - 6979
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4455 - 4458
[14] Chemical Communications, 2014, vol. 50, # 97, p. 15341 - 15344
[15] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9942 - 9959
[16] Patent: JP5871223, 2016, B2, . Location in patent: Paragraph 0039
[17] Patent: WO2018/71740, 2018, A1, . Location in patent: Page/Page column 27
48
[ 56-91-7 ]
[ 71989-31-6 ]
[ 164470-64-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 2 h;
(4-aminomethyl)-benzoic acid (4.9 g, 1. 1 equiv. ) was dissolved in 5percent NaHCO3 150 ml in water and stirred. N- (9- Fluorenylmethoxycarbonyl) -L-proline (Fmoc, 1 equiv. , lOg) was dissolved in an equivalent amount of dioxane and added. The reaction was allowed to stir at room temperature. After two hours, 10percent citric acid in water 75 ml was added. A white solid precipitated upon addition. The solid was washed filtered and washed with hexane. The solid was dissolved in THF and allowed to dry overnight over MGSO. The following day, the solution was filtered, crystallized from THF and hexane, and placed under a drying vacuum (90percent yield). ESIMS: (M+H) + Calcd, 373.1 ; Found, 374.1.
Reference：
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[2] Patent: WO2004/99106, 2004, A2, . Location in patent: Page 18-19; 27-28
49
[ 56-91-7 ]
[ 82911-69-1 ]
[ 164470-64-8 ]
Yield
Reaction Conditions
Operation in experiment
23%
With sodium hydrogencarbonate In water; acetone at 20℃;
4-(Aminomethyl)benzoic acid (304 mg, 2.0 mmol) was stirred in 10percent Sodium hydrogencarbonate (sat aq, 10 ml). N-(9-Fluorenylmethoxycarbonyloxy)succinimide (680 mg, 2.0 mmol) and acetone (10 ml) was added and thick suspension was formed. Water (10 ml) was added to give an almost clear mixture that was stirred at room temperature over week-end. The mixture was washed with dichloromethane (a thick precipitate was formed in the water layer). The water layer was acidified with HCI (1 M) and extracted with dichloromethane (the precipitate moved into the dichloromethane layer). The precipitate was filtered off, dissolved in acetone and the insoluble material was filtered off. This latter filtrate was evaporated and dried on pump to yield a pure product (174 mg, 0.466 mmol, 23 percent). H NMR (400 MHz, DMSO-cfe) δ ppm 4.25 (m, 3 H) 4.38 (d, J^6.6 Hz, 2 H) 7.26 - 7.46 (m, 6 H) 7.70 (d, J=7.6 Hz, 2 H) 7.81 - 7.99 (m, 5 H) 12.85 (br. s., 1 H). 3C NMR (101 MHz, DMSO-cfe) δ ppm 43.55, 46.82, 65.33, 120.1 1 , 125.14, 126.96, 127.03, 127.59, 129.37, 140.78, 143.86, 144.90, 156.41 , 167.19.
Reference：
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[3] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 1, p. 161 - 175
[4] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4423 - 4427
[5] Patent: WO2015/63694, 2015, A1, . Location in patent: Page/Page column 39
[6] Chemical Communications, 2010, vol. 46, # 8, p. 1221 - 1223
[7] Organic Process Research and Development, 2001, vol. 5, # 4, p. 445 - 449
[8] Biological Chemistry, 2015, vol. 396, # 1, p. 45 - 52
50
[ 56-91-7 ]
[ 28920-43-6 ]
[ 164470-64-8 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6518 - 6524
[2] Tetrahedron, 1998, vol. 54, # 50, p. 15063 - 15086
[3] Organic Letters, 2008, vol. 10, # 10, p. 1881 - 1884
[4] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 873 - 879
[6] Patent: US9422239, 2016, B1, . Location in patent: Page/Page column 89
With thionyl chloride; at 20℃; for 4.5h;Cooling with ice; Reflux;
Example 1 Preparation of p-aminomethylbenzoic acid ethyl ester In 250mL neck round bottom flask was added 7.5g (50mmol) p-aminomethylbenzoic acid. Added with 100mL anhydrous ethanol. In an ice bath, was slowly added thionyl chloride 20.8g (175mmol), after the addition was complete, stirring at room temperature after 30min, was heated at reflux for 4h. After stopping the heating, removal of the ethanol under reduced pressure to give a white solid. The solid was dissolved with 150mL ethyl acetate in an ice bath was slowly added 35% NaOH aqueous solution to pH 7-8. Still stratification, washed three times with saturated saline aqueous layer was removed, and the organic layer, each 30mL. Dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid, 90% yield.
With sulfuric acid; at 20℃; for 48h;
General procedure: Samples were prepared in2mLHPLCvials using anAndrewAlliance pipetting robot. The 24 analyte compounds wereprepared in 0.05% H2SO4 in three different solvents (methanol,ethanol, and isopropanol) for esterification to the b, c,and d compounds by adding a few crystals of each analytecompound to the vials and mixing. Dissolved analytes werestored at room temperature for 2 d to allow for esterificationof the carboxylic acid to occur.
With potassium carbonate; triethylamine In Carbon tetrachloride at 25℃; for 4h;
1.S4; 2.S4; 3.S4 Step S4
Add the intermediate 3, N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide prepared in step S3 into the reaction kettle,At a temperature of 80°C, the reflux reaction was carried out for 2h, and then triethylamine and potassium carbonate were added at a speed of 200r/min.At a temperature of 25°C, the reaction was carried out for 4 hours to obtain p-aminomethyl benzoic acid.
60%
With ammonium hydroxide; ammonium bicarbonate In lithium hydroxide monohydrate at 20 - 50℃; for 1h;
1.2; 2.2; 3.2; 4.2
2) Add 67.96g of ammonium carbonate, 193.55g of 21% ammonia water, 185ml of purified water to the reaction flask, stir and dissolve at room temperature,43.01 g of p-bromomethylbenzoic acid in step 1) was added, the temperature was raised, and the reaction was carried out at 50° C. for 1 h. Filtration, the filtrate was concentrated until viscous,Suction filtration to obtain a filter cake. Add 193.55g ammonia water to the filter cake,Dissolve with stirring at room temperature, concentrate to pH=7.5 of the feed solution, filter with suction,The filter cake is high-purity 4-aminomethylbenzoic acid, the mass is 20.28 g, the purity is 99.93%, and the single-step amination yield is 60%.
With ammonium hydroxide
Multi-step reaction with 2 steps
1: anhydrous sodium carbonate; Etamon / lithium hydroxide monohydrate / 1.8 h / 115 °C
2: aluminum(III) oxide; ammonia / toluene / 18 h / 210 °C / 45004.5 Torr
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 24h;
97%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate for 16h;
Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In tetrahydrofuran
4.1
Stage 1 - Boc protection; 4-(Aminomethyl)benzoic acid (10.0Og, 65.36mmol) was stirred with BoC2O (28.0Og, 130.72mmoi) in H2O (10OmL) and THF (10OmL) at RT. Sat NaHCO3(aq) was added until pH ~ 6 was reached and the reaction was allowed to stir for 16h. The reaction was then carefully acidified to pH ~ 3 with 1 M HCIaq which caused a solid to precipitate out. This EPO 60 was filtered and dried to give the product as a white solid (16.1g, 97%). m/z = 274 [M+Na]+.
97%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 16h;
Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In lithium hydroxide monohydrate
73.1
Example 73; Cvclopentyl (2S)-cvclohexyl((4-r({3-r(1 E)-3-(hvdroxyamino)-3-oxoprop-1-en-1- yl1benzyl)amino)rnethvϖbenzyl)amino)acetate; The title compound was prepared by the following methodology:Intermediate J1Stage 4NaBH(OAc)3, DCEExample 12 ioxane Stage 1 - Preparation of 4-[(te/t-butoxycarbonyl)amino]methyl}benzoic acid; 4-(Aminomethyl)benzoic acid (10.0Og1 65.36mmol) was stirred with BoC2O (28.0Og, 130.72mmol) in H2O (10OmL) and THF (10OmL) at RT. Sat. NaHCO3 solution was added until pH ~ 6 was reached and the reaction was allowed to stir for 16h. The reaction was then carefully acidified to pH ~ 3 with 1 M HCIaq which caused a solid to precipitate out. This was filtered and dried to give the product as a white solid (16.1g, 97%). m/z = 274 [M+Na]+.
96%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In ethanol; lithium hydroxide monohydrate at 0 - 20℃;
Stage #2: With aqueous citric acid In lithium hydroxide monohydrate
4-Aminomethylbenzoic acid (10.0 g, 66 mmol) was dissolved in a mixture of 10 % aqueous NaOH (90 niL) and EtOH (250 mL). The solution was cooled to 0 0C and di-tert-butyl- dicarbonate (15.2 g, 73.0 mmol) was added slowly. The reaction mixture was stirred for 18 h at ambient temperature and TLC showed the consumption of amino acid. The ethanol was removed in vacuo and water (500 mL) was added. The aqueous layer was acidified slowly with a saturated solution of citric acid (20 mL) and the precipitate formed was filtered under suction, and dried in vacuo to afford the title compound as a white solid. No further purification was required. Yield: 16.0 g, 96 %. 1H NMR (300 MHz, CDCl3) δ ppm 7.88 (2H, d, J 8.1 Hz), 7.45 (IH, br s), 7.33 (2H, d, J 8.1 Hz), 4.18 (2H, d), 1.30 (9H, s)
96%
With sodium hydroxide In lithium hydroxide monohydrate; propan-2-one Inert atmosphere;
95%
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 4 - 20℃; for 15h;
4-(((/er/-Butoxycarbonyl)amino)methyl)benzoic acid (11):
4-(Aminomethyl)benzoic acid (2.0 g, 13.1 mmol, 1 eq) was dissolved in dioxane (32 mL) and water (16 mL) at RT. 1M NaOH (aq) (16 mL, 15.7 mmol, 1.2 eq) was added and the solution was cooled to 4 °C in an ice bath. Di- /c/T-butyl dicarbonate (3.1 g, 14.4 mmol, 1.1 eq) was added and the solution was allowed to warm slowly to room temperature. After 15 hours, the dioxane was removed under reduced pressure. The remaining aqueous solution was acidified to pH 2 with 10% KHSCri (aq) and extracted with EA. The organic layer was dried over NaiSCL, filtered and condensed to give 11 as a white solid (3.2 g, 95%). NMR (400 MHz, DMSO) d 7.89 (d, J= 8.4 Hz, 2H), 7.48 (t, 1H), 7.33 (d, 7= 8.0 Hz, 2H), 4.18 (d, J = 6.4 Hz, 2H), 1.39 (s, 9H).
94%
With potassium hydroxide; lithium hydroxide monohydrate In tetrahydrofuran for 1h; Ambient temperature;
92%
With sodium hydroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol for 18h;
92%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With potassium carbonate In lithium hydroxide monohydrate at 20 - 40℃; Cooling with ice;
Stage #2: With aqueous citric acid In lithium hydroxide monohydrate
12.1
(1) Synthesis of 4-[(tert-butoxycarbonylamino)methyl]benzoic acid 2.00 g (13.2 mmol) of 4-(aminomethyl)benzoic acid suspended in water (20 ml) was mixed with 3.81 g (27.6 mmol) of potassium carbonate and then with 3.57 g (16.4 mmol) of di-tert-butyl bicarbonate under cooling with ice. The mixture was allowed to react at 40° C. for 2.5 hours and stirred at room temperature overnight. Then, water (7 ml) and 5.6 g of citric acid monohydrate were gradually added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (3.05 g, yield 92%).
92%
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0℃; for 1h;
4-[(tert-Butoxycarbonyl)amino]methyl}benzoic acid (9)
4-(Aminomethyl)benzoic acid (5.0 g, 33.1 mmol) was dissolved in a mixture of dioxane (60mL), H2O (30 mL) and 1 M NaOH (40 mL). The resulting solution was cooled to 0 °C in an ice bath and di-tert-butyl dicarbonate (7.46 g, 34.2 mmol) was added. The reaction mixture was stirred for 1 h at 0 °C and a white precipitate was formed. The solvent was concentrated to 40 mL under reduced pressure and 1 M NaHSO4 solution was added to adjust the pH value to 2. The resulting suspension was extracted with EtOAc (ca. 100 mL) and the organic layer was washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure to yield 9. Colorless solid, mp 169 °C, yield 7.63 g (92 %). C13H17NO4 (251.1). Rf = 0.18 (ethyl acetate:cyclohexane = 1:1, detection: 254 nm). 1H NMR (400 MHz, DMSO-D6): δ [ppm] = 1.39 (s, 9H, (H3C)3C), 4.19 (d, J = 6.2 Hz, 2H, NHCH2), 7.34 (d, J = 8.0 Hz, 2H, 3-HB, 5-HB), 7.46 (t, J = 6.1 Hz, 1H, NHCH2), 7.89 (d, J = 8.1 Hz, 2H, 2-HB, 6-HB), 12.84 (s, 1H, CO2H). 13C NMR (101 MHz, DMSO-D6): δ [ppm] = 28.2 (3C, (H3C)3C), 43.2 (1C, NHCH2), 77.9 (1C, (H3C)3CO), 126.9 (2C, C-3B, C-5B), 129.2 (1C, C-1B), 129.3 (2C, C-2B, C-6B), 145.3 (1C, C-4B), 155.8 (1C, OCONH), 167.2 (1C, CO2H). FT-IR: ν [cm-1] = 3352 (N-H) 3074 (C-HAr), 2982, 2932, 2886, 2839 (C-Haliph.) 2677, 2558 (CO2H), 1682 (C=O), 1612, 1578, 1504 (C=CAr), 1427 (C-Haliph. deform.), 1242 (C-Ctert-butyl), 1161 (C-O), 841 (Arout of plane). HRMS (APCI): m/z = 252.1233 (calcd. 252.1230 for C13H18NO4 [M+H]+). HPLC: tR = 17.8 min, purity 99.9 %.
91%
In 1,4-dioxane; methanol; lithium hydroxide monohydrate Alkaline conditions;
90%
With sodium hydroxide In 1,4-dioxane at 0℃; for 0.666667h;
90%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate for 16h;
Stage #2: With phosphoric acid In lithium hydroxide monohydrate at 0℃;
2.2A
A solution of 4-aminomethylbenzoic acid (5.67 g, 37.5 mmol) triethylamine (5.20 mL, 37.5 mmol) and di-tert-butyl dicarbonate (9.5 mL, 41.2 mmol) in aqueous 1,4-dioxane (1/1) was stirred for 16 hours, reduced in volume under vacuum, cooled to 0 °C, acidified with 1M H3PO4, then extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4) and evaporated to provide the title compound (8.47 g, 90%). MS (APCI-) m/e 250 (M- H)-.
90%
With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 25℃;
90%
With sodium hydroxide In tetrahydrofuran at 20℃; for 12h;
90%
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 6h;
86%
With sodium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate for 12h;
Preparation of 4-[(tert-Butoxycarbonyl)aminomethyl]benzoic acidTo a solution of commercially available 4-aminomethylbenzoic acid (10.078 g, 66.7 mmol, 1 eq.) in aqueous NaOH (5.866 g, 146.6 mmol, 2.2 eq.) in water (25 ml) and THF (tetrahydrofuran; 50 ml) was added di-te/t-butyl dicarbonate (16 g, 73.3 mmol, 1.1 eq.). After stirring for 12 h the mixture was washed with hexane (2 x 50 ml), the aqueous phase cooled to 5° C and adjusted to pH3 with aqueous saturated citric acid. The resulting white precipitate was extracted with ethyl acetate (3 x 50 ml) and the organic extracts combined and dried (MgSO4). Concentration in vacuo yielded the title carbamate as white needles (14.43 g, 86%) from EtOAc.R, = 0.43 (SiO2 petrol: EtOAc; 1 :3); υmax (neat)/cm~1 3357 (m), 2968 (w), 2930 (w), 2884 (w), 2488 (m), 1682 (s), 1510 (m), 1409 (m), 1291 (m), 1244 (m), 1 172 (m), 944 (m), 879 (m), 783 (m); δH (DMSO-d6) 1 .39 (9 H, s, 3 x CH3), 4.18 (2 H, d, J = 6.3, CH2), 7.34 (2 H, d, J = 8.1 , H-3, 5), 7.48 (1 H, t, J = 6.1 , NH), 7.89 (2 H, d, J = 8.2, H-2, 6), 12.87 (1 H, s, br, COOH); δc (DMSO-d6) 28.2 (3 x CH3), 43.2 (CH2), 77.9 (C(CH3)3), 126.9 (CH), 129.2 (C-1 ), 129.3 (CH), 145.3 (C-4), 155.8 (C=O), carbamate), 167.2 (C=O, acid).
86%
With sodium hydroxide In 1,4-dioxane for 24h;
Synthesis of N-Boc-aminomethylbenzoic acid 4
4-aminomethyl benzoic acid (0.75 g, 5 mmol, 1 equiv.) was dissolved in a mixture of 1,4-dioxane (15 mL)and NaOH 0.5 N (15 mL) at 0° C and di-tert-butyldicarbonate (1.20 g, 5.5 mmol, 1.1 equiv.) was added.Then the mixture was allowed to react at room temperature, under magnetic stirring for 24 hours. Then thereaction was stopped, concentrated to 1/3 volume and acidified to pH=2 with HCl 2 N. The obtained mixturewas then extracted with ethyl acetate (3 x 10 mL), and the combined organic phases were dried overNa2SO4, filtered off and concentrated under reduced pressure, to give the desired intermediate 4 withoutfurther purification step in 86% yield.
85%
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃;
84%
In 1,4-dioxane; lithium hydroxide monohydrate for 12h; Ambient temperature;
81%
With sodium hydroxide; lithium hydroxide monohydrate In 1,4-dioxane at 0 - 20℃; for 1.16667h;
81%
With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃; for 1.16667h;
81%
With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 16h; Inert atmosphere;
41.41A 41 A: 4-(((/c/7-Butoxy carbonyl )amino)methyl (benzoic
To a solution of 4-(aminomethyl)benzoic acid (3.000 g, 19.85 mmol) in a solvent mixture of tetrahydrofuran (25 mL) and water (25 mL), was added di-/c77-butyl dicarbonate (9.22 mL, 39.7 mmol) followed by sodium bicarbonate solution (pH>8) at room temperature. After being stirred for 16 h under nitrogen atmosphere, the reaction mixture was extracted with ethyl acetate (2*100 mL). The aqueous layer was acidified with 1.5N HC1 solution (pH=l) and extracted with ethyl acetate (3*100 mL). The combined organic layer was washed with brine dried over anhydrous Na2S04 and concentrated in vacuo to afford 4-(((fert-butoxycarbonyl)amino)methyl)benzoic acid (4.200 g, 81%) as an off-white solid. 1H NMR (300 MHz, chlorofomwf) d ppm 8.08 (d, .7=8.31 Hz, 2H), 7.39 (d, .7=8.31 Hz, 2H), 5.00 (br. s. 1H), 4.41 (d, =5.67 Hz, 2H), 1.49 (s, 9H); LCMS (ES); m/z 252 A [M +H]+.
79%
With hydrogenchloride; sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate
1.1 (1-1)
(1-1) Synthesis of 4-(N-t-Butyloxycarbonylaminomethyl)benzoic Acid: In 150 ml of a mixture of dioxane and water (2:1 by volume) was dissolved 7.6 g of 4-aminomethylbenzoic acid, and 50 ml of an aqueous 1 mol sodium hydroxide solution and 25 ml of a dioxane solution of 12.0 g of di-t-butyl dicarbonate were added dropwise to the solution over a period of 10 minutes. Then, after stirring the mixture for 2.5 hours at room temperature (about 20° to 30° C.), the reaction mixture was concentrated under reduced pressure to about 1/3 of the original volume on a water bath of external temperature of from 50° C. to 60° C. and about 40 ml of 1N hydrochloric acid was added dropwise to the reaction mixture under ice-cooling to adjust the pH thereof to from 3 to 4. Then, the reaction product was extracted three times, each time with 40 ml of ethyl acetate, the organic layer thus obtained was washed with 30 ml of purified water and 30 ml of a saturated aqueous sodium chloride solution, and after drying it with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were washed with isopropyl ether and then recrystallized from ethyl acetate to provide 9.9 g (yield 79%) of a colorless powder of 4-(N-t-butyloxycarbonylaminomethyl)benzoic acid.
79%
In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 2h;
78%
With Sodium hydrogenocarbonate In tetrahydrofuran at 20℃; for 48h;
1
Stage 1 - 4-[(ter/-butoxycarbonyl)amino]methyl}benzoic acid; To a solution of 4-aminomethyl benzoic acid (19.22 g, 126 mmol) in THF (200 mL) was added saturated sodium hydrogen carbonate solution (300 mL) and di-tert-butyl dicarbonate (42.72 g, 195.7 mmol). The mixture was stirred at room temperature for 48 hours, then poured into ethyl acetate (250 mL). The aqueous layer was washed with ethyl acetate (250 mL), then acidified with 2M HCl solution. The precipitate was collected by filtration and dried under high vacuum to yield the desired product (24.6 g, 78% yield). LC/MS: m/z 274 [M+Na]+
78%
With sodium hydroxide In tetrahydrofuran at 20℃; for 8h;
Synthesis of 4-(((tert-butoxycarbonyl)amino)methyl)benzoicacid (2)
To a solution of compound 1 (605 mg, 4.0 mmol) in 8.8mL of 1 N NaOH, was added a solution of (Boc)2O (960 mg, 4.4 mmol)in tetrahydrofuran (THF, 2 mL). After stirring themixture at room temperature for 8 h, THF was evaporated in vacuum with theresidues being adjusted to pH 4-5 with 1 N aqueous citric acid. Then themixture was extracted with EtOAc (3 × 25 mL). The extractions were combined,washed with brine (3 × 20 mL), dried over MgSO4 and evaporated togive compound 2 (yield: 78 %) as a white solid. 1H-NMR (MeOH-d4, 400 MHz): δ 1.41 (s, 9H), 4.34 (s, 2H,), 7.32(d, J = 7.6 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H). 13CNMR (MeOH-d4): δ 26.7, 42.6, 78.2, 125.8, 128.5, 128.8, 144.3, 157.1, 167.6. HR-MS m/z: calcd for C13H17NNaO4,274.1050 [M-Na]+, found 274.1047 [M-Na]+.
78%
With triethylamine In methanol Reflux;
3.2. 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid 6
4-(aminomethyl)benzoic acid 5 (13.2mmol), Di-tert-butyl dicarbonate (15.9 mmol) and triethylamine (19.9 mmol) were stirred in methanol (30 mL) and reflux until the TLC (dichloromethane/methanol=15/1, v/v) showed the disappearance of the starting material. After the reaction was complete, the mixture was washed with petroleum ether twice, then removed the petroleum ether layer and water was added to the remaining solution. The resulting solution was acidified with citric acid to a pH of 3-4 and the resulting suspension was stirred for 10 minutes, and the precipitate was filtered and then dried to give white solid powder 6.
78.8%
With triethylamine In methanol at 100℃;
1.3 3. Preparation of 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid
Add 4-aminomethylbenzoic acid (13.2mmol),Di-tert-butyl dicarbonate (15.9 mmol),Triethylamine (19.9 mmol),And anhydrous methanol (30 ml) were sequentially added to the reaction flask,After the materials were mixed, a white turbid liquid was heated and refluxed for 6 hours.The reaction was detected by TLC (TLC eluent preparation: methylene chloride: methanol = 15: 1), and the reaction system changed from turbid to clear.After the reaction system was washed twice with petroleum ether, the petroleum ether layer was removed.Water was added to the remaining solution, and the reaction system changed from clear to cloudy again. The citric acid was used to adjust the pH of the system to 4-5, and white precipitation continued to precipitate.The system was then extracted with dichloromethane. The organic phase was washed 3 times with water and spin-dried.Get white solid powder,That is 4-(((tert-butoxycarbonyl) amino) methyl) benzoic acid. Yield 78.8%,
73%
Stage #1: p-aminomethylbenzoic acid With triethylamine In methanol at 20℃; for 0.5h;
Stage #2: di-<i>tert</i>-butyl dicarbonate In methanol for 2h; Reflux;
68%
In sodium hydroxide
5.A Step A
Step A 4-(N-Boc-aminomethyl)benzoic Acid (Compound 29) To a solution of 4-(aminomethyl)benzoic acid (1 g, 6.62 mmol) in 4M NaOH (21 ml) at room temperature was added di-tert-butyldicarbonate (1.67 ml, 7.28 mmol) and the mixture stirred for 19 hours. The reaction was acidified to pH 2.0 with concentrated hydrochloric acid and the mixture extracted with ethyl acetate (3*50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (1.136 g, 68%) as a solid.
66%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With Sodium hydrogenocarbonate In 1,4-dioxane at 0 - 20℃; for 16h;
Stage #2: With hydrogenchloride In lithium hydroxide monohydrate
4.1
To a stirred solution of 4-(aminomethyl)benzoic acid (5 g, 33 mmol) in 1,4-dioxane (50 mL) and H2O (25 mL) was added NaHCO3 (8.3 g, 99.2 mmol) followed by Boc anhydride (10.8 g, 49.6 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of reaction (by TLC), the volatiles were evaporated under reduced pressure and the residue was neutralized using cold 1N HCl solution. The precipitated solid was filtered and dried under reduced pressure to afford 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid (5.5 g, 66%) as a white solid.
63%
With sodium hydroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol for 18h; Ambient temperature;
63.8%
With sodium hydroxide In 1,4-dioxane at 20℃; for 12h;
60%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In 1,4-dioxane for 1h;
Stage #2: With hydrogenchloride In 1,4-dioxane; lithium hydroxide monohydrate
16.1; II
To a solution of 4-Aminomethyl-benzoic acid (5.0 g, 33.1 mmol) in 1,4-dioxane (60.0 mL) were added 1M sodium hydroxide (30 mL), BOC-anhydride (6.8 mL, 29.8 mmol) drop wise at ice temperature and it was stirred at same temperature over a period of 60 min. The resulting mixture acidified (PH=:5.0) with 1.5 N hydrochloric acid and extracted with ethyl acetate (3X100 mL), dried over sodium sulphate. Volatiles were evaporated under reduced pressure to obtain 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid as a colourless solid (5.0 g, 60 %).
60%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In 1,4-dioxane for 1h; Cooling with ice;
Stage #2: With hydrogenchloride In 1,4-dioxane; lithium hydroxide monohydrate
II; 16.1
To a solution of 4-Aminomethyl-benzoic acid (5.0 g, 33.1 mmol) in 1,4-dioxane (60.0 mL) were added 1M sodium hydroxide (30 mL), BOC-anhydride (6.8 mL, 29.8 mmol) drop wise at ice temperature and it was stirred at same temperature over a period of 60 min. The resulting mixture acidified (PH=5.0) with 1.5 N hydrochloric acid and extracted with ethyl acetate (3*100 mL), dried over sodium sulphate. Volatiles were evaporated under reduced pressure to obtain 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid as a colourless solid (5.0 g, 60%).
60%
With anhydrous sodium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 0 - 20℃;
47%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In 1,4-dioxane; lithium hydroxide monohydrate at 0℃; for 1h;
Stage #2: With sulfuric acid potassium salt; lithium hydroxide monohydrate In 1,4-dioxane; ethyl acetate
103.A
Example 103 TERT-BUTYL(4-[3-[(PYRIDIN-3-YLMETHYL)AMINO]CARBONYL}-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-10(11H)-YL]CARBONYL}BENZYL)CARBAMATE Step A. 4-[(tert-Butoxycarbonyl)amino]methyl}benzoic acid; To a solution of 4-(aminomethyl)benzoic acid (5.00 g, 0.0331 mol) in dioxane (60 mL), water (30 mL), and 1 M sodium hydroxide (34 mL, 0.034 mol) at 0° C. was added di-tert-butylpyrocarbonate (7.94 g, 0.0364 mol) and the reaction mixture stirred at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo to 30 mL, ethyl acetate (80 mL) added and the mixture acidified to pH 4 by the addition of 1 M aqueous potassium hydrogen sulfate solution with vigorous stirring. The organic phase was separated, washed with water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a white solid. Recrystallization from ethyl acetate (60 mL) gave the title compound (3.94 g, 47%) as a white crystalline solid, m.p. 165° C. MS [(-)ESI, m/z]: 250 [M-H]- Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 61.74; H, 6.51; N, 5.42.
46.5%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In lithium hydroxide monohydrate; butan-1-ol at 0 - 20℃; for 3h;
Stage #2: With aqueous citric acid In lithium hydroxide monohydrate; butan-1-ol at 0℃;
1.2
Step 2; Preparation of 4-((t-butoxycarbonylamino)niethyI)benzoic acid.; To a solution of 4-aminomethylbenzoic acid (5 g, 33 mmol) in water maintained at 0 0C, was added 5% aqueous NaOH solution (100 mL), followed by dropwise addition of Boc anhydride (15 mL, 66 mmol) in n-butanol (10 mL). Subsequently, the reaction mixture was stirred at room temperature for 3 hours. Upon completion, as monitored by TLC using DCM:MeOH (9: 1) as the eluent, the reaction mixture was poured in ice water, acidified with citric acid upto pH 4. On standing at room temperature for 10 minutes the precipitate formed was filtered, washed with water (100 mL) and dried to give the Boc protected product (6.5 g. 46.5 % yield).
46.5%
Stage #1: p-aminomethylbenzoic acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In lithium hydroxide monohydrate; butan-1-ol at 0 - 20℃;
Stage #2: With aqueous citric acid In lithium hydroxide monohydrate; butan-1-ol Cooling with ice;
1.2 Preparation of 4-((t-butoxycarbonylamino)methyl)benzoic acid
To a solution of 4-aminomethylbenzoic acid (5 g, 33 mmol) in water maintained at 0° C., was added 5% aqueous NaOH solution (100 mL), followed by dropwise addition of Boc anhydride (15 mL, 66 mmol) in n-butanol (10 mL). Subsequently, the reaction mixture was stirred at room temperature for 3 hours. Upon completion, as monitored by TLC using DCM:MeOH (9:1) as the eluent, the reaction mixture was poured in ice water, acidified with citric acid up to pH 4. On standing at room temperature for 10 minutes the precipitate formed was filtered, washed with water (100 mL) and dried to give the Boc protected product (6.5 g, 46.5% yield).
39%
With sodium hydroxide In ethanol at 0 - 20℃; for 18h;
With sodium hydroxide In 1,4-dioxane
In <i>tert</i>-butyl alcohol
With sodium hydroxide In 1,4-dioxane at 0℃; for 0.5h;
With sodium hydroxide In 1,4-dioxane at 20℃;
With triethylamine In 1,4-dioxane; lithium hydroxide monohydrate
With sodium hydroxide In lithium hydroxide monohydrate; <i>tert</i>-butyl alcohol
84.A 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid
EXAMPLE 84A 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid A solution of 4-(aminomethyl)benzoic acid (1.51 g, 10 mmol), di(tert-butyl) dicarbonate (2.62 g, 12 mmol), and sodium hydroxide (0.48 g, 12 mmol) in tert-butanol (20 mL) was stirred for 16 hours, treated with water (200 mL), and extracted with hexanes. The aqueous layer was cooled to 5° C., adjusted to pH 4 with 1M NaHSO4, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/z 252 (M+H)+, 269 (M+NH4)+; 1H NMR (DMSO-d6) δ8.06 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 4.95 (br s, 1H), 4.40 (d, J=5.9 Hz, 2 H), 1.48 (s, 9H).
In tetrahydrofuran; sodium hydroxide
29.1 Preparation of 1-N,N-Dimethylcarbamoyl-3-{4-[1H-2-trifluoromethylimidazo[4.5-c]pyrid-1-yl)methyl]benzoyl}indole
Step 1: 4-(N-tert-Butoxycarbonylaminomethyl)benzoic acid. To a solution of 4-aminomethylbenzoic acid (11.1 g, 73.4 mmol) in 1N aqueous NaOH (100 mL) was added THF (100 mL) and di-tert-butyldicarbonate (16.8 g, 77.1 mmol). The reaction mixture was stirred for 2 hours at ambient temperature, then acidified to pH 2 and extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 4-(N-tert-butoxycarbonylaminomethyl)benzoic acid (18.3 g) as white crystals which was used without further purification.
With hydrogenchloride In tetrahydrofuran; lithium hydroxide monohydrate
12 N,N'-Bis(N-(4-aminomethylbenzamido)-4-aminobutyric)-p-xylylene diamide
To a solution of di-tert-butyl dicarbonate (1.2 g, 8.0 mmol, 1 equiv) in tetrahydrofuran (15 mL) was added a solution of 4-(aminomethyl)benzoic acid (1.9 g, 8.7 mmol, 1.1 equiv) in tetrahydrofuran (35 mL). The solution was stirred for 24 hours. The solution was concentrated in vacuo. Water (50 mL) was added and decanted. A solution of 0.1N HCl was added (50 mL). The product, N-Boc-4-(aminomethyl)benzoic acid was removed by filtration and dried in vacuo.
With triethylamine In dichloromethane
29
Prepared according to the initial preparation used to prepare Example 11 but Steps M and N are inserted prior to the removal of the ester alcohol. Aminomethylbenzoic acid was first protected with 1 equivalent of BOC and then the N-protected amine was methylated with methyl iodide. The BOC group was subsequently removed and the N-methylaminomethylbenzoic acid was coupled with the tetrapeptide. Step M: Proctection of AmineThe amine (9.9 mmole) and triethylamine (9.9 mole) was dissolved in dry dichloromethane and (Boc)2O was added. The reaction was stirred overnight under nitrogen. Workup: the reaction was concentrated on a rotary evaporator and the residue was taken up with ethyl acetate and then washed with water, citric acid, sodium bicarbonate, and brine. The organic solvent was dried over MgSO4 (86%).
1.1
Example 1: Preparation of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-l- oxoisoindolin-2-yl) methyl)benzamideStep 1 : Preparation of methyl 4-(aminomethyl)benzoate hydrochloride4-Aminomethylbenzoic acid (2.0 g, 13 mmol) was dissolved in MeOH(5.0 mL), thionylchloride (2.9 mL, 3 equiv.) was slowly added thereto at 0 °C and fluxed for 24 hrs. The mixture thus obtained was distilled under a reduced pressure to remove the solvent and thionyl chloride, and dried under vacuum to obtain the title compound (2.7 g, 99 %).1H NMR (300 MHz, D2O): δ 7.93 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 4.12(s, 2H), 3.79 (s, 3H).
99%
With thionyl chloride at 0 - 20℃;
98%
With hydrogenchloride for 5h; Heating;
98%
With thionyl chloride for 4h; Reflux; Inert atmosphere;
98%
With thionyl chloride for 12h; Reflux;
97%
With chloro-trimethyl-silane at 20℃; for 24h;
95%
With hydrogenchloride In water Reflux;
93%
With acetyl chloride at 0 - 75℃; for 5h;
3.1.1.1. Methyl 4-(aminomethyl)benzoate hydrochloride (6).
Compound 5 (1.5 g, 10 mmol) was dissolved in 200 mL MeOH, thenacetyl chloride (2.4 g, 30 mmol) was added dropwise at 0 °C; themixed solution was refluxed at 75 °C for 5 h. The solvent wasevaporated under vacuum, the product was washed by diethylether to give compound 6, a white solid powder (1.7 g, 93%).
62%
for 0.166667h; Heating;
With thionyl chloride at 70℃;
With thionyl chloride at 20℃; for 12h; Inert atmosphere;
With hydrogenchloride In water Reflux;
With thionyl chloride for 12h; Reflux;
2.1 Synthesis Example of axle component
4- (aminomethyl) benzoic acid 9.06 g (60.0 mmol) was dissolved in methanol 400 mL, and then thionyl chloride 20 mL was added dropwise, and refluxed for 12 hours. Excess thionyl chloride and the solvent were distilled off under reduced pressure to obtain a white solid, which was then washed with ethyl acetate, & vacuum dried to give 8.16 g of 4- (methoxycarbonyl) benzyl ammonium hydrochloride.
With hydrogenchloride Reflux;
2 Intermediate formation
6050 mg (40 mmol) of 4-(aminomethyl)benzoic acid was dissolved in 200 mL of methanol, to which was added 6 mLs of concentrated HC1 in one portion. The mixture was refluxed overnight and the volatiles condensed under vacuum. The resulting white solid was suspended in ethyl ether and separated via vacuum filtration to yield the benzoate HC1 salt. This compound was dissolved in a 1:2 mixture of ethyl acetate and water and chilled to 0°C to which 11040mg (80 mmol) was added followed by addition of 5623 mg benzoyl chloride (40 mmol). The vessel was warmed to room temperature and stirred for 2 additional hours. The mixture was separated via acid/base extraction, washing the water phase twice with ethyl acetate. All organic phases were combined and condensed under vacuum to yield a white solid. This was suspended in 200 mL of methanol and 10000 mg (200 mmol) of hydrazine water salt was added. The solution was refluxed for 48 hours, cooled to room temperature, and volatiles were removed under vacuum. This intermediate N-(4-(hydrazinecarbonyl)benzyl)benzamide (2sm) was used as the starting material for all further reactions for this family.
With thionyl chloride for 6h; Inert atmosphere; Reflux;
With sodium hydrogencarbonate; In water; acetone; at 20℃;
4-(Aminomethyl)benzoic acid (304 mg, 2.0 mmol) was stirred in 10% Sodium hydrogencarbonate (sat aq, 10 ml). N-(9-Fluorenylmethoxycarbonyloxy)succinimide (680 mg, 2.0 mmol) and acetone (10 ml) was added and thick suspension was formed. Water (10 ml) was added to give an almost clear mixture that was stirred at room temperature over week-end. The mixture was washed with dichloromethane (a thick precipitate was formed in the water layer). The water layer was acidified with HCI (1 M) and extracted with dichloromethane (the precipitate moved into the dichloromethane layer). The precipitate was filtered off, dissolved in acetone and the insoluble material was filtered off. This latter filtrate was evaporated and dried on pump to yield a pure product (174 mg, 0.466 mmol, 23 %). H NMR (400 MHz, DMSO-cfe) delta ppm 4.25 (m, 3 H) 4.38 (d, J^6.6 Hz, 2 H) 7.26 - 7.46 (m, 6 H) 7.70 (d, J=7.6 Hz, 2 H) 7.81 - 7.99 (m, 5 H) 12.85 (br. s., 1 H). 3C NMR (101 MHz, DMSO-cfe) delta ppm 43.55, 46.82, 65.33, 120.1 1 , 125.14, 126.96, 127.03, 127.59, 129.37, 140.78, 143.86, 144.90, 156.41 , 167.19.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 12h;Reflux;
To a stirred suspension of 4-(aminomethyl)benzoic acid (lOg, 66.2mmol) in tetrahydrofurane (100mL) lithium aluminium hydride (lOg, 264.8mmol) was addedportionwise at 0C. The mixture was heated to reflux and stirred overnight before cooling down again to 0CC. l0mL of H20 were added, then l5mL of 10% NaOH and 30mL of H20. The mixture was kept at 000 for 1 hour. Then the mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated to afford 4-(aminomethyl)benzyl alcohol as a yellow oil that crystallized to a beige solidafter several minutes. The solid obtained was washed with Et20 to afford 4- (aminomethyl)benzyl alcohol (8.8g, yield 97%) as a light-beige powder. 1H NMR (250 MHz, CD3OD) 6 7.32 (s, 4H), 4.58 (s, 2H), 3.78 (s, 2H). 130 NMR (63 MHz, CD3OD) 6142.21, 141.50, 128.53(x2), 128.26(x2), 64.96, 46.32.
With sodium hydroxide; lithium aluminium tetrahydride; In water;
A] 4-(Aminomethyl)benzoic acid (20 g, 0.132 mole) was added to a suspension of lithium aluminium hydride (5.5 g, 0,145 moles) in 300 ml of THF, at room temperature. The suspension was refluxed for 4 hours, the cooled to room temperature and added with, successively, a mixture THF/water 7:1 (32 ml), 32% sodium hydroxide (10 ml) and water (40 ml). The formed solid was filtered off and the solvent evaporated under vacuum to provide 7 g of 4-(aminomethyl)benzyl alcohol che was directly used in the next step.
With sodium hydroxide; In tetrahydrofuran; water;
EXAMPLE 44 Di-4-(N,N-dibutylaminomethyl)benzyl carbonate dihydrochloride A! 4-(Aminomethyl)benzoic acid (20 g, 0.132 mole) was added to a suspension of lithium aluminium hydride (5.5 g, 0,145 moles) in 300 ml of THF, at room temperature. The suspension was refluxed for 4 hours, the cooled to room temperature and added with, successively, a mixture THF/water 7:1 (32 ml), 32% sodium hydroxide (10 ml) and water (40 ml). The formed solid was filtered off and the solvent evaporated under vacuum to provide 7 g of 4-(aminomethyl)benzyl alcohol che was directly used in the next step.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4h;Inert atmosphere; Reflux;
To a an ice-bath cooled suspension of lithium aluminum hydride (629 mg, 16.55 mmol) in anhydrous THF (40 mL), 4-(aminomethyl)benzoic acid 8 (1.0 g, 6.62 mmol) was added portion-wise. The reaction mixture was stirred at 0 C for 1 h then it was heated under reflux for 3 h. The mixture was cooled to 0 C and water was added. The aqueous phase was extracted with a mixture of dichloromethane/isopropanol (4:1). Addition of a few drops of aqueous solution of Rochelle salt avoids emulsion formation. Combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give compound 9 as a yellow solid (250 mg, 28%). 1H NMR (CD3OD) delta: 7.32 (m, 4H, H-phenyl), 4.58 (s, 2H, OCH2), 3.79 (s, 2H, NCH2) ppm.
With borane-THF; In tetrahydrofuran; for 8h;Reflux;
20.0 g (0328) (132 mmol) of 4-(aminomethyl)benzoic acid was dispersed in 100 mL of anhydrous THF, and 350 mL (2.65 equiv.) of 1M borane-THF in THF was added dropwise. The reaction mixture was heated to reflux for eight hours, and then allowed to cool to room temperature. 100 mL of MeOH was added to quench the remaining borane-THF, and the reaction was stirred for an additional 15 minutes. The reaction solution was then filtered over celite and evaporated in vacuo to give a light yellow solid. 250 mL of DCM was then added to the reaction flask containing the crude intermediate product, followed by 37 mL (2 equiv.) of triethylamine. The reaction was cooled to 0C, 21 mL (1.1 equiv.) of trifluoroacetic anhydride was added dropwise and the reaction was allowed to stir overnight, allowing it to gradually reach room temperature. After 22 hours of reaction time, all of the starting material had been consumed as evidenced by TLC. 250 mL of water was added to the reaction and the organic layer was separated. The aqueous layer was extracted once more with 250 mL of DCM, the combined organics were washed with water (100 mL), and were dried over sodium sulfate, filtered and evaporated in vacuo to give a thick yellow oil. This oil was purified via automated flash chromatography (EPCLC W-Prep 2XY, Yamazen Corp., Yodogawa-Ku Osaka, Japan) using DCM/MeOH as the eluents. The fractions containing the desired product were combined and evaporated to give 15.87 g (51.44% yield for both steps) of 3 as a white solid. lH NMR (300 MHz, CDC13) delta 7.34 (d, J = 8.17 Hz, 2H), 7.26 (d, J = 8.16 Hz, 2H), 6.86 (s, br, 1H), 4.66 (s, 2H), 4.49 (d, J = 5.86 Hz, 2H), 2.02 (s, 1H).
To a solution of 4-(aminomethyl)benzoic acid (300 g, 1.98 mol) in methanol (5 L) was added thionylchloride (473 g 3.97 mol). The reaction mixture was refluxed for 6 h, followed by the removal of the solvent under reduced pressure to obtain the crude product. The crude was purified by acid-base work up to afford methyl-4-(aminomethyl)benzoate (300 g, 92%) as a liquid.
90.5%
With thionyl chloride; at 0℃;
1 g of 4- (aminomethyl) benzoic acid (0.0066 mol) was dissolved in 20 ml of methanol and stirred for 5 mins in an ice bath.Slowly add 0.71mlThionyl chloride, dripped, stirred under ice bath for 10mins, then raised to 60 C, and stirred at reflux overnight.After the reaction was monitored by TLC, methanol was distilled off under reduced pressure. After drying, 0.98 g of a white solid was obtained with a yield of 90.5%. The product was directly used in step two.
88 - 89%
EXAMPLE In a 1200 1 stirred vessel made of steel and enamel, 60 kg of 4-(aminomethyl)benzoic acid, 480 kg of methanol and 89 kg of 30% hydrochloric acid are heated to boiling at reflux. After a reaction time of 7 h, the reaction mixture is cooled to 10 C. Addition of 290 kg of 4% sodium hydroxide solution initially adjusts the pH of the reaction mixture to a pH of 6-7, before a methanol/water mixture is distilled off under reduced pressure. Subsequently, 400 kg of methylene chloride are added and the pH of the aqueous phase is adjusted to a value of 10-11 at a temperature of 5-10 C. The lower organic phase is removed. The aqueous phase is extracted once more with 265 kg of methylene chloride. The organic phases are combined and stored at 0-5 C. The content of the solution is determined by means of quantitative HPLC chromatography. The yield of methyl 4-(aminomethyl)benzoate is 88-89%.
82%
With thionyl chloride; In methanol; at 0 - 60℃; for 12h;
Intermediate VI: methyl (2E)-3-14-(AMINOMETHVLOPHENYLLACRVLATE, HYDROCHLORIDE SALT; 5 TEP A) FO/WON of methyl-(4-aminomethyl)benzoate; To a solution of (4-aminomethyl) benzoic acid (125 g, 0.83 mol) in methanol (1.5 L) was added THIONYLCHLORIDC (350 g, 3 eq. ) at 0C with stirring and then allowed to stir at rt for overnight and finally REFLUXED at 60C for 12 H for the completion of the reaction. The reaction mixture was concentrated and crude hydrochloric salt was neutralized using 10% aqueous NaHCO3 solution to pH 8. The aqueous layer was concentrated and kept at 0C overnight. The solid obtained was filtered, washed with cold water and dried under suction to give the title compound (112 g, 82%).
79%
With thionyl chloride; at 70℃; for 3.5h;
4-aminomethyl benzoic acid (6.69 g, 44.09 mmol) was dissolved methanol (200 mL). SOCl2 (12 mL) was added via syringe. The mixture was stirred at 70C for 3.5 h. After cooling, the reaction mixture was evaporated and the crude product was dissolved in CH2Cl2 (500 mL). The organic layer was washed with aqueous K2CO3 10% (300 mL), dried with MgSO4, filtered and evaporated. Methyl 4-(aminomethyl)benzoate was obtained (5.78 g, 79 %) as a white solid. [] MW: 165.19; Yield: 79 %; White Solid; Mp (C): 73.3.1H-NMR (CDCl3,delta): 1.53 (s, 2H, NH2), 3.94 (s, 1H, CH3), 3.96 (s, 2H, N-CH2), 7.39 (d, 2H, J = 8.4 Hz, ArH), 8.02 (d, 2H, J = 8.4 Hz, ArH).
37%
With hydrogenchloride; In water;Reflux;
Step 1. Synthesis of methyl 4-(aminomethyl)benzoate To a solution of 4-(aminomethyl)benzoic acid (0.500 g, 3.31 mmol) in methanol (15.0 mL) was added concentrated HCl(aq) (0.8 mL). After the reaction mixture was reflux for overnight and cooled to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4(s), filtered, and concentrated to give a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (100% ethyl acetate and 15% MeOH in CH2Cl2) to give methyl 4-(aminomethyl)benzoate (200 mg, 37%). 1H NMR (CDCl3, 400 MHz) delta 7.98 (d, 2H), 7.36 (d, 2H), 3.91 (s, 2H), 3.88 (s, 3H).
With sulfuric acid; at 60℃; for 12h;
To a solution of 4-(aminomethyl)benzoic acid (1 g, 7 mmol) in MeOH (10 mL) was added dropwise concentrated H2S04 (1 mL). Upon completion of addition, the reaction mixture was heated to 60 C where it stirred for 12h. After this time, the reaction mixture was concentrated under reduced pressure to yield a residue. The residue was dissolved in ethyl acetate and then carefully neutralized with a 10% NaOH solution. The organic layer was separated and washed successively with water and brine. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to afford methyl 4-(aminomethyl)benzoate (2.5 g) as a white solid. LCMS Method O: retention time 0.49 min, [M+l] = 166.2.
With diazomethyl-trimethyl-silane; In benzene; for 1h;
Preparation of ester 14: To a solution of 4-(aminomethyl)benzoic acid (1 eq.) in benzene (0.3 mL) and MeOH (0.3 mL) was added TMSCHN2 (1.3 eqs.). The reaction mixture was stirred for 1.0 h, after which the reaction mixture was concentrated in vacuo. Ester 14 was used without further purification.
With sulfuric acid; at 20℃; for 48h;
General procedure: Samples were prepared in2mLHPLCvials using anAndrewAlliance pipetting robot. The 24 analyte compounds wereprepared in 0.05% H2SO4 in three different solvents (methanol,ethanol, and isopropanol) for esterification to the b, c,and d compounds by adding a few crystals of each analytecompound to the vials and mixing. Dissolved analytes werestored at room temperature for 2 d to allow for esterificationof the carboxylic acid to occur.
With thionyl chloride; In methanol; at 0 - 25℃; for 12h;
General procedure: To a solution of 4a-4e (1.0 equiv) in MeOH was added SOCl2 (1.5 equiv) dropwise at 0 C. The mixture was stirred for 12 h at 25 C. The solvent was evaporated under vacuum. The crude product was recrystallized to give 5a-5e (yield 85%-90%) as white solid.
Synthesis of N-Acetyl-aminomethylbenzoic acid 3
4-aminomethyl benzoic acid (0.75 g, 5 mmol, 1 equiv.) was dissolved in 15 mL dry THF, acetic anhydride(4.7 mL, 50 mmol, 10 equiv.) was then added at 0° C, followed by triethylamine (0.77 mL, 5.5 mmol, 1.1equiv.). The mixture which was stirred at room temperature overnight. After reaction completion, solventwas evaporated and crude product solution was acidified with HCl 1 N until precipitation. Solid was filteredand rinsed with cold HCl 1M. Crude product was recrystallized from HCl 1 N to give the title compound 3in 78% yield.
57%
In tetrahydrofuran at 20℃; for 4h;
2
To a solution of 4- (aminomethyl)-benzoic acid (100 mg), in THF (1.3 ml, 0.5 M), was added acetic anhydride (620 al, 10 eq). The reaction mixture was stirred at RT for 4 hours. The solvent was removed under reduced pressure. The residue was triturated with 1M HC1 and then, the reaction mixture was acidified by 3M HCI. The 4- (acetylamino- methyl) benzoic acid was collected by filtration, washed with water and dried. The product was obtained as a white powder (57% yield). To a solution of 4- (acetylamino-methyl) benzoic acid (73 mg, 1 eq), HOBt (67 mg, 1.3 eq), EDCI. HCI (94 mg, 1.3 eq) and N-methylmorpholine (47 1, 1.3 eq) in DMF (1.5 ml) was added 4-amino-pyridine (1 eq). The reaction mixture was stirred at RT for 72 hours. The solvent was evaporated and the resulting oil was diluted with DCM. The solution was washed with aqueous 1M Na2CO3. The organic layer was evaporated. The residue was purified by flash chromatography (DCM/2M NH3 in MeOH 95/5), yielding the title product as a white powder (10% yield NMR (300 MHz, DMSO-d6): 1.88 ppm (s, 3H); 4.31 ppm (d, 2H, J= 6. 0Hz) ; 7.39 ppm (d, 2H, J= 8.4Hz) ; 7.76 ppm (dd, 2H, J= 1.5 & 4.8Hz) ; 7.90 ppm (d, 1H, J= 8.4Hz) ; 8.45 ppm (d, 2H, J= 4.8Hz) ; 10. 51 ppm (s, 1H).
With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 16h;
Benzyl chloroformate (10.3 mL, 72.7 mmol) and 2 M NaOH solution (33 mL, 66 mmol) were simultaneously added dropwise to a stirred solution of 4-aminomethylbenzoic acid (29) (10.0 g, 66.2 mmol) in 2 M NaOH solution (33 mL) and THF (30 mL) at 0 C. The mixture was stirred at 20 C for 16 h, then the organic solvent was evaporated and the residue acidified with 2 M HC1 until the pH of the mixture was 2-3. The precipitate was filtered, washed with water (250 mL), washed with EtOH (50 mL), and finally washed with Et20 (100 mL). The solid was dried under vacuum to give acid 2 (16.43 g, 87%) as a white powder: mp 190-192 C [lit. (Loge et. al., J. Enzyme Inhibit. Med. Chem. 2002, 17, 381-390) mp (toluene) 194-195 C; 1H NMR δ 7.85 (br d, 2 H, H-2, H-6), 7.82 (br t, J = 6.1 Hz, 1 H, NHC02), 7.30-7.40 (m, 5 H, H-2', H-3', H-4', H-5', H-6'), 7.27 (br d, J = 8.2 Hz, 2 H, H-3, H-5), 5.05 (s, 2 H, OCH2), 4.24 (d, J = 6.1 Hz, 2 H, CH2N).
87%
With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 16h;
Benzyl chloroformate (10.3 mL, 72.7 mmol) and 2 M NaOH solution (33 mL, 66 mmol) were simultaneously added dropwise to a stirred solution of 4-aminomethylbenzoic acid (29) (10.0 g, 66.2 mmol) in 2 M NaOH solution (33 mL) and THF (30 mL) at 0 C. The mixture was stirred at 20 C. for 16 h, then the organic solvent was evaporated and the residue acidified with 2 M HCl until the pH of the mixture was 2-3. The precipitate was filtered, washed with water (250 mL), washed with EtOH (50 mL), and finally washed with Et2O (100 mL). The solid was dried under vacuum to give acid 2 (16.43 g, 87%) as a white powder: mp 190-192 C. [lit. (Loge et. al., J. Enzyme Inhibit. Med. Chem. 2002, 17, 381-390) mp (toluene) 194-195 C.; 1H NMR δ 7.85 (br d, 2H, H-2, H-6), 7.82 (br t, J=6.1 Hz, 1H, NHCO2), 7.30-7.40 (m, 5H, H-2', H-3', H-4', H-5', H-6'), 7.27 (br d, J=8.2 Hz, 2H, H-3, H-5), 5.05 (s, 2H, OCH2), 4.24 (d, J=6.1 Hz, 2H, CH2N).
87%
With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 16h;
Benzylchloroformate (10.3 mL, 72.7 mmol) and 2 M NaOH solution (33 mL, 66 mmol) weresimultaneously added dropwise to a stirred solution of 4-aminomethylbenzoicacid (1) (10.0 g, 66.2 mmol) in 2 M NaOH solution (33 mL) and THF (30 mL) at 0C. The mixture was stirred at 20 C. for 16 h, then the organic solvent wasevaporated and the residue acidified with 2 M HCl until the pH of the mixturewas 2-3. The precipitate was filtered, washed with water (250 mL), washed withEtOH (50 mL), and finally washed with Et2O (100 mL). The solid was dried undervacuum to give acid 2 (16.43 g, 87%)
32%
With sodium hydrogencarbonate; In water; acetone; at 0 - 20℃;
4-(Aminomethyl)benzoic acid (4.53 g, 30.0 mmol) was dissolved in acetone (50 mL), sodium hydrogen carbonate (sat, 50 mL), and water (50 mL). After cooling to 0 C and an additional adding of ice (ca 10 mL) to the reaction mixture, benzyl chloroformate (4.5 mL, 31.5 mmol) in acetone (25 ml) was added dropwise. The mixture was allowed to attain room temperature and then stirred overnight. The mixture was diluted with water and washed with dichloromethane. The water layer was acidified with HCI (1 M) and extracted with ethyl acetate. The organic layer was basified with NaOH (aq) and a precipitate was formed. This was filtered off, washed with acetone and dichloromethane. Recrystallization from methanol yielded pure product (2.76 g, 9.67 mmol, 32%). 3C NMR (101 MHz, DMSO-cfe) δ ppm 43.77, 65.79, 127.31 , 128.01 , 128.16, 128.69, 129.45, 129.69, 137.32, 145.24, 156.72, 167.39
With hydrogenchloride; In tetrahydrofuran; sodium hydroxide;
Step A. Preparation of 4-(N-CBz-aminomethyl)-benzoic acid 10.0 g (66 mmol) of 4-aminomethylbenzoic acid was dissolved in 33 ml of 2N NaOH solution (66 mmol) and 30 ml of THF. 12.45 g (73 mmol) of benzyl chloroformate and 37.5 ml of 2N NaOH solution was added in aliquots at 0 C. over 20 minutes. The reaction was stirred at room temperature over night and concentrated in vacuo to remove THF. 2N HCl was added to acidify to pH2-3. The precipitated solid was recovered by filtration and washed with ether to remove excess benzyl chloroformate. The solid was dried in vacuo to give 18.8 g of the desired product. 400 MHz 1H NMR (CD3OD): 4.31 (s, 2H); 5.09 (s, 2H); 7.30 (m, 7H); 7.91 (d, 2H).
With potassium carbonate; In water; for 16h;
Compound 34 (4.00 g, 26.5 mmol) in aq. K2CO3 (1.0 M, 144 mL) was stirred vigorously with BnOCOCl (4.52 g, 26.5 mmol) for 16 h. The precipitate was collected by filtration and dried. This material was stirred with SOCl2 (10 mL) under Ar for 16 h. The evaporation residue was suspended in CH2Cl2 and filtered. Evaporation gave the crude acyl chloride, which was used immediately. This acyl chloride in dry THF (70 mL) was stirred with 2-aminobenzamide 12 (1.96 g, 14.4 mmol), pyridine (1.48 g, 18.7 mmol) and DMAP (0.35 g, 2.88 mmol) under Ar for 16 h. The evaporation residue, in EtOAc, was washed twice with water and twice with brine. Drying, evaporation and chromatography (EtOAc/CH2Cl2 2:3) gave 35 (5.1 g, 88%) as a white solid: mp 180-183 C;
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 2h;
(4-aminomethyl)-benzoic acid (4.9 g, 1. 1 equiv. ) was dissolved in 5% NaHCO3 150 ml in water and stirred. N- (9- Fluorenylmethoxycarbonyl) -L-proline (Fmoc, 1 equiv. , lOg) was dissolved in an equivalent amount of dioxane and added. The reaction was allowed to stir at room temperature. After two hours, 10% citric acid in water 75 ml was added. A white solid precipitated upon addition. The solid was washed filtered and washed with hexane. The solid was dissolved in THF and allowed to dry overnight over MGSO. The following day, the solution was filtered, crystallized from THF and hexane, and placed under a drying vacuum (90% yield). ESIMS: (M+H) + Calcd, 373.1 ; Found, 374.1.
9 4.1.9. 4-((2,2,2-Trifluoroacetamido)methyl)benzoic acid (18)
Trifluoroacetic anhydride (4 mL) was dropwise added to compound 17 (1.00 g, 6.62 mmol) under the ice baths. The suspension was stirred at room temperature for 2 h, and quenched by adding ice water. Compound 18 was collected via filtration and dried under vacuum to get a white solid (1.50 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 10.09 (t, J = 5.9 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H).
88%
at 25℃; for 2h;
88%
at 0 - 25℃; for 2h;
3
Trifluoroacetic anhydride (5.9 mL, 41.34 mmol) was added in small portions to solid 4-(aminomethyl) benzoic acid (2.5 g, 16.54 mmol), while applying external cooling in an ice-bath. Upon completion of addition, the reaction mixture was homogeneous. Stirring was continued at 25° C. for 2 h, and then ice water was added to precipitate the product. The white solid was collected by filtration, washed with water and dried. Yield: 3.63 g (88%), mp: 199-203° C.; 1H NMR (CDCl3; 300 MHz): δ 7.91 (d, J=7.8 Hz, 2H), 7.37 (d, J=7.8 Hz, 2H), 4.44 (d, J=5.7 Hz, 2H). The above compound (3.63 g, 14.68 mmol) was added portion wise over 1 h to 90% nitric acid (20 mL) at -5° C. The mixture was stirred further for 1.5 h at 0° C. and then poured onto ice to precipitate the product. The precipitated solid was filtered, washed with plenty of water to neutral pH, and lyophilized to provide an offwhite solid (3.95 g, 92%). mp: 210° C.; 1H NMR (CDCl3; 300 MHz): δ 8.61 (d, J=1.6 Hz, 1H), 8.17 (dd, J=1.6, 8.1 Hz, 1H), 7.507 (d, J=8.1 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H). A solution of compound 2 (0.68 g, 2.33 mmol) and K2CO3 (0.81 g, 5.88 mmol) in MeOH-H2O (1:1, v/v; 16 mL) was maintained at 25° C. for 10 h. The dark yellow solution was concentrated, and DMF (3×10 mL) was added and each time removed in vacuo. The resultant solid was dissolved in dioxane-H2O (1:1, v/v; 10 mL) to form a solution. Di-tert-butyl dicarbonate (0.77 g, 3.54 mmol) was added, and after 2.5 h, the reaction mixture was concentrated in vacuo. Ether and water were added, and the aqueous phase was washed with ether, brought to pH 3.0 with 10% aqueous citric acid, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title product as a yellow solid (0.67 g, 97%), m.p. 124-126° C.; 1H NMR (CDCl3; 300 MHz): δ 8.74 (d, J=1.6 Hz, 1H), 8.30 (dd, J=1.6, 8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 4.65 (d, J=6.3 Hz, 2H), 1.44 (s, 9H).
84%
at 4 - 20℃; for 2h;
84%
at 20℃; for 2h; Cooling with ice;
10.6 Compound 6: 4-((2,2,2-trifluoroacetamido)methyl)benzoic acid
Weighed into a 100 ml round-bottomed flask were 2.38 g (15.7 mmol) of 4-(aminomethyl)benzoic acid. The round-bottomed flask was put into a bath of water and ice and 5.6 ml (59 mmol) of trifluoroacetic anhydride were slowly added. At the end of the addition, the reaction mixture was left to return to ambient temperature and the reaction mixture was left stirring for two hours. 16.5 ml of water at 4° C. were added. The precipitate was filtered over a frit, rinsed with 2*3 ml of water at 4° C. and dried under vacuum in the presence of phosphorus pentoxide for 48 h. A white solid (3.27 g-13.2 mmol-84%) was obtained corresponding to the desired product. MS (ES-) m/z: [M-H+] 246.2.
71.19%
With triethylamine In dichloromethane at 20℃; for 4h; Cooling with ice;
Synthesis of 4-((2,2,2-trifluoroacetamido)methyl)benzoic acid (6).
21.16 g (140 mmol) of 4-(aminomethyl) benzoic acid was suspended in 450 mL of dichloromethane, followed by 42.0 mL (301 mmol) of triethylamine. The reaction was then cooled in an ice bath, and 60.44 g (2.06 eq.) of trifluoroacetic anhydride in 50 mL of dichloromethane was added dropwise over the course of 1 hour. The reaction was stirred for an additional three hours while being allowed to gradually warm to room temperature. 500 mL of aqueous saturated sodium bicarbonate solution was then slowly added to the reaction mixture in portions, and the solution was acidified with 4 N HCl (pH < 3). The resultant precipitate was collected via filtration, and the filter cake was washed three times with water and twice with ice-cold ether. The solid was dissolved in ethyl acetate, dried over sodium sulfate, filtered, transferred to a round bottom flask and evaporated to give an off-white solid. The product was recrystallized from ethyl acetate/hexanes three times to give 24.63 g (71.19% yield) of 6 as a white solid. lH NMR (300 MHz, DMSO) δ 10.15 (t, J = 5.91 Hz, 1H), 8.13 (d, J = 8.36 Hz, 2H), 7.51 (d, J = 8.38 Hz, 2H), 4.52 (d, J = 5.97 Hz, 2H). 13C NMR (75 MHz, DMSO) δ 167.97, 162.96, 145.92, 131.66, 130.49, 128.91, 127.95, 43.27.
With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere;
at 0 - 25℃; for 2h;
89 %
In dichloromethane at 4 - 20℃;
95 %
at 20℃;
2 Preparation of 4-((2,2,2-trifluoroacetylamino)methyl)benzoic acid (13a):
Slowly add 10 mL of trifluoroacetic anhydride to 4-(aminomethyl)benzoic acid ( 3.0 g, 20 mmol), and reacted at room temperature for 2 hours after dropping.After the reaction was complete, 100 mL of ice water was added to quench the reaction, then filtered, and the filter cake was dried to obtain 13a (4.43 g, 95%).
Step A 4-[(isobutyrylamino)methyl]benzoic acid A suspension of 4-(aminomethyl)benzoic acid (0.214 g, 1.4 mmol) in dry CH2Cl2 (10 mL) was treated with triethylamine (0.98 mL, 7.0 mmol) and 2-methylpropanoyl chloride (0.16 mL, 1.5 mmol). The resulting mixture was stirred for 132 h. Water (5 mL) and EtOAc (10 mL) were added, and the aqueous layer was acidified to pH 1 with 1 N HCl. The layers were separated, and the aqueous phase was extracted with additional EtOAc (3*10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound as a slightly yellow solid (0.318 g, quantitative), which was used in subsequent steps without further purification. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.14 (d, J=7.0 Hz, 6H), 2.37-2.60 (m, 1H), 4.33-4.47 (m, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.97 (d, J=8.6 Hz, 2H).
[0261] To a solution of 5.0 g of 4-aminomethylbenzoic acid in 40 ml of dioxane-water (1:1) was added 6.0 g of NaHCO3 and a solution of 7.6 g of di-tertiary butyl dicarbonate in 20 ml of dioxane in order at room temperature, and the mixture was stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and the residue was neutralized with aqueous hydrochloric acid. The precipitated solid was collected by filtration, and dried under reduced pressure to give 8.0 g of a carboxylic acid. The carboxylic acid (0.85 g) was dissolved in 10 ml of THF, to which was added 0.60 g of 1,1'-carbonylbis-1H-imidazole under ice-cooling, and the mixture was stirred at 50° C. for 40 minutes. To the resulting solution was added 0.43 g of N,O-dimethylhydroxylamine hydrochloride and 0.7 ml of triethylamine (Et3N) in order under ice-cooling, and the mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate (EtOAc). The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.98 g of an amide. The amide (0.98 g) was dissolved in 10 ml of THF, to which was added 0.12 g of lithium aluminum hydride at -78° C., and the mixture was stirred at the same temperature for 40 minutes. There was added 2.0 g of Na2SO4.10H2O and the mixture was warmed up to room temperature and stirred for 3 hours. The reaction mixture was filtered and evaporated under reduced pressure to give 0.76 g of tertiary (t-)butyl 4-formylbenzylcarbamate.
Aminomethyl benzoic acid (6.0 g, 39.7 mmol) and Na2CO3 (8.41 g, 79.4 mmol) were dissolved in H2O (40 mL). To this mixture was added a solution Cbz-Osu (10.4 g, 41.7 mmol) in THF (40 mL). The resulting solution was stirred at room temperature overnight, then concentrated. The residue was acidified with 2N HCl to pH=2, which led to a solid precipitate. The product was collected by filtration and dried in vacuum overnight to give 9.6 g, 85% of a white solid (4).
Synthesis Example 41-1: Synthesis of 4-(N-Cbz aminomethyl) benzoic acid (Compound XVII-4) 5 mg of commercially available 4-aminomethyl benzoic acid was dissolved in 33 ml of a 1 mol/l sodiumhydroxide aqueous solution. Under stirring at room temperature, 5.2 ml of benzylchloroformate, and 40 ml of a 1 mol/l sodium hydroxide aqueous solution were gradually added to the solution at the same time. After 3 hours, a 1 mol/l hydrochloric acid was added to the reaction solution to adjust the pH thereof to pH = 3. A precipitated product was filtrated through a glass filter G4. Then, filtrate was washed with water, and with hexane, followed by drying under reduced pressure. Consequently, 8.162 g of the above-mentioned compound was obtained as a white solid product. 1H-NMR(500MHz,DMSO-d6):δ=4.26 (2H,d,J=6.3Hz), 5.05 (2H,s), 7.30-7. 40 (7H,m), 7.88 (2H,d,J=8.3Hz), 7.91 (1H,t,J=6.3Hz).
With hydrogenchloride; sodium hydroxide; In 1,4-dioxane;
C. 4-Benzyloxycarbonylaminomethylbenzoic acid 4-(Aminomethyl)benzoic acid 15.1 g (100 mmol) was dissolved in 200 mL dioxane and 100 mL 1.000 N NaOH and cooled in a 0 C. ice bath. The mixture was treated dropwise with benzylchloroformate 14.3 mL (100 mmol) followed by the dropwise addition of 100 mL of 1.000 N NaOH. The mixture was stirred at room temperature for 18 hours. The mixture was neutralized by adding 100 mL of 1.000 N HCl followed by dilution with dichloromethane. A white solid precipitated out which was filtered. The solid was dried in vacuo to afford 10.8 g (38.9%). 1H NMR (300 MHz, DMSO-d6): δ 4.24 (d, 2H, J=6.2 Hz); 5.01 (s, 2H); 7.31-7.34 (m, 7H); 7.84-7.88 (m, 3H); 12.85 (s, 1H).
With hydrogenchloride; sodium hydroxide;
Example 41-1 Synthesis of 4-(N-Cbz-aminomethyl)benzoic acid (Compound XVII-4) Commercially available 4-aminomethylbenzoic acid (5 g) was dissolved in 1 mol/l aqueous solution of sodium hydroxide (33 ml). Benzylchloroformate (5.2 ml) and 1 mol/l aqueous solution sodium hydroxide (40 ml) were gradually and simultaneously added while stirring at roomtemperature. After 3 hours, 1 mol/l hydrochloric acid was added to the reaction solution to adjust the pH to 3, and the deposited precipitate was collected by filtration through glass filter G4. The precipitate was washed with water and hexane, and dried under reduced pressure to obtain the title compound (8.162 g) as a white solid. 1H-NMR(500MHz,DMSO-d6):δ=4.26(2H,d,J=6.3Hz),5.05(2H,s), 7.30-7.40(7H,m),7.88(2H,d,J=8.3Hz),7.91(1H,t,J=6.3Hz).
Aminomethyl benzoic acid 79(560 mg, 2.98 mmol) was refluxed in 30mL of ethanol with 1 mL of HCl 12 N overnight. The solvent was evaporated toobtain aminomethyl benzoic ester 80as hydrochloride salt (640 mg, quantitative yield). The ester derivative (640mg, 2.97 mmol, 1 equiv) was dissolved in a dioxane/water solution, then TEA(911 muL, 6.53 mmol, 2.2 equiv) and Boc2O (779 mg, 3.57 mmol,1.2 equiv) were added and the solution was stirred at 0 C for 1 h, then overnight at rt. The solvent wasevaporated, the slurry was taken up in EtOAc, washed with a solution of citricacid 10% (3 X 10 mL), water (2 X 10 mL), dried over Na2SO4,filtered and evaporated in vacuum to give 78as oil (810 mg, quantitative yield). 1H NMR (200MHz, DMSO-d6) delta 7.88 (s, 2H), 7.40 (m, 1H), 7.32- 7.24 (m, 1H), 5.17(br, NH), 4.31-4.28 (m, 4 H), 1.39 (s, 9H), 1.34-1.30 (m, 3H) ppm.
With thionyl chloride; at 0℃; for 3.0h;Heating / reflux;
4-Aminomethylbencoic acid-ethylester hydrochloride (1):; 20.0 g (132 mM) of 4- aminomethylbencoic acid were suspended in 200 ml EtOH abs. and cooled with ice. 28.0 g (17 ml) (236 mM) thionylchloride were added drop by drop. The clear mixture was then refluxed for 3 hours. After cooling to room temperature, EtOH was evaporated. 50 ml of toluene/EtOH 1/1 were added and evaporated three times. The residue was dried to get 27 g of 1.
9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide[ No CAS ]
[ 56-91-7 ]
[ 497-19-8 ]
[ 164470-64-8 ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane;
4-[(9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acid (S23). To 4-aminomethyl-benzoic acid (10.6 g, 70.1 mmol) in dioxane (130 mL) was added 9% aqueous Na2CO3 (150 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (26 g, 77 mmol). The solution was heated to 40 C. for 12 h and then cooled to room temperature. The reaction was acidified with 1 M HCl (500 mL), and extracted with ether (300 mL) to obtain acid S23 as a fluffy white solid (25.9 g, 69.4 mmol, 99%). 1H NMR (500 MHz, d6-DMSO): delta12.85 (broad s, 1H), 7.90 (m, 4H), 7.70 (m, 2H), 7.39 (m, 2H), 7.31 (m, 4H), 4.37 (d, 2H, J=6.8 Hz), 4.24 (d, 2H, J=5.8 Hz), 4.23 (t, 1H, J=6.8 Hz). APCI/MS: 372 (M+H+).
In 1,4-dioxane;
4-[(9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acid (S23). To 4-aminomethyl-benzoic acid (10.6 g, 70.1 mmol) in dioxane (130 mL) was added 9% aqueous Na2CO3 (150 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (26 g, 77 mmol). The solution was heated to 40 C. for 12 h and then cooled to room temperature. The reaction was acidified with 1 M HCl (500 mL), and extracted with ether (300 mL) to obtain acid S23 as a fluffy white solid (25.9 g, 69.4 mmol, 99%). 1H NMR (500 MHz, d6-DMSO): delta12.85 (broad s, 1H), 7.90 (m, 4H), 7.70 (m, 2H), 7.39 (m, 2H), 7.31 (m, 4H), 4.37 (d, 2H, J=6.8 Hz), 4.24 (d, 2H, J=5.8 Hz), 4.23 (t, 1H, J=6.8 Hz). APCI/MS: 372 (M+H+).
4-[2,2-(diphenyl)ethoxycarbamoyl-methyl]benzoic acid[ No CAS ]
[ 110-54-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
With CDI; In tetrahydrofuran; sodium hydroxide;
A. A mixture of 2,2-diphenylethanol (6 g, 30 mmoles), CDI (4.9 g, 30 mmoles) in THF (30 ml) was stirred at room temperature for 2 hours, then a solution of 4-aminomethylbenzoic acid (4.6 g, 30 mmoles) in 1N sodium hydroxide (30 ml) was added thereto. The reaction mixture was stirred at room temperature for 3 hours, then acidified with HCl, THF was evaporated in the cold, then the aqueous solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated off. The resulting crude was treated with warm n-hexane and filtered to give 10 g of 4-[2,2-(diphenyl)ethoxycarbamoyl-methyl]benzoic acid (90% yield); m.p.=102-105 C. 1 H-NMR d 12.7 (s, 1H, exchange with D2 O), 7.91 (d, 2H), 7.78 (t, 1H), 7.50-7.20 (m, 12H), 4.61 (d, 2H), 4.38 (t, 1H), 4.23 (d, 2H).
2-[(4-carboxyphenyl)methyl]amino-5-chloro-3-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.15 g (57.5%)
With hydrogenchloride; potassium carbonate In methanol
11.i (i)
(i) 2-[4-carboxyphenyl)methyl]amino-5-chloro-3-nitrobenzoic acid A mixture of 2,5-dichloro-3-nitrobenzoic acid [K. Lehmstedt and K. Schrader, Berichte, 70, 1526 (1937)] (23.60 g, 100 mmol), powdered potassium carbonate (41.4 g, 300 mmol) and 4-(aminomethyl)benzoic acid (400 mmol, 60.04 g) in 250 mL of methanol was stirred at reflux under argon. After 16 hours at reflux, the reaction mixture was poured into 650 mL of 10% hydrochloric acid solution, and the solid which formed was filtered. The collected solid was triturated with ethyl acetate to remove the product. The ethyl acetate solution was concentrated in vacuo to give 20.15 g (57.5%) of a yellow-orange solid.
Preparation of methyl 4-[[(6-chloro-5-amino) pyrimidin-4-yl]aminomethyl]benzoate (3-1):
Preparation of methyl 4-[[(6-chloro-5-amino) pyrimidin-4-yl]aminomethyl]benzoate (3-1): Step (a) Hydrogen chloride gas was blown into methanol (250 ml) on ice with stirring to prepare a methanol solution of hydrogen chloride (44.4 g). To the solution, 4-aminomethylbenzoic acid (25.70 g) was added at room temperature and the mixture was heated under reflux with stirring for 28 hours to obtain an almost homogeneous solution. The solvent was evaporated under reduced pressure from the solution to obtain methyl 4-aminomethylbenzoate hydrochloride (33.11 g) as a colorless solid.
4-[N-(2-Benzyloxy-5-bromobenzyl)aminomethyl]benzoic acid[ No CAS ]
[ 366-84-7 ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
A mixture of 4-aminomethylbenzoic acid (25 g) and concentrated sulphtiric acid (25 ml) in ethanol (250 ml) was heated at reflux for 18 hours. The volume of solvent was reduced to a third by evaporation. The residue poured onto ice (500 g) and basified with concentrated aqueous ammonia. The product was extracted with ethyl acetate (3*200 ml) and the extracts dried and evaporated to give ethyl 4-aminomethylbenzoate.
Commercially available methyl bromomethylbenzoate (manufactured by Aldrich Corporation) (10.0 g) was dissolved in DMF (100 ml), and the solution was added with potassium phthalimide (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (9.70 g) and the whole was stirred at room temperature for 1.5 hours. After completion of the reaction, the solution was concentrated and added with water, followed by extraction with chloroform. The resultant was washed with a saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining a white solid (12.9 g). Subsequently, 7.56 g of the solid was dissolved in methanol (100 ml), and the solution was added with hydrazine monohydrate (manufactured by Nacalai Tesque, Inc.) (6.25 ml) and the whole was stirred at 60C for 1.5 hours. After completion of the reaction, the precipitated solid was filtrated out and the solvent was distilled off. The resultant was added with water and subjected to extraction with chloroform. The resultant was washed with a 0.3 mol/l sodium hydroxide aqueous solution and a saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off. Methanol (120 ml) and 2-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (2.35 g) were added to the resultant and the whole was stirred at room temperature for 2 days. After completion of the reaction, the precipitated solid was filtrated out. The liquid layer was concentrated and evaporated to dryness, and washing was performed by adding anhydrous methanol (30 ml). Then, the solid was filtrated out. The resultant solid and the solid that had been previously filtrated out were suspended in methanol (86 ml), and sodium borohydride (1.42 g) was added under ice-cooling. The solution was stirred at room temperature for 1 hour, and the solvent was distilled off. After addition of water, extraction was performed with chloroform, and the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure and drying, thereby obtaining a colorless oily substance (4.32 g). 4.28 g of the oily substance was dissolved in DMF (65 ml), and the solution was added with di-t-butyldicarbonate (8.90 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform, followed by washing with a saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and THF (43 ml), methanol (43 ml), and a 1 mol/l sodium hydroxide aqueous solution (43 ml) were added to the resultant, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, and water (5.0 ml) was added to the resultant. Further, 1 mol/l hydrochloric acid was carefully added to the solution, and the acid-precipitate was filtrated out and dried, thereby obtaining the subject compound (4.87 g) as a white solid. MS(FAB,Pos.):m/z=332[M+H]+
2) adding methyl 4-aminomethylbenzoate to the concentrated sulfuric acid solution,The molar ratio of sulfuric acid to 4-aminomethylalkyl benzoate is 1:1.The reaction was stirred at 50 C for 1.5 h, and after the reaction was completed, it was cooled to room temperature.Add water (the amount of water is 20 times the amount of methyl 4-aminomethylbenzoate), then add sodium hydroxide solution dropwise to the solution to make the solution alkaline.There is a lot of solids to precipitate, filter, wash,And dried to give a white solid aminomethylbenzoic acid.
With sodium hydroxide; water;
Commercially available methyl bromomethylbenzoate (manufactured by Aldrich Corporation) (10.0 g) was dissolved in DMF (100 ml), and the solution was added with potassium phthalimide (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (9.70 g) and the whole was stirred at room temperature for 1.5 hours. After completion of the reaction, the solution was concentrated and added with water, followed by extraction with chloroform. The resultant was washed with a saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining a white solid (12.9 g). Subsequently, 7.56 g of the solid was dissolved in methanol (100 ml), and the solution was added with hydrazine monohydrate (manufactured by Nacalai Tesque, Inc.) (6.25 ml) and the whole was stirred at 60C for 1.5 hours. After completion of the reaction, the precipitated solid was filtrated out and the solvent was distilled off. The resultant was added with water and subjected to extraction with chloroform. The resultant was washed with a 0.3 mol/l sodium hydroxide aqueous solution and a saturated saline solution and dried with anhydrous sodium sulfate, and the solvent was distilled off. Methanol (120 ml) and 2-imidazole carboxaldehyde (manufactured by Aldrich Corporation) (2.35 g) were added to the resultant and the whole was stirred at room temperature for 2 days. After completion of the reaction, the precipitated solid was filtrated out. The liquid layer was concentrated and evaporated to dryness, and washing was performed by adding anhydrous methanol (30 ml). Then, the solid was filtrated out. The resultant solid and the solid that had been previously filtrated out were suspended in methanol (86 ml), and sodium borohydride (1.42 g) was added under ice-cooling. The solution was stirred at room temperature for 1 hour, and the solvent was distilled off. After addition of water, extraction was performed with chloroform, and the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure and drying, thereby obtaining a colorless oily substance (4.32 g). 4.28 g of the oily substance was dissolved in DMF (65 ml), and the solution was added with di-t-butyldicarbonate (8.90 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform, followed by washing with a saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and THF (43 ml), methanol (43 ml), and a 1 mol/l sodium hydroxide aqueous solution (43 ml) were added to the resultant, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off, and water (5.0 ml) was added to the resultant. Further, 1 mol/l hydrochloric acid was carefully added to the solution, and the acid-precipitate was filtrated out and dried, thereby obtaining the subject compound (4.87 g) as a white solid. MS(FAB,Pos.):m/z=332[M+H]+
4-guanidinomethylbenzoic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In sodium hydroxide; water;
(a) Preparation of 4-guanidinomethylbenzoic acid hydrochloride 17.7 Grams of S-methyl isothiourea sulfate was dissolved in 100 ml of 2N sodium hydroxide under cooling, followed by addition of 2N sodium hydroxide up to pH 11 and by subsequent addition of a solution of 10 g p-aminomethylbenzoic acid in 50 ml of boiling water. The resulting solution was allowed to stand overnight at room temperature and thereafter cooled. Crystals thus precipitated were collected by filtration, neutralized by washing with cold water and then dried in vacuo. 99 ml of 1N hydrochloric acid was added to the resulting crystals, and the solution was then heated. Upon removal of insoluble material by filtration, the filtrate was evaporated in vacuo. The residue was recrystallized from water-methanol (1:1) to give 8.4 g of 4-guanidinomethylbenzoic acid hydrochloride as white crystals. mp: 227-230 C. IR(KBr) numax(cm-1): 3400-3000, 1680.
Step 1 Synthesis of ethyl 4-(aminomethyl)benzoate: 3 g (19.9 mmol) of 4-aminomethylbenzoic acid was suspended in 100 ml of ethanol. 10 ml of ethanol containing 25 % of hydrogen chloride was added to the suspension, and they were heated under reflux for 8 hours. The solvent was evaporated, and the title compound was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant. Yield: 1.19 g (6.77 mmol) (34 %) H-NMR (CDCl3) delta 1.35 (3H, t), 4.05 (2H, brs), 4.30 (2H, q), 6.60 (2H, d), 7.85 (2H, d)
[Referential Example 53] Methyl 4-(N-tert-butoxycarbonylaminomethyl)benzoate In the same manner as in Referential Example 44, a reaction was conducted using 4-aminomethylbenzoic acid as a starting material, whereby the title compound was obtained. 1H-NMR (CDCl3) delta: 1.47(9H,s), 3.91(3H,s), 4.37(2H,d,J=5.4Hz), 4.92(1H,br), 7.35(2H,d,J=8.3Hz),8.00(2H,d,J=8.3Hz). Elementary analysis for C14H19NO4 Calculated: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.20; H, 7.02; N, 5.58.
Preparation of N-FMOC-4-aminomethylbenzoic acid To a solution of 1.5 grams (0.01 mol) of 4-aminomethyl benzoic acid in 26 ml of 10% Na2CO3 at 13 ml of dioxane at 0 C. was added a solution of fluorenylmethoxychloroformate in 20 ml of dioxane dropwise. A thick glutinous mixture formed. The mixture was stirred over night at room temperature and then diluted with 100 ml of water and was washed with EtOAc (3*20 ml). The aqueous phase was acidified with concentrated HCl added dropwise with cooling and stirring. A white precipitate formed which was collected by filtration and dried in vacuo to give desired product. 1H-NMR (CDCl3 300 MHz): 4.15 (t, 1H); 4.31 (d, 2H); 4.40 (d, 2H); 6.0 (t, 1H); 7.22 (t, 4H); 7.32 (t, 2H); 7.52 (d, 2H); 7.69 (d, 2H); 7.70 (d, 2H); 7.92 (d, 2H).
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 10℃; for 1.16667h;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
1
N,N-carbonyldiimidazole (1.62g, 10mmol) is dissolved in 10ml of anhydrous tetrahydrofuran while controling temperature at 0-10 °C using an ice bath. A mixed solution of VI (10mmol) and 10ml of anhydrous tetrahydrofuran is added in three portions in 10 minutes. Reacting continuously at 0-10 °C for 1 hour, and the reaction solution becomes clear. The above mixed solution is drop-added to a mixed solution of II (10mmol) and sodium hydroxide aqueous solution (10ml, 1mol/L). Stirring continuously at room temperature 4 hours and stopping the reaction. 5N hydrochloric acid is added to adjust pH to about 4.5, and the reaction solution becomes clear. About 15ml of the solvent is evaporated out under reduced pressure. Large amount of solids are precipitated, filtrated and dried to obtain the intermediate III. N,N-carbonyldiimidazole (1.62g, 10mmol), 3-pyridylmethanol (1.08g, 10mmol), p-aminobenzoic acid (1.52g, 10mmol) are used according to the method for the production of intermediate III in Method two, are used to obtain 2.47g of 4-[(3-pyridylmethoxyacyl)aminomethyl]benzoic acid (intermediate M-1) as a white solid, with a yield of 86.2%.
86.2%
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 10℃; for 1h;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
1
N,N-carbonyldiimidazole (1.62 g, 10 mmol) is dissolved in 10 ml of anhydrous tetrahydrofuran while controling temperature at 0-10° C. using an ice bath. A mixed solution of VI (10 mmol) and 10 ml of anhydrous tetrahydrofuran is added in three portions in 10 minutes. Reacting continuously at 0-10° C. for 1 hour, and the reaction solution becomes clear. The above mixed solution is drop-added to a mixed solution of II (10 mmol) and sodium hydroxide aqueous solution (10 ml, 1 mol/L). Stirring continuously at room temperature 4 hours and stopping the reaction. 5N hydrochloric acid is added to adjust pH to about 4.5, and the reaction solution becomes clear. About 15 ml of the solvent is evaporated out under reduced pressure. Large amount of solids are precipitated, filtrated and dried to obtain the intermediate III.; N,N-carbonyldiimidazole (1.62 g, 10 mmol), 3-pyridylmethanol (1.08 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol) are used according to the method for the production of intermediate III in Method two, are used to obtain 2.47 g of 4-[(3-pyridylmethoxyacyl)aminomethyl]benzoic acid (intermediate M-1) as a white solid, with a yield of 86.2%.
83%
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 10℃; for 1.16667h;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 5h;
2.2.2. Synthesis of 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl Benzoic Acid (1)
To a suspension of N,N'-carbonyldiimidazole (CDI, 10mmol) in dry THF (10 mL), pyridin-3-ylmethanol (10 mmol)was added dissolved in THF (10 mL) in three portions within10 min at 0-10°C, and the mixture was stirred for an additional1 h. The resulting solution was added to a solution of4-(aminomethyl)benzoic acid (10 mmol) dissolved in sodiumhydroxide solution (10 mL, 1mol/L) at 0-10°C. After stirringfor 5 h at room temperature, the mixture was evaporated andthen dissolved in water (25 mL). The solution was acidifiedwith HCl (5 mol/L) to pH 5 and the white solid precipitatedwas collected by filtration, washed with water twice anddried to give pure 1. Yield: 83%; mp: 206-208°C (lit. [12],mp: 207-208°C). 1H NMR (400 MHz, DMSO-d6, ppm): δ12.96 (s, 1H, H-15), 8.60 (s, 1H, H-1), 8.54 (d, J= 4.2 Hz,1H, H-5), 7.96 (t, J= 6.2 Hz, 1H, H-16), 7.90 (d, J= 8.8 Hz,2H, H-11 and H-13), 7.79 (dd, J= 8.0, 4.0 Hz, 1H, H-3),7.32-7.49 (m, 3H, H-4, H-10 and H-14), 5.1 (s, 2H, H-6),4.28 (d, J= 6.1 Hz, 2H, H-8); 13C NMR (100 MHz, DMSOd6,ppm): δ 167.62 (C-15), 156.72 (C-7), 149.60 (C-1),149.57 (C-5), 145.23 (C-9), 136.23 (C-3), 133.11 (C-2),129.86 (C-11, C-13), 129.82 (C-12), 127.45 (C-10, C-14),124.00 (C-4), 63.75 (C-6), 44.10 (C-8).
80%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran
79.1%
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In acetonitrile at 10 - 20℃; for 0.25h; Sonication;
Stage #2: p-aminomethylbenzoic acid In acetonitrile at 20 - 40℃; for 1h; Sonication;
2.1 (1) Preparation of 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (Compound I)
To 65 ml of tetrahydrofuran was added N,N'-carbonyldiimidazole (CDI) (6.32 g , 39mmol), the solution placed in the ultrasonic cleaner, open the ultrasound, control temperature 10 ~ 20 , to the solution was added pyridinemethanol (3.27 g, 30 mmol) and reacted for 15 min. The reaction was monitored by TLC. To the reaction solution was added 4-aminomethylbenzoic acid (6.05 g, 40 mmol). The reaction was monitored by TLC. The solvent was distilled off under reduced pressure. The residue was added with water (130 ml) and sonicated for 30 min. A large amount of solid was precipitated, filtered and dried to give 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (6.79 g, yield 79.1%).
58.1%
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h;
Stage #2: p-aminomethylbenzoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine In tetrahydrofuran at 20℃; for 6h; Cooling with ice;
5.5-1 Synthesis of 4 - (((pyridin-3-ylmethoxy) carbonyl) amino) methyl) benzoic acid
Carbonyldiimidazole (4.05 g) was dissolved in tetrahydrofuran (19 mL), and 3-pyridinemethanol (14) (2.73 g) dissolved in tetrahydrofuran (8 mL) was added dropwise under ice cooling. After stirring the reaction solution at room temperature for 1 hour, 4- (aminoethyl) benzoic acid (15) (3.78 g) suspended in tetrahydrofuran (40 mL) and diazabicycloundecene ( 3.81 g), triethylamine (2.53 g) was added dropwise, and the mixture was stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in water and adjusted to pH 5 with 1 N hydrochloric acid aqueous solution. The resulting precipitate was collected by filtration and washed with water (50 mL) and methanol (10 mL) to give the title compound (16) (4.16 g, yield 58.1%) as a white solid.
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran for 1.41667h;
Stage #2: p-aminomethylbenzoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine In tetrahydrofuran at 20℃; Cooling;
Stage #3: With hydrogenchloride In water Cooling with ice;
A
4-[([(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]benzoic acid. A solution of CDI (107 g, 662 mmol) in dry THF (700 mL) was treated with a solution of pyridin-3-ylmethanol (72.2 g, 662 mmol) in THF (300 mL) dropwise over 10 minutes. The resulting solution was stirred for 1.25 hours and then added dropwise over 15 minutes to a water bath cooled suspension of 4- (aminomethyl)benzoic acid (100 g, 662 mmol), Et3N (92 mL, 662 mmol) and DBU (100 mL, 662 mmol) in dry THF (1400 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue suspended in water (2500 mL), cooled in an ice-water bath and the pH adjusted to 5 with 6 N HCl (-300 mL). The precipitate was collected by filtration, washed with cold MeOH and dried to give 4-[([(pyridin- 3-ylmethyl)oxy]carbonyl}amino)methyl]benzoic acid as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 12.82 (br s, IH), 8.56 (d, J= 1.8 Hz, IH), 8.51 (dd, J= 4.8 and 1.8 Hz, IH), 7.93 (t, J= 6.3 Hz, IH), 7.87 (d, J= 8.4 Hz, 2H), 7.76 (t, J= 8.4 Hz, IH), 7.38 (dd, J= 7.2 and 4.8 Hz, IH), 7.33 (d, J= 8.4 Hz, 2H), 5.07 (s, 2H), 4.25 (d, J= 6.3 Hz, IH).
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran
Stage #2: p-aminomethylbenzoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine In tetrahydrofuran
65 g
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In tetrahydrofuran at 10 - 20℃; for 1h;
Stage #2: p-aminomethylbenzoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 14h;
2.1 Reference example 2 Step 1
Reference example 2 The example of WO 2009/076206 Al was reproduced. Step 1 To suspension of carbonyl diimidazole in THF (214 mL) cooled to 10°C was added 3-pyridinemetanol in THF (90 mL) and the mixture was stirred at RT for 1 hour. The mixture prepared above was added dropwise to mixture of 4-(aminomethyl)benzoic acid, DBU, triethylamine in THF (415 mL) and was stirred at RT for 14 hours. TLC analysis showed no starting material. The THF was evaporated, and the mixture was diluted with water (600 mL) and was acidified while stirring to pH = 5. The resulting white precipitate was filtered, washed with water (600 ml) and methanol (150 mL) and dried to give 65.0 g of product.
450 g
Stage #1: 3-hydroxymethylpyridin; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 8℃;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide In N,N-dimethyl-formamide for 16h;
1 Preparation of 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl) benzoic acid.
A mixture of carbonyldiimidazole (321.8g) in dimethyl formamide (1000 mL) was cooled to 8°C and a solution of Pyridin-3-yl methanol (216.4 g) in dimethyl formamide (500 mL) was slowly added to it. 4-(aminomethyl)benzoic acid (250 g) was combined with 1 N sodium hydroxide solution (1500 mL) at 29°C and the above mixture was added by dropwise addition. Stirred the reaction mixture for 16 hours and quenched the reaction mixture with saturated brine solution (250 mL) at 27°C. The reaction mixture was cooled to 8°C and adjusted the pH to 5 - 6 with concentrated HC1. Stirred the reaction mixture for 1 hour at 10°C. Filtered the reaction mixture and washed with cold water (2 x 1250 mL) and methanol (2 x 250 mL). The solid was dried at 45 °C for 8 hours to obtain the title compound as white solid. Yield: 450 g; Purity by HPLC: 98.73%
4-[([(4-[(tert-butoxycarbonyl)amino methyl}benzyl)oxy]carbonyl}amino) methyl]benzoic acid. To a suspension of CDI (340 mgd, 2.1 mmol) in THF (1.6 mL) was added tert-butyl [4-(hydroxymethyl)benzyl]carbamate (500 mg, 2.1 mmol)) in THF (0.7 mL) and the mixture was aged for 1 hour at ambient temperature. The resulting mixture was then added to a stirring solution of 4-(aminomethyl)benzoic acid (320 mg, 2.1 mmol), TEA (0.3 mL, 2.1 mmol), and DBU (0.3 mL, 2.1 mmol)) in THF (3.5 mL). After stirring at ambient temperature for 5 hours the reaction mixture was concentrated in vacuo, diluted with water, then acidified with HCl. The white precipitate was filtered away, washed with water then dissolved in DCM:EtOAc (some MeOH was added for solubility) dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound. cal'd [M+Na]+437, exp. 437
Stage #1: 1-(3-Pyridyl)ethanol; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 5 - 10℃; for 2h;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide In N,N-dimethyl-formamide at 20℃;
Stage #3: With hydrogenchloride In N,N-dimethyl-formamide at 0℃;
9.1
1-(3-pyridyl)ethan-l-ol was treated with carbonyl diimidazole in DMF at 5-10 0C for 2 hours. After this time, 4- aminomethylbenzoic acid and 1 N NaOH were added and the reaction mixture stirred at rt overnight. The reaction mixture was then treated with HCl at 0 C for 2 and the product 9A was isolated in 41% yield as a white solid. 1H NMR (500 MHz, DMSO-^) δ 12.88 (bs), 8.55 (d), 7.87 (m), 7.34 (m), 5.74 (d), 4.24 (s), 1.50 (d). MS: 323 (M+ Na).
Stage #1: Cinnamic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 20℃; for 3h;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide In tetrahydrofuran; water at 20℃; for 8h;
3 Example 3. (Comparison Example) Preparation of 4-[N-cinnamoylaminomethyl]benzoic acid
To a suspension of 0.33 g (2.01 mmol) of N, N'-carbonyldiimidazole in tetrahydrofuran (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0 °C, Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C17H15NO3: 281.3242. Found: 281.3240. MA calcd for C17H15NO3: C, 72.58%; H, 5.38%; N, 4.98. Found: C, 72.42%; H, 5.37%; N, 4.87%.
87.9%
Stage #1: Cinnamic acid With thionyl chloride In dichloromethane for 4h;
Stage #2: p-aminomethylbenzoic acid With sodium hydroxide at 20℃; for 5h; Cooling with ice;
Stage #3: With hydrogenchloride In water
25
Compound I (10mmol), and thionylchloride (4.72g, 40mmol) are dissolved in 10ml of a solvent A and heated at flux for 4 hours. The solvent and the unreacted thionylchloride are evaporated under reduced pressure. The obtained product is drop-added to a mixed solution of Compound II(10mmol) and sodium hydroxide(10ml, 1mol/L) under ice bath, stirring continuously at room temperature five hours after drop-adding. The reaction is stopped and 5N hydrochloric acid is added to adjust pH to about 4.5. Large amount of solids are precipitated, filtered and dried to obtain intermediate III; Cinnamic acid (1.48g, 10mmol), thionylchloride (4.72g, 40mmol), dichloromethane (10ml), p-aminobenzoic acid (1.52g, 10mmol), and 10ml of 1mol/L sodium hydroxide are used according to the method of the production of compound III in Method one to obtain 2.47g of 4-(cinnamoylaminomethyl)benzoic acid (intermediate M-14) as a white solid, with a yield of 87.9%.
3 4.1.4.3 (4-(Benzo[d]thiazol-2-yl)phenyl)methanamine (6c)
General procedure: A mixture of 2-aminothiophenol (1equiv) and different substituted amino-carboxylic acids (4-aminobenzoic acid, 4-aminophenylacetic acid, 4-(aminomethyl)benzoic acid, 4-aminobutyric acid and 4-aminohexanoic acid) (1equiv) in polyphosphoric acid (15g) was stirred at 220°C for 4h. The resulting brown oil was dissolved in 5M NaOH (50mL) to obtain basic yellow solution and this solution was extracted with DCM (2×30mL). The total organic phase was then extracted with 0.1N HCl (2×30mL) and afterwards washed DCM (50mL). The aqueous phase was basified to pH ∼10-12 with 5M NaOH, and it was extracted with DCM (2×30mL). The total organic phase was dried over anhydrous Na2SO4, and the solvent evaporated. The brown oil obtained was treated with HCl-saturated methanol until pH ∼1, the solution was evaporated, and the residue was recrystallized from acetonitrile.
53%
With polyphosphoric acid (PPA) at 220℃; for 4h; Reflux;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6.0h;
General procedure: A solution of <strong>[883535-89-5]2-(2-methyl-1H-indol-1-yl)ethanamine</strong> (4a) (65 mg, 0.373 mmol) and 4-(piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ?5 mg) in dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6h. At the conclusion of the reaction (TLC), water (15 mL) was added to quench the reaction. The product was extracted with ethyl acetate (20mL×3). Organics were washed with dilute HCl (10 mL), saturated NaHCO3 solution (10 mL), water (10 mL) and brine solution (10 mL) and dried over Na2SO4 and concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40% ethyl acetate in hexane to furnish 7k (TG7-152) (100mg, 74% yield). 1H NMR (CDCl3): delta 7.52 (d, J=5.6Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.30 (d, J=8Hz, 1H), 7.07 (m, 2H), 6.80 (d, J=8.2Hz, 2H), 6.23 (s, 1H), 5.98 (t, J=5.4Hz, 1H), 4.33 (t, J=6Hz, 2H), 3.76 (q, J=6Hz, 2H), 3.25 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.6 (m, 6H). LCMS (ESI): >97% purity at lambda 254, MS; m/z, 362 [M+H]+. Anal. Calcd. for C23H27N3O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59.
With sodium carbonate; In 1,2-dimethoxyethane; water; at 20 - 55℃; for 1h;Inert atmosphere;
Step 1-To a solution of 4-aminomethylbenzoic acid (0.7 g) andsodium carbonate (1.0 g) in water (25 mL) was added 2-carbomethoxy-3-chlorosulfoxylthiophene (1.2 g) in 1,2-dimethoxyethane(25 mL). The reaction mixture was stirred at room temperaturefor 30 min followed by an additional 30 min of stirring at 55 C.Water (100 mL) was added and the resulting solution was filtered.The filtrate was acidified with concentrated HCl to give a precipitateof the methylester-acid. The crystals were collected by vacuumfiltration, rinsed with water, and dried at 95 C.Step 2-A mixture of 3-(4-carboxybenzylsulfamoyl)thiophene-2-carboxylic acid methyl ester (0.7 g), potassium hydroxide (1.0 g),and water (10 mL) was heated at 85 C for 40 min. After coolingto room temperature an additional 5 mL of water was added. Theproduct was precipitated by the drop wise addition of concentratedhydrochloric acid. After drying at 95 C, 3-(4-carboxybenzylsulfamoyl)thiophene-2-carboxylic acid was obtained in 37% yield.
I-14.1 Synthesis of 4-[(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)methyl]benzoic acid
Into a 250-mL 3-necked round-bottom flask, was placed sodium carbonate (3.7 g, 34.91 mmol, 0.54 equiv), water (66 mL), 4-(aminomethyl)benzoic acid (9.7 g, 64.17 mmol, 1.00 equiv) and ethyl l,3-dioxo-2,3-dihydro-lH-isoindole-2-carboxylate (14.6 g, 66.61 mmol, 1.04 equiv). The resulting solution was stirred for 3 h at 25 °C. The pH value of the solution was adjusted to 4 with hydrogen chloride (1 mol/L). The solids were collected by filtration. The filter cake was washed with 1x100 mL of water. This resulted in 15.7 g (87%) of 4-[(l,3-dioxo-2,3-dihydro-lH-isoindol-2- yl)methyl]benzoic acid as a white solid. MS (ESI) m/z 282 ([M + H]+)
2-6. Synthesis of Methyl 4-(Aminomethyl)benzoate Compound of Chemical Formula 13 The mixture of 4-(aminomethyl)benzoic acid (1.0 g, 6.61 mmol) and chlorotrimethylsilane (3.35 mL, 26.44 mmol) was stirred for 30 minutes at room temperature, and anhydrous methanol (20 mL) was added thereto. The reaction mixture was stirred for 48 hours and then vacuum distilled to give methyl 4-(aminomethyl)benzoate (1.25 g, 94%). 1H NMR (500 MHz, D2O) delta 8.02 (d, 2H, J=6.4 Hz), 7.51 (d, 2H, J=8.2 Hz), 4.20 (s, 2H), 3.88 (s, 3H).
3.1.1. General Procedure for the Preparation of 2a and 2b[32]
General procedure: 4-((2,2,2-trifluoroacetamido)methyl)benzoic acid (2a).Tri uoroacetic anhydride (5.9 mL, 41.3 mmol) was added insmall portions to solid 4-(aminomethyl) benzoic acid (2.5 g,16.5 mmol) at 4°C. Upon completion of addition, the reactionmixture was homogeneous. Stirring was continued atroom temperature for 2 h, and then ice water was added toprecipitate the product. The white solid 2a was precipitatedand collected by ltration. (3.3 g, 81% yield). mp:214-215C, 1H-NMR(400 MHz DMSO-d6): 4.47 (d, J = 6.0 Hz,2H), 7.40 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 10.07(s, 1H), 12.94 (s, 1H). ESI-MS m/z: 248.5 [M + H]+.
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-dihydroxyphenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: p-aminomethylbenzoic acid; 1,3-dihydroxybenzaldehyde; 1,2-bis(4-methoxyphenyl)-1,2-ethanedione With ammonium acetate; acetic acid at 100℃; for 12h;
Stage #2: tert-butyl {2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 6h;
Stage #3: With trifluoroacetic acid In dichloromethane at 20℃; for 1.5h;
98 Example 98
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-dihydroxyphenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide. 1,3-dihydroxybenzaldehyde (50 mg, 362 µmol), 4-aminomethyl benzoic acid (72 mg, 470 µmol), 4,4'-dimethoxybenzyl (127 mg, 470 µmol) and ammonium acetate (167 mg, 2.2 mmol) were dissolved in acetic acid, heated at 100 °C and stirred for 12 hours. The temperature was decreased to room temperature, and a reaction mixture was diluted with ethyl acetate and then washed with water and a saline solution. An organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture obtained thereby was purified by flash column chromatography (CH2Cl2:MeOH = 10:1), thereby obtaining a compound with a yield of 73%. The acid obtained as described above (30 mg, 58 µmol), t-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (13 mg, 86 µmol), EDC (12 mg, 75 µmol) and DMAP (2 mg, 17 µmol) were dissolved in DMF, and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and a saline solution. An organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained mixture was purified by flash column chromatography (CH2Cl2:MeOH = 10:1). A compound obtained thereby was dissolved in 75% TFA-CH2Cl2 and stirred at room temperature for 1.5 hours. A high-volatile material was removed under reduced pressure, and dissolved in CH2Cl2. The resultant solution was washed with water, saturated NaHCO3 and a saline solution. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture obtained thereby purified by flash column chromatography (CH2Cl2:MeOH = 10:1), thereby obtaining a target compound with a yield of 75%: 1H NMR(CD3OD, 400MHz) δ7.65(d, J=8.0Hz, 2H), 7.35(d, J=8.8Hz, 2H), 7.11(d, J=8.4Hz, 2H), 6.88(d, J=8.8Hz, 2H), 6.85(d, J=8.0Hz, 2H), 6.76(d, J=8.8Hz, 2H), 6.53(s, 2H), 6.35(s, 1H), 5.21(s, 2H), 3.78(s, 3H), 3.73(s, 3H), 3.63-3.53(m, 10H), 2.84-2.82(m, 2H); 13C NMR(CDCl3, 100MHz) δ169.8, 161.5, 160.1, 160.0, 149.5, 142.6, 138.7, 134.6, 133.5, 133.2, 130.2, 129.4, 129.1, 128.6, 128.5, 128.0, 127.9, 127.3, 123.7, 115.4, 114.5, 108.8, 108.9, 104.8, 71.5, 71.3, 70.5, 55.7, 55.6, 47.2, 41.5, 40.8; The obtained value of MALDI-TOF-MS calculated for C37H41N4O7 [M+H]+ 653.2900 was 653.1543.
4-(((6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 4.0h;Inert atmosphere;
General procedure: To a solution of 7a (50.0 mg, 0.32 mmol) and aminomethyl-benzoic acids 8a (40.6 mg, 0.27 mmol) in triethylamine (66.8 mkL,0.48 mmol), anhydrous DMF (1.5 mL) was added and the reaction mixture was stirred at 80 C for 4 h. The reaction mixture was diluted with ethyl acetate (8 mL) and was washed with water (3x4 mL). The ethyl acetate layer was then dried with anhydrous Na2SO4, and concentrated to give a residue that was subjected to purification through the column chromatography on silica gel with DCM and MeOH (10:1) as eluent to afford the titled compounds 1a (31.1 mg, 43%) as a yellow solid.
4-((2-(prop-2-yn-1-yloxy)acetamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: methyl-2-(prop-2-yn-1-yloxy)acetate With dicyclohexyl-carbodiimide In acetonitrile Cooling with ice;
Stage #2: p-aminomethylbenzoic acid In acetonitrile at 0℃; for 1h;
4-((2-oxo-2H-chromene-3-carboxamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: 2-oxo-2H-chromene-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: p-aminomethylbenzoic acid With trifluoroacetic acid In tetrahydrofuran at 20℃; for 10h;
1 General procedure for the synthesis of 4-((2-oxo-2H-chromene-3-carboxamido) methyl) benzoic acid derivatives (6a-u)
General procedure: The corresponding 2-oxo-2H-chromene-3-carboxylic acids (3a-v, 5mmol) was added to a suspension of 1, 1-carbonyldimidazole (CDI, 25mmol) in dry tetrahydrofuran (THF, 10mL) and the mixture was stirred for 2h at rt. Then 4-(aminomethyl) benzoic acid (5, 25mmol) and trifluoroacetic acid (TFA, 1.2mL) were added and stirred for additional 10hat rt. The mixture was evaporated to remove THF and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Further purification was done with preparative thin layer chromatography for some compounds (6p and 6q). Due to very low solubility of compounds 6g, 6i and 6m, we could not report 13C NMR data for these compounds. 4.5.1 4-((2-oxo-2H-chromene-3-carboxamido) methyl) benzoic acid (6a) White solid; yield:78%; mp: 261-263°C; Rf=0.56 (petroleum ether: ethyl acetate=3:1); IR (KBr): νmax (cm-1) 3312 (NH), 1709 1602 (CO); 1H NMR (300MHz, DMSO-d6) δ 4.63 (d, 2H, J=6.0Hz,CH2), 7.44-7.54 (m, 4H, Ar-H), 7.77 (t, 1H, J=6.0Hz, Ar-H), 7.92 (d, 2H, J=9.0Hz, Ar-H), 7.99 (d, 1H, J=9.0Hz, Ar-H), 8.90 (s, 1H, CH), 9.23 (t, 1H, J=6.0Hz, NH); 13C NMR (75MHz, DMSO-d6) δ 43.04, 116.62, 118.94, 119.57, 125.62, 127.78, 129.88, 130.06, 130.75, 134.61, 144.56, 148.08, 154.40, 160.73, 161.96, 167.60; Anal. calcd. for C18H13NO5: C, 66.87; H, 4.05; N, 4.33; found: C 66.80, H 4.09, N 4.24.
4-((6-bromo-2-oxo-2H-chromene-3-carboxamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: 6-bromocoumarin-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: p-aminomethylbenzoic acid With trifluoroacetic acid In tetrahydrofuran at 20℃; for 10h;
7 General procedure for the synthesis of 4-((2-oxo-2H-chromene-3-carboxamido) methyl) benzoic acid derivatives (6a-u)
General procedure: The corresponding 2-oxo-2H-chromene-3-carboxylic acids (3a-v, 5mmol) was added to a suspension of 1, 1-carbonyldimidazole (CDI, 25mmol) in dry tetrahydrofuran (THF, 10mL) and the mixture was stirred for 2h at rt. Then 4-(aminomethyl) benzoic acid (5, 25mmol) and trifluoroacetic acid (TFA, 1.2mL) were added and stirred for additional 10hat rt. The mixture was evaporated to remove THF and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Further purification was done with preparative thin layer chromatography for some compounds (6p and 6q). Due to very low solubility of compounds 6g, 6i and 6m, we could not report 13C NMR data for these compounds.
N-(4-((2-aminophenyl)carbamoyl)benzyl)-7-ethoxy-2-oxo-2H-chromene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 20 °C
1.2: 10 h / 20 °C
2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 60 °C
2.2: 16 h / 20 °C
4-((7-ethoxy-2-oxo-2H-chromene-3-carboxamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 7-ethoxy-2-oxo-2H-chromene-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: p-aminomethylbenzoic acid With trifluoroacetic acid In tetrahydrofuran at 20℃; for 10h;
5 General procedure for the synthesis of 4-((2-oxo-2H-chromene-3-carboxamido) methyl) benzoic acid derivatives (6a-u)
General procedure: The corresponding 2-oxo-2H-chromene-3-carboxylic acids (3a-v, 5mmol) was added to a suspension of 1, 1-carbonyldimidazole (CDI, 25mmol) in dry tetrahydrofuran (THF, 10mL) and the mixture was stirred for 2h at rt. Then 4-(aminomethyl) benzoic acid (5, 25mmol) and trifluoroacetic acid (TFA, 1.2mL) were added and stirred for additional 10hat rt. The mixture was evaporated to remove THF and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Further purification was done with preparative thin layer chromatography for some compounds (6p and 6q). Due to very low solubility of compounds 6g, 6i and 6m, we could not report 13C NMR data for these compounds.
N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-oxo-7-propoxy-2H-chromene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 20 °C
1.2: 10 h / 20 °C
2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 60 °C
2.2: 16 h / 20 °C
4-((2-oxo-7-propoxy-2H-chromene-3-carboxamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: 2-oxo-7-propoxy-2H-chromene-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: p-aminomethylbenzoic acid With trifluoroacetic acid In tetrahydrofuran at 20℃; for 10h;
6 General procedure for the synthesis of 4-((2-oxo-2H-chromene-3-carboxamido) methyl) benzoic acid derivatives (6a-u)
General procedure: The corresponding 2-oxo-2H-chromene-3-carboxylic acids (3a-v, 5mmol) was added to a suspension of 1, 1-carbonyldimidazole (CDI, 25mmol) in dry tetrahydrofuran (THF, 10mL) and the mixture was stirred for 2h at rt. Then 4-(aminomethyl) benzoic acid (5, 25mmol) and trifluoroacetic acid (TFA, 1.2mL) were added and stirred for additional 10hat rt. The mixture was evaporated to remove THF and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Further purification was done with preparative thin layer chromatography for some compounds (6p and 6q). Due to very low solubility of compounds 6g, 6i and 6m, we could not report 13C NMR data for these compounds.
4-((7-methoxy-2-oxo-2H-chromene-3-carboxamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: 7-methoxycoumarin-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: p-aminomethylbenzoic acid With trifluoroacetic acid In tetrahydrofuran at 20℃; for 10h;
4 General procedure for the synthesis of 4-((2-oxo-2H-chromene-3-carboxamido) methyl) benzoic acid derivatives (6a-u)
General procedure: The corresponding 2-oxo-2H-chromene-3-carboxylic acids (3a-v, 5mmol) was added to a suspension of 1, 1-carbonyldimidazole (CDI, 25mmol) in dry tetrahydrofuran (THF, 10mL) and the mixture was stirred for 2h at rt. Then 4-(aminomethyl) benzoic acid (5, 25mmol) and trifluoroacetic acid (TFA, 1.2mL) were added and stirred for additional 10hat rt. The mixture was evaporated to remove THF and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Further purification was done with preparative thin layer chromatography for some compounds (6p and 6q). Due to very low solubility of compounds 6g, 6i and 6m, we could not report 13C NMR data for these compounds.
To a suspension of 0.33 g (2.01 mmol) of N, N'-carbonyldiimidazole in furan tetrahydrofuran (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0 C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C16H14N2O3; 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3· C, 68.07%; H, 5,00%, N, 9.92. Found: C, 68.21%; H, 5.03%; N, 9.90%.
2) adding <strong>[366-84-7]ethyl 4-aminomethylbenzoate</strong> to the concentrated sulfuric acid solution,The molar ratio of sulfuric acid to 4-aminomethylalkyl benzoate is 2:1,The reaction was stirred at 80 C for 1 h, and after completion of the reaction, it was cooled to room temperature.Add water (the amount of water is 20 times the amount of m<strong>[366-84-7]ethyl 4-aminomethylbenzoate</strong>), then add ammonia water dropwise to the solution to make the solution alkaline.There is a lot of solids to precipitate, filter, wash,Drying gave a white solid aminotoluic acid.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;
A conjugation reaction was performed using the rigid linker / aminomethyl benzoic acid and DOTA-monoamide NHS ester to provide compound 4 in quantitative yield. Next, compound 5 was obtained by treating compound 4 with TSTU in presence of trimethylamine and followed by removal of fert-Butyl group using TFA/CH2CI2 to produce a reactive intermediate 6 in high yield. Ligands L3 and L4 were obtained in good yields after a simple conjugation reaction between 6 with 3b and 3d.
With ammonium peroxydisulfate; 2,2'-azobis-(2,4-dimethylvaleronitrile); hydrogen bromide In tetrachloromethane at 45℃; for 15h;
1; 2; 3; 4 example 4
(1) 80 g of p-toluic acid and 1000 g of carbon tetrachloride were added to the reactor.160g of 30% aqueous solution of HBr, stirred and dissolved,Add 8g ammonium persulfate and 4g azobisisoheptanenitrile,Carrying out the bromination reaction, the bromination reaction temperature is 45 ° C,The bromination reaction time is 15 hours;(2) The reaction liquid obtained in the step (1) is cooled to 20 ° C for filtration, and the filter cake is p-bromomethylbenzoic acid.Heat the filtrate and recover carbon tetrachloride.The remaining filtrate is retained as part of the mother liquor;(3) adding p-bromomethylbenzoic acid and 1000 g of 10% aqueous ammonia to the reactor, stirring and dissolving,Add 164.6 g of urotropine to carry out the aminolysis reaction.The aminolysis reaction temperature is 10-20 ° C, and the aminolysis reaction time is 5 hours;(4) The temperature of the reaction liquid obtained in the step (3) is below 50 ° C, and the negative pressure discharges excess ammonia gas.Ammonia gas is absorbed back, and NaOH is added to the reaction solution to a pH of 6.8-8.0;(5) filtering the reaction liquid obtained in the step (4),The obtained filter cake is dried at 50 ° C for 5 hours, which is aminotoluic acid.The filtrate obtained is retained as another part of the mother liquor;(6) adding 25 g of NaOH to the mother liquor of steps (2) and (5) to make p-toluic acid and ammonia toluene in the mother liquorAcid is precipitated, and the remaining water is distilled off.600 g of ethanol was added to the remaining residue, heated for 3 hours, cooled to below 20 ° C, and filtered.The obtained filter cake is NaBr.The obtained filtrate is distilled to recover ethanol;(7) adding 38 g of concentrated sulfuric acid to the NaBr of the step (6),Make HBr and wait for reuse.
Multi-step reaction with 2 steps
1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2 h / 80 °C
2: triethylamine; potassium carbonate / tetrachloromethane / 4 h / 25 °C
2-(4-((2-(6-amino-3-iminio-3H-xanthen-9-yl)benzamido)methyl)benzamido) benzenaminium 2,2,2-trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; trifluoroacetic acid;
Example 1 2-(4-((2-(6-amino-3-iminio-3H-xanthen-9-yl)benzamido)methyl)benzamido) benzenaminium 2,2,2-trifluoroacetate (LL66) 4-(aminomethyl)benzoic acid (755 mg, 5 mmol) was dissolved in 15 mL 1 mol/L NaOH aqueous solution, to which was added 1308 mg Boc2O and 2 mL THF. The mixture was stirred overnight and THF condensed under vacuum. The residue was acidification by diluted hydrochloric acid and the resulting white solid was filtered to yield Boc-protected intermediate. The Boc-protected compound, 1925 mg TBTU and 1 mL TEA were dissolved in 50 mL DCM. 30 mins later, 1,2-diaminobenzene (650 mg, 6 mM) was added and the mixture was allowed to stir at room temperature overnight. Volatiles were removed under vacuum, the residue was recrystallized by ethyl estate and hexane to yield a white solid. This was dissolved in 10 mL mixed solution of DCM and TFA (1:1), the solution was stirred at room temperature for 1 hour. The volatiles were evaporated under vacuum to afford a color less oil. 110 mg oil was dissolved in 5 mL DMF then 193 mg N,N-Diisopropylethylamine and 114 mg <strong>[13558-31-1]Rhodamine 110 chloride</strong> was added. After the reaction finished, 30 mL water was added and the mixed solution was extracted by ethyl estate. The organic phase was dried by MgSO4 and evaporated under vacuum. The crude residue was purified on C18 reverse phase columns eluted with acetonitrile and water (containing 0.2% TFA) to yield the pure product. The NMR and mass spectrometry characterization of LL-66 is as follows: 1H NMR (400 MHz, DMSO-d6) delta 9.57 (s, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.67 (d, 8.2 Hz, 2H), 7.60-7.50 (m, 2H), 7.12 (d, J=7.3 Hz, 1H), 7.03-6.91 (m, 5H), 6.77 (dd, J=8.0, 1,1 Hz, 1H), 6.60 (t, J=7.5 Hz, 1H), 6.31 (d, J=1.8 Hz, 2H), 6.16-6.11 (m, 4H), 4.15 (s, 2H). ESI/MS m/z: 554.17 [H+H]+
6-amino-9-(2-((4-(2-propylhydrazine-1-carbonyl)benzyl)carbamoyl)phenyl)-3H-xanthen-3-iminium 2,2,2-trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium cyanoborohydride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; trifluoroacetic acid;
Example 5 6-amino-9-(2-((4-(2-propylhydrazine-1-carbonyl)benzyl)carbamoyl)phenyl)-3H-xanthen-3-iminium 2,2,2-trifluoroacetate (LL65) 4-(aminomethyl)benzoic acid (755 mg, 5 mmol) was dissolved in 15 mL 1 mol/L NaOH aqueous solution, to which was added 1308 mg Boc2O and 2 mL THF. The mixture was stirred overnight and THF condensed under vacuum. The residue was acidification by diluted hydrochloric acid and the resulting white solid was filtered to yield Boc-protected intermediate. The Boc-protected compound, 1925 mg TBTU and 1 mL TEA were dissolved in 50 mL DCM. 30 mins later, Hydrazinehydrate (0.5 g, 10 mM) was added and the mixture was allowed to stir at room temperature overnight. Volatiles were removed under vacuum, the residue was recrystallized by ethyl estate and hexane to yield a white solid. This compound and 348 mg propionaldehyde were dissolved in 50 mL ethanol and reacted for 2 hours. Vacuum evaporation afforded the desired intermediate which was dissolved in 50 mL methanol, to this solution was added 5 mg methyl orange and 1256 mg sodium cyanoborohydride. Mixture of methanol and concentrated hydrochloric acid (1:1) was added dropwise until the solution turned and stayed red. 6 hours later, volatiles were removed under vacuum and purified on reverse phase columns eluted with acetonitrile and water to yield pure product. This intermediate was dissolved in 10 mL mixed solution of DCM and TFA (1:1), the solution was stirred at room temperature for 1 hour. The volatiles were evaporated under vacuum to afford a color less oil. 105 mg oil was dissolved in 5 mL DMF then 193 mg N,N-Diisopropylethylamine and 114 mg <strong>[13558-31-1]Rhodamine 110 chloride</strong> was added. After the reaction finished, 30 mL water was added and the mixed solution was extracted by ethyl estate. The organic phase was dried by MgSO4 and evaporated under vacuum. The crude residue was purified on C18 reverse phase columns eluted with acetonitrile and water (containing 0.2% TFA) to yield the pure product.
Multi-step reaction with 3 steps
1.1: triethylamine / methanol / Reflux
2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 °C
2.2: 20 °C
3.1: hydrogenchloride / methanol; water / 20 °C
Multi-step reaction with 3 steps
1.1: triethylamine / methanol / 100 °C
2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 °C
2.2: 20 °C
3.1: hydrogenchloride; methanol / water / 20 °C
With ammonium hydroxide In methanol at 80℃; for 0.5h;
1-4; 1 Example 1
Add 200.0 g of 4-chloromethylbenzoic acid (1) to a mixture of 4000 mL of methanol and 320.0 g of ammonia water (concentration 25% to 28%) to dissolve it.Flow into the reactor A unit at a flow rate of 0.2 mL/min,The residence time of the reaction solution was 0.5 hours, the reaction pressure was 1.0 MPa, and the reaction temperature was controlled at 80° C. After the reaction solution flowed out of the reactor A unit, the solvent was concentrated and recovered, and the residue was added to 2L of ethanol, and adjusted with 20% sodium hydroxide solution. The pH value is 9-10 to dissolve the system, and then the pH is adjusted to 7.5-8.0 with concentrated hydrochloric acid, the product is precipitated, filtered and dried to obtain aminotoluic acid (2). The purity is 99.5%, and the yield is 95%.
Stage #1: p-(chloromethyl)benzoic acid With hexamethylenetetramine In methanol; lithium hydroxide monohydrate for 1h;
Stage #2: With ammonia In methanol; lithium hydroxide monohydrate at 50 - 60℃;
4-((2-(4-bromophenyl)quinoline-4-carboxamido)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.3%
Stage #1: 2-(4'-bromophenyl)quinoline-4-carboxylic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃;
Stage #2: p-aminomethylbenzoic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine In tetrahydrofuran at 20℃;
4.4. General procedure for the synthesis of 4-((2-methylquinoline-4-carboxamido) methyl)benzoic acids or 4-((2-arylquinoline-4-carboxamido)methyl)benzoic acids (8a-t)
General procedure: The corresponding quinoline-4-carboxylic acid ( 4a, 4b-i, 4k-p or 4q-t , 1mmol) was added to a suspension of CDI (2 mmol for 2- methylquinoline-4-carboxylic acids ( 4a or 4b-i ) and 4 mmol for 2- aryl quinoline-4-carboxylic acids ( 4k-p or 4q-t ) in dry THF and the mixture was stirred until the reaction was complete. The result- ing solution was added to a suspension of 4-(aminomethyl)benzoic acid (1 mmol), triethylamine (1 mmol) and DBU (1 mmol) in dry THF and was stirred. The reaction progress was monitored by TLC, after the reaction was completed, the solvent was removed by ro- tary evaporator, the residue dissolved in water, acidified with HCl and then the resulting solid was collected by filtration, washed with water and methanol to get the compounds 8a - t .
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