* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium 2-methyl-2-adamantoxide; dichlorobis(dicyclohexylphosphinomethylpyridine)-ruthenium (II); hydrogen; sodium hydride In toluene; mineral oil at 160℃; for 24 h; Inert atmosphere; Autoclave
General procedure: Under a continuous Ar flow, 2-methyl-2-adamantanol (16.6 mg, 0.1 mmol), NaH (60percent oil dispersion, 4.0 mg, 0.1 mmol), anhydrous toluene (1.5 mL) and a magnetic stirring bar were placed in a dried Teflon tube (21 mL capacity). The Teflon tube was stoppered with a rubber septum, and the mixture was stirred at room temperature for 2 h under Ar. After removing the septum, under a continuous Ar flow, to the mixture was added RUPCY (7.50 mg, 0.01 mmol) and N-benzylbenzamide (105.6 mg, 0.5 mmol). The Teflon tube was quickly inserted into an autoclave and the inside of the autoclave was purged several times with hydrogen gas (>5 MPa). The autoclave was pressurized with an 8 MPa of hydrogen gas at 25°C, and heated at 160°C for 24 h under stirring (800 rpm). The autoclave was cooled to room temperature in an ice–water (0°C) bath,and the reaction mixture was quenched with NH4Cl (5.3 mg, 0.1 mmol). The organic phase was removed in vacuo (ca. 100 mmHg, 40 °C). The residue was diluted with CDCl3, and analyzed by 1H NMR. The yields of benzyl alcohol (92percent) and benzylamine (92percent) were calculated based on the integral ratio among the signals of these compounds with respect to an internal standard (1,1,2,2-tetrachloroethane). Afterward, the reaction mixture was purified by column chromatography on silica gel (silica gel (ca. 100 g) was pretreated with Et3N (small amount)–Et2O/hexane (vol percent: 2/3), eluent; Et2O/hexane = 2/3, then EtOAc/Et3N = 100/1) to give N-benzylbenzamide (7.7 mg, 0.036 mmol, 7percent), benzyl alcohol (47.4 mg, 0.438 mmol, 88percent) and benzylamine (44.1 mg, 0.4187 mmol, 82percent).
90 %Spectr.
With sodium 2-methyl-2-adamantoxide; C24H38Cl2N2P2Ru; hydrogen In toluene at 130 - 160℃; for 44 h; Autoclave; Sealed tube
1) Preactivation of Catalyst In an argon gas atmosphere, a stirrer, a ruthenium complex (Compound 2b; RUPIP2) (0.0067 mmol, 3.98 mg) and sodium-2-methyl-2-adamantoxide (0.067 mmol, 12.6 mg) were placed in a dried fluororesin tube (30 mL). Thereafter, the tube containing this compound was rapidly inserted into an autoclave, and toluene (2.0 mL) was added in an argon atmosphere. Subsequently, the autoclave was hermetically sealed while being grounded, and hydrogen gas was introduced into the autoclave from a hydrogen compressed gas cylinder connected via a stainless-steel pipe, thereby substituting the inside of the autoclave with hydrogen gas. More specifically, 1-MPa hydrogen gas pressure was applied inside the autoclave, and then the hydrogen gas pressure was removed through a leak valve. This operation (substitution and desubstitution) was repeated 10 times. Finally, the hydrogen gas inside the autoclave was set to 1 MPa, and a reaction was performed for 5 hours using a constant-temperature bath at 160° C. (2) Hydrogenation Reaction of Substrate (0285) After the reaction was completed, the autoclave was cooled to substantially room temperature by being immersed in an icy bath. Then, the leak valve of the autoclave was opened and the hydrogen gas inside the autoclave was released into the air. Subsequently, in an argon gas atmosphere, the reaction solution (1.5 mL) was obtained from the autoclave using a gas-tight syringe, and placed in another autoclave (a stirrer, and N-benzylbenzamide (0.5 mmol, 105.63 mg) were placed in a dried fluororesin tube (30 mL) in an argon gas atmosphere; thereafter, the tube containing this compound was rapidly inserted into an autoclave, and the inside of the autoclave was substituted with argon). Subsequently, the autoclave was hermetically sealed while being grounded, and hydrogen gas was introduced into the autoclave from a hydrogen compressed gas cylinder connected via a stainless-steel pipe, thereby substituting the inside of the autoclave with hydrogen gas. More specifically, 1-MPa hydrogen gas pressure was applied inside the autoclave, and then the hydrogen gas pressure was removed through a leak valve. This operation (substitution and desubstitution) was repeated 10 times. Finally, the hydrogen gas inside the autoclave was set to 1 MPa, and a reaction was performed for 24 hours using a constant-temperature bath at 110° C. For 1H NMR analysis, an internal standard substance (mesitylene) was added to the solution. Based on the hydrogen atom amount of the internal standard substance, the yield of the reaction product was calculated. The results of the analysis showed that the yields of benzyl alcohol and benzylamine were both 86percent (corresponding to Entry 8 in Table 2 described later). A hydrogenation reaction was performed in the same manner as in Reaction Example A5, except that the conditions specified in Table 2 were used. Tables 2 and 3 show the results.
Reference：
[1] Chemical Communications, 2014, vol. 50, # 76, p. 11211 - 11213
[2] Canadian Journal of Chemistry, 1958, vol. 36, p. 147,149
[3] Angewandte Chemie - International Edition, 2011, vol. 50, # 44, p. 10377 - 10380
[4] Tetrahedron Letters, 2013, vol. 54, # 21, p. 2674 - 2678
[5] Patent: US9463451, 2016, B2, . Location in patent: Page/Page column 46-50
[6] ChemCatChem, 2017, vol. 9, # 22, p. 4275 - 4281
[7] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2559 - 2565
2
[ 60-32-2 ]
[ 4048-33-3 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: at 40℃; for 0.333333 h; Sonication Stage #2: at 90℃; for 16.5 h; Reflux Stage #3: With water In ethylene glycol
(1) By volume ratio, 1 part of 6-aminohexanoic acid was added to the reactor containing 15 parts of diethyl ether or dry toluene solution, At 40 deg.C constant temperature, At 1500rpm / min speed, rapidly inject 2 parts of a solution of sodium borohydride. At 250W, ultrasonic treatment 20min. Then add dropwise under reflux 8 parts of ethylene glycol solution. Dropwise addition time was 30min. Finally at 90 deg.C and at a rate of 800rpm/min, maintain temperature under stirring and react for 16 h to obtain the reaction crude product.(2) By the amount of parts count, step (1) preparation of 1 part of the reaction crude was added 6 parts water for hydrolysis. Undrego vacuum distillation, collecting 125 deg.C fraction, to obtain 6-amino-1-hexanol product .
Reference：
[1] Patent: CN105669471, 2016, A, . Location in patent: Paragraph 0038; 0039; 0040
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 22, p. 6346 - 6349
3
[ 629-11-8 ]
[ 4048-33-3 ]
Reference：
[1] Patent: US2012/232292, 2012, A1, . Location in patent: Page/Page column 10; 12
[2] Patent: JP2016/27052, 2016, A, . Location in patent: Paragraph 0088; 0103
[3] Patent: CN103502212, 2016, B, . Location in patent: Paragraph 0207-0208; 0214
[4] Patent: CN105622436, 2016, A, . Location in patent: Paragraph 0029; 0035-0043
With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 220℃; for 6 h;
HDO (5 mmol), catalyst (50 mg), and tert-butanol(5 mL) were loaded into a 50 mL stainless steel reactor. Thereactor was flushed with H2 for three times and then pressurizedwith 1 MPa H2 at room temperature. After being heatedto the desired temperature, NH3 was introduced into the reactorwith a high-pressure liquid pump (Hangzhou ZhijiangPetrochemical Equipment, China) to the desired pressure.The reaction was conducted while stirring the reaction mixturewith a magnetic stirrer (1200 r/min). After reaction, thereactor was cooled and depressurized carefully and the residualNH3 was removed by water. The products were identifiedby gas chromatograph-mass spectrometer (GC-MS; Agilent5975/6890N, USA; HP-5 capillary column) and electrosprayionization mass spectrometry (ESI-MS). The products werequantitatively analyzed by GC (Shimadzu GC-2010, Japan;Rtx-50 capillary column) using n-octanol as an internalstandard. The conversion was calculated by moles of HDOconsumed divided by initial moles of HDO used and theselectivity was determined by moles of product i divided bytotal moles of products obtained.
68.8 %Chromat.
With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 220℃; for 6 h;
HDO (5 mmol), catalyst (50 mg), and tert-butanol(5 mL) were loaded into a 50 mL stainless steel reactor. Thereactor was flushed with H2 for three times and then pressurizedwith 1 MPa H2 at room temperature. After being heatedto the desired temperature, NH3 was introduced into the reactorwith a high-pressure liquid pump (Hangzhou ZhijiangPetrochemical Equipment, China) to the desired pressure.The reaction was conducted while stirring the reaction mixturewith a magnetic stirrer (1200 r/min). After reaction, thereactor was cooled and depressurized carefully and the residualNH3 was removed by water. The products were identifiedby gas chromatograph-mass spectrometer (GC-MS; Agilent5975/6890N, USA; HP-5 capillary column) and electrosprayionization mass spectrometry (ESI-MS). The products werequantitatively analyzed by GC (Shimadzu GC-2010, Japan;Rtx-50 capillary column) using n-octanol as an internalstandard. The conversion was calculated by moles of HDOconsumed divided by initial moles of HDO used and theselectivity was determined by moles of product i divided bytotal moles of products obtained.
19.1 %Chromat.
With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 220℃; for 6 h;
HDO (5 mmol), catalyst (50 mg), and tert-butanol(5 mL) were loaded into a 50 mL stainless steel reactor. Thereactor was flushed with H2 for three times and then pressurizedwith 1 MPa H2 at room temperature. After being heatedto the desired temperature, NH3 was introduced into the reactorwith a high-pressure liquid pump (Hangzhou ZhijiangPetrochemical Equipment, China) to the desired pressure.The reaction was conducted while stirring the reaction mixturewith a magnetic stirrer (1200 r/min). After reaction, thereactor was cooled and depressurized carefully and the residualNH3 was removed by water. The products were identifiedby gas chromatograph-mass spectrometer (GC-MS; Agilent5975/6890N, USA; HP-5 capillary column) and electrosprayionization mass spectrometry (ESI-MS). The products werequantitatively analyzed by GC (Shimadzu GC-2010, Japan;Rtx-50 capillary column) using n-octanol as an internalstandard. The conversion was calculated by moles of HDOconsumed divided by initial moles of HDO used and theselectivity was determined by moles of product i divided bytotal moles of products obtained.
Reference：
[1] Patent: US2012/232293, 2012, A1, . Location in patent: Page/Page column 12; 16
[2] Science China Chemistry, 2017, vol. 60, # 7, p. 920 - 926
[3] Science China Chemistry, 2017, vol. 60, # 7, p. 920 - 926
[4] Science China Chemistry, 2017, vol. 60, # 7, p. 920 - 926
Reference：
[1] Journal of the Chemical Society, 1958, p. 1489,1497
[2] Journal of the Chemical Society, 1958, p. 1489,1497
16
[ 371-34-6 ]
[ 4048-33-3 ]
Reference：
[1] Pr. Irish Acad., 1958, vol. 59 B, p. 345,349
17
[ 124-09-4 ]
[ 111-49-9 ]
[ 4048-33-3 ]
[ 109-05-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1992, # 6, p. 939 - 947
18
[ 4048-33-3 ]
[ 6404-29-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 6, p. 1253 - 1262
19
[ 4048-33-3 ]
[ 60142-89-4 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 24, p. 7504 - 7507
20
[ 4048-33-3 ]
[ 501-53-1 ]
[ 17996-12-2 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 1 h;
6-Aminohexanol (5.0 g, 42.7 mmol) dissolved in a mixture of tetrahydrofuran (50 mL) and water (15 mL) was added benzylchloroformate (7.3 mL, 51.2 mmol) dropwise at 0 °C. Sodium hydroxide (1 N, 12 mL) was added at the same temperature for 30 min to keep the pH of the reaction solution at 8–9 then stirred at ambient temperature for additional 30 min. The reaction mixture was extracted with diethyl ether (30 mL × 3), dried and evaporated under vacuum. After recrystallized in a mixed solvent of dichloromethane and hexane, the desired compound was obtained as a white crystalline solid (3.85 g, 90percent yield). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H, Ar), 5.07 (s, 2H, PhCH2), 4.73 (br, NH), 3.61 (t, J = 6.4 Hz, 2H, CH2O), 3.16 (dt, J = 6.8, 6.8 Hz, 2H, NCH2), 1.61–1.32 (m, 8H, CH2); 13C NMR (100 MHz, CDCl3): 156.4 (C, C=O), 136.6, 128.5, 128.1 (CH, Ar), 66.6 (CH2, PhCH2), 62.7 (CH, CH2OH), 40.9 (CH, NHCH2), 32.5 (CH2, CH2CH2OH), 29.9 (CH2, NHCH2CH2), 26.3 (CH2, CH2CH2CH2OH), 25.3 (CH2, NCH2CH2CH2).
86%
With sodium carbonate In tetrahydrofuran; water at 5 - 20℃; for 2.75 h;
a) 6-Benzyloxycarbonylaminohexan-1-ol (7); 1 g of 6-aminohexanol (6) (8.53 mmol, 1 eq.) and 466 mg Na2CO3 (4.4 mmol, 2.2 eq.) are dissolved in 8 mL of water and 4 mL of THF. The medium is cooled to 5° C. 1.33 mL of benzyl chloroformate (9.4 mmol, 1.1 eq.), dissolved in 2.5 mL of THF, are then added dropwise. The reaction is left stirring for 2 hours 45 minutes at room temperature. The THF is evaporated off. The solid formed is filtered off under vacuum, washed with water, and then dried under vacuum to give 1.848 g of a white solid (yield 86percent)1H NMR 300 MHz (CDCl3): δ (ppm)=1.20-1.50 (m, 8H, CH2-(CH2)4-CH2); 3.14 (m, 2H, CH2-NH); 3.55 (m, 2H, CH2-OH); 4.70 (s, broad, 1H, NH); 5.05 (s, 2H, CH2Ph); 7.30 (m, 5H, aromatic).IR (KBr): νCH=3384 cm-1; νNH=3335 cm-1; νCsp2 Harom=3061 cm-1 and 3030 νCsp3=2942 cm-1 and 2859 cm-1; νCO=1685 cm-1; νCC=1530 cm-1 and 1464 cm-1; νC-O ester=1290 cm-1 and 1253 cm-1.Melting point=86° C.
86%
Stage #1: With sodium carbonate In 1,4-dioxane; water for 1 h; Stage #2: Cooling with ice
Aminohexanol (Compound 9, 70 g, 0.597 mol, commercially available) and Na2C03 (110.79 g, 1.059 mol, 1.75 eq.) were added to a mixture of 1,4-dioxane (1400 mL) and water (300 mL) in a 3.0 L bottom flask equipped with mechanical stirrer and stirred for 1 hour to dissolve the salt. The resulting clear solution was cooled in an ice bath and benzyl chloroformate (178.32g, 1.045 mol, 1.75 eq.) was added dropwise by addition funnel. The mixture was stirred overnight and allowed to warm slowly to room temperature resulting in the formation of a white precipitate. The precipitate was filtered and washed with ethyl acetate and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with saturated NaHC03 (500 mL), brine (500 mL), dried over Na2S04, filtered and the filtrate was evaporated under reduced pressure to provide a white solid. The white solid was suspended in hexanes, filtered and rinsed with fresh hexanes to provide purified Compound 10 (129.0 g, 86 percent). The structure of Compound 10 was confirmed by LCMS and HNMR.
86%
Stage #1: With sodium carbonate In 1,4-dioxane; water for 1 h; Stage #2: at 20℃; Cooling with ice
Aminohexanol (Compound 9, 70 g, 0.597 mol, commercially available) and Na2CO3 (110.79 g, 1.059 mol, 1.75 eq.) were added to a mixture of 1,4-dioxane (1400 mL) and water (300 mL) in a 3.0 L bottom flask equipped with mechanical stirrer and stirred for 1 hour to dissolve the salt. The resulting clear solution was cooled in an ice bath and benzyl chloroformate (178.32 g, 1.045 mol, 1.75 eq.) was added dropwise by addition funnel. The mixture was stirred overnight and allowed to warm slowly to room temperature resulting in the formation of a white precipitate. The precipitate was filtered and washed with ethyl acetate and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with saturated NaHCO3 (500 mL), brine (500 mL), dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to provide a white solid. The white solid was suspended in hexanes, filtered and rinsed with fresh hexanes to provide purified Compound 10 (129.0 g, 86percent). The structure of Compound 10 was confirmed by LCMS and 1H NMR.
85%
With triethylamine In methanol at 20℃; for 5 h;
To 6-AMINOHEXAN-1-OL (26,0. 49 g, 100 molpercent) in MEOH (25 mL) were added benzylchloroformate (1.0 mL, 165 molpercent) and triethylamine (1.0 mL, 165 MOLpercent). The reaction mixture was stirred for 5 hours at room temperature then concentrated to dryness to give a residue which was purified by silica gel column chromatography using 1: 1 hexanes: EtOAc to give 0.9 g (85percent yield) of title compound 27. H NMR (CDC13, 300 MHz) 8 7. 37 (M, 5H), 5.13 (S, 2H), 3.67 (M, 2H), 3.24 (M, 2H), 1.56 (M, 4H), 1.35 (M, 2H)
79%
With sodium carbonate In water at 0 - 20℃;
To an ice-bath cooled solution of sodium carbonate (2.12 g, 20 mmol) and 6-aminohexan-1-ol 3 (1.17 g, 10 mmol) in water (30 mL) was added dropwise benzyl chloroformate (2.41 mL, 17 mmol). The reaction mixture was stirred overnight at room temperature then filtered. The precipitate was dissolved in dichloromethane and the organic layer was washed with water, dried over Na2SO4, filtered then concentrated in vacuo to give a solid which was recristallised from cyclohexane to give compound 4 as a white solid (1.98 g, 79percent yield). Mp = 80-81 °C; 1H NMR (DMSO-d6) δ: 7.39-7.23 (m, 5H, 5 * H-phenyl), 7.21 (m, 1H, NH), 5.00 (s, 2H, CH2Ph), 4.33 (t, 1H, J = 5.2 Hz, OH), 3.36 (q, 2H, J = 5.2 Hz, CH2O), 2.97 (q, 2H, J = 6.6 Hz, CH2N), 1.40-1.20 (m, 8H, 4 * CH2) ppm; 13C NMR (DMSO-d6) δ: 156.9 (NHCOO), 138.18 (C-phenyl ipso), 129.19 (2 * C-phenyl meta, C-phenyl para), 128.56 (2 * C-phenyl ortho), 65.91 (OCH2Ph), 61.50 (CH2OH), 41.11 (CH2), 33.34 (CH2), 30.33 (CH2), 27.02 (CH2), 26.08 (CH2) ppm; MS(ESI): m/z (percent) 525 (70) [2M+Na]+, 274 (83) [M+Na]+, 252 (100) [M+H]+; HRMS (ESI): m/z: calcd for C14H21NO3 + Na: 274.1419; found: 274.1423.
74%
With potassium carbonate In diethyl ether; water at 20℃; for 15 h;
Example 5: Preparation of 6-Cbz-hexanol (0046) The synthesis route was as shown in Scheme V below. Cbz-aminohexanol was prepared as follows. (0047) 6-aminohexanol (8.30 g, 70.8 mmol) and potassium carbonate (5.86 g, 40.2 mmol) was added to a 100 mL round-bottom reaction flask, a magnetic stir was placed, and then water (35 mL) was added and stirred vigorously. Then, benzyl chloroformate (CbzCl; 12.1 g, 70.9 mmol) dissolved in diethyl ether (12 mL) was slowly added dropwise, and reacted overnight at room temperature (about 15 hrs, during which a white particle-like was precipitated out). After reaction, the solution was filtered through a G3 suction funnel under reduced pressure. The solid was rinsed with a small amount of water (about 20 mL) and hexane (about 30 mL). The solid was collected, dissolved in ethyl acetate (300 mL), and transferred to an extractor. The organic phase was washed with 1 M HCl (200 mL×1) and saturated saline (200 mL×1). The organic phase was removed of remaining water over magnesium sulfate, filtered, concentrated under reduced pressure (in a water bath at 45° C.) and dried under high vacuum, to obtain 13.3 g of a white solid product (Yield: 74percent). (0048) Analytic Data of Compound: (0049) C14H21NO3; TLC (EtOAc/toluene=5:5) Rf=0.41; 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (5H, m), 5.09 (2H, s), 4.77 (1H, br), 3.63 (2H, q, J=6.3 Hz), 3.20 (2H, q, J=6.6 Hz), 1.58-1.36 (9H, m); ESI-MS: calcd for 252.15. found: m/z 252.16 [M+H]+.
73.2%
With sodium carbonate In diethyl ether; water at 20℃; for 2 h; Cooling with ice
VI. Synthesis of Compound 6 (6-(N-Benzyloxycarbonyl)aminohexanol)6-aminohexanol (5.9 g, 50.0 mmol) was dissolved in water (20 mL), sodium carbonate (3.2 g, 30.0 mmol) was added, and the solution was placed in an ice bath. A solution of benzyl chlorocarbonate (7.3 g, 50.0 mmol) dissolved in diethyl ether (20 mL) was slowly added dropwise. After addition, the solution was stirred at room temperature for another 2 h, and filtered, and a resulting solid was washed with a small amount of diethyl ether, and removed of solvent in a vacuum system, to obtain Product 1 (9.2 g, 73.2percent).Analysis data of Compound 6 is as shown in FIG. 6A and FIG. 6B.IR (neat) v 3382 and 1530 (NH), 3336 (OH), 1688 (CO) cm-1. 1H NMR (CDCl3) δ 7.34 (m, 5H, Ph), 5.08 (s, 2H, PhCH2), 4.90 (br, 1H, NH), 3.60 (t, J=6.5 Hz, 2H, CH2OH), 3.17 (q, J=6.6 Hz, 2H, NHCH2), 1.93 (br, 1H, OH), 1.52 (m, 4H, CH2CH2CH2CH2CH2O), 1.35 (m, 4H, CH2CH2CH2CH2O). 13C NMR (CDCl3) δ 156.45 (CO), 136.55, 128.42 and 127.99 (Ph), 66.51 (CH2OH), 62.52 (PhCH2), 40.82 (NHCH2), 32.45 (CH2CH2OH), 29.84 (NHCH2CH2), 26.28 (CH2CH2CH2OH), 25.22 (CH2CH2CH2CH2OH). MS m/z 251 (M+).
73.2%
Stage #1: With sodium carbonate In waterCooling with ice Stage #2: at 20℃; for 2 h;
Synthesis of 6′-(N-Benzyloxycarbonyl)aminohexanol [0092] Dissolve 6′-aminohexanol (5.9 g, 50.0 mmol) in 20 mL water, add with sodium carbonate (3.2 g, 30.0 mmol) and set the solution in an ice bath. Dissolve benzyl chlorocarbonate (7.3 g, 50.0 mmol) in 20 mL diethyl ether and slowly drop this solution into the above solution. Then stir the mixture at room temperature for 2 hours. Filter the mixture and wash solid with a little amount of diethyl ether. Remove the solvent from the solid in a vacuum system to get 6′-(N-Benzyloxycarbonyl) aminohexanol (9.2 g, 73.2percent). Compound Data of the Product: [0093] IR (neat) v 3382 and 1530 (NH), 3336 (OH), 1688 (CO) cm−1. [0094] 1H NMR (CDCl3) δ 7.34 (m, 5H, Ph), 5.08 (s, 2H, PhCH2), 4.90 (br, 1H, NH), 3.60 (t, J=6.5 Hz, 2H, CH2OH), 3.17 (q, J=6.6 Hz, 2H, NHCH2), 1.93 (br, 1H, OH), 1.52 (m, 4H, CH2CH2CH2CH2CH2O), 1.35 (m, 4H, CH2CH2CH2CH2O). [0095] 13C NMR (CDCl3) δ 156.45 (CO), 136.55, 128.42 and 127.99 (Ph), 66.51 (CH2OH), 62.52 (PhCH2), 40.82 (NHCH2), 32.45 (CH2CH2OH), 29.84 (NHCH2CH2), 26.28 (CH2CH2CH2OH), 25.22 (CH2CH2CH2CH2OH). MS m/z 251 (M+).
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 41, p. 9716 - 9719
[2] Canadian Journal of Chemistry, 1988, vol. 66, p. 1651 - 1655
[3] Chemistry - An Asian Journal, 2011, vol. 6, # 7, p. 1800 - 1810
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 4, p. 912 - 921
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 8, p. 1343 - 1350
[6] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 15, p. 2287 - 2294
[7] Patent: US2012/10161, 2012, A1, . Location in patent: Page/Page column 14
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2718 - 2733
[9] Patent: WO2018/67900, 2018, A1, . Location in patent: Page/Page column 39
[10] Patent: US10098959, 2018, B2, . Location in patent: Page/Page column 79-80
[11] Patent: WO2005/30258, 2005, A2, . Location in patent: Page/Page column 116
[12] Journal of the American Chemical Society, 2004, vol. 126, # 14, p. 4543 - 4549
[13] Molecules, 2010, vol. 15, # 8, p. 5708 - 5720
[14] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3165 - 3168
[15] Steroids, 2012, vol. 77, # 12, p. 1177 - 1191,15
[16] Steroids, 2012, vol. 77, # 12, p. 1177 - 1191
[17] Patent: US2017/183372, 2017, A1, . Location in patent: Paragraph 0046; 0047; 0048; 0049
[18] Patent: US2012/9669, 2012, A1, . Location in patent: Page/Page column 7
[19] Patent: US2014/31533, 2014, A1, . Location in patent: Paragraph 0092; 0093; 0094; 0095
[20] Journal of Medicinal Chemistry, 1992, vol. 35, # 16, p. 2983 - 2987
[21] Carbohydrate Research, 1973, vol. 31, p. 339 - 346
[22] Tetrahedron Letters, 2003, vol. 44, # 3, p. 535 - 538
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[24] Patent: US5294734, 1994, A,
[25] Patent: WO2015/179955, 2015, A1, . Location in patent: Paragraph 00125
[26] Synthesis (Germany), 2017, vol. 49, # 12, p. 2761 - 2767
21
[ 13139-17-8 ]
[ 4048-33-3 ]
[ 17996-12-2 ]
Yield
Reaction Conditions
Operation in experiment
83%
With triethylamine In dichloromethane at 20℃; for 1 h; Inert atmosphere
00568] Compound 1001 - Starting compound 1000 (10 g, 85.38 mmol) was added to the reaction flask, evacuated and purged with argon. The starting material was dissolved in dichloromethane and triethylamine (23.79 rriL, 170.7 mmol) was added via syringe. N- (Benzyloxycarbonyloxy)succinimide (31.9 g, 128 mmol) was dissolved in anhydrous dichloromethane and then added to the reaction mixture via syringe. The reaction was stirred at room temperature for 1 hour. The reaction was checked by TLC (50percent EtOAc/hexanes) and the reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane, added to separation funnel and organic layer was washed with 10percent citric acid solution. The organic layer was separated and washed with a brine solution. The organic layer was separated and dried with sodium sulfate. The solid was filtered off and the mother liquor was concentrated. The residue was purified by flash chromatography on silica gel (10percent to 100percent EtOAc/hexanes) and the product fractions combined and concentrated on reduced pressure to yield 17.9g, (83percent) of 1001. NMR (400 MHz, DMSO-de): δ 7.40 - 7.25 (m, 4H), 7.21 (t, J = 5.7 Hz, 1H), 4.99 (s, 2H), 4.31 (t, J = 5.1 Hz, 1H), 3.36 (m, 2H), 2.96 (q, J = 6.7 Hz, 2H), 1.38 (m, 4H), 1.32 - 1.17 (m, J = 5.2, 4.6 Hz, 4H).
Reference：
[1] Patent: WO2018/136620, 2018, A2, . Location in patent: Paragraph 00568
[2] Patent: US4550163, 1985, A,
22
[ 4048-33-3 ]
[ 1885-14-9 ]
[ 17996-12-2 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate In dichloromethane; water
Example 1 Preparation of N-Carbobenzyloxy-6-Aminohexan-1-ol, 4 6-Aminohexan-1-ol (11.7 g, 100 mmol) and potassium carbonate (16.58 g, 120 mmol) were dissolved in 100 mL water and 70 mL dichloromethane. Benzylchloroformate (14.27 mL, 100 mmol) was added dropwise over 30 minutes at a temperature of 25°-30° C. The resulting mixture stood overnight, then the dichloromethane layer was separated, washed with water (3*200 mL), 2N HCl (3*50 mL) and finally with water (3*100 mL), dried, and evaporated to give a white solid. The solid was recrystallized in hexane-ethylacetate (8:2) to give a solid, which was collected and dried under vacuum at room temperature. Yield: 23 g (91percent).
Reference：
[1] Patent: US5891862, 1999, A,
23
[ 60-29-7 ]
[ 4048-33-3 ]
[ 501-53-1 ]
[ 17996-12-2 ]
Reference：
[1] Patent: EP797579, 2000, B1,
24
[ 4048-33-3 ]
[ 137160-76-0 ]
[ 17996-12-2 ]
Reference：
[1] Synthesis, 1991, # 9, p. 713 - 716
25
[ 4048-33-3 ]
[ 7677-24-9 ]
[ 501-53-1 ]
[ 17996-12-2 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1987, vol. 96, # 7, p. 555 - 556
Stage #1: caprolactam With sodium hydroxide In toluene at 80℃;
Stage #2: In toluene at 100℃; for 16h;
Stage #3: With ammonium chloride for 0.25h;
1-12 The method for synthesizing 6-amino-1-hexanol in this embodiment is achieved through the following steps:
S1: Add 75ml of toluene and 15g of caprolactam to the reaction vessel and stir,Dissolve caprolactam in toluene, add 5.3g of sodium hydroxide to the reaction vessel during the stirring process, and heat to 80°C. After the sodium hydroxide is completely dissolved,The heating was stopped and the reaction temperature was lowered to room temperature to obtain a preliminary reaction solution.S2: slowly drip 105 g of red aluminum solution into the preliminary reaction solution,The red aluminum solution contains 70% toluene solution, which is dripped within 1 hour. After the dripping is completed, the temperature is raised to 100°C and reacted at this temperature for 15 hoursSampling and analysis, after the raw materials are consumed completely, stop heating to obtain a two-step reaction solution.S3: Cool down the second-step reaction solution. When the temperature of the second-step reaction solution drops to 60°C,Add 70ml of saturated ammonium chloride solution dropwise to the second step reaction solution. After the addition is complete, continue to stir for 15 minutes.Add 8g diatomaceous earth to the reaction vessel and stir for 15 minutes, then filter, and wash the filtered cake with a small amount of tolueneThe filtered filtrate is distilled under reduced pressure at a temperature of 123-130,Collecting the fractions, 13.6 g of 6-amino-1-hexanol product with a purity of 98.3% is obtained, and the yield is 87.2%.
77%
With [RuCl2(Ph2PCH2CH2NH2)2]; potassium <i>tert</i>-butylate; hydrogen; zinc(II) trifluoroacetate In 1,4-dioxane at 100℃; for 18h; Inert atmosphere; Autoclave;
With ethanol; sodium
23 %Spectr.
With cis-[Ru(CH3CN)2(η3-C3H5)(CO1,5-cyclooctadiene)]BF4; hydrogen; potassium hexamethylsilazane; (2-aminoethyl)diphenylphosphane In tetrahydrofuran at 100℃; for 24h; Autoclave;
92 %Spectr.
With sodium 2-methyl-2-adamantoxide; dichlorobis(dicyclohexylphosphinomethylpyridine)-ruthenium (II); hydrogen; sodium hydride In toluene; mineral oil at 160℃; for 24h; Inert atmosphere; Autoclave;
Representative procedure for hydrogenation of amides with (RUPCY/base = 1/10):The reaction of N-benzylbenzamide (3a) (conditions A Table 1,entry 1): no preactivation of catalyst.
General procedure: Under a continuous Ar flow, 2-methyl-2-adamantanol (16.6 mg, 0.1 mmol), NaH (60% oil dispersion, 4.0 mg, 0.1 mmol), anhydrous toluene (1.5 mL) and a magnetic stirring bar were placed in a dried Teflon tube (21 mL capacity). The Teflon tube was stoppered with a rubber septum, and the mixture was stirred at room temperature for 2 h under Ar. After removing the septum, under a continuous Ar flow, to the mixture was added RUPCY (7.50 mg, 0.01 mmol) and N-benzylbenzamide (105.6 mg, 0.5 mmol). The Teflon tube was quickly inserted into an autoclave and the inside of the autoclave was purged several times with hydrogen gas (>5 MPa). The autoclave was pressurized with an 8 MPa of hydrogen gas at 25°C, and heated at 160°C for 24 h under stirring (800 rpm). The autoclave was cooled to room temperature in an ice-water (0°C) bath,and the reaction mixture was quenched with NH4Cl (5.3 mg, 0.1 mmol). The organic phase was removed in vacuo (ca. 100 mmHg, 40 °C). The residue was diluted with CDCl3, and analyzed by 1H NMR. The yields of benzyl alcohol (92%) and benzylamine (92%) were calculated based on the integral ratio among the signals of these compounds with respect to an internal standard (1,1,2,2-tetrachloroethane). Afterward, the reaction mixture was purified by column chromatography on silica gel (silica gel (ca. 100 g) was pretreated with Et3N (small amount)-Et2O/hexane (vol%: 2/3), eluent; Et2O/hexane = 2/3, then EtOAc/Et3N = 100/1) to give N-benzylbenzamide (7.7 mg, 0.036 mmol, 7%), benzyl alcohol (47.4 mg, 0.438 mmol, 88%) and benzylamine (44.1 mg, 0.4187 mmol, 82%).
90 %Spectr.
With sodium 2-methyl-2-adamantoxide; C24H38Cl2N2P2Ru; hydrogen In toluene at 130 - 160℃; for 44h; Autoclave; Sealed tube;
A6
1) Preactivation of Catalyst In an argon gas atmosphere, a stirrer, a ruthenium complex (Compound 2b; RUPIP2) (0.0067 mmol, 3.98 mg) and sodium-2-methyl-2-adamantoxide (0.067 mmol, 12.6 mg) were placed in a dried fluororesin tube (30 mL). Thereafter, the tube containing this compound was rapidly inserted into an autoclave, and toluene (2.0 mL) was added in an argon atmosphere. Subsequently, the autoclave was hermetically sealed while being grounded, and hydrogen gas was introduced into the autoclave from a hydrogen compressed gas cylinder connected via a stainless-steel pipe, thereby substituting the inside of the autoclave with hydrogen gas. More specifically, 1-MPa hydrogen gas pressure was applied inside the autoclave, and then the hydrogen gas pressure was removed through a leak valve. This operation (substitution and desubstitution) was repeated 10 times. Finally, the hydrogen gas inside the autoclave was set to 1 MPa, and a reaction was performed for 5 hours using a constant-temperature bath at 160° C. (2) Hydrogenation Reaction of Substrate (0285) After the reaction was completed, the autoclave was cooled to substantially room temperature by being immersed in an icy bath. Then, the leak valve of the autoclave was opened and the hydrogen gas inside the autoclave was released into the air. Subsequently, in an argon gas atmosphere, the reaction solution (1.5 mL) was obtained from the autoclave using a gas-tight syringe, and placed in another autoclave (a stirrer, and N-benzylbenzamide (0.5 mmol, 105.63 mg) were placed in a dried fluororesin tube (30 mL) in an argon gas atmosphere; thereafter, the tube containing this compound was rapidly inserted into an autoclave, and the inside of the autoclave was substituted with argon). Subsequently, the autoclave was hermetically sealed while being grounded, and hydrogen gas was introduced into the autoclave from a hydrogen compressed gas cylinder connected via a stainless-steel pipe, thereby substituting the inside of the autoclave with hydrogen gas. More specifically, 1-MPa hydrogen gas pressure was applied inside the autoclave, and then the hydrogen gas pressure was removed through a leak valve. This operation (substitution and desubstitution) was repeated 10 times. Finally, the hydrogen gas inside the autoclave was set to 1 MPa, and a reaction was performed for 24 hours using a constant-temperature bath at 110° C. For 1H NMR analysis, an internal standard substance (mesitylene) was added to the solution. Based on the hydrogen atom amount of the internal standard substance, the yield of the reaction product was calculated. The results of the analysis showed that the yields of benzyl alcohol and benzylamine were both 86% (corresponding to Entry 8 in Table 2 described later). A hydrogenation reaction was performed in the same manner as in Reaction Example A5, except that the conditions specified in Table 2 were used. Tables 2 and 3 show the results.
98 %Chromat.
With [fac-8-(2-diphenylphosphinoethyl)aminotrihydroquinoline]RuH(η1-BH4)(CO); hydrogen In isopropyl alcohol at 120℃; for 36h; Autoclave;
95 %Spectr.
With potassium phosphate; C30H34BNOPRu; hydrogen In tetrahydrofuran at 150℃; for 24h; Glovebox; Autoclave;
Molecule 3 was prepared according to the reported method.S2 2.34 g 6-Amino-1-hexanol (20 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0 C in an ice bath. 4.80 g Boc2O (1.1 eq., 22 mmol) was added and the reaction mixture was stirred overnight at room temperature. Solvent was removed by rotary evaporation and crude product was extracted with EtOAc from 10 % aqueous citric acid, saturated NaHCO3, and brine. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation to yield compound 3 quantitatively. 1H NMR (400 MHz, CDCl3) delta 4.55 (s, 1H), 3.63 (t, J = 6.5 Hz, 2H), 3.11 (q, J = 6.6 Hz, 2H), 1.68-1.20 (m, 18H).
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 18h;
Step-1: Synthesis of compound 3
To a solution of 6-aminohexanol (1) (1 eq.) in DCM (500 mL) was added DMAP (0.1 eq.) at ambient temperature and reaction mixture was cooled to 0 °C. Triethyl amine (1.5 eq.) and tert-butyldimethylsilyl chloride (1.2 eq) were added sequentially. Reaction mixture was allowed to come to ambient temperature and stirred at same temperature for 18 h. TLC (10 % methanol in DCM, stain visualization-ninhydrin) showed that starting material was consumed. After completion, reaction mixture was concentrated under vacuum and suspension was filtered off. Filterate was concentrated under reduced pressure to afford 6-((tert-butyldimethylsilyl)oxy)hexan-1-amine (3). Yield: 99.3 %; colourless oil which was used as such for further reactions LC-MS (ESI) m/z calculated for C16H30N30SiCl (M + H)+: 231.20. 1HNMR (400 MHz, chloroform-d1): δ 5.80-5.60 (s, b, 2H), 3.60 (s, 2H), 2.83-2.88 (m, 2H), 1.66 (m, 2H), 1.28-1.54 (m, 6H), 0.83 (br, s, 9H), 0.00 (s, 6 H); 13C NMR (101 MHz, DMSO-d6): δ 63.0, 41.5, 32.7, 32.5, 25.9, 25.9, 25.5, 18.2, 18.2, 18.2, 5.4, 5.4; Anal. calcd. (%) for C12H29NOSi: C, 62.27; H, 12.63; N, 6.05; found (%): C, 62.39; H, 12.56; N, 6.07.
95%
With dmap In dichloromethane at 20℃; for 15h;
Et3N (45.0 mL, 323 mmol) and TBSCI (38.8 g, 257 mmol) were added sequentially to a stirred solution of 6-aminohexanol 101 (25.0 g, 213 mmol) and DMAP (3.00 g, 24.6 mmol) in CH2CI2 (375 mL) at rt. The reaction was stirred for 15 h at rt whereupon it was judged complete by TLC (CH2Cl2/MeOH, 9:1 , stained ninhydrin dip). The mixture was concentrated under vacuum, dissolved in Et20 (250 mL) and washed with sat. aq. NaHC03 (3 x 200 mL) and brine (200 mL). The isolated organic layer was dried over Na2S04, filtered and concentrated to a crude yellow oil. Purification of the crude material was achieved by flash chromatography on silica gel (eluting CH2CI2 to CH2Cl2/MeOH, 9: 1 ) to afford the desired silyl ether 102 (47 g, 95%) as a colourless oil; 1H NMR (CDCI3, 400 MHz) δ 3.46 (2H, t, J = 6.5 Hz, CH2-C1 ), 3.24 (2H, bs, NH2), 2.55 (2H, m, CH2-C6), 1 .36 (4H, m, CH2-C5 and CH2-C6), 1 .20 (4H, m, CH2-C4 and CH2-C3), 0.74 (9H, s, CHs-'BuSi), 0.00 (6H, s, CH3-MeSi); 13C NMR (CDCI3, 100 MHz) δ 63.0 (CH2-C1 ), 41 .5 (CH2-C6), 32.7 (CH2-C2), 32.5 (CH2-C5), 25.9 (CH2-C3 and CH2-C4), 25.54 (CHs-'BuSi), 18.25 C-'BuSi), 5.4 (CHs-MeSi).
86%
In pyridine
11.2 g
With 1H-imidazole In N,N-dimethyl-formamide Ambient temperature;
With sodium carbonate; In 1,4-dioxane; at 0 - 25℃; for 12h;
1) Dissolve 5.3 g of fluorenyl methoxycarbonyl chloride in 40 mL of 1,4-dioxane, Add 2g of 6-amino-1-hexanol at 0C, Fully dissolve, then slowly add 20mL of 10% Na2CO3 solution, Reaction at 25 for 12h, The product was extracted with methanol-dichloromethane (methanol, dichloromethane volume ratio 1:19), Combine the organic phases, spin dry the solvent on a rotary evaporator, Use a mixed solvent (consisting of dichloromethane, ethyl acetate and petroleum ether in a volume ratio of 1:3:6) Obtained (yield: 98%);
97%
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 1h;
Fmoc-6-aminohexanol (3). 6-Amino-hexan-1-ol (1.5 g, 12 mmol) was added to a vigorously stirred solution of Na2CO3 in H2O at 0 C. Dioxane (30 mL) was added, providing an opaque mixture. A solution of FmocCl, in dioxane (36 mL) was added dropwise at 0 C. The mixture was then allowed to warm to room temperature and was stirred for 1 hour. AcOEt (300 mL) was added, followed by HCl 0.1M (200 mL). The organic layer was washed with H2O (200 mL) and brine (50 mL), then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH, 97:3 to 90:10) to afford 3 as a white solid (3.95 g, 97%).
Stage #1: 6-amino-1-hexanol; N-(Benzyloxycarbonyl)glycine With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; Molecular sieve;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 0 - 20℃;
3 Synthesis of Z-G-ah Benzyl(6-hydroxyhexylcarbamoyl)methylcarbamate
Put 6-aminohexanol (ah) (1.5 g, 12.82 mmole), Z-glycine (2.2 g, 10.68 mmole), and 4 molecular sieve into a 100 ml round-bottom flask and run a pump to create vacuum for 2 hours. Then dissolve in 25 ml anhydrous DMF and stir at room temperature for 5 minutes (min). Next add anhydrous N-Hydroxybenzotrizole (HOBt) (1.72 g, 12.82 mmole), and N,N-Diisopropylethylamine (DIEA) (2.23 mL, 12.82 mmole) into the solution in turn and the solution temperature is decreased into 0□. After being added with 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2.45 g, 12.82 mmole), the solution is stirred at room temperature overnight. The suspension is filtered and diluted with dichloromethane solution. Then use 1N HCl, saturated sodium bicarbonate (NaHCO3), water and Brine (50 mL) in turn for extraction. After being washed, the dichloromethane solution is dried by anhydrous sodium sulfate and then filter and dry in vacuum to get white solid product Z-G-ah (2.29 g, 7.5 mmole). The yield rate is 70%. [0054] Compound Data of the Product (Including FT-IR Data, NMR Data, and ESI-MS Data): [0055] IR (KBr) 3386 and 3265 (NH), 2918 (CH2), 1690 and 1650 (CO) cm-1. [0056] 1H-NMR (CD3OD, 300 MHz): 7.40 (m, 5H), 5.10 (s, 2H), 3.73 (d, 2H), 3.53 (t, 2H), 3.18 (t, 2H), 1.50 (m, 4H), 1.36 (m, 4H). [0057] 13C-NMR (CD3OD, 75 MHz): 170.92, 157.85, 136.93, 128.30, 127.88, 127.76, 66.67, 61.69, 43.76, 39.15, 32.36, 29.22, 26.54, 25.43. [0058] ESI-MS: m/z 331.20 (M+Na)+.
45%
Stage #1: N-(Benzyloxycarbonyl)glycine With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃;
Stage #2: 6-amino-1-hexanol In tetrahydrofuran at 20℃;
{synthesis of Z-G-ah, (Benzyl(6-hydroxyhexylcarbamoyl) methylcarbamate)}
Scale 4 g 4A molecular sieve, Cbz-Glycine (Z-Gly-OH, 2.09 g, 10 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 3.09 g, 15 mmole), and N-hydroxysuccinimde (NHS, 1.38 g, 12 mmole) and put them into a 100 ml round-bottom flask and pump to create vacuum for 2 hours. Add 30 ml anhydrous THF into the solution, stir the solution at room temperature overnight. Then suction filter by using a ceramic funnel and take the filtrate, add with 6-aminohexanol (ah, 1.17 g, 10 mmol), and stir the solution at room temperature overnight. Concentrate the solution under reduced pressure and pump to create vacuum overnight. With an ice bath, stir the solution with 300 ml 50% ethyl alcohol for 30 min. Then suction filter by using a ceramic funnel, take the filtrate, add methanol, and concentrate in vacuo and dry at 35□. Set the solution in a vacuum system and pump overnight. Then stir the solution with 150 ml EtOAc for 30 min with an ice bath. Next suction filter by using a ceramic funnel, take the solid. At last, set the solid in a vacuum system and pump overnight to get white solid Z-G-ah (1.4 g, 45%). Compound Data of the Product [0046] IR(neat) vN-H=3386 cm-1, 3265 cm-1, vC═O=1690 cm-1, 1650 cm-1. [0047] 1H-NMR(CDCl3) δ 7.38 (m, 5H, Ph-H), 6.18 (br, 1H, C6-NH), 5.57 (br, 1H, C8-NH), 5.12 (s, 2H, C10-H2), 3.83 (d, 2H, C8-H2), 3.63 (t, 2H, C1-H2), 3.24 (t, 2H, C6-H2), 1.83 (br, 1H, OH), 1.55 (m, 4 H, C2-H2 & C5-H2), and 1.35 (m, 4 H, C3-H2 & C4-H2). [0048] 13C-NMR(CDCl3) δ 169(C7), 158(C9), 137(C10), 128(C12, C13, C14, C15 & C16), 67(C10), 62(C1), 44(C8), 39(C6), 32(C2), 29(C5), 27(C4), and 25(C3). [0049] MS: m/z 331 [(M+Na)]+°
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In chloroform Ambient temperature;
Stage #1: 6-aminohexan-1-ol With potassium hydroxide In dimethyl sulfoxide at 30℃; for 0.5h;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide at 60℃; for 4h;
95%
Stage #1: 6-aminohexan-1-ol With potassium hydroxide In dimethyl sulfoxide at 30℃; for 0.5h;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide at 60℃; for 4h;
2.3.1. Synthesis of amine functional terpyridine compound, NH 2 -Tpy
6-Aminohexyl 4’-(2,2’:6’,2’’-terpyridinyl) ether (NH2 -Tpy) was prepared according to procedures in the literature [19,20]. Briefly, to a stirred suspension of powdered KOH in dry DMSO at 30 °C, 6-amino-hexan-1-ol was added. After 30 min, 4’-chloro-2,2’:6’,2’’-terpyridine (Tpy-Cl) was added, and then the mixture was stirred for 4 h at 60 °C and precipitated dropwise into 1.5 L of ice-cooled, distilled water. After 2 h of stirring, the precipitate was collected, washed with distilled water, and dried in a vacuum overnight. The pure product was obtained in a 95% yield. The characterization results obtained were fully consistent with a previous study [20]. Tpy-NH2 : 1 H NMR (ppm) (CDCl3 , 400 MHz): δH 8.69 (2H, d, Tpy6-6’’), 8.60 (2H, d, Tpy3,3’’), 8.00 (2H, s, Tpy3’,5’), 7.84 (2H, t, Tpy4,4’’), 7.36 (2H, t, Tpy5,5’’), 4.20 (2H,-CH2 O-), 2.60 (2H, NH2 CH2 -), 1.85 (2H, -CH2 CH2 O-), and 1.50 (6H, -CH2 CH2 CH2 -).
87%
Stage #1: 6-aminohexan-1-ol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In N,N-dimethyl-formamide at 80℃; Further stages.;
83.3%
With potassium hydroxide In dimethyl sulfoxide at 60℃; for 48h;
83.3%
With potassium hydroxide In dimethyl sulfoxide at 60℃; for 48h;
Synthesis of 6-(2,2':6',2"-Terpyridine-4'-yloxy)-hexylamine
Synthesis of 6-(2,2':6',2"-Terpyridine-4'-yloxy)-hexylamine To a suspension of KOH (2.70 g, 48 mmol) in anhydrous DMSO (50 mL) was added 6-Amino-1-hexanol (1.17 g, 10 mmol). The suspension was warmed up to 60° C. and stirred for additional 30 min, followed by addition of 4'-chloro-2,2':6',2"-terpyridine (2.68 g, 10 mmol). The reaction mixture was kept stirring for 2 d at the same temperature. The solution was then allowed to cool down to R.T., poured into deionized water (500 mL), stirred and allowed to precipitate overnight. The product was filtered off and dried up under high vacuum to give 2 as a pale yellow solid (2.90 g, 83.3%). 1H NMR (400 MHz, CDCl3): δ 1.47-1.86 (m, 8H), 2.74 (t, J=6.5 Hz, 2H, NCH2), 4.22 (t, J=6.5 Hz, 2H, OCH2), 7.34 (dd, J=2.0 Hz, 5.0 Hz, 2H, H5,5"(terpy)), 7.84 (td, J=2.0 Hz, 7.5 Hz, 2H, H4,4"(terpy)), 8.03 (s, 2H, H3',5'(terpy), 8.67 (d, J=8.5 Hz, 2H, H3,3"terpy)), 8.70 (d, J=5.0 Hz, 2H, H6,6"(terpy)). GC-MS: m/z 348 (100%) (M+).
83%
Stage #1: 6-aminohexan-1-ol With potassium hydroxide In dimethyl sulfoxide for 0.5h;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide for 24h;
74%
Stage #1: 6-aminohexan-1-ol With potassium hydroxide In dimethyl sulfoxide at 79.84℃; for 0.5h; Inert atmosphere;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide at 79.84℃; for 24h; Inert atmosphere;
73.9%
Stage #1: 6-aminohexan-1-ol With potassium hydroxide In dimethyl sulfoxide at 84.84℃; for 0.5h; Schlenk technique;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide for 24h; Schlenk technique; Heating;
Stage #1: 6-aminohexan-1-ol With potassium hydroxide In dimethyl sulfoxide at 60℃; for 1h;
Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide at 60℃; for 36h;
With potassium hydroxide In dimethyl sulfoxide at 70℃;
With sodium hydrogencarbonate In methanol; water at 20℃;
55%
Stage #1: NBD chloride With potassium carbonate In ethanol; water at 20℃; for 0.166667h;
Stage #2: 6-amino-1-hexanol In ethanol; water at 25℃; for 24h;
51%
With pyridine In ethanol; water at 20℃; for 6h;
Synthesis of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexan-1-ol (40)
Pyridine (0.54 mL, 6.8 mmol) and 6-aminohexan-1-ol (588.3 mg, 5.0 mmol) were added to a solution of 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (575 mg, 2.89 mmol) in 42 mL of a mixture EtOH:H2O (0.3:1). The reaction mixture was stirred at room temperature for 6 h, and then the aqueous phase was extracted with CHCl3 (5 20 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure to provide a crude solid that was finally purified by column chromatography on SiO2 gel eluting with a mixture CHCl3/MeOH (100:1). 1H NMR (DMSO) δ 1.35-1.70 (m, 8H,NCH2CH2CH2CH2CH2CH2O), 3.38-3.40 (t, 2H, NCH2CH2), 3.46 (m,2H, CH2CH2OH), 4.33-4.35 (t, 1H, CH2OH), 6.41 (d, 1H, CH benzoxadiazole ring), 8.51 (d, 1H, CH benzoxadiazole ring), 9.55 (s, 1H,NH). MS-ESI, m/z: 281 [M + H]+.
With sodium hydrogencarbonate In water at 0 - 25℃;
75%
With sodium hydrogencarbonate at 0 - 25℃;
55%
With sodium hydrogencarbonate In water at 0 - 20℃; for 0.833333h; Inert atmosphere;
52%
With sodium hydrogencarbonate In water at 0℃; for 2h;
With sodium hydrogencarbonate In water at 0℃; Inert atmosphere;
With sodium hydrogencarbonate In water at 0℃; for 1.5h;
34.1
Step 1 : To a 100 mL round bottom flask was added 6-amino-1 -hexanol (1 .00g, 6.44 mmol) in saturated NaHC03aqueous solution (12.0 mL). The mixture was cooled at 0°C, and N- methoxycarbonylmaleimide (0.750 g, 6.44 mmol) was added. The reaction mixture was stirred at 0°C for 1 .5 hours. Then the reaction mixture was acidified at 0°C with 2 M HCI to pH1 . The acidified reaction mixture was extracted with ethyl acetate (AcOEt). The organic layer was concentrated. The residue was dissolved in DCM, loaded onto a silica gel column, and eluted with MeOH/DCM (0-4%) to obtain 1 -(6-hydroxyhexyl)-1 H-pyrrole- 2,5-dione as white solid, MS m/z 198.2 (M+1 ).1H NMR (400 MHz, CDCI3): δ 6.68 (s, 2H), 3.63 (t, d = 6.4 Hz, 2H), 3.52 (t, d = 7.2 Hz, 2H), 1 .63-1 .52 (m, 4H), 1 .43-1 .28 (m, 4H).
With sodium hydrogencarbonate In water at 0℃; for 1.5h;
3-34.1
Step 1: To a 100 mL round bottom flask was added 6-amino-1-hexanol (1.OOg, 6.44mmol) in saturated NaHCO3 aqueous solution (12.0 mL). The mixture was cooled at 0°C, and Nmethoxycarbonylmaleimide (0.750 g, 6.44 mmol) was added. The reaction mixture was stirred at 0°C for1.5 hours. Then the reaction mixture was acidified at 0°C with 2 M HC1 to pHi. The acidified reaction mixture was extracted with ethyl acetate (AcOEt). The organic layer was concentrated. The residue was dissolved in DCM, loaded onto a silica gel column, and eluted with MeOH/DCM (0-4%) to obtain 1-(6- hydroxyhexyl)-1H-pyrrole-2,5-dione as white solid, MS m/z 198.2 (M+1). ‘H NMR (400 MHz, CDC13): ö 6.68 (s, 2H), 3.63 (t, d = 6.4 Hz, 2H), 3.52 (t, d = 7.2 Hz, 2H), 1.63-1.52 (m, 4H), 1.43-1.28 (m, 4H).
1.2.1 1.2.1 N-(6-Hydroxyhexyl)-3-nitroanilin
19,7 g 3-Fluornitrobenzol und 88,3 g 6-Amino-1-hexanol wurden in 300 ml Dimethylsulfoxid gelöst, und der Ansatz wurde 60 h bei 100 °C gerührt. Nach dem Abkühlen wurde der Ansatz in 1 I Wasser gegeben. Das Gemisch wurde mehrfach mit Methyl-tert.-butylether extrahiert und am Rotavapor bis zur Trockne eingeengt, wobei das Produkt als dunkelbraunes Öl erhalten wurde. Ausbeute 29,0 g (87 %)
In ethanol (35 ML), <strong>[28593-24-0]6-chloro[1,2,4]triazolo[4,3-b]pyridazine</strong> (3.55 g) was suspended; 6-aminohexanol (6.73 g) was added, followed by refluxing under heating for 16 hours.. After cooling, the reaction mixture was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1).. The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was washed with diethyl ether and dried to yield the title compound (5.67 g).1H-NMR (CDCl3) delta ppm: 1.38-1.80 (8H, m), 3.11 (1H, q, J = 6.4 Hz), 3.37 (2H, q, J = 6.4 Hz), 3.67 (2H, t, J = 6.1 Hz), 5.12 (1H, brs), 6.61 (1H, d, J = 9.8 Hz), 7.78 (1H, d, J = 10.0 Hz), 8.74 (1H, s). Process B: Production of 6-[6-(methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine 6-(6-Hydroxyhexylamino)[1,2,4]triazolo[4,3-b]pyridazine (3.26 g) was suspended in tetrahydrofuran (60 ML); N-ethyldiisopropylamine (3.59 g) and methanesulfonyl chloride (3.17 g) were added, followed by stirring at room temperature for 4 hours.. brine was added; the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and dried over magnesium sulfate.. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1).. The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was washed with diethyl ether, and dried, to yield the title compound (3.24 g). Melting point: 103-105C Process C: 6-[6-(Methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine (0.810 g) was dissolved in N,N-dimethylformamide (15 ML); 4-(diphenylmethoxy)piperidine (0.829 g), potassium carbonate (0.428 g), and potassium iodide (0.515 g) were added, followed by stirring at 60C.. for 4 hours.. After cooling, brine was added; the reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate.. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1).. The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethanol-ethyl acetate (1:5), washed with diethyl ether, recrystallized in the same manner, and dried to yield the title compound (599 mg).. Melting point: 124-127C..
1.1
N-(3-Morpholinopropyl) isothiocyanate (1.68 g, 10 mmol) was dissolved in 15 ml of dry methylene chloride, and cooled on a water bath. To the solution, 6-aminohexanol (1.17 g, 10 mmol) was added, and the mixture was stirred overnight at room temperature. After addition of water to the reaction mixture, the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated to obtain Compound (I-I-A) (2.7 g, yield: 95%). The NMR spectrum data are shown below. [00154] 1H-NMR (CDCl3): δ=1.35-1.85 (m, 12H), δ=2.40-2.60 (m, 6H), δ=3.45 (br, 2H), δ=3.65 (t, 2H), δ=3.75 (t, 4H).
With bromine; triethylamine; In sodium hydroxide; dichloromethane; water;
a) N-t-BOC-6-amino-1-bromohexane was first prepared by adding di-tert-butyldicarbonate (3.675 g, 16.4 mmol) to a solution of 6-aminohexan-1-ol (1.6 g, 13.66 mmol) in 10% aqueous sodium hydroxide solution (40 ml). After stirring for 4 hours, the mixture was treated with water (150 ml) and extracted with ethyl acetate (4*50 ml). The combined extracts were washed with water (2*50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a flash chromatography on silica gel eluding with 20% methanol/dichloromethane to provide N-t-BOC-6-amino-hexan-1-ol (2.4 g). A solution of bromine (1.60 g, 10 mmol) in dichloromethane (10 ml) was added to a solution of triphenyl phosphine (2.62 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (10 ml) at 0 C. After stirring at 0 C. for 30 minutes, a solution of N-t-BOC-6-amino-hexan-1-ol (2.4 g) in dichloromethane (10 ml) was added dropwise. After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluding with 20%ethyl acetate/hexane to provide N-t-BOC-6-amino-1-bromohexane (2.5 g).
With bromine; triethylamine; In aqueous sodium hydroxide; dichloromethane; water;
a) N-t-BOC-6-amino-1-bromohexane was first prepared by adding di-tert-butyldicarbonate (3.675 g, 16.4 mmol) to a solution of 6-aminohexan-1-ol (1.6 g, 13.66 mmol) in 10% aqueous sodium hydroxide solution (40 ml). After stirring for 4 hours, the mixture was treated with water (150 ml) and extracted with ethyl acetate (4*50 ml). The combined extracts were washed with water (2*50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a flash chromatography on silica gel eluding with 20% methanol/dichloromethane to provide N-t-BOC-6-amino-hexan-1-ol (2.4 g). A solution of bromine (1.60 g, 10 mmol) in dichloromethane (10 ml) was added to a solution of triphenyl phosphine (2.62 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (10 ml) at 0 C. After stirring at 0 C. for 30 minutes, a solution of N-t-BOC-6-amino-hexan-1-ol (2.4 g) in dichloromethane (10 ml) was added dropwise. After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluding with 20% ethyl acetate/hexane to provide N-t-BOC-6-amino-1-bromohexane (2.5 g).
5 EXAMPLE 5
EXAMPLE 5 One mole equivalent of maleic anhydride and one mole equivalent of 6-amino hexanol are dissolved in anhydrous acetic acid and the solution is heated under reflux for eight hours. The acetic acid is distilled off in a rotary evaporator. The residue is dissolved in diethyl ether and washed once with 1 N NaOH, and twice with water. After drying over MgSO4 and evaporating the diethyl ether, the residue is crystallized from isopropyl ether to produce N-(6-hydroxyhexyl) maleimide.
N-(6-Hydroxyhexyl)carbamic acid (1-benzyl-4-piperidinyl)-ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine; 1,1'-carbonyldiimidazole; In tetrahydrofuran;
EXAMPLE 1 N-(6-Hydroxyhexyl)carbamic acid (1-benzyl-4-piperidinyl) ester (8; R=benzyl) A stirred suspension of N,N'-carbonyldiimidazole (3.24 g, 20 mmol) in The (40 mL) was warmed up to 50 C., and a solution of <strong>[4727-72-4]1-benzyl-4-hydroxypiperidine</strong> (3.82 g, 20 mmol) in THF (17 mL) was added dropwise over 10 min. Stirring was continued for 2 hrs. at room temperature (RT), and a solution of 6-aminohexanol (3.50 g, 30 mmol) and triethylamine (3.04 g, 30 mmol) in THF (40 mL) was added dropwise over 10 min. When the reaction mixture turned cloudy, the rate of stirring was increased, and a clear solution was obtained within 20-30 min. The mixture was refluxed for 2 hrs., concentrated in vacuo, and the residue was partitioned between ether (70 mL) and water (35 mL). An alternative partitioning between ethyl acetate and water was equally effective. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give the title compound (6.68 g, yield 100%) as a light, yellowish oil. TLC (chloroform-5% methanol) showed a single spot at Rf 0.5; 1 H NMR (300 MHz, CDCl3) delta1.37 (m, 4H, CH2), 1.47-1.61 (m, 4H, CH2), 1.67 (m, 2H, CH2, piperidine ring axial protons), 1.88 (m, 2H, CH2, piperidine ring equatorial protons), 2.22 (t, J=9 Hz, 2H, CH--N--CH, piperidine ring axial protons), 2.69 (m, 2H, CH--N--CH, piperidine ring eq. protons), 3.16 (q, J=6.5 Hz, 2H, CH2 --NH), 3.49 (s, 2H, CH2 --Ph), 3.62 (t, J=6.5 Hz, 2H, CH2 --O), 4.66 (m, 1H, CH--O), 4.73 (t, J=6 Hz, 1H, NH), 7.23-733 (m, 5H, Ar--H).
A. 6-Phthalimido-1-bromohexane A solution of phthalic anhydride (32.0 g, 0.21 mol) and 6-aminohexanol (25.0 g, 0.21 mol) in 180 mL dry toluene was heated to reflux for 3 hrs. When the intermediate phthalimide was formed, PBr3 (18.2 mL, 0.58 mol in 20 mL toluene) was added dropwise and the reaction was stirred at 100 C. for 1.5 hrs. The reaction mixture was filtered thru a microfiber filter and the filtrate was concentrated in vacuo to give the crude product which then crystallized from toluene to give 6-phthalimido-1-bromohexane. (86% yield).
With phosphorus tribromide;
(a) N-(6-Bromohexyl)phthalimide A mixture of crystalline 6-aminohexanol (11.7 g., 0.1 mole) and phthalic anhydride (14.8 g., 0.1 mole) is heated at 170 for 1.5 hours in an argon atmosphere. The evolved water is then removed with heat and argon flow. The reaction mixture is cooled to 100 and phosphorus tribromide (7.2 ml., 0.086 mole) is added in portions via gas tight syringe to the reaction mixture. A vigorous reaction occurs with each addition. After addition is complete, the reaction mixture is heated at 100 for an additional 30 minutes. The cooled reaction mixture is diluted with ethanol (20 ml.) then poured over ice-water and refrigerated overnight. A yellow solid is filtered and washed several times with cold water until the filtrate is slightly acidic. The crude solid is recrystallized from ethanol to give 21.0 g. of N-(6-bromohexyl)phthalimide as a pale yellow solid; m.p. 54-55. Tlc (hexane-ethyl acetate; 1:1) shows a major spot at Rf =0.8.
With phosphorus tribromide;
(a) N-(6-Bromohexyl)phthalimide A mixture of crystalline 6-aminohexanol (11.7 g., 0.1 mole) and phthalic anhydride (14.8 g., 0.1 mole) is heated at 170 for 1.5 hours in an argon atmosphere. The evolved water is then removed with heat and argon flow. The reaction mixture is cooled to 100 and phosphorus tribromide (7.2 ml., 0.086 mole) is added in portions via gas tight syringe to the reaction mixture. A vigorous reaction occurs with each addition. After addition is complete, the reaction mixture is heated at 100 for an additional 30 minutes. The cooled reaction mixture is diluted with ethanol (20 ml.) then poured over ice-water and refrigerated overnight. A yellow solid is filtered and washed several times with cold water until the filtrate is nearly neutral. The crude solid is recrystallized from ethanol to give 21.0 g. of N-(6-bromohexyl)phthalimide as a pale yellow solid; m.p. 54-55. TLC (hexane-ethyl acetate; 1:1) shows a major spot at Rf =0.8.
With phosphorus tribromide;
(a) N-(6-Bromohexyl)phthalimide A mixture of crystalline 6-aminohexanol (11.7 g., 0.1 mole) and phthalic anhydride (14.8 g., 0.1 mole) is heated at 170 for 1.5 hours in an argon atmosphere. The evolved water is then removed with heat and argon flow. The reaction mixture is cooled to 100 and phosphorus tribromide (7.2 ml., 0.086 mole) is added in portions via gas tight syringe to the reaction mixture. A vigorous reaction occurs with each addition. After addition is complete, the reaction mixture is heated at 100 for an additional 30 minutes. The cooled reaction mixture is diluted with ethanol (20 ml.) then poured over ice-water and refrigerated overnight. A yellow solid is filtered and washed several times with cold water until the filtrate is slightly acidic. The crude solid is recrystallized from ethanol to give 21.0 g. of N-(6-bromohexyl)phthalimide as a pale yellow solid; m.p. 54-55. Tlc (hexane-ethyl acetate; 1:1) shows a major spot at Rf =0.8.
With phosphorus tribromide; In ethanol;
(a) N-(6-Bromohexyl)phthalimide A mixture of crystalline 6-aminohexanol (11.7 g., 0.1 mole) and phthalic anhydride (14.8 g., 0.1 mole) is heated at 170 C. for 1.5 hours in an argon atmosphere. The evolved water is then removed with heat and argon flow. The reaction mixture is cooled to 100 and phosphorus tribromide (7.2 ml., 0.086 mole) is added in portions via gas tight syringe to the reaction mixture. A vigorous reaction occurs with each addition. After addition is complete, the reaction mixture is heated at 100 C. for an additional 30 minutes. The cooled reaction mixture is diluted with ethanol (20 ml.) then poured over ice-water and refrigerated overnight. A yellow solid is filtered and washed several times with cold water until the filtrate is nearly neutral. The crude solid is recrytallized from ethanol to give 21.0 g. of N-(6-bromohexyl)phthalimide as a pale yellow solid; m.p. 54-55 C. TLC (hexane-ethyl acetate; 1:1) shows a major spot at Rf =0.8.
crude[2-(6-hydroxyhexyl)amino-2-oxoethoxy]-acetic acid[ No CAS ]
[ 4048-33-3 ]
[ 69078-60-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With pyridine; hydrogenchloride In dichloromethane; water
IX 4-(6-Piperidinohexyl)-3,5-dioxomorpholine.p-Toluenesulfonate STR18
EXAMPLE IX 4-(6-Piperidinohexyl)-3,5-dioxomorpholine.p-Toluenesulfonate STR18 [2-(6-Hydroxyhexyl)amino-2-oxoethoxy]acetic acid. To a solution of 58.5 grams (0.500 mole) of 6-aminohexanol in 3.5 liters of dichloromethane was added in the temperature range of from 20° to 28° C. during about 12 minutes, a warm solution of 58.0 grams (0.500 mole) of diglycolic anhydride in 5.0-5.2 liters of dichloromethane; the addition produced a cloudy mixture with oil depositing on the vessel wall. The mixture was stirred at 25°+-3° C. for about one hour; thereafter, the reaction mixture, which contained an insoluble white solid, was filtered to obtain 106.3 grams (91 percent yield) of an off-white solid having appropriate infrared and nuclear magnetic resonance spectra for the [2-(6-hydroxyhexyl)amino-2-oxoethoxy]acetic acid intermediate. 4-(6-Hydroxyhexyl)-3,5-dioxomorpholine. 96.3 grams (0.413 mole) of the crude[2-(6-hydroxyhexyl)amino-2-oxoethoxy]-acetic acid was heated to 220° C. to melt the solid; thereafter, the resulting liquid was heated at 220°+-10° C. (20+-5 torr.) for about 1.5 hours to remove the water and to cause cyclization to occur. The product as a result of these operations was a viscous oil which was distilled to obtain 74.4 grams (84 percent yield) of a purified 4-(6-hydroxyhexyl)-3,5-dioxomorpholine intermediate as a viscous yellow oil having the appropriate infrared and nuclear magnetic resonance spectra. 6-(3,5-Dioxomorpholino)hexyl p-toluenesulfonate. To 55.5 grams (0.258 mole) of 4-(6-hydroxyhexyl)-3,5-dioxomorpholine was added 82 milliliters of pyridine to obtain a yellow solution. The solution was cooled to 3° C. and to it was added with stirring during about 20 minutes at from 3° to 15° C., 49.2 grams (0.258 mole) of p-toluenesulfonyl (tosyl) chloride. After completion of the addition, stirring was continued at a temperature in the range of from 0° to 7° C. for about 1.5 hours to complete the formation of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate intermediate in the reaction mixture. Thereafter, the reaction mixture was poured into a mixture of 157 milliliters of concentrated hydrochloric acid and about 1 liter of ice. The resulting mixture then was extracted with 1500 milliliters of dichloromethane and the resulting dichloromethane solution washed successively with 500 milliliters portions of 1N aqueous hydrochloric acid, water and saturated aqueous sodium bicarbonate and finally with 250 milliliters of water. The washed solution was dried over magnesium sulfate and concentrated to recover the crude 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate intermediate as an amber oil in the amount of 83.7 grams (88 percent yield). The intermediate tosylate product had infrared and nuclear magnetic resonance spectral characteristics suitable for the tosylate intermediate.
1, 1'-carbonylbis-1H-imidazole (0.01 mol) was added portionwise to a mixture OF 4- CHLORO-2-NITROBENZOIC acid (0.01 mol) in DCM (40 ml) at RT and the mixture was stirred for 1 hour at RT, then 6-hydroxyhexylamine (0.01 mol) was added dropwise at RT and the reaction mixture was stirred for 1 hour at RT. The mixture was washed with water (40 ml) and with HC1 (1N, 40 ml). The organic layer was separated, dried, filtered off and the solvent was evaporated under reduced pressure, yielding 1.7 g (57 %) of intermediate 106.
Stage #1: 6-aminohexanoic acid With sodium tetrahydroborate at 40℃; for 0.333333h; Sonication;
Stage #2: In ethylene glycol at 90℃; for 16.5h; Reflux;
Stage #3: With water In ethylene glycol
6 Example 6
(1) By volume ratio, 1 part of 6-aminohexanoic acid was added to the reactor containing 15 parts of diethyl ether or dry toluene solution, At 40 deg.C constant temperature, At 1500rpm / min speed, rapidly inject 2 parts of a solution of sodium borohydride. At 250W, ultrasonic treatment 20min. Then add dropwise under reflux 8 parts of ethylene glycol solution. Dropwise addition time was 30min. Finally at 90 deg.C and at a rate of 800rpm/min, maintain temperature under stirring and react for 16 h to obtain the reaction crude product.(2) By the amount of parts count, step (1) preparation of 1 part of the reaction crude was added 6 parts water for hydrolysis. Undrego vacuum distillation, collecting 125 deg.C fraction, to obtain 6-amino-1-hexanol product .
With sodium tetrahydroborate; iodine In tetrahydrofuran
With (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene; palladium diacetate; sodium t-butanolate; In 1,2-dimethoxyethane; at 100℃; for 24h;Inert atmosphere;
General procedure: Pd(OAc)2 (0.86 mg, 0.0038 mmol) and CyPFtBu (4.26 mg, 0.0077 mmol) were dissolved in anhydrous DME (0.5 mL). The solution was stirred at room temperature under N2 for 10 min. To the solution were added substrate 5 (100 mg, 0.38 mmol), amine 3c (0.06 mL, 0.40 mmol), NaOtBu (93 mg, 0.95 mmol) and anhydrous DME (0.5 mL). The solution was stirred at 100 C for 4 h until substrate 5 was totally consumed as judged by TLC. The solution was cooled to the room temperature and evaporated under the vacuum. The crude product was purified by column chromatography to give pure 7c (124 mg, 95%).
Stage #1: 6-amino-1-hexanol; josamycin In diethyl ether; ethanol at 20℃; for 0.5h; Inert atmosphere;
Stage #2: With sodium tetrahydroborate In diethyl ether; ethanol for 120h; Inert atmosphere;
6-Aminohexanol (500 mg, 4.27 mmol) was slowly added to a stirring 48% hydrogen bromide solution (5.1 mL) at 0 C and the resulting mixture was stirred at 80 C for 20 h. The mixture was concentrated and crystallized from toluene/ethanol = 50/1 to give 6-bromohex-1-ylammonium bromide (674 mg, 2.6 mmol, 61%) as a white solid.Mp 130-133 C (toluene/ethanol = 50/1). 1H NMR (400 MHz, D2O): delta 1.37-1.48 (4H, m), 1.61-1.68 (2H, m), 1.82-1.87 (2H, m), 2.96 (2H, t, J = 8 Hz), 3.48 (2H, t, J = 7 Hz). 13C NMR (100 MHz, CD3OD): delta 26.6, 28.4, 28.6, 33.6, 34.2, 40.6. MS (FAB) m/z 180 (M-Br-). HRMS (FAB): Calcd for C6H15NBr (M-Br-): 180.0382. Found: 180.0395.
With hydrogen bromide; In water; for 20h;Reflux;
A solution of compound 25 (15,0 g, 128 mmol) in hydrobromic acid 48% aq. (350 mL) was refluxed for 20 h. The reaction mixture was cooled to rt and concentrated to afford compound 26 (33 g, crude) as a yellow solid and directly used for next step without purification: FontWeight="Bold" FontSize="10" H NMR (400 MHz, CD3OD) delta 3.46 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.8 Hz, 2H), 1.92-2.84 (m, 2H), 1 .72-1 .63 (m, 2H), 1.55-1.47 (m, 2H), 1 .46-1 .41 (m, 2H).
With hydrogen bromide; at 0 - 80℃; for 20h;
To a solution of 48% HBr (5.1 OmL) at 0 C was added 6-aminohexanol (0.5090 g, 4.27 mmol) slowly in portions. Once the 6-aminohexanol dissolved the reaction was warmed to room temperature, fitted with a reflux condenser, and heated to 80 C. The consumption of the starting alcohol was monitored by TLC (1 :1 EtOAc:MeOH) using a ninhydrin stain. The reaction was complete after 20 hoursand the solution was concentrated in vacuo yielding a tan solid. This was recrystallized from toluene/ethanol (50:1 ) to afford a white solid. Data: Rf 0.33 (1 : 1 EtOAc:MeOH) 1 HNMR (400 MHz, D20) delta 3.46-3.41 (2H, t, J = 7), 2.96 -2. 89 (2H, t, J = 8), 1 .84 -1 . 75 (2H, m), 1 .64 -1 .55 (2H, m), 1 .43-1 .30 (4H, m).
With ammonia In toluene at 155℃; for 12h; Inert atmosphere;
2
Ligand L, metal salt M, solvent and the stated alcohol were introduced as initial charge under an Ar atmosphere in a 160 ml Parr autoclave (hte, (stainless steel V4A)) with magnetically coupled slanted-blade stirrer (stirring speed: 200-500 revolutions/minute). The stated amount of ammonia was either precondensed at room temperature or directly metered in from the NH3 pressurized-gas bottle. If hydrogen was used, this was carried out by means of iterative differential pressure metering. The steel autoclave was heated electrically up to the stated temperature and heated (internal temperature measurement) for the stated time with stirring (500 revolutions/minute). After cooling to room temperature, decompressing the autoclave and outgassing the ammonia at atmospheric pressure, the reaction mixture was analyzed by means of GC (30 m RTX5 amine 0.32 mm 1.5 μm). Purification of the particular product can be carried out, for example, by distillation. The results for the amination of octanol (Table 1a and 1b), 1,4-butanediol (Table 2), diethylene glycol (Table 3), 1,9-nonanediol, 1,6-hexanediol, 1,10-decandiol (Table 4) and 1,2-dimethanolfuran (Table 5) are given below:
With (carbonyl)(chloro)(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 155℃; for 12h; Inert atmosphere; Autoclave;
Alcohol amination
General procedure: Ligand L, see below for the metal salt M or catalyst complex XIVb (manufacturing, inert atmosphere initial mass below), solvent and an alcohol of the reaction, under an argon atmosphere, a magnetic coupling type Parr autoclave of 160ml equipped with atilt wing stirrer (made of special steel V4A) (Stirring speed: were charged to the 200 to 500 rev / min) in. It described theamount of ammonia at room temperature, It is directly metered from the preliminarycondensed with or NH3 gas cylinder. Hydrogenis used Case, this was done by an iterative difference-pressure amount. Power to the temperature indicated the steel autoclave is NetsuNoboru temperature, for a period of time described, has been heated under stirring (500 rev / min) (internal temperature Measurement). The autoclave was cooled to room temperature, depressurized, row outgassing of ammonia at atmospheric pressure after becoming, the reaction mixture was analyzed by GC (30m RTX5 Amin 0.32mm,1.5μm). The amination of 1,4-butanediol result (the first 1a, 1b and the second table), diethylene glycol of the same result (the first 3a, 3b and Table 4), the resultof monoethylene glycol (Table 5), diethanolamine same result (table 6), 1,5-pentanediol, 1,9-nonanediol, 1,6-hexanediol and 1,10-decanediol same result of (table 7), as well as furan-2,5-dimethanol same result (table 8) are as described below.
With (carbonyl)(chloro)(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 155℃; for 12h; Autoclave; Inert atmosphere;
2 general procedure for the amination of alcohols with ammonia according
General procedure: The ligand L, the metal salt M, the solvent and the alcohol were introduced as an initial feed into a 160 ml Parr autoclave (hte) having a magnetically coupled tilt blade stirrer (stirring rate: 200 to 500 rpm) in an Ar atmosphere , (Stainless steel V4A)). The amount of ammonia is pre-concentrated at room temperature or directly from a cylinder pressurized with NH3. If hydrogen is used, this is done by adding a repeated differential pressure differential. The steel autoclave was electrically heated to the temperature and heated for the time (internal temperature measurement) with stirring (500 revolutions per minute). After cooling to room temperature, the autoclave was decompressed and ammonia was withdrawn at atmospheric pressure, and the reaction mixture (30 m RTX5 amine 0.32 mml. 5 [mu] [pi]) was analyzed by GC. Purification of a specific product can be carried out, for example, by distillation. Octyl alcohol (Table 1), 1,9-nonanediol, 1,6-hexanediol, 1,10_ The amination results of diols (Table 4) and 2,5-dimethanolfuran (Table 5) are given below.
With ammonia; hydrogen; calcium carbonate at 290℃; for 1.5h;
21
General procedure: A method for preparing 6-amino-1-hexanol with calcium carbonate as catalyst is carried out by using calcium carbonate as the reaction catalyst, and 1,6-hexanediol, ammonia and hydrogen are heated at a temperature of 270-290 ° C and a pressure of 150 -180Mpa under the conditions of mixed heating reaction 1.5 - 2 hours to produce 6 - amino - 1 - hexanol. Catalyst three:Ultra-fine calcite powder, purchased from Huayu Nano Powder Group,CaCO3 active ingredient content ≥ 8%Iron content ≤ 0.1%,Manganese content ≤ 0.008%.
Multi-step reaction with 2 steps
1.1: toluene / 0.5 h / 0 °C
1.2: 1 h
1.3: 2.5 h / 20 - 50 °C
2.1: hydrogenchloride / water / 3 h / Reflux
Multi-step reaction with 2 steps
1.1: toluene / 0.5 h / 10 °C
1.2: 1 h
1.3: 2.5 h / 20 - 85 °C
2.1: trifluoroacetic acid / 12 h / 20 °C
With triethylamine In dichloromethane at 0 - 20℃; for 12h;
f
(f) Synthesizing 6-amino-1-hexyl-2,3,4,6-tetra-O-acetyl-β-galactopyranoside1.0 g (8.53 mmole) of 6-aminohexanol is dissolved in a mixed solution of 17 mL of methylene chloride and 3.6 mL (26 mmol) of triethylamine. After 1 mL (8.53 mmol) of p-fluorobenzoyl chloride is slowly added at 0° C., ice-bath is ended to raise temperature to a room temperature for reaction for 12 hrs. After the reaction, cold water is added to stop the reaction and 20 mL of methylene chloride is used to extract an organic layer to be dried with MgSO4, filtrated and concentrated. Then, re-crystallization is processed in a mixed solution of dichloromethane/n-hexane for obtaining a product of 4-fluoro-N-(6-hydroxyhexyl)-benzamide with a weight of 1.83 g and a yield of 90%. The reactant is confirmed through NMR to be 4-fluoro-N-(6-hydroxyhexyl)-benzamide with a result as follows:1H NMR (CDCl3, 200 MHz): δ 7.78-7.71 (m, 2H, ph-H), 7.12-7.02 (m, 2H, ph-H), 6.23 (br, NH), 3.64-3.58 (m, 2H), 3.46-3.37 (m, 2H), 1.63-1.34 (m, 8H, CH2)
90%
With triethylamine In dichloromethane at 0 - 20℃;
2.1.3 Synthesis of 4-fluoro-N-(6-hydroxyhexyl)-benzamide (FHB, 3)
6-Aminohexanol (1.0 g, 8.5 mmol), dissolved in dichloromethane (17 mL) containing triethylamine (3.6 mL, 26.0 mmol) was added p-fluorobenzoyl chloride (1.0 mL, 8.5 mmol) dropwise at 0 °C. The mixture was stirred overnight at ambient temperature. The crude product was washed with cold pure water (30 mL × 2), dried and evaporated under vacuum. After recrystallized in a mixed solvent of dichloromethane and hexane, the desired compound was obtained as a white crystalline solid (1.8 g, 90% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.44 (br, 1H, NH), 7.89 (dd, J = 8.5 Hz, JHF = 6.0 Hz, 2H, Ar), 7.26 (dd, J = 8.5 Hz, JHF = 7.0 Hz, 2H, Ar), 3.38-3.35 (m, 2H, CH2O), 3.38-3.35 (m, 1H, OH), 3.21 (dt, J = 6.5, 6.5 Hz, 2H, NCH2), 1.51-1.48 (m, 2H, NCCH2), 1.41-1.38 (m, 2H, CH2CO), 1.30-1.21 (m, 4H, CH2); 13C NMR (125 MHz, DMSO-d6): 165.0 (C=O), 163.8 (d, JCF = 246.8 Hz, F-C), 131.2 (Ar), 29.7 (d, JCF = 9.1 Hz, Ar), 115.1 (d, JCF = 21.5 Hz, Ar), 60.6 (CH2OH), 39.1 (NHCH2), 32.4 (CH2CH2OH), 29.1 (NHCH2CH2), 26.4, 25.2 (CH2); HRESI-MS: calcd for C13H18FNNaO2+ 262.1214 (M+Na+), found 262.1205 (M+Na+).
Stage #1: 4,5-Dihydro-thiazol-2-ylamin With hydrogen bromide In water; acetonitrile for 0.0833333h;
Stage #2: 6-amino-1-hexanol In water; acetonitrile at 110℃; Further stages;
Representative experiment for the preparation of 1-(3-aminopropyl)-3-(2-mercaptoethyl)guanidine (8k)
General procedure: 2-Amino-2-thiazoline (2, 306 mg, 3.0 mmol) was dissolved in acetonitrile-water (5 mL, 3:2), and 40% hydrobromic acid (0.6 mL) was added. After the mixture was stirred for 5 min, compound 3k (12.0 mmol) was added. The solution was heated in a sealed vessel at 110 °C for 1-2 h. After cooling to 0 °C, water (5 mL) and carbon disulfide (0.5 mL) were added with stirring, and the mixture was kept at 0 °C for 12 h. The yellow solid formed was filtered, washed with ethanol and ether, and dried to give compounds 4k as a yellowish solid in 45% yield, which will be used directly in the next step. Compound 4k was dissolved in MeOH (5 mL), and 4 N HCl in MeOH (5 mL) was added. The solution was heated to 40-50 °C and stirred until all of the yellow solid was dissolved (2-3 h). Next, the reaction mixture was concentrated and the residue was purified by HPLC to give compound 8k as a yellowish oil (42%).
3
Samples of 50 mg N-methyl, N'-(6'-hydroxyhexyl)phthalic diamide were dissolved in 1 ml deprotection solution (as indicated in Figure 8) and incubated under the variable conditions b), c) and d). After different time intervals, 0.1 ml aliquots were withdrawn, diluted with 0.6 ml D20 and analyzed by ^-NMR. The spectra were compared with those from a) the starting material and e) 6-amino hexanol, respectively (see Figure 8). Almost quantitative deprotection within < 30 min occured at 20° under conditions c) and d), i.e. by 40% aq. MeNH2 and by 24% aq. NH3 / 40% MeNH2 1 :1 (AMA), respectively. In contrast, a two-phase process was observed at condition b) by 24% aq. NH3 at 55°: after 30 min 65% were deprotected and after 3 h 70%, respectively. Under these conditions, the direct elimination of the linker amine from the methyl substituted starting material (according to the upper processes in Fig. 5) seems to be fast, whereas the elimination of the linker amine from the NH2-derivative (obtained with ammonia according to the lower processes in Fig. 5) seems to be slow. Figure 8 gives an overview over the results of the deprotection reaction under the tested conditions by -NMR spectroscopy (300 MHz) in D20. Shown are partial spectra (1.0 - 4.0 ppm): a) Spectrum of starting material. b,c,d): Right side - Spectra of reaction mixtures, diluted with D20 and recorded after the indicated time; Left side - reaction conditions and results, e) Spectrum of the product. S: l 3C-satellite signals from the MeNH2 signal.
General procedure: General synthetic procedure: To a solution of 1,8-dihydroxyanthracene-9,10-dione (1) (0.2g; 0.82mmol) in pyridine (5mL) was added the copper (II) salt (1.6mmol). The aminoalcohol (16mmol) was then added, or dissolved in pyridine (2mL) and then added, dropwise under stirring at room temperature, and the mixture was stirred at 80C for 5-10h, until no starting material could be detected by TLC (20% EtOAc in DCM). The reaction mixture was subsequently transferred into a large vessel and deionised water (20mL) was added. The resulting low viscosity mixture was acidified with hydrochloric acid (2M) to pH 2 under constant stirring. The mixture was partitioned between water and dichloromethane and the product extracted into the organic phase. The extract was dried (MgSO4), concentrated under reduced pressure, and applied to a silica gel flash chromatography column. Elution with ethyl acetate in dichloromethane and a gradient between 5 and 60% gave the title compound as a chromatographically homogeneous orange-yellow solid.
Stage #1: maleiimide With 4-methyl-morpholine; methyl chloroformate In ethyl acetate at 0℃; for 0.5h;
Stage #2: 6-amino-1-hexanol With sodium hydrogencarbonate In water; ethyl acetate for 0.5h;
16 Example 16
Example 16 Methyl chloroformate (1.0 ml, 13.0 mmol) was slowly added dropwise to a solution of H-pyrrole-2,5-dione (1.0 g, 10.3 mmol) and N-methylmorpholine (1.5 ml, 13.6 mmol) in ethyl acetate (10 ml) at 0° C. After stirring for 30 min, 6-aminohexan-1-ol (1.4 g, 11.9 mmol) was added followed by the addition of saturated aqueous sodium bicarbonate (2 ml). After stirring for an additional 30 minutes, the solution was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on silica gel (40 g) with methylene chloride:ethylacetate as the eluent 100:0 to 0:100 over 20 min to afford 0.5 g (25% yield) of 1-(6-hydroxyhexyl)-1H-pyrrole-2,5-dione, 269, as a clear oil.
Stage #1: 6-amino-1-hexanol With (6-di-tert-butylphosphinomethyl-2,2’-bipyridyl)Ru(CO)HCl; water; sodium hydroxide In 1,4-dioxane for 24h; Schlenk technique; Inert atmosphere; Glovebox; Reflux;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
81%
Stage #1: 6-amino-1-hexanol With ((CH3C6H4CH(CH3)2)RuI(C6H4NC3H2NCH3)); potassium hydroxide In m-xylene for 16h; Schlenk technique; Reflux;
Stage #2: With hydrogenchloride In water; m-xylene Schlenk technique;
75%
With ((CH3C6H4CH(CH3)2)RuI(C6H4NC3H2NCH3)); potassium hydroxide In m-xylene at 145℃; for 24h; Schlenk technique;
2.4.1. A typical reaction under the optimized reaction condition
General procedure: To a 25mL Schlenk flask, an NHC-Ru complex (one of [Ru-1]-[Ru-7], 1.56 μmol), an alcohol (25mmol), KOH (1.68g, 30mmol), a stirring bar, and m-xylene (3.0mL) were added. The flask was equipped with a reflux condenser, and the reaction mixture was stirred at a refluxing temperature in open air. After the assigned reaction period, the flask was cooled to room temperature. Water (10mL) and ethyl acetate (20mL) were added, and the two layers were separated. The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (3× 20mL). Subsequently, the organic layers were combined, dried over Na2SO4, concentrated via a rotary evaporator, dried with a vacuum pump to afford the unreacted alcohol, which was weighed to obtain its yield. Afterwards, 3N HCl (around 12mL) was added to the aqueous layer, which was extracted with ethyl acetate (3× 20mL). The organic layers were combined, dried over Na2SO4, concentrated and dried to afford the desired carboxylic acid, which was weighed to determine its yield.
62%
Stage #1: 6-amino-1-hexanol With C29H44Cl2N2Ru; sodium hydroxide In water for 24h; Reflux;
Stage #2: With hydrogenchloride In water
Multi-step reaction with 3 steps
1: toluene / 4.25 h / 100 °C
2: triethylamine / dichloromethane / 4.58 h / 0 °C
3: hydrazine hydrate / ethanol / 16 h / 20 °C
N-6-Hydroxyhexylphthalimide (6)
A solution of 3-hydroxyphthalic anhydride (0.89 g, 5.42 mmol) in toluene(15 mL) was warmed to 80°C and 6-amino-1-hexanol (0.69 g,5.96 mmol) was added and the mixture was stirred at 135°Cfor 14 h. After cooling to room temperature, the reactionmixture was evaporated in vacuo. The residue was purified by column chromatography (CHCl3-MeOH=18 : 1) togive 6 (1.28 g, 90%) as a white powder; 1H-NMR (CD3OD)δ: 1.32-1.44 (4H, m), 1.53 (2H, m), 1.66 (2H, m), 3.53 (2H,t, J=6.6 Hz), 3.61 (2H, t, J=7.2 Hz), 7.14 (1H, d, J=8.5 Hz),7.30 (1H, d, J=7.3 Hz), 7.58 (1H, dd, J=7.3, 8.5 Hz), 13C-NMR(CD3OD) δ: 26.2 (t), 27.4 (t), 29.2 (t), 33.2 (t), 38.2 (t), 62.5 (t),115.6 (d), 116.2 (s), 124.1 (d), 134.9 (s), 137.0 (d), 156.5 (s),169.5 (s), 169.8 (s), HR-MS-ESI (m/z): Calcd for C14H17NO3(M+Na)+ 286.1050. Found 286.1044.
With diisopropyl-carbodiimide In chloroform; water at 30℃; for 4h;
Synthesis of Intermediate G-10
10 mL of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 100 mL of chloroform and 5.53 g of N, N'-diisopropylcarbodiimide were added to 200 mL three-necked flask equipped with a thermometer, dropping funnel, cooling tube and nitrogen flow tube , And stirred at 30 degrees.Therein, 4.68 g of aminohexyl alcohol was dissolved in 100 mL of water and added dropwise using a dropping funnel. After 4 hours, 50 mL of chloroform was added, the liquid separation operation was carried out, and the organic layer was extracted.The solvent was distilled off under reduced pressure by an evaporator. The obtained concentrate was purified by silica gel column chromatography (chloroform / ethyl acetate = 10/1 (volume ratio)) to obtain 7.25 g of a product. .The yield was 52%. Compounds were identified by 1 H-NMR and 13 C-NMR with an NMR analyzer (ECX-400 P manufactured by JEOL RESONANCE), and it was confirmed that the compound was the desired product.
(3aR,4S,7R,7aS)-2-(6-hydroxyhexyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In toluene for 6h; Reflux; Dean-Stark;
5 Synthesis of (3αR,4S,7R,7αS)-2-(6-Hydroxyhexyl)-3α,4,7,7α-tetrahydro-1H-4,7- methanoisoindole-1,3(2H)-dione (A1)
A stirred mixture of 6-aminohexanol (6.25 g, 53.3 mmol) and norbornene (8.34 g, 50.7 mmol) in toluene (40 mL) was heated to reflux, and water was removed via a Dean-Stark trap. Full consumption of the starting materials After 6 h, 1H-NMR analysis indicated full consumption of norbornene. The mixture was cooled to room temperature and sat. NaHCO3 (20 mL) was added. The organic layer was separated and washed again with sat. NaHCO3 (20 mL), then dried over Na2SO4 filtered concentrated in vacuo. This furnished 13.22 g (98% yield) 3αR,4S,7R,7αS)-2-(6- hydroxyhexyl)-3α,4,7,7α-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (A1) as a colorless viscous oil (1H-NMR (CDCl3): 6.29 (2H, s), 3.62 (2H, t, J=6.44 Hz), 3.46 (2H, t, J=7.62 Hz), 3.27 (2H, s), 2.67 (2H, s), 1.44-1.66 (m, 5H), 1.24-1.44 (4H, m), 1.22 (1H, d, J=9.96 Hz)).
N-(6-hydroxyhexyl)-3-(3,4,5-trimethoxyphenyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
General procedure: Carboxylic acid (2-4 or 6-8) (Scheme 1) (1 mmol) wasdissolved in dichloromethane (20 mL) and phosphorus oxychloride(1 mmol) was added at room temperature. After 30 min, the reactionalmixture was placed at 0 C and the corresponding aminoalcohol (1.2 mmol) and N,N-diisopropylethylamine (4 mmol) wereadded. The reaction was stirred for 2 h at room temperature. Themixture was then extracted, dried and evaporated to obtain thedesired compound.
General procedure: Carboxylic acid (1, 4, 5 or 8) (Scheme 1) (1mmol) wasdissolved in dichloromethane (40 mL) and triethylamine (2 mmol).Then, ethylchloroformate (2 mmol) was added dropwise to thestirred solution and kept in an ice bath. The reaction conditions andwork-up have been previously described [23].
N-(6-hydroxyhexyl)-3-(3,4-dimethoxyphenyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: 3,4-methoxycinnamic acid With trichlorophosphate In dichloromethane at 20℃; for 0.5h;
Stage #2: 6-amino-1-hexanol With N-ethyl-N,N-diisopropylamine In dichloromethane at 220℃;
A2
General procedure: Carboxylic acid (2-4 or 6-8) (Scheme 1) (1 mmol) wasdissolved in dichloromethane (20 mL) and phosphorus oxychloride(1 mmol) was added at room temperature. After 30 min, the reactionalmixture was placed at 0 °C and the corresponding aminoalcohol (1.2 mmol) and N,N-diisopropylethylamine (4 mmol) wereadded. The reaction was stirred for 2 h at room temperature. Themixture was then extracted, dried and evaporated to obtain thedesired compound.
Procedure for the synthesis of 6a-9e:
General procedure: An appropriateamine alcohol (2 mmol) was added in portion to a stirredsolution of the corresponding anhydride 3a-5 (2 mmol) inethanol (96%, 20 ml). The reaction mixture was refluxed for4 h. After cooling to room temperature, the formed solid wasfiltrated off, washed with distilled water and recrystallizedfrom absolute ethanol to give product of high purity.
Multi-step reaction with 3 steps
1: triethylamine / dichloromethane / 2 h / 20 °C
2: triethylamine / dichloromethane / 5 h / 0 - 20 °C
3: triethylamine / 1,4-dioxane; water / 1 h / 60 °C
Multi-step reaction with 4 steps
1: methanol / 2 h / 20 °C
2: triethylamine; dmap / dichloromethane / 0 - 20 °C
3: potassium carbonate; sodium iodide / acetonitrile / 80 °C / Inert atmosphere
4: palladium on activated charcoal; hydrogen / methanol / 40 °C
Stage #1: 6-aminohexan-1-ol; di-<i>tert</i>-butyl dicarbonate With triethylamine for 2h;
Stage #2: With methanesulfonyl chloride; triethylamine at 0℃; for 5h;
Stage #3: methylamine at 60℃; for 1h;
Stage #1: menthoxyacetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.166667h;
Stage #2: 6-aminohexan-1-ol In N,N-dimethyl-formamide at 20℃;
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