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Structure of 42055-15-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With lithium aluminium tetrahydride In tetrahydrofuran; water at 0℃; for 3 h; Heating / reflux
34b. 3-(Methylamino)propan-1-ol A solution of the product of Example 34a (8.60 g, 83.3 mmol) in 10 mL of THF was added to LAH in THF (1M, 100 rL) at 0° C. The mixture was heated reflux for 3 hours. Water was added (3.79 mL) followed by NaOH solution (10percent, 11.4 mL) and water (3.79 mL). The resulting solid was removed via filtration and the solid washed with additional THF (10 mL). The filtrate was collected and the solvent removed under reduced pressure to give the title compound (4.40 g, 59percent yield) as a yellow oil which was used without further purification. 1H NMR (300 MHz, CDCl3); δ 3.74 (m 2H), 2.78 (m, 2H), 2.38 (s, 3H), 1.66 (q, J=5.0, 2H).
Reference：
[1] Patent: EP1820799, 2007, A1,
[2] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 77-78
[3] Synthesis, 1986, # 4, p. 338 - 340
[4] Patent: US2004/24057, 2004, A1, . Location in patent: Page/Page column 44
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 12, p. 2757 - 2762
[6] Journal of Organic Chemistry, 1979, vol. 44, # 15, p. 2718 - 2722
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 11, p. 3072 - 3077
[8] Tetrahedron, 2010, vol. 66, # 1, p. 68 - 79
2
[ 67-56-1 ]
[ 156-87-6 ]
[ 42055-15-2 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 23, p. 7368 - 7377
[2] Catalysis Letters, 2016, vol. 146, # 7, p. 1182 - 1193
Reference：
[1] Chemical Biology and Drug Design, 2014, vol. 83, # 1, p. 106 - 118
[2] Monatshefte fuer Chemie, 1964, vol. 95, p. 922 - 941
5
[ 74-89-5 ]
[ 627-30-5 ]
[ 42055-15-2 ]
Yield
Reaction Conditions
Operation in experiment
100.4 g
at 0 - 30℃; for 17 h;
615.0 gr of a 40percent methylamine aqueous solution is added to a three-necked flask connected to a thermometer, cooled to 0 to 5 ° C, and 150.0 gr of 3-chloropropane-1-ol is slowly added thereto.When the addition is completed, the reaction solution is heated. After completion of the addition, the reaction mixture is stirred at 25 to 30 ° C for 17 hours and the filtrate is concentrated under reduced pressure to remove methylamine and aqueous solution.Distillation under reduced pressure at 45 to 48 ° C was carried out using a high vacuum pump (0.2 torr) to obtain 100.4 gr of 3- (N-methylamino) propan-1-ol. 100 g of the obtained 3- (N-methylamino) propan-1-ol was introduced into a three-necked flask connected to a thermometer at 0-5 DEG C with 380 g of 47percent HBr.When the addition is completed, the temperature of the reaction solution is raised, and water is continuously removed while keeping the temperature higher than 100 ° C.After removing a certain amount of water, 1600 mL of cold acetone is added, followed by heating to reflux. When the reaction solution becomes a clear solution, the solution is slowly cooled and crystallization proceeds.The mixture was further stirred at 0 ° C for 1 hour, filtered and dried to obtain 131.2 g of 3-bromo-N-methylpropanamine-bromate as a white solid.
Reference：
[1] Synthetic Communications, 2003, vol. 33, # 13, p. 2263 - 2268
[2] Tetrahedron Letters, 1994, vol. 35, # 10, p. 1545 - 1548
[3] Patent: KR2018/54180, 2018, A, . Location in patent: Paragraph 0125; 0126; 0128; 0129
The 3-bromopropanol (10.0 g, 71 . 94 mmol) under cooling in ice dropping slowly added to the methylamine aqueous solution in (50 ml). After the completion of the dropping, the obtained mixture at the room temperature reaction 14 hours. Then obtained directly to the pressure of the concentrated to obtain yellow oily mixture (6.0 g), directly used for the next step reaction.
Reference：
[1] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0256; 0257; 0258
8
[ 67-56-1 ]
[ 156-87-6 ]
[ 42055-15-2 ]
[ 3179-63-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2002, vol. 41, # 18, p. 3476 - 3479
9
[ 503-30-0 ]
[ 74-89-5 ]
[ 42055-15-2 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2789
[2] Journal of the American Chemical Society, 1937, vol. 59, p. 2280
10
[ 2213-08-3 ]
[ 42055-15-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 1739 - 1745
[2] Collection of Czechoslovak Chemical Communications, 1960, vol. 25, p. 2179 - 2190
[3] Gazzetta Chimica Italiana, 1976, vol. 106, p. 111 - 118
Reference：
[1] Journal of the American Chemical Society, 1928, vol. 50, p. 242
13
[ 79-22-1 ]
[ 156-87-6 ]
[ 42055-15-2 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1991, vol. 40, # 9.2, p. 1911 - 1913[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, # 9, p. 2154 - 2157
Reference Example 87 A tetrahydrofuran solution (100 mL) of the compound in Reference Example 86 (10.67 g, 0.10 mol) was added gradually dropwise to a tetrahydrofuran suspension (100 mL) containing lithium aluminum hydride (6.6 g, 0.17 mol) at room temperature. After dropwise addition, the mixture was heated under reflux for 5 hours. Aqueous 7.5N potassium hydroxide solution (20 mL) was added gradually dropwise to the reaction solution previously ice-cooled. After dropwise addition, the mixture was heated under reflux for 30 minutes. The reaction solution was cooled, and the insoluble matter was separated by filtration. The insoluble matter was washed with tetrahydrofuran, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The concentrated residue obtained was purified by distillation under reduced pressure (25mmHg, 90-92°C), to obtain 3-(methylamino)-1-propanol (7.95 g, 86.6percent) as a colorless oil. 1H-NMR (CDCl3) delta:1.65-1.75 (2H,m),2.43 (3H, s), 2.72 (2H,t,J=5.9Hz),3.78-3.84(2H,m),6.08(1H,brs),8.20(1H,s)ppm
59%
With lithium aluminium tetrahydride; In tetrahydrofuran; water; at 0℃; for 3h;Heating / reflux;
34b. 3-(Methylamino)propan-1-ol A solution of the product of Example 34a (8.60 g, 83.3 mmol) in 10 mL of THF was added to LAH in THF (1M, 100 rL) at 0° C. The mixture was heated reflux for 3 hours. Water was added (3.79 mL) followed by NaOH solution (10percent, 11.4 mL) and water (3.79 mL). The resulting solid was removed via filtration and the solid washed with additional THF (10 mL). The filtrate was collected and the solvent removed under reduced pressure to give the title compound (4.40 g, 59percent yield) as a yellow oil which was used without further purification. 1H NMR (300 MHz, CDCl3); delta 3.74 (m 2H), 2.78 (m, 2H), 2.38 (s, 3H), 1.66 (q, J=5.0, 2H).
5-chloro-6-(2,6-difluoro-4-(3-(methylamino)propoxy)phenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
General procedure: General Procedure B: [0101] According to a reported procedure, (Zhang et al, J. Med. Chem., 2007, 50, 319-327; Zhang et al, Bioorg. Med. Chem., 2009, 11 1-1 18) to a suspension of NaH (4.0 equiv) in a 2: 1 mixture of DMSO and THF (0.35 M) was added the aminoalcohol (4.0 equiv), and the mixture was heated to 60 °C for 1 h. The resulting yellow turbid solution was treated with a solution of trifluoroarene (1.0 equiv) in a 1 : 1 mixture DMSO and THF (0.5 M). The reaction mixture was stirred at 60 °C for 3 h and monitored by LCMS. If the starting material remained after 3 h, additional NaH (4.0 equiv) and aminoalcohol (4.0 equiv) were added, sequentially, and the reaction mixture was heated for 12 h. Following complete consumption of the starting material, the reaction mixture was cooled to room temperature and diluted with 0 and EtOAc. The organic layer was washed with H20 and brine, and the combined aqueous layers were extracted with EtOAc (x3). The combined organic layers were dried (MgSC^), filtered, and concentrated. The crude products were purified by reverse-phase HPLC. 5-Chloro-6-(2,6-difluoro-4-(3-(methylamino)propoxy)phenyl)-7V-(2,2,2-trifluoroethyl)- [l,2,4]triazolo[l,5-]pyrimidin-7-amine [0102] Following General Procedure B using 3-(methylamino)-l-propanol and 5-chloro-N- (2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-amine, reverse- phase HPLC purification afforded the title compound as a colorless solid (6.1 mg, 0.014 mmol, 13percent yield): MS (ESI+) 450.69 [M+H+].
EXAMPLE 4 5-Chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine Succinate Salt Dihydrate To a suspension of NaH (40.9 g, 1.02 mol, 60percent in oil) in anhydrous THF (750 mL) is added 3-methylamino-propan-1-ol (115 g, 1.21 mol) at about 20-30° C. dropwise over 30 min. The mixture is stirred for 30 min. Then, a solution of [5-chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-((1S)-2,2,2-trifluoro-1-methyl-ethyl)-amine (150 g, 0.379 mol) in THF (150 mL) is added slowly over 15 min. The mixture is heated to 60° C. and stirred for 16 h, then cooled to 0-6° C. Cold water (1500 mL) is added dropwise while maintain the temperature between 10+-3° C.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 65℃; for 12h;
One equivalent of compound (1), 0.5 equivalents of potassium carbonate, and 0.01 equivalents of potassium iodide are added sequentially to a solution of 3- methylaminopropan-1-ol (one equivalent) in DMF. The resulting mixture is stirred at 65 0C for 12 h.The reaction mixture is evaporated in vacuo and partitioned between ethyl acetate and water. The combined organic layers are dried (Na2SO4), filtered, and evaporated to give a residue. Purification of the residue by flash column chromatography produces the compound of formula (2).
N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide[ No CAS ]
3-(N-methyl-N-(pyridin-4-yl)amino)propanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
The starting material was prepared as follows: Using a procedure analogous to that described for the starting material in Example 46, 4-chloropyridine (885 mg, 59 mmol) and 3-(methylamino)propanol (2.1 g, 0.23 mmol), (Tetrahedron Lett. 1994, 35, 1545-1548), were heated for 8 hours to give 3-(N-methyl-N-(4-pyridyl)amino)propanol (979 mg, 61percent). 1 H NMR Spectrum: (CDCl3; CD3 COOD) 1.8-1.9(m, 2H); 3.16(s, 3H); 3.6-3.75(m, 4H); 6.8(br s, 2H); 8.30(d, 2H) MS - ESI: 166 [MH]+
erucoyl-1,3-propanediol-phosphoric acid dichloride[ No CAS ]
[ 220756-50-3 ]
Yield
Reaction Conditions
Operation in experiment
The conversion of the formed erucoyl-1,3-propanediol-phosphoric acid dichloride into the target product takes place by reaction with N-methylpropanolamine via an intermediate six-membered ring. This is done by adding a solution of 16 g of N-methylpropanolamine (MW 89.14; 0.18 mol) and 35.4 g of triethylamine (MW 101.19; 0.35 mol) in 250 ml of THF dropwise to the stirred reaction mixture in such a way that the temperature does not exceed 350 C. After the dropwise addition, the reaction mixture is kept at 250 C. for 30 minutes. The precipitated triethylamine hydrochloride is filtered off. The filtrate contains the intermediate (Rf 0.25 in CHCl3/ethyl acetate 1:1, parts by volume) and is converted by adding 60 ml of 2 N HCl with ring opening into erucoyl-1,3-propanediol-phospho-N-methylpropylammonium (Rf 0.45 in CHCl3/CH3OH/glacial acetic acid/H2O 100/80/10/5, parts by volume). The THF solution of the product is mixed with 200 ml of 0.2 M sodium phosphate solution (pH8.0) and adjusted to pH 6-7. The product is precipitated by adding 1 l of acetone, and the crystals are isolated by filtration with suction at 40 C. Erucoyl-1,3-propanediol-phospho-N-methylpropylammonium is sometimes slightly impure. Chromatography on silica gel with CHCl3/CH3OH/H2O can be employed for purification. The yield of pure productbased on erucoyl-1,3-propanediolis 65 g (MW 547.8; 79percent). Microanalysis C29H58NO6P calc.: C, 63,59; H, 10,67; N, 2,56; O, 17,53; P, 5,66. found: C, 63,34; H, 10,49; N, 2,49; O, -; P, 5,59.
With sodium hydride; In dimethyl sulfoxide; at 20 - 60℃; for 2h;
To a solution of 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (251 mg, 0.58 mmol) and 3-(methylamino)propan-1-ol (267 mg, 3.0 mmol) in 3 mL of dimethylsulfoxide at room temperature is added sodium hydride (60percent in mineral oil, 120 mg, 3.0 mmol). The mixture is stirred at 60° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (*3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluding with a gradient of ethyl acetate to 50percent methyl alcohol in ethyl acetate. Concentration provides 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine as a light tan solid (181 mg, mp 48-50° C.). MS: m/z 503.1 (M+H).
EXAMPLE 1 In a 3 L flask, 3-chloro-1-propanol (50.0 g, 0.53 mol, 98percent, Aldrich C4,640-3) is dissolved in methylamine solution (1 L, 40 wt. percent in water, Aldrich 42,646-6) and heated to reflux for 3 days. The reaction is cooled to room temperature and the solvent is reduced in vacuo to about 150 mL. To the reaction mixture, potassium carbonate (50 g) is added and the remainder of solvent is removed. The residue is suspended in methanol (200 mL) and filtered through a plug of silica gel (200 g). The plug is washed with methanol (2*100 mL), the organic layers are combined, and the solvents are removed to give an orange oil. The oil is distilled at about 1-2 mm Hg from room temperature to 60° C. with an oil bath and a distillation trap. The distillation afforded 3-methylamino-propan-1-ol as a clear, colorless liquid (22.0 g), BP 165-167° C. (760 torr), C4H11NO, MW 89.14.
EXAMPLE 2 A mixture of 30 g of sodium iodide, 500 g of 3-chloro-1-propanol and 4000 mL of methylamine solution (40 wt. percent in water, Aldrich 42,646-6) is stirred at room temperature for about 17 h. The solvent is reduced in vacuo to about 700-800 mL. To the reaction mixture, potassium carbonate (500 g) is added and the remainder of water is removed to a residue which is distilled with toluene to afford a residue. The residue is suspended in methanol (2000 mL), filtered and the cake washed with methanol (2*1000 mL). The methanol layers are combined, and the solvents are removed to give an oil. The oil is distilled to afford 3-methylamino-propan-1-ol as a clear, colorless liquid (352.0 g), BP 90-95° C. (8 mm), C4H11NO, MW 89.14.
With nitric acid; acetic anhydride; In ethanol; water; at 0℃; for 3.25h;
34c. Methyl(3-(nitrooxy)propyl)amine The product of Example 34b (750.0 mg, 4.28 mmol) dissolved in EtOH was cooled to 0° C. One equivalent of fuming nitric acid (90percent, 199.8 muL 4.28 mmol) was added and the mixture stirred for 15 minutes. The resulting solution was added drop-wise to a mixture of fuming nitric acid (90percent, 300 muL, 6.42 mmol) and acetic anhydride (913 muL, 9.84 mmol) at 0° C. and the solution mixture stirred for 3 hours The excess solvent was removed under reduced pressure. Ether was added and the sample sonicated for 15 minutes. The excess ether was decanted off and the sample dried under vacuum overnight to give a yellow oil (1.29 g) that was used without further purification. 1H NMR (300 MHz, CDCl3); delta 4.60-4.56 (m, 2H), 3.23-3.16 9M, 2H), 2.80 (br s, 3H), 2.28-2.19 (m, 2H).
The starting material was prepared as follows: A solution of 4-chloro-2,6-dimethylpyridine (2.12 g, 15 mmol) and 3-(N-methylamino)-propan-1-ol (4g, 45 mmol) containing 2N hydrogen chloride in ether (10 drops) was heated at 140°C for 1 hour. The mixture was diluted with water (10ml) and poured onto a suspension of MgSO4 (125g) in ethyl acetate (200ml). The mixture ws filtered. The filtrate was evaporated and the residue was triturated with ether. The solid was filtered and dried under vacuum to give 3-((N -(2,6-dimethyl-4-pyridyl)-N -methyl)amino)propan-1-ol (1.76 g, 61percent). MS-EI: 194 [M.]+ 1H NMR Spectrum: (CDCl3) 1.75-1.95 (m, 2H); 2.4 (s, 6H); 3.0 (s, 3H); 3.48 (t, 2H); 3.7 (t, 2H); 6.25 (s, 2H)
3-([N-(tert-butylcarbonyl)-N-methyl]amino)-1-propanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In tetrahydrofuran; water;
The staring material was prepared as follows: A solution of di-tert-butyl dicarbonate (4.9 g, 22 mmol) in THF (12 ml) was added dropwise to a solution of 3-methylamino-1-propanol (2 g, 22 mmol), (J.Am.Chem.Soc., 1954, 76,2789), in a mixture of THF (12 ml) and water (12 ml). The mixture was stirred for 18 hours at ambient temperature, the THF was removed by evaporation. The aqueous residue was extracted with ether. The extracts were combined, washed with 0.1M hydrochloric acid, and then brine, dried (MgSO4 and the solvent removed by evaporation to give 3-([N-(tert-butylcarbonyl)-N-methyl]amino)-1-propanol (3.95 g, 95percent). 1H NMR Spectrum: (CDCl3) 1.46(s, 9H); 1.6-1.8(m, 2H); 2.83(s, 3H); 3.3-3.4(br s, 2H); 3.5-3.6(br s, 2H); MS-(EI): 190 [MH]+.
3-(N-dodecyl-N-methylamino)propanol A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R. Kupper, and C. J. Michejda, J. Org. Chem., 44, 2718,1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96percent) of the title material as an oil, b.p. 100-105° C./0.04 torr.
6.33 g (96%)
3-(N-dodecyl-N-methylamino)propanol A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R. Kupper, and C. J. Michejda, J. Org. Chem., 44, 2718, 1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96percent) of the title material as an oil, b.p. 100-105° C./0.04 torr.
a. N,N'-dimethyl-N,N'-bis(3-hydroxypropyl)-1,3-diaminopropane 15 g of anhydrous potassium carbonate are added to a solution of 9 g of 3-methylaminopropanol and 10 g of 1,3-dibromopropane in 100 ml of ethanol, and the reaction mixture is stirred and refluxed for 24 hours. The mixture is allowed to cool, filtered, the filtrate is evaporated, and the residue is distilled. 6 g of N,N'-dimethyl-N,N'-bis(3-hydroxypropyl)-1,3-diaminopropane are obtained; b.p.: 150°-154° C/2 mmHg, nD20 = 1.4793.
11-chloromethyl-2,4-dimethyl-dibenz[b,f](1,4)oxazepine[ No CAS ]
[ 66706-76-1 ]
Yield
Reaction Conditions
Operation in experiment
In water; toluene;
A. A solution of 2.7 g 11-chloromethyl-2,4-dimethyl-dibenz[b,f](1,4)oxazepine in 24 ml toluene is added at room temperature with stirring to a solution of 10.9 g gamma-methylaminopropanol in 17 ml toluene. The mixture is stirred for 6 hours, after which 10 ml water is added during a 15-minute period. The toluene layer is subsequently separated, washed with water and dried over sodium sulphate. The solution thus obtained is stirred during a 15-minute period into a suspension of 1.4 g LiALH4 in 36 ml dry ether. The mixture is then cooled to about 0° C. After addition of 6 ml water, the mixture is filtered and the filtrate is evaporated to dryness under vacuum. Yield 3.2 g 10,11-dihydro-11-{N-(3-hydroxypropyl)-N-methyl}aminomethyl-2,4-dimethyl-dibenz[b,f](1,4)oxazepine as a colourless oil. Rf in toluene:ethanol (9:1)=0.16 (SiO2).
trans-(2-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;
7.12; A solution of 1.02 g (3.00 mmol) of trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl- amino] -ethylj-cyclohexanecarboxylic acid in 30 mL of CH2Cl2 was treated at RT with 2 drops of DMF, followed by 0.28 mL (3.30 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 15 mL Of CH2Cl2 and added to a solution of 0.80 g (9.00 mmol, 3 eq) of 3-(methylamino)-l-pro- panol [Powell et al., Synthesis (4) 338-340 (1986)] and 2.09 mL (15.00 mmol, 5 eq) OfEt3N in 12 mL OfCH2Cl2 at 00C. The reaction was kept at RT for Ih then partitioned between Et2O (x3)/.aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10percent NaCl, dried over Na2Spsi4 and evaporated. Purification by flash-chromatogra- phy on 90 g silica gel (EtOAcCH2Cl2 1:1 to 4:1) gave 0.95 g (77percent) of pure trans-(2-{4-[(3- hydroxy-propyl)-methyl-carbamoyl] -cyclohexyl} -ethyl) -methyl-carbamic acid 4-chloro- phenyl ester, MS: 411 (MH+, ICl).
trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexylmethyl}-methyl-carbamic acid 4-chloro-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
In dichloromethane; at 0 - 20℃;
6.4; A solution of 0.09 g (0.276 mmol) of trans-4-{ [ (4-chloro-phenoxycarbonyl) -methyl - amino] -methyl} -cyclohexanecarboxylic acid in 2.5 mL OfCH2Cl2 was treated at RT with 1 drop of DMF. 0.026 mL (0.304 mmol, 1.1 eq) of oxalyl chloride were added within 5 min and stirring was continued for 90 min. The solution was evaporated, redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.197 mL (2.21 mmol, 7.2 eq) of 3-(methylamino)-l- propanol [Powell et al., Synthesis (1986), (4), 338-40] at O0C. The reaction was kept over .bul. EPO <DP n="42"/>night at RT, then partitioned between Et2O (x3)/ aqueous saturated NaHCC>3. The organic phases were washed once with aqueous 10percent NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 5 g silica gel (EtOAcCH2Cl2 1:9 to 9:1) gave 0.064 g (58percent) of pure trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohex7lmeth- yl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 397 (MH+, ICl).
With triethylamine; In dichloromethane; at 20℃; for 11h;
Dissolve 3- (methylamino) -1-propanol (33) (1.81 g, 20.3 mmol) and triethylamine (3 mL) in dichloromethane (30 mL) and add di-tert-butyl dicarbonate (3.72 g After the mixture was stirred for 5 minutes, the reaction solution was returned to room temperature and stirred for 11 hours. Under ice cooling, a 1 N hydrochloric acid aqueous solution was added to the reaction solution and further diluted with dichloromethane.After separating the organic layer, the obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 3: 2 to 1: 1) to give the title compound (34) (3.35 g, qy) As a colorless oil.
99%
With triethylamine; In methanol; at 20℃;
At room temperature, triethylamine (TEA, 0.18 ml, 1.27 mmol) and 3-(methylamino)-1-propanol (0.10 ml, 1.06 mmol) in 3.50 ml of methanol were added to Boc anhydride (0.27 ml, 1.15 mmol). The mixture was stirred overnight, and then treated with NaHCO3. The reaction mixture was diluted with EtOAc, and the organic layer was extracted three times with EtOAc (15 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The mixture was separated by silica gel-based chromatography (EtOAc:hexane=1:1), thereby obtaining compound 1a (99%, 198 mg, 1.04 mmol). (0079) The results were confirmed by 1H NMR (600 MHz, CDCl3), 13C NMR (150 MHz, CDCl3), and high-resolution MS (ESI).
90%
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of 3-(methylamino)propan-l-ol (13, 22.6 g, 254 mmol) and triethylamine (25.7 g, 35 mL, 254 mmol) in DCM (500 mL) was added di-tert-butyl dicarbonate (55.3 g, 254 mmol) portionwise. The resulting mixture was stirred at room temperature for 1 hour until no more gas development was observed. The mixture was washed with 1M HC1, dried over Na2S04, and concentrated to provide Boc-protected amine 14 (43 g, 230 mmol, 90%) as a clear oil.
87%
With dmap; In acetonitrile; for 2h;
To 3-(methylamino)propan-1-ol 12 (250 mg, 6.28 mmol) in acetonitrile was added BOC anhydride (680 mg, 12.56 mmol) and a catalytic amount of DMAP. The reaction was stirred for 2 hours until the disappearance of alcohol 12. The crude mixture was subjected to column chromatography (Hexane: EtOAc 55:45) and dried under reduced pressure to obtain (460 mg, 2.43 mmol, 87%) of the desired product. TLC (Hexane: EtOAc 1:1): Rf = 0.46. 1H NMR (300 MHz, CDCl3) delta = 1.45 (s, 9H), 1.66-167 (m, 2H), 2.62 (s, 3H), 3.37 (s, 2H), 3.52 (s, 2H). 13C NMR (75 MHz, CDCl3) delta = 28.35, 29.63, 34.13, 44.21, 58.08, 79.96, 157.19. To the above compound (90 mg, 0.475 mmol) in dichloromethane was added p-toluene sulfonylchloride (136 mg, 0.713 mmol) and triethylamine (96 mg, 0.951 mmol) and the mixture was stirred at 0C for 4 h. The reaction mixture was then quenched with water and extracted using diethyl ether. The ethereal layer was washed with brine and dried over MgSO4 to yield the crude product which was further subjected to column chromatography using Hexane: EtOAc 13: 7 to yield 135 mg (0.393 mmol, 84%) of 13 as white oily liquid. TLC (Hexane: EtOAc 1:1): Rf = 0.46. 1H NMR (300 MHz, CDCl3) delta = 1.41 (s, 9H), 1.81-1.90 (m, 2H), 2.44 (s, 3H), 2.78 (s, 3H), 3.23 (t, 2H, J = 6.9 Hz), 4.02 (t, 2H, J = 6.3 Hz), 7.34 (d, 2H, J = 7.8 Hz), 7.77 (d, 2H, J = 8.4 Hz). 13C NMR (75 MHz, CDCl3) delta = 21.63, 27.53, 28.35, 34.59, 45.28, 68.2, 79.62, 125.94, 127.87, 129.10, 129.88, 132.86, 144.87, 155.60. MS (ESI): m/z = 244.13 [M-Boc] +,Mass Calculated: 244.08[M-Boc] +.
87%
In dichloromethane; at 0 - 25℃; for 1h;
To a solution of 3- (methylamino)propan-l-ol (0.6 g, 6.7 mmol) in DCM (8 mL) at 0-5C was added dropwise a solution of di-tert-butyl dicarbonate(1.6 g, 7.4 mmol) in DCM (3 mL). The mixture was stirred at 25C for 1 hr then quenched with aqueous HC1 (0.1 N, 5 mL) at 0-5C,a nd extracted with DCM. The combined organic layers were washed with H2O and brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (1.1 g, 87% yield) as yellow oil.
51.9%
With triethylamine; In dichloromethane; at 0 - 20℃; for 1.5h;
To a solution of compound 105-1 (1.0 g, 11.22 mmol) and triethylamine (2.27 g, 22.44 mmol) in 15 mL of DCM was cooled to 0C and added dropwise di-tert- butyl dicarbonate (2.94 g, 13.46 mmol). Then the mixture was stirred at RT for l.5h (Checked by TLC). The reaction mixture was extracted with DCM (15 mL x2), washed with water (10 mL xl), brine (20 mL xl), dried over Na^SCL and concentrated in vacuo. The residue was purified by flash column chromatography (PE/ EA = 2: 1) on silica gel to give compound 105-2 (1.1 g, 51.9%) as a white oil.
In dichloromethane; at 0℃;Inert atmosphere;
b. (3-Hydroxy-propyl)-methyl-carbamic acid tert-butyl ester; The product of the previous step (2.3 g, 0.026 mol) was dissolved in dichloromethane and cooled to 0 C. A solution of di-tert-butyl dicarbonate (5.67 g, 0.026 mol) in dichloromethane (10 mL) was added dropwise over 5 min. The reaction was stirred for 1 h then quenched with 0.1N HCl and extracted with dichloromethane (2×). The crude product was washed with brine (2×), dried over sodium sulfate, filtered, and concentrated to dryness to give the title compound which was used without further purification. 1H NMR (DMSO, 400 mHz) delta (ppm): 4.39 (t, J=4.89 Hz, 1H), 3.37 (q, J=6.46 Hz, 2H), 3.17 (t, J=7.24 Hz, 2H), 2.75 (bs, 3H), 1.58 (m, 2H), 1.37 (s, 9H).
In chloroform; at 20℃;
(1) Di-t-butyl dicarbonate (5.1 ml) was added to a solution of 3-(methylamino)-1-propanol (1.8 g) in chloroform (30 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone:triethylamine = 50:10:0.2 to 20:10:0.2) to obtain a protected compound (2.6 g).
2.05 g
In methanol; at 20℃; for 120h;Cooling with ice;
Preparation Example 18 To a mixture of 1.0 g of 3-(methylamino)propan-1-ol and 10 mL of methanol was added 3.0 g of di-tert-butyl dicarbonate under ice cooling, followed by stirring for 5 days at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7), thereby obtaining 2.05 g of tert-butyl (3-hydroxypropyl)methylcarbamate.
6.7 g
With triethylamine; In dichloromethane; at 20℃; for 14h;Cooling with ice;
Under room temperature, will 3-methylaminopropanol (6.0 g, 67.3 mmol) dissolved in dichloromethane (100 ml) in. To obtain added in the mixture of the triethylamine (29.0 g, 0 . 287 mol). Then the ice obtained by cooling the mixture to slowly dropping Boc2O (22.0 g, 0 . 101 mol). After the dropping, the obtained mixture at the room temperature reaction 14 hours. The pressure of a mixture of concentrated to obtain crude product. The resulting crude product is purified by silica gel column chromatography (PE:EA=50:1) to obtain 6.7 g of anhydrous oil.
3-methylamino-1-propanol (0.15 g, 1.7 mmol) under argon protectionDissolve in dichloromethane (1.6 mL) and add triethylamine dropwise.Until the test solution is alkaline, the resulting solution is stirred for 15 minutes and used;Di-tert-butyl dicarbonate (0.34 g, 1.6 mmol) dissolved in dichloromethane (5.0 mL)The above alkaline mixture was added dropwise through a constant pressure dropping funnel, and the dropwise addition time was 1 h. The reaction was performed at room temperature overnight. Wash three times with saturated aqueous NaHCO3,The organic phase was dried over anhydrous NaSO4 overnight.The target compound III is a colorless, viscous liquid that is directly concentrated after its next synthesis.
Example 27 S-rMethyl^-lf-^-methylpyridin-S-vDquinazolin-sigma-yllaminolbenzvDaminolpropan-l-ol; [6-(4-methylpyridin-3-yl)quinazolin-2-yl]amino}benzaldehyde (Example 56, 80 mg, 0.23 mmol) and 3-(methylamino)propan-l-ol (0.13 ml, 126 mg, 1.41mmol, 6 equiv) in 5 ml <n="39"/>MeOH (with 3 A molecular sieves) and 3 ml DCM were stirred at room temperature whereupon a few drops of acetic acid was added. NaBH3CN (24 mg, 1.6 equiv) was then added and the reaction mixture was stirred at 300C for 48 hours followed by quenching with NaOH (IN, aq., ~5 ml). The reaction mixture was extracted with EtOAc, and the water layers were then extracted with EtOAc three times. The combined organic layers were washed with water and brine, evaporated and purified by Gilson HPLC (0.1percent formic acid in CH3CN and water) to give 46 mg (41percent) of the desired product. NMR: 9.96 (s, IH), 9.34 (s, IH), 8.46 (m, 2H), 8.18 (s, IH), 7.93 (m, 3H), 7.86 (m, IH), 7.72 (d, IH), 7.38 (d, IH), 7.24 (d, 2H), 3.46 (m, 4H), 2.43 (m, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.62 (m, 2H); m/z 414.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 80℃; for 32.5h;
To an ice-cooled suspension of lithium aluminum hydride (26 g, 0.67 mol) in THF (500 mL) was added at 0C a solution of ethyl tert-butyl (3- hydroxypropyl)carbamate (12, 88 g, 0.34 mol) in THF (250 mL) dropwise. After complete addition the mixture was stirred at room temperature for 30 minutes and 16 hours at 70C. The mixture was cooled to room temperature and then quenched by the dropwise addition at 0C of KOH (20%, 107 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered over Celite and the filtrate was dried over Na2S04 and concentrated. NMR showed still some Boc intact. The material was dissolved in THF (500 mL) and LiAlH4 (13 g, 0.34 leq.) was added. The mixture was stirred at 80C for 16 hours. The mixture was cooled to room temperature. At 0C the reaction was quenched by the slow addition of KOH (20%, 54 mL) and the resulting mixture was stirred for 2 hours at room temperature. The mixture was filtered over Celite and the filtrate was dried over Na2S04 and concentrated to provide Boc- methylaminopropanol (22.6 g, 170 mmol, 50%) as a clear oil.
Preparation 15: Methyl-(3-oxo-propyl)-carbamic acid tert-butyl ester; a. (3-Hydroxy-propyl)-methyl amine; (3-Hydroxy-propyl)-carbamic acid tert-butyl ester (5.0 g, 0.028 mol) was dissolved tetrahydrofuran (100 mL) and cooled to 0° C. Lithium aluminum hydride (2.0 M in THF, 21.4 mL, 0.043 mol) was added dropwise over 20 min. The reaction mixture was heated at reflux for 17 h, cooled to room temperature, and quenched with sodium sulfate decahydrate. The suspension was filtered and concentrated to dryness to give the crude title compound as a clear oil (2.3 g, 90percent yield).
21.5 g (79 mmol) 4-(3-chloropropoxy)benzophenone was dissolved in 150 mL acetonitrile. The mixture was heated to reflux and 38.5 mL (0.39 mol) 3-(methylamino)-1-propanol was added. The reaction was allowed to continue for 20 hours at reflux. The mixture was allowed to cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in 150 mL t.butyl methyl ether. The organic layer was extracted with 200 mL 0.1 N hydrochloric acid. The aqueous layer was removed. The organic layer was extracted three times with 100 mL 0.1 N hydrochloric acid. The three aqueous fractions were pooled and the pH was adjusted to 12, using a 5 N NaOH solution. The alkaline solution was extracted with 200 mL t.butyl methyl ether. The organic fraction was dried over MgSO4 and evaporated under reduced pressure. 17.5 g of the crude intermediate was isolated.
2-(3-chloropropoxy)-9H-thioxanthen-9-one[ No CAS ]
[ 1198775-24-4 ]
Yield
Reaction Conditions
Operation in experiment
The synthesis of INI-13 : [Show Image] 5.1 g (17 mmol) 2-(3-chloropropoxy)-9H-thioxanthen-9-one was dissolved in 80 mL acetonitrile. The mixture was heated to reflux and 8 mL (84 mmol) 3-(methylamino)-1-propanol was added. The reaction was allowed to continue for 24 hours at reflux. 0.35 g sodium iodide was added and the reaction was allowed to continue for an additional 24 hours at reflux. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. The residue was dissolved in 150 mL t.butyl methyl ether and extracted once with 300 mL 0.1 N hydrochloric acid and once with 150 mL 0.1 N hydrochloric acid. The aqueous fraction was pooled and the pH was adjusted to 12 using 5 N NaOH. The mixture was extracted with 200 mL t.butyl methyl ether. The organic fraction was dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude intermediate was used without further purification.
trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarboxylic acid[ No CAS ]
[ 79-37-8 ]
trans-(2-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
A solution of 1.02 g (3.00 mmol) of trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarboxylic acid in 30 mL of CH42Cl2 was treated at RT with 2 drops of DMF, followed by 0.28 mL (3.30 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 15 mL of CH2Cl2 and added to a solution of 0.80 g (9.00 mmol, 3 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (4) 338-340 (1986)]and 2.09 mL (15.00 mmol, 5 eq) of Et3N in 12 mL of CH2Cl2 at 0° C. The reaction was kept at RT for 1 h then partitioned between Et2O (.x.3)/ aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10percent NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 90 g silica gel (EtOAc:CH2Cl2 1:1 to 4:1) gave 0.95 g (77percent) of pure trans-(2-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 411 (MH+, 1Cl).
trans-4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexane carboxylic acid[ No CAS ]
trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexylmethyl}-methyl-carbamic acid 4-chloro-phenyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
A solution of 0.09 g (0.276 mmol) of trans-4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 2.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF. 0.026 mL (0.304 mmol, 1.1 eq) of oxalyl chloride was added within 5 min and stirring was continued for 90 min. The solution was evaporated, redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.197 mL (2.21 mmol, 7.2 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (1986), (4), 338-40]at 0° C. The reaction was kept over night at RT, then partitioned between Et2O (.x.3)/aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10percent NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 5 g silica gel (EtOAc:CH2Cl2 1:9 to 9:1) gave 0.064 g (58percent) of pure trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexylmethyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 397 (MH+, 1Cl).
3-(methylamino)propan-1-ol (3b, 660 muL, 6.96 mmol) was dissolved in anhydrous DCM, and the solution was cooled to -78° C. Methyl adipoyl chloride (490 muL, 3.15 mmol) was added, and the reaction mixture was stirred for 2 h at 0° C. under nitrogen.Solvent was removed in vacuo and the residue was purified by SiO2 column chromatography (EtOAc/CHCl3, stepwise gradient from 1/1 to 1/0) to yield 4b as a colorless oil (303 mg, 42percent).1H NMR (400 MHz, CDCl3) delta 4.00 (t, 1H, J=7.0 Hz), 3.67 (d, 3H, J=3.2 Hz), 3.53 (t, 2H, J=3 Hz), 3.47 (dt, 2H, J=7.2 Hz, 5.4 Hz), 2.99 (s, 3H), 2.36 (m, 4H), 1.69 (m, 4H).13C NMR (100 MHz, CDCl3) delta 174.08, 173.94, 57.85, 51.60, 43.90, 35.42, 33.81, 32.99, 29.41, 24.63, 24.55. MS-ESI (m/z): [M+H]+ calculated for C11H22NO4, 232.1; found, 232.1. [M+Na]+ calculated for C11H21NNaO4, 254.1; found, 254.1.
A stirred solution of 2-[bis(2-chloroethyl)amino]-3,5-dirutrobenzoic acid (22) (1.50 g, 4.26 mmol) in SOCl2 (15 mL) and DMF (3 drops) was heated under reflux for 3 h, then cooled to room temperature and the excess SOCl2 was removed under reduced pressure. The resulting crude 2- [bis(2-chloroethyl)amino]-3,5-dinitrobenzoyl chloride was dissolved in THF (12 mL) and slowly added to a stirred solution of 3-(mediylamino)propanol (prepared according to the literature procedure; J. Org.Chem. 1979, 44, 2718) (1.14 g, 12.78 mmol) in THF (12 mL) at -10 0C. The mixture was stirred for 20 nun at -10 °C, then treated with aqueous HCl (0.5 M, 12 mL) to pH ~ 3 before being ectracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, concentrated under reduced pressure and the residue was recrystalkzed from CH2Cl2/hexane to give 2-[bis(2-chloroethyl)amino]-iV-(3-hydroxyrhoropyl)-N-methyl-3,5-dinitro benzamide (27) (1.30 g, 72percent) as a yellow solid: m.p. 125-128 0C. 1HNMR [(CD,)2SO] (mixture of rotamers) delta 8.70 (d J = 2.8 Hz, IH), 8.28 (2d,/ = 2.8, 1.0 Hz, IH), 4.55, 4.38 (2t J = 5.1 Hz, IH), 3.71-3.67 (m, 4H), 3.54-3.44 (m, 5H), 3.36-3.26 (m, 3H), 3.00, 2.90 (2s, 3H), 1.81-1.74 (m, IH), 1.70- 1.66 (m, IH). Anal. Calcd for C15H20Cl2N4O6: C, 42.6; H, 4.8; N, 13.2percent; found: C, 42.7; H, 4.8; N, 12.9percent.
Example 6-3 [Show Image] To Compound 1 (154 mg) were added acetonitrile (5 ml)-THF (5 ml), then N,N'-disuccinimidyl carbonate (323 mg) and N,N'-dimethylaminopyridine (6 mg), and the mixture was stirred at room temperature for 20 hours. Then, thereto was added Compound 2 (178 mg), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 5percent aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 ml), and thereto were added water (2.5 ml) and potassium carbonate (346 mg) with stirring under ice cooling. The mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol-ethyl acetate 3:97 to 12:88 gradient) to give Compound 3 (91 mg) as a colorless oil. MS (APCI) 424 [M+H]+
Synthesis of (6Z,9Z,28Z,3 l )-heptatriaconta-6.9,2831 -tetraen- 19-yl (3- hydroxypropyl (methyl carbamate[0346] A solution of trichloromethyl chloroformate (340 mu, 2.8 mmol) in anhydrous Et20 (5 mL) was cooled (-15°C) and treated with a solution of dilinoleyl methanol (1.0 g, 1.9 mmol) and pyridine (230 mu, 2.8 mmol) in Et20 (5mL). After stirring (1 h) the reaction mixture was filtered through a frit and the filtrate was added, dropwise, to a cool (0°C) solution of 3-mefhylamino-propan-l-ol (1.1 mL, 11.3 mmol) in Et20 (5 mL). After stirring (5 min) the reaction mixture was filtered and concentrated. The crude material was subjected to chromatography (12percent--> 20percent EtOAc-hexanes) to yield (6Z,9Z,28Z,31Z)-heptatriaconta- 6,9,28,3i-ictraeii-19-yl (3-hydroxypropyl)(methyl)carbamate (960 mg, 79percent) as a colorless oil. Rf 0.17 (10percent EtOAc-hexanes), FW 644.07, C42H77N03.
Step 1. To a mixture of l -(tert-butyl)-4-isocyanatobenzene (200 mg, 1.14 mmol) in 10 mL of DCM was added 3-(methylamino)propan-l-ol (104 mg, 1.20 mmol) and the resultant mixture was stirred at room temperature overnight. Then HC1 (5percent, 15 mL) was added and the mixture was extracted with DCM (15 mL x3). The organic phase was evaporated to afford 170 (294 mg, yield: 98 percent) as white solid. ESI-MS (m/z): 265.7 [M+l]+.
With triethylamine; In dichloromethane; at -18℃;Cooling with ice;
Synthesis of Compound 2b A solution of 9-fluorenylmethoxycarbonyl chloride (15.22 g, 58.85 mmol) in dichloromethane (100 ml) was added over 1 h to an ice-cooled solution of 3-methylamino-1-propanol (5.25 g, 58.85 mmol) and triethylamine (9.0 ml, 64.74 mmol) in dichloromethane (50 ml). The resultant suspension was left overnight at -18° C., and then diluted with brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 1:4 ethyl acetate/dichloromethane to give (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (100percent yield).
6-((3-hydroxypropyl)(methyl)amino)pyrimidine-2,4(1H,3H)-dione trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.3%
With potassium iodide; In water; at 120℃; for 2h;Microwave irradiation;
6-((3-hydroxypropyl)(methyl)amino)pyrimidine-2,4(lH,3H)-dione3-(Methylamino)propan-l-ol (588 mg, 6.6 mmol), 6-chloropyrimidine-2,4(lH,3H)-dione (440 mg, 3.0 mmol), KI (4.98 mg, 0.03 mmol) and water (6 mL) were added to a microwave reaction tube. The mixture was heated to 120 °C by microwave radiation (Biotage Initiator) and stirred for 2 h at 120 °C. The reaction mixture was purified by Mass Directed Auto Prep to give 6-((3- hydroxypropyl)(methyl)amino)pyrimidine-2,4(lH,3H)-dione, trifluoroacetic acid salt (538 mg, 1.718 mmol, 57.3 percent yield) as a white solid.LC-MS (ESI): m/z 200 [M + Eta] +; 0.46 min (ret time).
D1: 6-((3-hydroxypropyl)(methyl)amino)pyrimidine-2,4(1H,3H)-dione <strong>[42055-15-2]3-(Methylamino)propan-1-ol</strong> (588 mg, 6.6 mmol), 6-chloropyrimidine-2,4(1H,3H)-dione (440 mg, 3.0 mmol), KI (4.98 mg, 0.03 mmol) and water (6 mL) were added to a microwave reaction tube. The mixture was heated to 120° C. by microwave radiation (Biotage Initiator) and stirred for 2 h at 120° C. The reaction mixture was purified by Mass Directed Auto Prep to give 6-((3-hydroxypropyl)(methyl)amino)pyrimidine-2,4(1H,3H)-dione, trifluoroacetic acid salt (538 mg, 1.718 mmol, 57.3percent yield) as a white solid. LC-MS (ESI): m/z 200 [M+H]+; 0.46 min (ret time).
57.3%
<strong>[42055-15-2]3-(Methylamino)propan-1-ol</strong> (588 mg, 6.6 mmol), 6-chloropyrimidine-2,4(1H,3H)-dione (440 mg, 3.0 mmol), KI (4.98 mg, 0.03 mmol) and water (6 mL) were added to a microwave reaction tube. The mixture was heated to 120° C. by microwave radiation (Biotage Initiator) and stirred for 2 h at 120° C. The reaction mixture was purified by Mass Directed Auto Prep to give 6-((3-hydroxypropyl)(methyl)amino)pyrimidine-2,4(1H,3H)-dione, trifluoroacetic acid salt (538 mg, 1.718 mmol, 57.3percent yield) as a white solid.
Synthesis of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-hydroxypropyl)(methyl)carbamate A solution of trichloromethyl chloroformate (340 muL, 2.8 mmol) in anhydrous Et2O (5 mL) was cooled (-15° C.) and treated with a solution of dilinoleyl methanol (1.0 g, 1.9 mmol) and pyridine (230 muL, 2.8 mmol) in Et2O (5 mL). After stirring (1 h) the reaction mixture was filtered through a frit and the filtrate was added, dropwise, to a cool (0° C.) solution of 3-methylamino-propan-1-ol (1.1 mL, 11.3 mmol) in Et2O (5 mL). After stirring (5 min) the reaction mixture was filtered and concentrated. The crude material was subjected to chromatography (12percent?20percent EtOAc-hexanes) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-hydroxypropyl)(methyl)carbamate (960 mg, 79percent) as a colorless oil. Rf 0.17 (10percent EtOAc-hexanes), FW 644.07, C42H77NO3.
AAB. N-(3-Hydroxypropyl)-N-methyl-3-oxobutanamide A solution of 20 g (0.23 mol) of 3-methylamino-1-propanol in 50 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.21 mol) in 200 ml tetrahydrofuran -5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 29.2 g (0.17 mol, 79percent yield) of a colorless oil. IR (neat, cm-1): 3407, 2936, 1718, 1622, 1493, 1402, 1358, 1310, 1161, 1128, 1058, 945. LC-MS: 156 (M-OH), 174 (M+H), 196 (M+Na). 1H-NMR (CDCl3, 400 MHz): delta [ppm]=3.8 bis 3.4 (7H), 2.9 (3H), 2.2 (3H), 1.7 (2H).
N-(3-hydroxypropyl)-N,3-dimethyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l- yljbutanamide. To a solution of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l- yl)butanoic acid (2.0 g, 7.99 mmol) and isobutyl chloroformate (1.2 g, 8.79 mmol) in 50 ml dry THF, N-methyl morphorline (0.88 ml) was added at 0°C. The resultant mixture was stirred for 30 minutes at 0°C, and 3-N-methylpropanol (0.85 g, 9.59 mmol) added. The resultant mixture was stirred at room temperature overnight. The compound was directly purified by silica chromatography using heptane and ethyl acetate as eluent to give a yield of 100percent. 1H NMR (300 MHz, CD2C12) delta 3.2-3.6 (m, 4 H, NCH2+ CH20), 2.8-3.1 (m, 5H, NCH3+CH2), 2.12 (s, 3H, CH3), 2.93 (s, 6H, CH3), 1.5-1.7 (m, 2H, CH2), 1.42 (s, 6H, CH3); MS (m/e): 322.1.
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