* 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 borane-THF In tetrahydrofuran at 0℃; for 23.33 h; Heating / reflux
General Procedure for the Synthesis of Compounds Starting from β-Amino Acids.; A solution of borane:tetrahydrofurane complex (1M, 3-4 mL per mmol=3-11 equiv. of β-amino acid) was added dropwise over a period of 1 hour to a cold (0° C.) suspension of beta amino acid (1 equiv.) in THF (1 mL per mmol). The mixture was stirred 20 minutes at room temperature at the end of the addition. It was then heated at reflux for 22 hours. The mixture was then cooled to 0° C.; and methanol (2 mL per mmol) was added over a period of 30 minutes. The mixture was then heated at reflux for 20 minutes and concentrated to a thick oil. The oil was co-evaporated with methanol (3.x.200 mL). The solid obtained was dried in vacuo to afford the coresponding 3-substituted 3-amino-1-propanol derivative as a white waxy solid (quantitative yield). An aqueous solution of HBr (48percent, 2 mL per equiv. of the alcohol) was added slowly to a flask containing a 3-substituted 3-amino-1-propanol (1 equilv.). The mixture was heated at reflux for 6 hours, and then concentrated to dryness. The crude material was used directly in the next step. The 1-substituted 3-bromo-1-propylamine hydrobromide (obtained in step 2) was added to a solution of sodium sulfite (1.0 equiv. of the 1-substituted 3-bromo-1-propylamine) in water and 1,4-dioxane. The mixture was heated under reflux for 6 h then concentrated to dryness. The residual material was treated with concentrated HCl. The inorganic material was removed by filtration; and the filtrate was treated ethanol, causing precipitation of the corresponding sulfonic acid. The crude sulfonic acid was suspended in ethanol and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the solid material was collected by filtration, rinsed with ethanol and dried overnight in the vacuum oven at 60° C., giving the corresponding 3-substituted 3-amino-1-propanesulfonic acid as a fine white crystalline solid.
94.9%
With sodium hydroxide In tetrahydrofuran; water
Reference Example 257 3-Aminobutyric acid (5.1 g, 50 mmol) was added to a suspension of lithium aluminum hydride (5.7 g, 0.15 mmol) in tetrahydrofuran (100 mL) by cooling with ice. The reaction mixture was stirred and refluxed with heating for 1 day. The reaction mixture was cooled with ice, and water (5 mL), 15percent aqueous sodium hydroxide solution (5 mL) and water (10 mL) were added to the solution in this order. The reaction solution was dried with potassium carbonate, filtered and concentrated in vacuum to obtain 3-amino-1-butanol (4.23 g, 94.9percent) as a colorless oil. 1H-NMR(CDCl3)δ:1.15(3H,d,J=6.3Hz)1.43-1.68(2H,m), 3.10-3.17 (1H,m),3.68-3.86(2H,m)ppm FABMS:161(M+1)
73%
With sodium hydroxide In tetrahydrofuran; water
Step A: Preparation of 3-Amino-butan-1-ol. Lithium aluminum hydride (1.0 M in THF, 43.8 mL, 43.8 mmol) was added dropwise over one hour to a suspension of 3-aminobutyric acid (2.26 g, 21.9 mmol) in THF (100 mL) cooled to 0° C. The solution was then refluxed for 16 hours after which time it was cooled to 0° C. and quenched by the careful sequential addition of water (2 mL), 15percent aqueous NaOH (2 mL) and water (2 mL). The mixture was stirred for 15 minutes and was filtered through Celite.(R)., washing the filter pad with THF. Concentration of the filtrated provided the desired product (1.43 g, 73percent) as a clear oil.
28.7%
With sodium hydroxide; chloro-trimethyl-silane; lithium borohydride In tetrahydrofuran; methanol
A. 3-Aminobutanol A stirred solution of lithium borohydride (4.10 g, 0.19 mole) in dry THF (100 ml) under a nitrogen blanket is treated dropwise with trimethylsilyl chloride (40.56 g, 0.37 mole). The reaction mixture is maintained at 25-30° with an ice bath. The reaction is treated portionwise with DL-3-aminobutyric acid (9.69 g, 0.09 mole). Caution-reaction exothermic with foaming. After stirring at room temperature overnight, the reaction is treated cautiously with dry MeOH (140 ml). The reaction solution is concentrated under reduced pressure to leave a thick oil residue. The residue is treated cautiously with 20percent NaOH (250 ml) followed by extraction with 3*250 ml portions of CH2 Cl2. The extracts were pooled and dried over anhydrous Na2 SO4. The desiccant is removed and the filtrate concentrated under reduced pressure to yield the crude product I. The product is distilled at 50° 0.5 mmHg to yield 2.3 g (28.7percent) of material to be used as an intermediate in Part B.
Reference：
[1] Patent: US2006/223855, 2006, A1, . Location in patent: Page/Page column 171
[2] Patent: EP1820799, 2007, A1,
[3] Organic Letters, 2017, vol. 19, # 17, p. 4696 - 4699
[4] Patent: US2005/54701, 2005, A1,
[5] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 6, p. 1465 - 1473
[6] Izv.Akad.S.S.R.Otd.chim., 1956, p. 575;engl.Ausg.S.573
[7] Chemische Berichte, 1958, vol. 91, p. 2383,2385
[8] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 2, p. 123 - 138
[9] Patent: US5922703, 1999, A,
2
[ 42875-72-9 ]
[ 2867-59-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydrogen In methanol at 40 - 45℃;
Step-iii: Preparation of (R,S)-3-amino-l-butanol : 4-Hydroxy-2-butanone oxime was dissolved ( 10.0 g, 0.097 mol) in methanol (100 ml). 8.0 ml of Raney nickel was added to the reaction mixture and hydrogenated under 10 kg/cm2 pressure at 40- 45 °C for overnight. On completion of the reaction by thin layer chromatography, the reaction mixture was filtered on celite bed under nitrogen atmosphere. The filtrate was concentrated by rotary evaporator to obtain (ftS)-3-amino- l -butanoI (7.8 g, 90percent) as a thick pale yellow liquid.
80%
With hydrogen In methanol at 45 - 50℃;
To a solution of 4-hydroxy-2-butanone (5) (250.0 g, 2.84 mol) in methanol (2500 mL) at 20-25 °C, hydroxylamine hydrochloride (207.05 g, 2.9792 mol) was added. Afterwards sodium carbonate (180.45 g, 1.7024 mol) was added portionwise to the reaction mixture so as to maintain the temperatureat 25-30 °C. The mixture was then stirred for 2 h by keeping the temperature of about 45-50 °C. After the disappearance of the starting material which was monitored by TLC, the reaction mixture was filtered to remove inorganic salts which were washed with chilled methanol (250 mL). Then the combined filtrate and washed ones were transferred into a suitable vessel, and reduced using hydrogen in the presence of Raney Nickel at about 40-45 °C. The hydrogen pressure during reduction was maintained at 5-6 Kg/cm2. The reaction mass was cooled to 20-25 °C and filtered to remove the catalyst, and the filtrate was concentrated at 40-45 °C. Trimethylamine (25 m L) was added at 25-30 °C and the mixture was stirred by slowly increasing the temperature to about 100 °C. While increasing the temperature, the pressure in the vessel was slowly decreased to reach finally 5 mbar, when a colourless liquid compound (10) (202.0 g,80 percent) was obtained. The purity was checked by GC: 98.5percent. Chiral Purity by HPLC: R-Isomer: 50.5percent, S-Isomer: 49.5percent. 1H NMR (300 MHz, CDCl3) δ ppm: 3.81 (m, 2H), 3.45 (s,1H), 3.14 (broad s, 3H, NH2 and OH), 1.62 (m, 2H), 1.16 (d, 3H); IR (NEAT, cm-1): 3344, 3280, 2958, 2872, 1600, 1455, 1376, 1109, 1066, 846; ESI-MS: m/z 90.0929.
Reference：
[1] Patent: WO2014/128545, 2014, A2, . Location in patent: Page/Page column 23
[2] Letters in Drug Design and Discovery, 2017, vol. 14, # 12, p. 1371 - 1375
3
[ 5303-65-1 ]
[ 2867-59-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 399 - 406
[2] Journal of the American Chemical Society, 1957, vol. 79, p. 3839,3844
[3] Patent: WO2006/74003, 2006, A2, . Location in patent: Page/Page column 136
4
[ 126121-40-2 ]
[ 2867-59-6 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 27, p. 9473 - 9474
5
[ 626-34-6 ]
[ 2867-59-6 ]
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 18, p. 5328 - 5335
With borane-THF; In tetrahydrofuran; at 0℃; for 23.33h;Heating / reflux;
General Procedure for the Synthesis of Compounds Starting from beta-Amino Acids.; A solution of borane:tetrahydrofurane complex (1M, 3-4 mL per mmol=3-11 equiv. of beta-amino acid) was added dropwise over a period of 1 hour to a cold (0 C.) suspension of beta amino acid (1 equiv.) in THF (1 mL per mmol). The mixture was stirred 20 minutes at room temperature at the end of the addition. It was then heated at reflux for 22 hours. The mixture was then cooled to 0 C.; and methanol (2 mL per mmol) was added over a period of 30 minutes. The mixture was then heated at reflux for 20 minutes and concentrated to a thick oil. The oil was co-evaporated with methanol (3×200 mL). The solid obtained was dried in vacuo to afford the coresponding 3-substituted 3-amino-1-propanol derivative as a white waxy solid (quantitative yield). An aqueous solution of HBr (48%, 2 mL per equiv. of the alcohol) was added slowly to a flask containing a 3-substituted 3-amino-1-propanol (1 equilv.). The mixture was heated at reflux for 6 hours, and then concentrated to dryness. The crude material was used directly in the next step. The 1-substituted 3-bromo-1-propylamine hydrobromide (obtained in step 2) was added to a solution of sodium sulfite (1.0 equiv. of the 1-substituted 3-bromo-1-propylamine) in water and 1,4-dioxane. The mixture was heated under reflux for 6 h then concentrated to dryness. The residual material was treated with concentrated HCl. The inorganic material was removed by filtration; and the filtrate was treated ethanol, causing precipitation of the corresponding sulfonic acid. The crude sulfonic acid was suspended in ethanol and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the solid material was collected by filtration, rinsed with ethanol and dried overnight in the vacuum oven at 60 C., giving the corresponding 3-substituted 3-amino-1-propanesulfonic acid as a fine white crystalline solid.
94.9%
With sodium hydroxide; In tetrahydrofuran; water;
Reference Example 257 3-Aminobutyric acid (5.1 g, 50 mmol) was added to a suspension of lithium aluminum hydride (5.7 g, 0.15 mmol) in tetrahydrofuran (100 mL) by cooling with ice. The reaction mixture was stirred and refluxed with heating for 1 day. The reaction mixture was cooled with ice, and water (5 mL), 15% aqueous sodium hydroxide solution (5 mL) and water (10 mL) were added to the solution in this order. The reaction solution was dried with potassium carbonate, filtered and concentrated in vacuum to obtain 3-amino-1-butanol (4.23 g, 94.9%) as a colorless oil. 1H-NMR(CDCl3)delta:1.15(3H,d,J=6.3Hz)1.43-1.68(2H,m), 3.10-3.17 (1H,m),3.68-3.86(2H,m)ppm FABMS:161(M+1)
73%
With sodium hydroxide; In tetrahydrofuran; water;
Step A: Preparation of 3-Amino-butan-1-ol. Lithium aluminum hydride (1.0 M in THF, 43.8 mL, 43.8 mmol) was added dropwise over one hour to a suspension of 3-aminobutyric acid (2.26 g, 21.9 mmol) in THF (100 mL) cooled to 0 C. The solution was then refluxed for 16 hours after which time it was cooled to 0 C. and quenched by the careful sequential addition of water (2 mL), 15% aqueous NaOH (2 mL) and water (2 mL). The mixture was stirred for 15 minutes and was filtered through Celite, washing the filter pad with THF. Concentration of the filtrated provided the desired product (1.43 g, 73%) as a clear oil.
2.3 g (28.7%)
With sodium hydroxide; chloro-trimethyl-silane; lithium borohydride; In tetrahydrofuran; methanol;
A. 3-Aminobutanol A stirred solution of lithium borohydride (4.10 g, 0.19 mole) in dry THF (100 ml) under a nitrogen blanket is treated dropwise with trimethylsilyl chloride (40.56 g, 0.37 mole). The reaction mixture is maintained at 25-30 with an ice bath. The reaction is treated portionwise with DL-3-aminobutyric acid (9.69 g, 0.09 mole). Caution-reaction exothermic with foaming. After stirring at room temperature overnight, the reaction is treated cautiously with dry MeOH (140 ml). The reaction solution is concentrated under reduced pressure to leave a thick oil residue. The residue is treated cautiously with 20% NaOH (250 ml) followed by extraction with 3*250 ml portions of CH2 Cl2. The extracts were pooled and dried over anhydrous Na2 SO4. The desiccant is removed and the filtrate concentrated under reduced pressure to yield the crude product I. The product is distilled at 50 0.5 mmHg to yield 2.3 g (28.7%) of material to be used as an intermediate in Part B.
With lithium borohydride; In ethanol; at 0℃; for 4.0h;Heating / reflux;
Example 22; 3-Bromo-12-methyl-l l,12-dihydro-8H,10H-[l,4]oxazepino[4',3':l,2]imidazo[4,5- c]quinolin-6-amine; Part A; A suspension of lithium borohydride (26.57 g, 1.220 mol) in ethanol (800 mL) was cooled to approximately 0 0C, and a solution of ethyl 3-aminobutyrate (40.0 g, 0.305 mol) was slowly added. The reaction mixture was heated at reflux for four hours and allowed to cool to room temperature. A solid was present and was removed by filtration and washed with diethyl ether. The filtrate was concentrated under reduced pressure, and the residue was dissolved in diethyl ether. The resulting solution was washed with 10% sodium carbonate, and the aqueous phase was extracted three times with diethyl ether. The combined organic fractions were concentrated under reduced pressure to provide 27.98 g of 3-aminobutan-l-ol containing some starting material.
With ammonia; hydrogen; In ethanol; at 10 - 45℃; under 9750.98 Torr; for 20.0h;Autoclave;
Add 250.0g of absolute ethanol and 110.5g of 4-hydroxy-2-butanone to a 1L reaction flask. 85.3g of NH3 was passed in at 10 C. The reaction solution was transferred to an autoclave, and 8.0 g of Raney nickel was added.Nitrogen and hydrogen were replaced three times, pressurized to 1.3MPa with hydrogen, the mixture was stirred at 45 C for 20 hours. GC detection of 4-hydroxy-2-butanol was less than 1.0%. The product was filtered and concentrated under reduced pressure at 45 C in a water bath. The concentrated solution was dissolved in toluene and stirred at 110 C. for 4 hours. Water was separated to obtain a lower layer. After concentrating again in a water bath at 50 C, distillation under reduced pressure of -0.9 MPa was performed, and a fraction of 80-120 C was received. The fraction was diluted with 40 g of absolute ethanol, add dropwise to a 500ml reaction bottle containing 85.2g of absolute ethanol and 65.0g of L-mandelic acid. The solution was added dropwise for 1 hour and maintained at a temperature of 55 C, and then reacted at 75 C for 20 minutes. The temperature was slowly lowered for 24 hours to 12 C, a solid was precipitated and filtered to obtain a crude filter cake. Stir the crude product with 250.8 g of isopropanol at 85 C and slowly reduce the temperature to 13 C for 3 hours. Filter again to get a crude filter cake. The above-mentioned operation of beating crystal filtration was repeated three times in total. Drying gave 80.6 g of constant weight white crystals. A 250 ml reaction tank was charged with 60.0 g of methanol, 80.6 g of white crystals, and 56.4 g of a 30% sodium methoxide methanol solution. The reaction was refluxed at 65 C for 17 hours. The temperature was lowered to 3 C and stirred for 30 minutes. Filtration at 3 C and concentration at 37 C were repeated twice to obtain 43.0 g of a colorless liquid. Distillate under reduced pressure at 125 C and receive 80-120 C fractions. Yield: 28.0%, GC: 99.9%, ee value is greater than 99.9%.
With hydrogen bromide; In water; for 6.0h;Heating / reflux;
General Procedure for the Synthesis of Compounds Starting from beta-Amino Acids.; A solution of borane:tetrahydrofurane complex (1M, 3-4 mL per mmol=3-11 equiv. of beta-amino acid) was added dropwise over a period of 1 hour to a cold (0 C.) suspension of beta amino acid (1 equiv.) in THF (1 mL per mmol). The mixture was stirred 20 minutes at room temperature at the end of the addition. It was then heated at reflux for 22 hours. The mixture was then cooled to 0 C.; and methanol (2 mL per mmol) was added over a period of 30 minutes. The mixture was then heated at reflux for 20 minutes and concentrated to a thick oil. The oil was co-evaporated with methanol (3×200 mL). The solid obtained was dried in vacuo to afford the coresponding 3-substituted 3-amino-1-propanol derivative as a white waxy solid (quantitative yield). An aqueous solution of HBr (48%, 2 mL per equiv. of the alcohol) was added slowly to a flask containing a 3-substituted 3-amino-1-propanol (1 equilv.). The mixture was heated at reflux for 6 hours, and then concentrated to dryness. The crude material was used directly in the next step. The 1-substituted 3-bromo-1-propylamine hydrobromide (obtained in step 2) was added to a solution of sodium sulfite (1.0 equiv. of the 1-substituted 3-bromo-1-propylamine) in water and 1,4-dioxane. The mixture was heated under reflux for 6 h then concentrated to dryness. The residual material was treated with concentrated HCl. The inorganic material was removed by filtration; and the filtrate was treated ethanol, causing precipitation of the corresponding sulfonic acid. The crude sulfonic acid was suspended in ethanol and the mixture was heated at reflux for 1 hour. After cooling to room temperature, the solid material was collected by filtration, rinsed with ethanol and dried overnight in the vacuum oven at 60 C., giving the corresponding 3-substituted 3-amino-1-propanesulfonic acid as a fine white crystalline solid.
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃;
To a solution of 3-aminobutan-1-ol (2g, 22.4mmol) and NaHCO3 (2.8g 33.3mmol) in THF (30 mL) and H20 (5 mL) was added benzyl carbonochloridate (4.6g 27.Ommol) at 0C. After stirred at room temperature overnight, the mixture was extracted with EA(3 OmL). The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography to give crude benzyl 4-hydroxybutan-2-ylcarbamate as yellow oil (3g, 60%) LC-MS (ESI):223.7(M+ 1).
(7-bromo-3-nitroquinolin-4-yl)-[3-(tert-butyldimethylsilanyloxy)-1-methylpropyl]amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Part B;Triethylamine (73.5 g, 726 mmol) and the material from Part A were added to a solution of 7-bromo-4-chloro-3-nitroquinoline (34.8 g, 121 mmol, U.S. patent application publication no. US 2004/0147543, Example 1, Parts A through D) in DMF (300 mL), and the reaction mixture was stirred overnight at room temperature. Additional triethylamine (48.97 g, 67.46) and t°t-butyldimethylsilyl chloride (40.1 g, 266 mmol) were then added, and the reaction was stirred for two hours at room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in chloroform. The solution was washed twice with a 2:1 mixture of saturated aqueous sodium bicarbonate and water and three times with 10% aqueous sodium carbonate and then concentrated under reduced pressure. The resulting oil was passed through a plug of basic alumina to provide (7-bromo-3-nitroquinolin-4-yl)-[3-(tert-butyldimethylsilanyloxy)-l- methy lpropy 1] amine .
2-[ethyl-(2-methoxyphenyl)-amino]-ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With sodium hydroxide; CuI;
Example 94 2-[Ethyl-(2-methoxyphenyl)amino] ethanol A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %) and NaOH (83.0 mg, 2.08 mmol). 2-(aminoethyl)-ethanol (101 muL, 1.04 mmol), 2-iodoanisole (162 muL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90 C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3*10 mL). The organics were washed with 0.1 M NaOH (2*10 mL), washed with brine (1*15 mL), dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using methylene chloride/ethyl acetate (70:30). The product was obtained as a pale yellow, viscous oil in 72% yield (145.8 mg).
7,8-Dihydro-7-(4-hydroxybutyl)-N-(2-methoxybenzyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Reference Example 7 7,8-Dihydro-7-(4-hydroxybutyl)-N-(2-methoxybenzyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide The compound as obtained in Reference Example 4 was reacted with 3-amino-1-butanol and treated in the same manner as in Reference Example 5, to obtain the entitled compound as colorless crystals. m.p. 205-206 C. (recrystallized from methanol-ethyl ether) NMR(200 MHz, CDCl3) ppm: 1.57(2H,m), 1.95(2H,m), 2.33(3H,s), 2.71(1H,bs), 3.66(2H,t,J=6.0 Hz), 3.75(3H,s), 4.00-4.15(2H,m), 4.29(2H,d,J=6.2 Hz), 6.59(1H,bt), 6.71-6.92(3H,m), 7.04-7.30(5H,m), 7.41(1H,dd,J=8.4,4.4 Hz), 7.62(1H,dd,J=8.4,1.4 Hz), 8.82(1H,dd,J=4.4,1.4 Hz).
2-(2',3'-epoxypropoxy)-β-phenyl-propiophenone[ No CAS ]
[ 2867-59-6 ]
2-[2'-Hydroxy-3'-(4-hydroxybut-2-ylamino)-propoxy]-β-phenyl-propiophenone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.9 g (40.5%)
In methanol; isopropyl alcohol; toluene;
EXAMPLE 1 2-[2'-Hydroxy-3'-(4-hydroxybut-2-ylamino)-propoxy]-beta-phenyl-propiophenone hydrochloride 5 g of 2-(2',3'-epoxypropoxy)-beta-phenyl-propiophenone and 1.55 g of 4-hydroxy-but-2-ylamine were dissolved in 100 ml of isopropanol and the solution was refluxed on a waterbath for 8 hours. After the mixture had been cooled, the solvent was distilled off under reduced pressure, and 5.5 g of oily residue remained. The crude product was purified over a silica gel column (eluant: a 70:30 mixture of toluene and methanol) and the pure fractions were converted into the hydrochloride. Yield: 2.9 g (40.5%); melting point: 88.5 C. (acetone/ether).
tert-butyl N-(3-hydroxy-1-methylpropyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With dmap; In dichloromethane; at 20℃; for 16.0h;
[00528] Synthesis of tert-butyl 4-hydroxybutan-2-ylcarbamate (179): 3-Aminobutan-l- ol (178; 2 g, 22.5 mmol) was dissolved in DCM (50 mL). DMAP (0.3 g, 2.3 mmol) and (Boc)20 (5.4 g, 24.8 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL), washed with saturated NaHC03 (50 mL), water, brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give 3 g of tert-butyl 4-hydroxybutan-2-ylcarbamate (179), which was used in next step without further purification (71% yield).
32%
With dmap; triethylamine; In acetonitrile; at 20℃; for 40.0h;
Intermediate W: 3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole- 8-carboxylic acid Step 1: Synthesis of tert-butyl (4-hydroxybutan-2-yl)carbamateTo a solution of 3-aminobutan-1-ol (1.0 g, 11.2 mmol), 4-dimethylamino pyridine (137.0 mg, 1.1 mmol) and triethylamine (1.7 mL, 12.3 mmol) in acetonitrile (20 mL) is added di-tert-butyl dicarbonate (2.9 g, 13.5 mmol). The reaction mixture is stirred for 40 h at room temperature. The solvent is removed and the residue is partitioned between CH2CI2 and saturated NaHC03. The aqueous is extracted with CH2CI2 and the combined organic layers are dried (Na2S04) and concentrated. The crude residue is purified by flash column chromatography using methanol in CH2CI2 to afford the title compound (680 mg, 32%).
In dichloromethane;
b 3-(N-BOC-amino)-butan-1-ol A solution of 18.33 g (0.084 mol) of di-tert-butyl dicarbonate in 50 ml of methylene chloride is added dropwise to a solution of 7.13 g (0.08 mol) of 3-aminobutan-1-ol [Chem. Ber. 91, 2383 (1958)] in 50 ml of methylenchloride and the mixture is stirred at room temperature for 22 hours. The reaction mixture is then evaporated and the residue obtained as an oil is purified by means of flash chromatography on silica gel using methylene chloride. After evaporation of the product-containing fractions, the title compound is obtained as an oil, Rf value=0.54 (silica gel/methylene chloride:methanol (9:1)).
Reference Example 258 A toluene solution (20 mL) of the compound (4.23 g, 47.5 mmol) in Reference Example 257 and phthalic anhydride (8.44 g, 57.0 mmol) was stirred and refluxed with heating for 17 hours. The reaction mixture was concentrated in vacuum, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate / 3:2) to obtain 2-(3-hydroxy-1-methylpropyl)-isoindole-1,3-dione (2.29 g, 22.1%) as a colorless solid. 1H-NMR(CDCl3)delta:1.55(3H,d,J=6.8Hz),1.80(1H,br),1.92-2.04 (1H,m),2.20-2.33(1H,m),3.56-3.68(1H,m),7.70-7.74(2H,m), 7.81-7.84 (2H,m)ppm FABMS:220(M+1)
With acetic acid; In water; isopropyl alcohol;Reflux;
EXAMPLES; 1. Enantiomer Separation of Racemic 3-amino-1-butanol; 1.1 Preparation of the (S)-mandelic Salt of (R)-3-amino-1-butanol; A mixture of racemic 3-amino-1-butanol (638 g, 7.16 mol), isopropanol (4.3 1) and water (8.6 ml) was admixed successively while stirring with (S)-mandelic acid (544 g, 3.58 mol) and acetic acid (214.8 g, 3.58 mol). The reaction mixture was heated to boiling until the precipitated salts had dissolved completely. The mixture was then allowed to cool to 20 C. with stirring, in the course of which precipitate formation set in at 42 C. The precipitated crystals were filtered off with suction and washed with isopropanol (200 ml). After drying under air, 822 g (47.5% based on the racemate used; 95% based on the (R)-3-amino-1-butanol present in the racemate) of (S)-mandelic salt of (R)-3-amino-1-butanol were obtained with an optical purity of 88.4% ee in the bound amine.The resulting (S)-mandelic salt of (R)-3-amino-1-butanol was suspended in isopropanol (3 I) and the mixture was heated to boiling. The resulting clear solution was cooled to 20 C. with stirring. The salt which precipitated out was filtered off with suction, washed with isopropanol (100 ml) and dried under air. This gave 590 g of (S)-mandelic salt of (R)-3-amino-1-butanol with an optical purity of 98.5% ee in the bound amine.The (S)-mandelic salt of (R)-3-amino-1-butanol obtained from this recrystallization was suspended in isopropanol (2.4 l) and water (35 ml), and the mixture was heated to boiling. The resulting clear solution was cooled to 20 C. with stirring. The salt which precipitated out was filtered off with suction, washed with isopropanol (100 ml) and dried in a vacuum drying cabinet. This gave 556 g (overall yield: 32.2% based on the racemate used) of (S)-mandelic salt of (R)-3-amino-1-butanol with an optical purity of 99.6% ee in the bound amine.1H NMR (400 MHz, D2O) delta=1.30 (d, J=7 Hz, 3 H); 1.75 (mc, 1 H); 1.90 (mc, 1 H); 3.45 (mc, 1 H); 1.65-1.80 (m, 2 H); 5.00 (s, 1 H); 7.35-7.50 (m, 5 H).Melting point: 133-135 C.Optical rotation: [alpha]D=77.4 (c=3.0 in H2O)
In ethanol; at 55 - 75℃; for 1.33333h;
Add 250.0g of absolute ethanol and 110.5g of 4-hydroxy-2-butanone to a 1L reaction flask. 85.3g of NH3 was passed in at 10 C. The reaction solution was transferred to an autoclave, and 8.0 g of Raney nickel was added.Nitrogen and hydrogen were replaced three times, pressurized to 1.3MPa with hydrogen, the mixture was stirred at 45 C for 20 hours. GC detection of 4-hydroxy-2-butanol was less than 1.0%. The product was filtered and concentrated under reduced pressure at 45 C in a water bath. The concentrated solution was dissolved in toluene and stirred at 110 C. for 4 hours. Water was separated to obtain a lower layer. After concentrating again in a water bath at 50 C, distillation under reduced pressure of -0.9 MPa was performed, and a fraction of 80-120 C was received. The fraction was diluted with 40 g of absolute ethanol, add dropwise to a 500ml reaction bottle containing 85.2g of absolute ethanol and 65.0g of L-mandelic acid. The solution was added dropwise for 1 hour and maintained at a temperature of 55 C, and then reacted at 75 C for 20 minutes. The temperature was slowly lowered for 24 hours to 12 C, a solid was precipitated and filtered to obtain a crude filter cake. Stir the crude product with 250.8 g of isopropanol at 85 C and slowly reduce the temperature to 13 C for 3 hours. Filter again to get a crude filter cake. The above-mentioned operation of beating crystal filtration was repeated three times in total. Drying gave 80.6 g of constant weight white crystals. A 250 ml reaction tank was charged with 60.0 g of methanol, 80.6 g of white crystals, and 56.4 g of a 30% sodium methoxide methanol solution. The reaction was refluxed at 65 C for 17 hours. The temperature was lowered to 3 C and stirred for 30 minutes. Filtration at 3 C and concentration at 37 C were repeated twice to obtain 43.0 g of a colorless liquid. Distillate under reduced pressure at 125 C and receive 80-120 C fractions. Yield: 28.0%, GC: 99.9%, ee value is greater than 99.9%.
With C42H40N2OP2Rh; potassium tert-butylate; In tetrahydrofuran; toluene; tert-butyl alcohol; at 135℃; for 72.0h;Inert atmosphere;
N2 protection,A mixture of 3-amino-1-butanol,Cyclohexanol or cyclohexanone,The complex 1, tert-butyl alcohol was placed in a 50 ml single-necked flask in the proportions shown in the table below,Add 2 ml of toluene and 0.5 ml of THF,The mixture was heated at 135 C and refluxed for 24-72 hours. After completion of the reaction, 10 ml of water was added and extracted with ethyl acetate (3 X 10 ml), concentrated with ethyl acetate:Petroleum ether = 2: 1 (by volume) TLC analysis, silica gel column using ethyl acetate: petroleum ether = 1: 50 (by volume) to give a pale yellowLiquid, yield as shown in Table 1 below.
With hydrogen; In methanol; at 40 - 45℃; under 7500.75 Torr;
Step-iii: Preparation of (R,S)-3-amino-l-butanol : 4-Hydroxy-2-butanone oxime was dissolved ( 10.0 g, 0.097 mol) in methanol (100 ml). 8.0 ml of Raney nickel was added to the reaction mixture and hydrogenated under 10 kg/cm2 pressure at 40- 45 C for overnight. On completion of the reaction by thin layer chromatography, the reaction mixture was filtered on celite bed under nitrogen atmosphere. The filtrate was concentrated by rotary evaporator to obtain (ftS)-3-amino- l -butanoI (7.8 g, 90%) as a thick pale yellow liquid.
80%
With hydrogen; In methanol; at 45 - 50℃;
To a solution of 4-hydroxy-2-butanone (5) (250.0 g, 2.84 mol) in methanol (2500 mL) at 20-25 C, hydroxylamine hydrochloride (207.05 g, 2.9792 mol) was added. Afterwards sodium carbonate (180.45 g, 1.7024 mol) was added portionwise to the reaction mixture so as to maintain the temperatureat 25-30 C. The mixture was then stirred for 2 h by keeping the temperature of about 45-50 C. After the disappearance of the starting material which was monitored by TLC, the reaction mixture was filtered to remove inorganic salts which were washed with chilled methanol (250 mL). Then the combined filtrate and washed ones were transferred into a suitable vessel, and reduced using hydrogen in the presence of Raney Nickel at about 40-45 C. The hydrogen pressure during reduction was maintained at 5-6 Kg/cm2. The reaction mass was cooled to 20-25 C and filtered to remove the catalyst, and the filtrate was concentrated at 40-45 C. Trimethylamine (25 m L) was added at 25-30 C and the mixture was stirred by slowly increasing the temperature to about 100 C. While increasing the temperature, the pressure in the vessel was slowly decreased to reach finally 5 mbar, when a colourless liquid compound (10) (202.0 g,80 %) was obtained. The purity was checked by GC: 98.5%. Chiral Purity by HPLC: R-Isomer: 50.5%, S-Isomer: 49.5%. 1H NMR (300 MHz, CDCl3) delta ppm: 3.81 (m, 2H), 3.45 (s,1H), 3.14 (broad s, 3H, NH2 and OH), 1.62 (m, 2H), 1.16 (d, 3H); IR (NEAT, cm-1): 3344, 3280, 2958, 2872, 1600, 1455, 1376, 1109, 1066, 846; ESI-MS: m/z 90.0929.
In methanol; at 35 - 40℃; for 1.0h;Resolution of racemate;
Step-i: Preparation of (R)-3-amino-l-butanol tartarate salt: D-(+) Tartaric acid ( 12.7 g, 0.085 mol) was added in to a solution of (i?,5)-3-amino- l -butnaol (7.5 g, 0.084 mol) in methanol ( 100 ml) at 40 C. The reaction mixture was stirred for about 1 hour at 35-40 C and the reaction mass was cooled to 0-5C and maintained for 30-40 minutes. The obtained solid was filtered and washed with chilled methanol ( 10 ml) at 0-5 C. The solid was dried to get ()-3-amino- l -butanol tartarate salt (8.0 g, 40%).
tert-butyl 2-(2-((3R,5R)-5-(tert-butyldimethylsilyloxy)-3-((R)-1,1-dimethylethylsulfinamido)-6-(2-nitrophenylsulfonamido)hexanoyl)-1-methylhydrazinyl)acetate[ No CAS ]
With C42H40N2OP2Rh; potassium tert-butylate; In tetrahydrofuran; toluene;Reflux; Inert atmosphere;
General procedure: Different amino butanol (22.4 mmol),Secondary alcohols(44.8 mmol) of KOtBu (44.8 mmol) and complex 1. Add to a mixed solvent of toluene and tetrahydrofuran (4: 1) (v / v) and reflux under nitrogen for 24-72 hours;The product was purified by silica gel column eluting with ethyl acetate / n-hexane as eluent
benzyl (4R/S,9aS/R)-4-methyl-6-oxo-2,3,4,7,9,9a-hexahydropyrazino[2,1-b][1,3]oxazine-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In dichloromethane; at 140℃; for 1.5h;Microwave irradiation;
in a microwave-tube, ethyl 2-[benzyloxycarbonyl(2-oxoethyi)amino]acetate (330 mg, 1 .18 mmol) was diluted in DCM (8 ml), then (+/-)-3-aminobutan-1-ol (1 16 mg, 1.24 mmol) and acetic acid (39 muIota, 673 prnol) were added to give a colorless solution. The reaction mixture was submitted to microwave heating for 1.5 h at 140 C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 50% EtOAc in heptane) to give the title compound (183 mg, 51 %) as a colorless oil. The relative stereochemistry of the product was unambiguously assigned by NOESY NMR experiments. (1085) MS (ESI, m/z): 305.2 [(M+H)+].
With ethyl acetate; In ethanol; at 80℃; for 12.0h;Inert atmosphere;
To a mixture of 3-aminobutan-l-ol (5.00 g, 56.09 mmol, 1.00 eq) and ethyl acetate (9.88 g, 112.18 mmol, 10.98 mL, 2.00 eq) in EtOH (30.00 mL) was added ethyl formate (9.88 g, 112.18 mmol, 10.98 mL, 2.00 eq) in one portion under N2. The mixture was stirred at 80 C for 12 hours. TLC (dichloromethane: (1041) methanol=10: 1) showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (6.00 g, 51.22 mmol, 91.31% yield) as yellow oil. NMR (400 MHz, CDCh) delta 8.17 (s, 1H), 5.75-5.97 (m, 1H), 4.13-4.43 (m, 1H), 3.53-3.68 (m, 2H), 3.27 (br s, 1H), 1.74-1.97 (m, 1H), 1.34-1.52 (m, 1H), 1.15-1.31 (m, 3H).
The 3-aminobutanol (10) (200 g, 2.2471 mol) was dissolved with methanol (280 mL) at 25-27 C, and D-(-)-tartaric acid (252.96 g, 1.6853 mol) was added portion wise. The mixture was then heated at 55-60 C under stirring for 1h. Then the reaction mixture was slowly cooled to room temperature and stirring was continued for about 5 hrs. The reaction mixture was filtered and the formed cake was washed with methanol (100 mL) to give crude solid of (R)-3-aminobutanol tartrate (11) (187.97 g). The crude tartrate 11 was dissolved in about 2 L of methanol and slowly heated atabout 55-60 C until almost half of the solvent methanol evaporated to get a concentrated solution of 11. The product was filtered, washed with methanol to get compound 11 as awhite crystalline solid. Yield: 161.1g (30%). Purity was checked by GC: 99.2%. Chiral Purity by HPLC: 99.89%. Melting Point: 138-151 C; Retention time, [alpha]D26 = -15.68 (c=5.0 DM Water). 1H NMR (300 MHz, CDCl3) delta ppm: 3.95 (s, 2H), 3.48 (m, 2H), 3.29 (m, 1H), 1.75 (t, J = 6.3 Hz, 1H), 1.58 (m, J = 6.6 Hz, 1H), 1.98 (d, J = 6.6 Hz, 3H); IR(NEAT, cm-1): 3869, 3400, 2975, 2532, 1878, 1724, 1618, 1459, 1395, 1305, 1134, 1065, 1020; ESI-MS+: m/z 90.0938: ESI-MS-: m/z 149.0089.
75 g of L-malic acid (0.56 mol) in 250 ml of absolute ethanol was stirred at room temperature and the system was dissolved, then 50 g of 3-amino-1-butanol (0.56 mol) in racemic mixture was added dropwise. , Warm up to 4050C, dissolve the system, add 0.2g(R)-3-amino-1-butanol L-malic acid salt was used as a seed crystal, and stirring was conducted while keeping warm. After half an hour, a solid precipitated and stirring was continued for 2 to 3 hours. The temperature was slowly lowered to room temperature, and the temperature was lowered to 5~ Stir at 10C for half an hour and suction filterThe (R)-3-amino-1-butanol L-malate was obtained with an optical purity of 89.8% ee.The obtained optical purity of 89.8%ee of (R)-3-amino-1-butanol L-malate was suspended in 200 ml of absolute ethanol, and the temperature was raised to reflux, the system was dissolved, slowly cooled, and the cooling process was solid. Gradually precipitated, cooled to room temperature, stirred for 1 to 2 hours, continued to cool down to 5 to 10C, and kept at agitation for 0.5 hour, filtered to obtain an optical purity of 98.3% ee.(R)-3-Amino-1-butanol L-malate.The above recrystallized L-malate salt of (R)-3-amino-1-butanol having an optical purity of 98.3% ee was suspended in 150 ml of absolute ethanol, and the temperature was raised to reflux. After the system was dissolved, the temperature was slowly lowered. The solids gradually precipitated, dropped to room temperature, incubated for 1 to 1.5 hours while stirring, and continued to cool down to 5 to 10 C. for half an hour, filtered by suction, and vacuum-dried at 50 C. to constant weight to give 54.3 g of an optical purity of 99.92% ee. R)-3-Amino-1-butanol L-malate, yield 43.4%.
75 g of D-malic acid (0.56 mol) in 250 ml of anhydrous ethanol, stirred at room temperature, the system was dissolved, then added dropwiseA 50 g mixture of 3-amino-1-butanol (0.56 mol) in racemic mixture was added dropwise and warmed to 30-40C. The system was dissolved and 0.5 g of (S)-3-amino-1-butanol was added. D Malate salt as a seed crystal, and stirring during heat preservation, the solid precipitated after half an hour, continue to stir for 2 to 3 hours, slowly to room temperature, and continue to cool to 5 to 10 C for half an hour, suction filtration, to obtain an optical purity of 90.8 %ee.The D-malate salt of (S)-3-amino-1-butanol.The resulting (S)-3-amino-1-butanol D-malate with an optical purity of 90.8% ee was suspended in 200 ml of anhydrous ethanol, warmed to reflux, and the system was dissolved, slowly cooled, and the cooling process was solid. Gradually precipitated, cooled to room temperature, stirred for 1~2 hours, continued cooling to 5~10C, and kept stirring for 0.5 hour. Filtered to obtain an optical purity of 98.7%e.The D-malate salt of (S)-3-amino-1-butanol.The above-mentioned recrystallized D-malate salt of (S)-3-amino-1-butanol having an optical purity of 98.7% ee was suspended in 150 ml of anhydrous ethanol, and the temperature was raised to reflux. After the system was dissolved, the temperature was slowly lowered. The solids gradually precipitated, dropped to room temperature, incubated for 1 to 1.5 hours while stirring, and continued to cool down to 5 to 10C for half an hour, filtered by suction, and vacuum dried at 50C to a constant weight to give an optical purity of 99.4% ee.(S). D-malate salt of 3-amino-1-butanol.The above-mentioned recrystallized D-malate salt of (S)-3-amino-1-butanol having an optical purity of 99.4%ee was suspended in 120 ml of absolute ethanol, and the temperature was raised to reflux. After the system was dissolved, the temperature was gradually lowered. Solids gradually precipitated, dropped to room temperature, incubated for 1 to 1.5 hours while stirring, and continued to cool to 5 to 10C for half an hour, filtered, and vacuum dried at 50C to constant weight.50.4 g of D-malate salt with an optical purity of 99.9% ee.(S)-3-amino-1-butanol are obtained,Yield 40.3%.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1.0h;
A mixture of 2,4-dichloro-6-nitro-quinazoline (80 mg, 0.33 mmol), THF (3.3 mL), 3- aminobutan-1-ol (35 mg, 0.39 mmol) and DIPEA (0.14 mL, 0.82 mmol) was stirred at RT for lh. LCMS (Method T2) Rt = 1.18 mins, mlz 297.08 [M+H]. Acetic acid (4 mL) was added directly to the mixture which was stirred at 70 00 for 16h. LCMS (Method T2) Rt = 0.85 mins, mlz 279.08 [M+H]. The solution was concentrated and the residue was taken up in methanol (5 mL). The solution was then purified using SCX-2 cartridge. The product was eluted with methanolic ammonia, affording 4-[(3-hydroxy-1-methyl-propyl)amino]-6-nitro-1 H-quinazolin-2- one (50 mg).
3-((2,5-dichloropyrimidin-4-yl)amino)butan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
In water; at 0℃; for 4.0h;
To a solution of 2,4,5-trichloropyrimidine(1.83 g, 10 mmol) in 2% Tween 20/water (50 mL) was added 3-aminobutan-1 -ol (880 mg, 10 mmol) at 0 C and stirred for 4 hrs. The reaction was concentrated and filtered. The solid was washed with CAN to give the title compound as a white solid (1 .5 g, yield 64%). LC-MS: 236.1 [M+H]+.
O-phenyl {4-[(3-chloro-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}carbamothioate[ No CAS ]
(+/-)-N-{4-[(3-chloro-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-N'-(4-hydroxybutan-2-yl)thiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
In N,N-dimethyl-formamide; at 60℃; for 4.0h;
O-phenyl {4-[(3-chloro-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-4-yl)oxy]- 3,5-difluorophenyl}carbamothioate (220 mg, 392 muetaetaomicronIota, intermediate 424) was dissolved in DMF (10 mL) and (+/-)-3-aminobutan-1 -ol (38 muIota_, 430 muetaiotaomicronIota) was added. The mixture was stirred at 60 C for 4 hours then cooled to room temperature and left to stand overnight. Ethyl acetate and brine were added and mixture was extracted with ethyl acetate (3x). The organic layers were combined, dried using magnesium sulfate, filtered and solvent was evaporated to afford a crude product. The crude product was purified by flash column chromatography on Silica 60 (eluent heptane:ethyl acetate, 2 : 3) to afford the desired titled product (499 mg, quant.) as a colourless oil. LC-MS (Method 8): Rt = 2.89 min; MS (ESIpos): m/z = 557 (M-OC2H4Si(CH3)3-OPh)+ 1H-NMR (400 MHz, CDCI3, characteristic signals) delta [ppm]: -0.06 (s, 9H), 0.80 - 0.94 (m, 4H), 1 .32 (d, 3H), 3.51 - 3.58 (m, 2H), 3.70 - 3.84 (m, 2H), 5.62 (d, 2H), 6.32 (d, 1 H), 8.13 (d, 1 H).
With acetic acid; In acetonitrile; for 5.0h;Reflux;
[00409] To a solution of Example 67a (10 g, 38mmol) in CH3CN/AcOH (80 mL/20 mL) was added Example 67b (5.1 g, 57 mmol). The mixture was heated at reflux for 5 h. After cooling to r.t., the mixture was concentrated under reduced pressure. The residue was dissolved in water and IN aqueous NaOH was added to adjust pH to 8. The resulting mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH= 10/1) to give the desired product ( Example 67c , 5.5 g, yield 62%) as yellow oil. LCMS [M+l]+ = 234
With triethylamine; In dichloromethane; at 20℃; for 12.0h;Inert atmosphere;
General procedure: Compound 1: A mixture solution of 3-aminopropanol (0.52 mL,6.77 mmol) and triethylamine (2.0 mL, 9.0 x 10-5 mol) in CH2Cl2was added dropwise to a solution of phenylthiono phosphonicdichloride (1 mL, 6.77 mmol) in CH2Cl2 with stirring. The mixturewas stirred for 12 h in room temperature, the precipitate wasfiltered off, the filtrate was washed with cold water (3 20 mL),dried with Na2SO 4, and the solvent was removed in vacuum. Thecrude productwas chromatographed on a silica gel (PE/EA 3:1), anda white granular solid was obtained. Yield: 37.4%.
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20 - 40℃;
To a solution of 3-aminobutan-1 -ol (500 mg, 5.61 mmol, 1 eq) in anhydrous DCM (25 ml_), cata- lytic amount of DMF (43 mI_, 0.56 mmol, 0.1 eq) was added, followed by dropwise addition of thionyl chloride (610 mI_, 8.414 mmol, 1.5 eq). The reaction was carried out 40C for 1 h, and continued at rt for further 16 h. The solvents were removed in vacuo. The residue was triturated using Et2<D to afford the title compound (900 mg, 6.25 mmol, yield 89%) as a brown solid. ESI- MS: 108 [M+H]+. 1H NMR (300 MHz, DMSO-ok) d 8.33 - 8.06 (m, 3H), 3.86 - 3.65 (m, 2H), 3.33 - 3.23 (m, 1H), 2.19 - 1.84 (m, 2H), 1.23 (d, J= 6.6 Hz, 3H).
With tributylphosphine In isopropyl alcohol at 80℃; for 20h;
1.1 Step 1: Synthesis of 3-(6-bromo-2H-indazole-2-butyl)-1-ol (ZA156)
Add 4-bromo-2-nitro-benzaldehyde (1.1447g, 5.0mmol) and 3-amino-1-butanol (490.3mg, 5.5mmol) into the eggplant-shaped bottle, then add 25ml of isopropanol, Heat and stir at 80°C for 4 hours.After the reaction, the reaction solution was cooled to room temperature, and thennBu3P (3.03g, 15mmol), heated at 80°C for 16 hours.After the reaction is completed, it is cooled to room temperature, the solvent is spin-dried, and then separated and purified by a chromatography column to obtain 1.25 g of the target compound.
With potassium <i>tert</i>-butylate; Br(1-)*C16H20MnN2O3S(1+); potassium hydroxide In tetrahydrofuran; toluene at 120℃; for 24h; Schlenk technique; Inert atmosphere; Sealed tube;
With potassium <i>tert</i>-butylate; Br(1-)*C16H20MnN2O3S(1+); potassium hydroxide In tetrahydrofuran; toluene at 120℃; for 24h; Schlenk technique; Inert atmosphere; Sealed tube;
With C31H29N3OPRu(1+)*Cl(1-); sodium tertiary butoxide In toluene at 120℃; for 24h; Inert atmosphere;
21 Preparation of a 2,3,4,5-tetrahydropyridine compound
In a 100 mL Shrek reaction flask, the pincer-shaped ruthenium catalyst (12.4 mg, 0.02 mmol, 0.02 equiv) prepared in Example 1, and sodium tert-butoxide (144.2 mg, 1.5 mmol, 1.5 equiv) were sequentially added, and the nitrogen gas was replaced three times. (136 mg, 1 mmol, 1.0 equiv), (133.7 mg, 1.5 mmol, 1.5 equiv) were added under nitrogen, 2 ml of toluene was added, and the mixture was stirred at 120° C. for 24 hours. After the reaction was completed, the reaction flask was cooled to room temperature, filtered, concentrated, and separated by column chromatography to obtain a light yellow oily product with a separation yield of 89%.
With 1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanimine; C31H29N3OPRu(1+)*Cl(1-); sodium tertiary butoxide In toluene at 120℃; for 24h; Inert atmosphere;
31 Preparation of a 2,3,4,5-tetrahydropyridine compound
In a 100mL Shrek reaction flask, the pincer-shaped ruthenium catalyst (12.4mg, 0.02mmol, 0.02equiv) prepared in Example 1, sodium tert-butoxide (144.2mg, 1.5mmol, 1.5equiv) were sequentially added, and the nitrogen was replaced three times. (152.2 mg, 1 mmol, 1.0 equiv), (133.7 mg, 15 mmol, 1.5 equiv) were added under nitrogen, 2 ml of toluene was added, and the mixture was stirred at 120° C. for 24 hours. After the reaction was completed, the reaction flask was cooled to room temperature, filtered, concentrated, and separated by column chromatography to obtain the product as a white solid with a separation yield of 77%.
With C31H29N3OPRu(1+)*Cl(1-); sodium tertiary butoxide In toluene at 120℃; for 24h; Inert atmosphere;
32 Preparation of a 2,3,4,5-tetrahydropyridine compound
In a 100 mL Shrek reaction flask, the pincer-shaped ruthenium catalyst (12.4 mg, 0.02 mmol, 0.02 equiv) prepared in Example 1, and sodium tert-butoxide (144.2 mg, 1.5 mmol, 1.5 equiv) were sequentially added, and the nitrogen was replaced three times. (152.2 mg, 1 mmol, 1.0 equiv), (133.7 mg, 1.5 mmol, 1.5 equiv) were added under nitrogen, 2 ml of toluene was added, and the mixture was stirred at 120° C. for 24 hours. After the reaction was completed, the reaction flask was cooled to room temperature, filtered, concentrated, and separated by column chromatography to obtain the product as a reddish-brown oil with a separation yield of 99%.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
