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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
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Structure of 13325-10-5 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Synthesis, 1990, # 8, p. 735 - 738
[2] Journal of the Chemical Society, 1951, p. 2225,2226, 2229
[3] Chemical and Pharmaceutical Bulletin, 1961, vol. 9, p. 485 - 491
[4] Journal of Heterocyclic Chemistry, 1967, vol. 4, p. 298 - 300
8
[ 110-63-4 ]
[ 123-75-1 ]
[ 93264-47-2 ]
[ 24715-90-0 ]
[ 41726-75-4 ]
[ 13325-10-5 ]
Reference:
[1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 12, p. 1756 - 1761[2] Zh. Org. Khim., 2016, vol. 52, # 12, p. 1765 - 1770,6
[3] Russian Journal of Organic Chemistry, 2016, vol. 52, # 12, p. 1756 - 1761[4] Zh. Org. Khim., 2016, vol. 52, # 12, p. 1765 - 1770,6
[5] Russian Journal of Organic Chemistry, 2016, vol. 52, # 12, p. 1756 - 1761[6] Zh. Org. Khim., 2016, vol. 52, # 12, p. 1765 - 1770,6
9
[ 412274-79-4 ]
[ 13325-10-5 ]
Yield
Reaction Conditions
Operation in experiment
3.3 g
With lithium aluminium tetrahydride In tetrahydrofuran for 1 h; Reflux
The intermediate D (5.15 g, 50 mmol) from Example 2 was added to a 100 mL flask containing 50 mL of dry tetrahydrofuran, and lithium aluminum hydride (2.28 g, 60 mmol) was weighed and slowly added to the flask, followed by stirring. The reaction was refluxed for 1 h; after the reaction was completed, ethyl acetate was added to remove excess lithium aluminum hydride. The 10percent NaOH solution was added dropwise, and the addition was stopped when a pale yellow solid appeared. Finally, the solid was filtered off to obtain an organic layer. The solvent was removed, and a yellow oily liquid product (3.3 g) was obtained by distillation under reduced pressure to give the desired product
Reference:
[1] Doklady Akademii Nauk SSSR, 1948, vol. 63, p. 283[2] Chem.Abstr., 1949, p. 2579
26
[ 67-56-1 ]
[ 13325-10-5 ]
[ 42042-68-2 ]
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
27
[ 13325-10-5 ]
[ 109-94-4 ]
[ 42042-68-2 ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: for 18 h; Reflux; Inert atmosphere Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran for 2 h; Reflux Stage #3: With sodium hydroxide In tetrahydrofuran; water
To a stirred solution of 9 (4.31 g, 48.4 mmol) in EtOH (50 mL) was added ethylformate (5.86 mL, 75.5 mmol) and the mixture was stirred at reflux for 18 hrs under N2. The solution was evaporated under reduced pressure, and the crude product was used for the next step without further purification. The crude reaction mixture was dissolved in THF (25 mL) and added to a suspension of LiAlH4 (5.50 g, 145 mmol) in THF (50 mL) dropwise under a drying tube while stirring. The reaction mixture was brought to reflux and monitored by TLC (20percent EtOH/80percent CHC13) and JH NMR (CDC13). After 2 hours, the starting material was consumed, and 0 (4.16 mL) was added to the cooled reaction mixture, followed by 4 M NaOH (4.16 mL) and 0 (12.5 mL) while stirring vigorously. The precipitate was then removed by filtration, and the filtrate concentrated in vacuo. The residue was re-dissolved in CHCI3, dried over Na2S04, filtered and concentrated under reduced pressure to give 20 as a colorless oil (2.76 g, 56percent); JH NMR (CDC13) δ 3.74 (br, 2H), 3.57 (t, 2H), 2.62 (t, 2H), 2.43 (s, 3H), 1.50-1.75 (m, 4H).18
Reference:
[1] Angewandte Chemie - International Edition, 2002, vol. 41, # 18, p. 3476 - 3479
29
[ 67-56-1 ]
[ 13325-10-5 ]
[ 123-75-1 ]
[ 42042-68-2 ]
[ 13330-96-6 ]
Reference:
[1] Angewandte Chemie - International Edition, 2002, vol. 41, # 18, p. 3476 - 3479
30
[ 50-00-0 ]
[ 13325-10-5 ]
[ 13330-96-6 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 22, p. 6346 - 6349
31
[ 928-51-8 ]
[ 13325-10-5 ]
[ 79448-06-9 ]
Reference:
[1] DRP/DRBP Org.Chem.,
32
[ 928-51-8 ]
[ 7664-41-7 ]
[ 13325-10-5 ]
[ 79448-06-9 ]
Reference:
[1] DRP/DRBP Org.Chem.,
33
[ 13325-10-5 ]
[ 67-64-1 ]
[ 42042-71-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With palladium 10% on activated carbon; hydrogen In ethanol
200 gm of 4-amino-1-butanol (II) was dissolved in a mixed solvent of 400 ml of acetone and 1000 ml of ethanol and, after adding 20 gm of 10percent Pd/C, hydrogenation was carried out under the pressure of 10 kg for 4-5 hours. The reaction solution was filtered to remove the catalyst and the filtrate obtained was concentrated to obtain desired compound in quantitative yield, as a colorless oily substance
Reference:
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7128 - 7137
[2] Patent: WO2017/60827, 2017, A1, . Location in patent: Page/Page column 11
[3] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 21, p. 6692 - 6704
[4] Patent: EP1400518, 2004, A1, . Location in patent: Page 21
34
[ 13325-10-5 ]
[ 24424-99-5 ]
[ 75178-87-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In acetonitrile at 0℃; for 6.5 h; Inert atmosphere
4-amino-1-butanol (0.5 g, 5.61 mmol) was dissolved in acetonitrile (56 ml). The solution was cooled to 0°C and Et3N (1.56 ml, 11.22 mmol, 2 eq.) was added followed by Boc2O (1.346 g, 6.17 mmol). The reaction was followed by TLC and quenched with water (20 ml) after 6.5 h. The solution was extracted with EtOAc (3x30ml), brine was used to help phase separation. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to give the title compound as a colorless oil (1.06 g, quantitative yield)
100%
With triethylamine In methanol at 0 - 20℃;
To the solution of 4-aminobutanol (100 μL) in 2 mL triethylamine/methanol (Et3N/MeOH, v/v, 1:7) di-tert-butyl dicarbonate (278 μL) in 2.5 mL methanol was added dropwise at 0 °C. The solution was stirred at the same temperature overnight and allowed to warm to room temperature during 2 h and kept at ambient temperature for another 6 h. Upon completion of the reaction monitored by TLC visualized by iodine and ninhydin, excess Boc2O and solvent were removed under vacuum. The residue was partitioned between dichloromethane (CH2Cl2) and brine and extracted with CH2Cl2 (3 * 50 mL). The combined organic layers were washed by brine, then dried over MgSO4, filtered and concentrated in vacuo to provide tert-butyl N-(4-hydroxybutyl)carbamate 2 as colorless oil (152 mg, 100percent). 1H NMR (300 MHz, CDCl3) δ 5.02 (s, 1H), 3.63 (t, J = 6.1 Hz, 2H), 3.40 (s, 1H), 3.13 (d, J = 5.9 Hz, 2H), 1.56 (dd, J = 7.2, 4.1 Hz, 4H), 1.44 (s, 9H).
100%
at 20℃; for 3 h;
Butanolamine (5g, 56.09 mmol, 1.0 eq) is introduced in a round-bottomed flask with THF (20 mL) before dropwise addition of di-tert-butylcarbonate (12 mL, 56.09 mmol, 1.0 eq) in THF (10 mL). The reaction mixture is stirred at room temperature for 3 h. After concentration under vacuum, the desired product is obtained as an amorph solid that crystalize upon standing (10 g, quantitative yield).
100%
at 20℃; for 3 h;
To a solution of 4-amino-1 -butanol (2.0 g, 22.5 mmole) in THF at RT was added Boc anhydride (4.90 g, 22.5 mmole). After 3 h, the reaction solution was concentrated under vacuum and the residue purified on silica gel (hexanes/EtOAc, 1 :1 ) to give the title compound (quant.) as a white solid: LCMS (ES) m/z = 190 (M+H)+
96%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 12 h;
General procedure: To a solution of 2a (or 2b–e, 20 mmol) in a mixture of dioxane (15 mL) and H2O (7 mL), wasadded 5N NaOH (4.8 mL) and a solution of Boc2O (5.0 g, 23 mmol) in dioxane at 0 °C. After stirred atrt overnight, the reaction mixture was concentrated in vacuo. The residue was extracted from 10percentcitric acid with AcOEt, and dried over anhydrous Na2SO4. Evaporation of the solvents gave the pureproduct 3a–e. 3a was obtained as a colorless oil (2.67 g, 83percent).
90.2%
at 0℃; for 4 h;
General procedure: tert-butyl 3-hydroxypropylcarbamate 13a: Boc anhydride(319.2g, 1.46 mol) was added drop wise to 3-aminopropan-1-ol (100.0g, 1.33mol) in methanol ( 1000ml )at 0 °C. Reaction mixture was allowed to stir for 4hr. Reaction mixture was concentrated and diluted with water(1000ml) and ethylacetate (1000ml). Layers were separated.Organic layer was washed with water (250ml), dried oversodium sulfate and concentrated. 202.3g of clear liquid was obtained with 87percent yield. tert-butyl 4-hydroxybutylcarbamate 13b: Followingthe same procedure for 13a, 191.5g of clear liquid with90.2percent yield was obtained. 1H NMR (CDCl3) = 1.44 (s, 9H), 1.48(s, 1 H), 1.52-1.59 (m, 4 H), 3.12-3.16 (m, 2H,),3.66-3.68 (m, 2 H), 4.60-4.69 (br, s, 1 H), 13C NMR (CDCl3)= 26.61, 28.44, 29.74, 40.34, 62.31, 79.21, 156.22.
90.5%
With triethylamine In dichloromethane at 20℃; for 12 h;
4-amino-1-butanol (40) (2.97 g) and triethylamine (5 mL) were added to dichloromethane (60ML), di-tert-butyl dicarbonate (6.61 g) was added under ice-cooling, and the mixture was stirred for 5 minutes. reactionThe solution was returned to room temperature and stirred for 12 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. Filtration and concentration under reduced pressure gave the title compound (41) (5.71 g, yield 90.5percent) as a pale yellow oil.
89%
at 20℃; for 1.5 h;
N-tert-Butoxycarbonyl-4-amino-1-butanol 4-Amino-1-butanol (1.0 g, 11.22 mmol) was dissolved in methanol (10 ml). To this solution, di-tert-butyl carbonate (2.53 g, 11.58 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was confirmed by TLC to be complete, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:acetone=9:1) to obtain N-tert-butoxycarbonyl-4-amino-1-butanol (1.88 g, yield: 89percent).
88%
With triethylamine In dichloromethane at 20℃; for 2 h;
To a mixture of 4-aminobutan-l-ol (4.0 g, 45 mmol) and TEA (7.5 mL, 54 mmol) in DCM (200 ml) was added (Boc)20 (10.2 g, 47.2 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with water (2x150 mL) and the solution of citric acid (100 mL). The organic layer was dried over anhydrous Na2S04 and concentrated to give the product as yellow oil 7.5 g. (yield 88percent).
82%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1.5 h;
4-Aminobutan-1-ol (1.0 g, 11.2 mmol) was suspended in a mixture of dioxane (20 ml), H2O (10 ml) and 1 M NaOH (10 ml) and cooled to 0 °C (ice-water bath) with stirring. Boc2O (2.69 g, 12.34 mmol) was added and stirring was continued at ambient temperature. After 5.5 h additional Boc2O (1.08 g, 4.95 mmol) was added and stirring was continued overnight. Next day additional Boc2O (1.35 g, 6.19 mmol) was added to the suspension. After 1.5 h sulfate buffer (40 ml) was added and the reaction mixture was transferred to a separating funnel and extracted with EtOAc (3 × 30 ml). The combined organic layers were washed with NaHCO3(90 ml) and brine (90 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography (60 percent EtOAc in n-heptane, v/v) gave carbamate 4 (1.62 g, 82percent) as a colourless oil.
54%
With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; for 24 h; Inert atmosphere
A mixture of 4-aminobutan-1-ol (10.0 g, 112.1 mmol, 10.4 mL, 1.0 eq), tert- butoxycarbonyl tert-butyl carbonate (25.7 g, 117.8 mmol, 27.1 mL, 1.05 eq) and DIEA (21.7 g, 168.2 mmol, 29.3 mL, 1.5 eq) in DCE (400 mL) was stirred at 20 °C for 24 h, diluted with water (400 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give compound 07-4-1 (12.0 g, 60.2 mmol, 54percent yield).1H NMR (CDCl3, 400 MHz): δ 3.67 (d, J=4.85 Hz, 2 H), 3.16 (d, J=5.29 Hz, 2 H), 1.54 - 1.62 (m, 4 H), 1.44 (s, 9 H).
7.54 g
at 20℃; for 24 h; Cooling with ice
Reference Example 35 tert-Butyl 4-hydroxybutylcarbamate (0486) (0487) To a mixture of 4-aminobutanol (3.57 g) and ethyl acetate (9 mL) was dropwise added a mixture of di-tert-butyl dicarbonate (8.73 g) and ethyl acetate (1 mL) under ice-cooling. After stirring at room temperature for 24 hrs., the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), and the mixture was washed with water (50 mL), 1N hydrochloric acid (40 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (7.54 g) as a colorless oil. (0488) 1H-NMR(CDCl3): 1.44 (9H, s), 1.47-1.61 (4H, m), 3.07-3.22 (2H, m), 3.61-3.76 (2H, m), 4.62 (1H, bs).
Reference:
[1] Organic Letters, 2009, vol. 11, # 9, p. 2019 - 2022
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 6, p. 2536 - 2543
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 191 - 200
[5] Inorganica Chimica Acta, 2016, vol. 452, p. 152 - 158
[6] Patent: WO2006/113837, 2006, A2, . Location in patent: Page/Page column 78
[7] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 8, p. 803 - 808
[8] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 3009 - 3018
[9] Synthesis, 1990, p. 366 - 368
[10] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 7050 - 7053
[11] Synthesis, 2011, # 24, p. 3991 - 3996
[12] Tetrahedron Letters, 2008, vol. 49, # 29-30, p. 4491 - 4493
[13] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7029 - 7043
[14] Tetrahedron Letters, 1998, vol. 39, # 32, p. 5697 - 5700
[15] Bioorganic Chemistry, 2002, vol. 30, # 2, p. 81 - 94
[16] Angewandte Chemie - International Edition, 2012, vol. 51, # 32, p. 8110 - 8113
[17] Molecules, 2013, vol. 18, # 11, p. 13957 - 13978
[18] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4924 - 4939
[19] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307
[20] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4183 - 4195
[21] Farmaco, 1991, vol. 46, # 12, p. 1517 - 1529
[22] Letters in Organic Chemistry, 2013, vol. 10, # 7, p. 518 - 522
[23] Patent: JP2017/71567, 2017, A, . Location in patent: Paragraph 0208-0210
[24] Patent: US2015/353489, 2015, A1, . Location in patent: Paragraph 0070; 0181; 0182
[25] Patent: WO2012/33858, 2012, A2, . Location in patent: Page/Page column 85
[26] Journal of Organic Chemistry, 2010, vol. 75, # 2, p. 518 - 521
[27] Helvetica Chimica Acta, 1996, vol. 79, # 8, p. 2137 - 2151
[28] Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6819 - 6843
[29] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 644 - 647
[30] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 7, p. 666 - 670
[31] Chemical Communications, 2006, # 20, p. 2156 - 2158
[32] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9673 - 9686
[33] Patent: WO2017/96045, 2017, A1, . Location in patent: Paragraph 00883
[34] Tetrahedron Letters, 1997, vol. 38, # 33, p. 5741 - 5744
[35] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4828 - 4832
[36] Journal of Medicinal Chemistry, 2004, vol. 47, # 24, p. 6055 - 6069
[37] Journal of Medicinal Chemistry, 2005, vol. 48, # 11, p. 3832 - 3839
[38] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 5, p. 923 - 927
[39] Tetrahedron Letters, 2004, vol. 45, # 38, p. 7081 - 7085
[40] Patent: US5965591, 1999, A,
[41] Patent: WO2003/105845, 2003, A1, . Location in patent: Page 88-89
[42] Patent: EP1602362, 2005, A1, . Location in patent: Page/Page column 50
[43] Patent: EP1607088, 2005, A1, . Location in patent: Page/Page column 53
[44] Biomacromolecules, 2012, vol. 13, # 5, p. 1632 - 1641
[45] Angewandte Chemie - International Edition, 2014, vol. 53, # 3, p. 883 - 887[46] Angew. Chem., 2013, vol. 53, # 3, p. 902 - 906
[47] Tetrahedron Letters, 2015, vol. 56, # 51, p. 7108 - 7111
[48] Patent: US2016/128945, 2016, A1, . Location in patent: Paragraph 0486; 0487; 0488
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[50] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7067 - 7083
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[53] ChemMedChem, 2018, vol. 13, # 18, p. 1957 - 1971
35
[ 13325-10-5 ]
[ 34619-03-9 ]
[ 75178-87-9 ]
Reference:
[1] Journal of the American Chemical Society, 2018, vol. 140, # 20, p. 6278 - 6287
36
[ 13325-10-5 ]
[ 33545-98-1 ]
Reference:
[1] Patent: US2012/108515, 2012, A1,
37
[ 13325-10-5 ]
[ 24566-81-2 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 6, p. 1431 - 1438
[2] British Journal of Pharmacology, 1996, vol. 117, # 4, p. 619 - 632
[3] Tetrahedron, 2013, vol. 69, # 36, p. 7699 - 7705
38
[ 13325-10-5 ]
[ 24424-99-5 ]
[ 99207-32-6 ]
Reference:
[1] Patent: EP1184373, 2002, A1, . Location in patent: Example 89
Preparation of this compound was according to the procedure reported by Krivickas S. J. et al. TBDMSCl (8.2 g, 54 mmol, 1.2 eq) was added to a mixture of 4-aminobutanol (4 g, 45 mmol) and pyridine (8 mL). Stirring was allowed for 12 h. TLC (MeOH/CHCl3 = 5/5) indicated the consumption of 4-aminobutanol (Rf = 0.13) and formation of product 4 (Rf = 0.40). The mixture was then concentrated under reduced pressure at 40 oC to provide a residue, which was dissolved by CH2Cl2 (50 mL). After extraction with satd. NaHCO3 (aq), the organic layer was dried over Na2SO4 and filtered through celite pad to provide the filtrate, which was concentrated under reduced pressure. The residue obtained was purified by flash chromatography using silica gel (50 g) with eluents of Et3N/MeOH/CHCl3=2/10/90 to provide colorless oil 4 in quantitative yield (8.8 g). Spectroscopic data is available in the literature. Anal. C10H25NOSi, MW: 203.4, ESI+ Q-TOF MS, M = 203.2 (m/z), [M+H]+ = 204.2; 1H-NMR (500 MHz, CD3OD): d 0.06 (s, 6H, HTBDMS), 0.90 (s, 9H, HTBDMS), 1.55-1.59 (m, 4H), 2.74 (dd, 2H), 3.66 (dd, 2H).
100%
With pyridine; In dichloromethane; for 12h;
2. 4-(tert-butyldimethylsilanyloxy)butan-1-amine (compound of formula 7) Preparation of this compound was according to the procedure reported by Krivickas S. J. et al. Tert-Butyldimethylsiyl Chloride (TBDMSCl) (8.2 g, 54 mmol, 1.2 eq) was added to a mixture of 4-aminobutanol (4 g, 45 mmol) and pyridine (8 mL). Stirring was allowed for 12 h. TLC (MeOH/CHCl3=5/5) indicated the consumption of 4-aminobutanol (Rf=0.13) and formation of compound of formula 7 (Rf=0.40). The mixture was then concentrated under reduced pressure at 40 C. to provide a residue, which was dissolved by CH2Cl2 (50 mL). After extraction with satd. NaHCO3 (aq), the organic layer was dried over Na2SO4 and filtered through celite pad to provide the filtrate, which was concentrated under reduced pressure. The residue obtained was purified by flash chromatography using silica gel (50 g) with eluents of Et3N/MeOH/CHCl3=2/10/90 to provide a colorless oil compound of formula 7 in quantitative yield (8.8 g). Spectroscopic data is available in the literature. Anal. C10H25NOSi, MW: 203.4, ESI+Q-TOF MS, M=203.2 (m/z), [M+H]+=204.2; 1H-NMR (500 MHz, CD3OD): δ 0.06 (s, 6H, HTBDMS), 0.90 (s, 9H, HTBDMS), 1.55-1.59 (m, 4H), 2.74 (dd, 2H), 3.66 (dd, 2H).
100%
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of 4-aminobutan-l-ol (2 g, 22 mmol) in dichloromethane (25 mL) at 0C were added triethyl amine (5.67 g, 56 mmol) followed by TBS chloride (5 g, 33 mmol) and the resulting reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and indicates the completion of the reaction. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium chloride solution and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 4- ((tert-butyldimethylsilyl)oxy)butan-l -amine (4.5 g, 100%). DIMS (ESI): m/z 204.14 (M+l).
100%
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of 4-aminobutan-l-ol (2 g, 22 mmol) in dichloromethane (25 mL) at 0C were added triethyl amine (5.67 g, 56 mmol) followed by TBS chloride (5 g, 33 mmol) and the resulting reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC and indicates the completion of the reaction. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium chloride solution and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 4- ((tert-butyldimethylsilyl)oxy)butan-l -amine (4.5 g, 100%). DIMS (ESI): m/z 204.14 (M+l).
92%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
To the solution of 4-aminobutanol (20 g, 0.224 mol) in dichloromethane (200 ml) was added triethylamine at 0 C. tert-butyldimethylchlorosilane (33.8 g, 0.224 mol) was added at the same temperature and stirred at room temperature for 4 h. The reaction mixture was diluted with water. The organic layer was washed with water, brine, dried over anh. sodium sulfate and concentrated. The crude product (42 g, 92%) was used for next step without purification.
88%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;
General procedure: A reaction vessel containing a stirring bar under argon` (balloon) was charged with the appropriate alcohol, imidazole (2.5 equivalents) and was dissolved in anhydrous CH2Cl2 (0.2 M). The suspension was cooled to 0 C and tert-butyldimethylsilyl chloride (1.1 equivalents) was added to the reaction vessel. The reaction was stirred at room temperature for 3 h.
88%
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;
General procedure: A reaction vessel containing a stirring bar under argon` (balloon) was charged with the appropriate alcohol, imidazole (2.5 equivalents) and was dissolved in anhydrous CH2Cl2 (0.2 M). The suspension was cooled to 0 C and tert-butyldimethylsilyl chloride (1.1 equivalents) was added to the reaction vessel. The reaction was stirred at room temperature for 3 h.
33%
With 1H-imidazole; In dichloromethane; at 20℃; for 1h;
Synthesis of O-(tert-butyldimethylsilyl)-4-amino-1-butanol. Synthesisof O-(tert-butyldimethylsilyl)-4-amino-1-butanol was adapted from a previous procedure.2Briefly, 4-amino-1-butanol (1.93 mL, 0.021 mol) and imidazole (2.72 g, 0.040 mol) weredissolved in 20 mL CH2Cl2. Tert-butyldimethylchlorosilane (TBDMS-Cl, 3.17 g, 0.021 mol) wasdissolved in 10 mL CH2Cl2 and slowly added to the ethanolamine/imidazole mixture over 5minutes. The reaction was stirred at RT for 1 hour. Deionized water (20 mL) was added, theorganic layer collected, and the aqueous layer washed twice more with CH2Cl2. The combinedorganic layers were dried over CaCl2 and concentrated in vacuo to yield a pale yellow oil (1.4 g;33% yield). ESI [M+H]+1 expected 204.18 Da, observed 204.13 Da
33%
With 1H-imidazole; In dichloromethane; at 20℃; for 1.08333h;
Synthesis of O-(tert-butyldimethylsilyl)-4-amino-1-butanol was adapted from a previous procedure. (Corson et al. ACS Med. Chem. Lett. 2016, 7(12).) Briefly, 4-amino-1-butanol (1.93 mL, 0.021 mol) and imidazole (2.72 g, 0.040 mol) were dissolved in 20 mL CH2Cl2. Tert-butyldimethylchlorosilane (TBDMS-Cl, 3.17 g, 0.021 mol) was dissolved in 10 mL CH2Cl2 and slowly added to the ethanolamine/imidazole mixture over 5 minutes. The reaction was stirred at room temperature for 1 hour. Deionized water (20 mL) was added, the organic layer collected, and the aqueous layer washed twice more with CH2Cl2. The combined organic layers were dried over CaCl2) and concentrated in vacuo to yield a pale yellow oil (1.4 g; 33% yield). ESI [M+H]+1 expected 204.18 Daltons (Da), observed 204.13 Da.
1H-imidazole;
REFERENCE EXAMPLE 2 4-(tert-Butyldimethylsilyloxy)-1-butylamine In a manner similar to that in Reference Example 1, 4-amino-1-butanol was reacted with tert-butyldimethylsilyl chloride in the presence of imidazole to give 4-(tert-butyldimethylsilyloxy)-1-butylamine. 1H-NMR (CDCl3)δ(ppm): 0.09 (s, 6H), 0.91 (s, 9H), 1.58 (m, 4H), 3.32 (q, J=6.3 Hz, 2H), 3.64 (t, J=5.8 Hz, 1H).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 24h;
Part A; Triethylamine (17.7 mL, 127 mmol), 4-dimethylaminopyridine (70 mg), and t~ butyldimethylsilyJ chloride (18.3 g, 121 mmol) were added to a 0 0C solution of 4-amino- 1-butanol (10.3 g, 116 mmol) in dichloromethane (100 mL). The mixture was allowed to warm to room temperature and was stirred for 1 day. The mixture was poured onto water (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 21.6 g of 4-[tert- butyl(dimethyl)sily]]oxy}butan-]-amine as an oil that contained minor impurities.
With triethylamine; In dichloromethane; at 0 - 22℃; for 18h;
To a solution of 4-aminobutanol (2.08 mL, 22.44 mmol, Aldrich) in DCM (20 mL) is added TEA (3.44 mL, 24.68 mmol) at 0C. Tert-butyldimethylchlorosilane (3.72 g, 24.68 mmol, Aldrich) is added at the same temperature and stirred at RT for 18 hours. The reaction mixture is diluted with water. The organic layer is washed with water and brine, dried over Mg504, filtered and concentrated to give crude 38a, which is used as such for the next step.
With 1H-imidazole; In dichloromethane; at 20℃; for 2h;
A mixture of 4-hydroxybutylamine (4.0 g, 44.9 mmol), tørt-butyldimethyl-silyl chloride (7.4 g, 49.3 mmol) and imidazole (6.7 g, 98.7 mmol) in dichloromethane (150 mL) was stirred at room temperature for 2 hours. The product mixture was washed successively with aqueous NaHCO3, water, EPO <DP n="67"/>and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. This intermediate silylated aminoalcohol was used without further purification. To a mixture of the amine (1.0 g, 4.9 mmol) and benzyloxyacetaldehyde (0.74 g, 4.9 mmol) in dichloroethane (15 mL) at room temperature, sodium triacetoxyborohydride (1.3 g, 6.3 mmol) was added. The reaction mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium carbonate. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title silyloxybutyl-amine. lH NMR (400 MHz, CDCI3) δ 7.33 -7.25 (m, 5H), 4.51 (s, 2H), 3.60 (m, 4H), 2.79 (br t, J = 4.9 Hz, 2H)52.60 (br t, 2 H), 1.52 (br signal, 5 H), 0.87 (s, 9H), 0.03 (s, 6H).
4-Amino-l-butanol (0.13 ml, 0.0014 mol) was added at room temperature to a mixture of l-(4-chloro-2-pyridinyl)- ethanone (200 mg, 0.0013 mol), pαrø-toluene sulfonic acid (123 mg, 0.00065 mol), and 3A molecular sieves in MeOH (4 ml). The mixture was stirred 6 hours at room temperature, cooled down to O0C, and sodium borohydride (98 mg, 0.0026 mol) was slowly added. The mixture was stirred at room temperature for 18 hours. Molecular sieves were filtered off, and the mixture was poured out into water and the solvent was evaporated. The aqueous layer was basified with a saturated solution of sodium hydrogen carbonate, and extracted 3 times with DCM. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (40-63 μm) (eluent: DCM/MeOH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 269 mg (91%) of intermediate 20 as a yellow oil.
With mesoporous Cs-B-Zr mixed oxide; In neat (no solvent); at 220℃; under 32253.2 Torr; for 0.5h;Autoclave; Inert atmosphere; Green chemistry;
General procedure: N-Alkylation reaction was performed in a volume of 500 ml stainless-steel autoclave batch reactor. A mixture of 2-aminoethanol (0.5 mol) with methanol (1.5 mol) was added to the reactor containing 4 wt% of catalyst (with respect to 2-aminoethanol). The N-alkylation reaction was conducted under the constant stirred with a speed 200 r min-1 at 220 C and 4.3 MPa (To maintain thepressure in the reaction kettle by adding nitrogen) for 35 min. The reaction products were identified by GC-MS analysis (Agilent 5973N-6890N, Agilent Technologies). The selectivity and chemical conversions of the products were determined by GC analysis (GC-17A, Shimadzu Co; FID detector and DB-1 ms capillary column, J&W).
5-chloro-6-[(4-hydroxy-butylamino)-methyl]-1<i>H</i>-pyrimidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.4%
With potassium carbonate; In N,N-dimethyl-formamide; at 95 - 100℃;
At room temperature, 5-Chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1,9.75g, 0.05mol), 4-aminobutan-1-ol (SM-2, 5.79g, 65.0mmol), potassium carbonate (16.59g, 0.12mol) were added to N,N-dimethylformamide (80mL), Temperature control 95-100 C reaction. After the detection reaction was completed, the reaction solution was filtered while hot, and purified water (300 mL) was added to the filtrate, dichloromethane (100mL×3) was extracted, washed with hydrochloric acid (1mol/L, 50mL×2), the organic phase was washed with purified water (50mL×2), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain compound 2, yield 95.4%, HPLC: 99.5%.
With palladium 10% on activated carbon; hydrogen; In ethanol; under 7500.75 Torr;
200 gm of 4-amino-1-butanol (II) was dissolved in a mixed solvent of 400 ml of acetone and 1000 ml of ethanol and, after adding 20 gm of 10% Pd/C, hydrogenation was carried out under the pressure of 10 kg for 4-5 hours. The reaction solution was filtered to remove the catalyst and the filtrate obtained was concentrated to obtain desired compound in quantitative yield, as a colorless oily substance
With hydrogen;platinum(IV) oxide; In ethanol; under 1520.1 - 2280.15 Torr; for 48.0h;
100.40 g of 4-amino-1-butanol was dissolved in a mixed solvent of 108 ml of acetone and 160 ml of ethanol and, after adding 2.1 g of platinum (IV) oxide, hydrogenation was carried out under the pressure of 2 to 3 atms for 48 hours.. A catalyst was removed by filtering the reaction solution and the filtrated was concentrated to obtain 147.64 g of the desired compound as a colorless oily substance.
With platinum(IV) oxide; hydrogen; at 20℃; for 168.0h;
To a solution of 4-aminobutan-1 -ol (2.7 ml, 29 mmol) in acetone (3.5ml, 47mmol) was added platinum(IV) oxide (67 mg, 0.29 mmol). The mixture stirred under H2 atmosphere at ambient temperature for 7 days. The reaction mixture was filtered through Celite, and concentrated under reduced pressure to afford a colorless oil (3.72 g 97%). 1 H NMR (400 MHz, Chloroform-d) d 3.43 (t, J = 5.3 Hz, 2H), 2.67 (hept, J = 6.3 Hz, 1 H), 2.50 (t, J = 5.7 Hz, 2H), 1 .49 (ddt, J = 13.2, 7.8, 4.7 Hz, 4H), 0.95 (d, (0157) J = 6.5 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) d 62.1 1 , 48.55, 46.92, 32.23, 28.80, 22.52
a) A mixture of <strong>[16263-52-8]3-chloro-1,2-benzisoxazole</strong> (0.08 mol), 4-amino-1-butanol (0.24 mol) and potassium iodide (1 g) was stirred for 4 days at 80 C. The reaction mixture was cooled, dissolved in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%)of 4-(1,2-benzisoxazol-3-ylamino)-1-butanol (interm. 7).
15.4 g (93%)
With Ki; In dichloromethane;
a) A mixture of <strong>[16263-52-8]3-chloro-1,2-benzisoxazole</strong> (0.08 mol), 4-amino-1-butanol (0.24 mol) and KI (1 g) was stirred for 4 days at 80 C. The reaction mixture was cooled, dissolved in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%) of 4-(1,2-benzisoxazol-3-ylamino)-1-butanol (interm. 1).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 16h;
(2E)-3-(2-Bromophenyl)acrylic acid (4.06 g, 17.9 mmol) in methylene chloride (60 mL) was treated in succession with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.84 g, 35.8 mmol), 1-hydroxybenzotriazole hydrate (2.42 g, 17.9 mmol), and neat 4-amino-1-butanol (3.19 g, 35.8 mmol) and stirred for 16 hours. The mixture was diluted with ethyl acetate and quenched with water. The aqueous phase was separated and extracted with ethyl acetate. [0290] All the ethyl acetate layers were combined, washed twice with a 1N aqueous HCl solution, twice with a saturated aqueous NaHCO3 solution, brine solution, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (CI+) m/z 299 (M+H)+.
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 100℃; for 2h;
23.a Example 23 (a):; 4-(6-NITRO-BENZOTHIAZOL-2-YLAMINO)-BUTAN-1-OL
In an oven fried vial charged with 4-amino-l-butanol (172 [JIT,] 2 eq.), [2-CHLORO-] 6-nitro-benzothiazol (200 mg, 0.93 [MMOL)] and [DIISOPROPYL-ETHYLAMINE] (1 [ML)] was added DMF (5 [ML).] The dark brown mixture was heated at 100 [C] for 2 hours. After cooling, the mixture was diluted with 20 [ML] of water and extracted with ethyl acetate (50 [ML).] The ethyl acetate layer was washed with brine, dried over MgSO4 and then evaporated to give a dark residue. This residue was subjected to silica gel chromatography (7% [2M] ammonia/methanol in [CH2CI2)] to give the desired product (45 mg, 18%). 1H NMR (CD30D) 8 : 8.55 (d, [1H,] J=2.3 Hz), [8.] 17 (dd, [1H,] J=2.3, 8.9 Hz), 7.47 (d, [1H,] J=8.9 Hz), 3.63 (m, [3H),] 3.53 (t, 2H, J=6.8 Hz), 1.80-1. 75 (m, 2H), 1.70- 1.65 (m, 2H); MS [(M+1,] 268).
To a stirring solution of <strong>[34662-29-8]2-chloro-4-cyanonitrobenzene</strong> from step i (2.48 g, 13.6 mmol) in 12 ml DMF was cooled in ice. 4-aminobutanol (5.50 ml, 59.3 mmol) was added and the reaction mixture was slowly allowed to warm to room temperature after which stirring was continued at room temperature for 72 h. H2O was added and the aqueous layer was extracted with CH2Cl2 (2×) The combined organic layers were washed with H2O (3×), dried (by a Water Repelling Filter) and evaporated under reduced pressure. The residue was chromatographed with Et2O/petroleum ether 4:1 as eluent to give 2.6 g (49%) of the amino-alkylated product
With potassium carbonate; In ethyl acetate; acetonitrile;
4-(4-Cyano-2-nitro-phenylamino)-butan-1-ol A mixture of 3-nitro-4-chloro-benzonitrile (20.4 g, 112.2 mmol), and 4-aminobutanol (10 g, 112 mmol) and K2CO3 (30.9 g, 224 mmol) in CH3CN (100 ml) was stirred at 23 C. for 12 h. Starting material remains by TLC analysis. Additional 4-aminobutanol (2 g, 22 mmol) was added and stirring continued for 24 h. The mixture is filtered and concentrated. The residue is dissolved in EtOAc and washed with water. The extracts are dried over MgSO4 and concentrated to give 26 g (99%) of 4-(4-cyano-2-nitro-phenylamino)-butan-1-ol as an orange solid. 1H NMR (CDCl3) delta: 1.62-1.75 (m, 2H), 1.84-1.90 (m, 2H), 3.40-3.44 (m, 2H), 3.74 (t, J=6.1 Hz, 2H), 6.92 (d, J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 8.45 (br s, 1H), 8.50 (s, 1H); MS m/e 235 (MH+).
(4R)-N-(4-hydroxybutyl)-2-oxothiazolidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25(a) (4R)-N-(4-Hydroxybutyl)-2-oxothiazolidine-4-carboxamide Following a procedure similar to that described in Example 16(a), but using 1.2 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.23 g of N-(4-hydroxybutyl)amine, 0.735 g of the title compound was obtained as colorless crystals, melting at 81-83 C. Nuclear Magnetic Resonance Spectrum (CDCl3 +hexadeuterated dimethyl sulfoxide) delta ppm:
With hydrogenchloride; p-toluenesulfonic acid monohydrate; triethylamine In hexane; dichloromethane; chloroform
107.2 2-(4-Hydroxybutyl)-1,1-dioxido-5,6-dihydro-[1,4]dioxino[2,3-d]benzisothiazol-3(2H)-one
Step 2: To an ice cold, stirred solution of 10 g of 4-aminobutanol and 25 mL of triethylamine in 250 mL of dichloromethane was added a solution of 21.5 g of 1,4-benzodioxane-6-sulfonylchloride in 100 mL of chloroform over 30 min. The mixture was allowed to warm and stir overnight, washed with 100 mL of 6N HCl and dried over MgSO4. To this solution was added 300 mL of dichloromethane, 20 mL of dihydropyran and 100 mg of p-toluenesulfonic acid monohydrate. After stirring for 12 h, the mixture was washed with 100 mL of saturated Na2 CO3, dried over MgSO4 and concentrated under reduced pressure. Chromatography on silica gel, eluding with 30% ethyl acetate in hexane gave, after drying overnight under vacuum, 13 g of N-(4-(2-tetrahydropyranyloxy)butyl)-1,4-benzodioxane-6-sulfonamide as a resin.
4-(3,5-Dimethyl-1,2,4-triazol-4-yl)butanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-methyl-pyrrolidin-2-one;
PREPARATION 17 4-(3,5-Dimethyl-1,2,4-triazol-4-yl)butanol STR72 <strong>[13148-65-7]<strong>[13148-65-7]2,5-Dimethyl-1,3,4-oxadiazol</strong>e</strong> (3.8 g), 4-aminobutanol (3.5 g) and N-methylpyrrolidone (10 ml) were heated at 150 for 18 hours. The mixture was evaporated under high vacuum and the residue chromatographed on silica eluding with a mixture of ethyl acetate and methanol. The fractions containing the product were evaporated under vacuum to leave the title compound, (5.1 g), which was used directly.
1
Example 1-Preparation and Testing of Amine-containing Lipids[00264] Lipid synthesis. Monomers were purchased from Aldrich (Milwaukee, WI), TCI (Portland, OR), Pfaltz & Bauer (Waterbury, CT), Matrix Scientific (Columbia, SC), Acros-Fisher (Pittsburg, PA), Scientific Polymer (Ontario, NY), Polysciences (Warrington, PA), and Dajac monomer-polymer (Feasterville, PA). The acrylate and amine monomers were used neat to prepare the lipids. All possible pair wise combinations of amine and acrylate monomers shown in Figure 1 were prepared in sealed vials. The vials were then incubated overnight at approximately 95 0C with shaking. The synthesized lipids were used without further purification.; In certain embodiments, the lipid is prepared by reacting amine 28 with acrylate ND to form lipid ND28. In certain embodiments, the lipid ND28 is of one of the formulae below:In other embodiments, the lipid is a composition of one or more of the above lipids.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;
To a solution of 6-quinolinecarboxylic acid (2) (200.0 mg, 1.16 mmol) in dry dichloromethane (20.0 ml_), triethylamine (162.0 mul_, 1.16 mmol), 1 - hydroxybenzotriazole hydrate (171.0 mg, 1.27 mmol) and lambda/-(3-dimethylaminopropyl)- lambda/'-ethylcarbodiimide hydrochloride (243.0 mg, 1.27 mmol) were added at 00C under argon atmosphere; the suspension was warmed to room temperature and stirred for 1 h. Then 4-amino-1-butanol (117.0 mul_, 1.27 mmol) was added and the mixture was stirred overnight at room temperature. The resulting suspension was evaporated and the crude product was purified by means of flash chromatography (10% methanol in chloroform) to give 275.0 mg of 3 as white solid (97% yield). Mp (methanol) 121 - 122C; 1H NMR1 SOO MHz, (CDCI3) delta 1.67-1.84 (m, 4H), 2.13 (br s, 1 H); 3.48-3.59 (m, 2H), 3.76 (m, 2H), 7.02 (br s, 1 H), 7.43 (m, 1 H), 8.01 -8.12 (m, 2H), 8.20 (d, 1 H, J = 8.5 Hz), 8.30 (m, 1 H), 8.94 (m, 1 H). ESI-MS m/z 511 [2M+Na]+, 267 [M+Na]+, 245 [M+H]+. Anal. (Ci4Hi6N2O2) C, H, N.
97%
To a solution of 6-quinolinecarboxylic acid (200.0 mg, 1 .16 mmol) in dry dichloromethane (20.0 ml_), triethylamine (162.0 mul_, 1 .16 mmol), 1 - hydroxybenzotriazole hydrate (171 .0 mg, 1 .27 mmol) and lambda/-(3- dimethylaminopropyl)-lambda/'-ethylcarbodiimide hydrochloride (243.0 mg, 1 .27 mmol) were added at 00C under argon atmosphere; the suspension was warmed to room temperature and stirred for 1 h. Then 4-amino-1 -butanol (1 17.0 mul_, 1 .27 mmol) was added and the mixture was stirred overnight at room temperature. The resulting suspension was evaporated and the crude product was purified by <n="13"/>means of flash chromatography (10% methanol in chloroform) to give 275.0 mg of the title compound as a white solid (97% yield).Mp (methanol) 121 -122C; 1H NMR, 300 MHz, (CDCI3) delta 1 .67-1 .84 (m, 4H), 2.13 (br s, 1 H); 3.48-3.59 (m, 2H), 3.76 (m, 2H), 7.02 (br s, 1 H), 7.43 (m, 1 H), 8.01 -8.12 (m, 2H), 8.20 (d, 1 H, J = 8.5 Hz), 8.30 (m, 1 H), 8.94 (m, 1 H). ESI-MS m/z 51 1 [2M+Na]+, 267 [M+Na]+, 245 [M+H]+. Anal. (C14H16N2O2) C, H, N.
10.a
A mixture of 3-bromomethyl-pentane (3.0 g, 20 mmol) and 4-amino-1-butanol (5.06 mL, 55 mmol) in ethanol (20 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (50 mL) and the aqueous layer extracted with dichloromethane (20 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as an oil (2.8 g). 1H NMR (d6-DMSO, 400 MHz) δ (ppm): 3.37 (t, J=6.0 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 2.37 (d, J=5.2 Hz, 2H), 1.43-1.41 (m, 4H), 1.31-1.24 (m, 5H), 0.81 (t, J=7.2 Hz, 6H).
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
4-Amino-1-butanol (commercially available, for example, from Aldrich) (0.5 ml, 5.4 mmol) was dissolved in dichloromethane (25 ml) together with triethylamine (4.5 ml, 32 mmol), and the stirred solution was cooled in an external ice-water bath under a nitrogen atmosphere. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (commercially available, for example, from Fluka) (1.5 ml, 16 mmol), dissolved in dichloromethane (15 ml), was added dropwise, using further dichloromethane (10 ml) to wash in. The reaction mixture was stirred under nitrogen and allowed to warm gradually to room temperature over three hours. The mixture was diluted with further dichloromethane (50 ml) and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with further dichloromethane (x 2). The combined organic solutions were dried (magnesium sulfate) and concentrated in vacuo to give the crude product (1.70 g). A portion of the crude material was purified by chromatography. The <n="56"/>brown oil (792 mg) was applied to a silica cartridge (50 g, Flashmaster 2), eluting with 0- 100% ethyl acetate-dichloromethane over 40 min to give the pure title compound as a colourless gum (621 mg, ca. 90%): LCMS RT = 2.15 min, ES+ve m/z 291 (M+NH4)+.
With triethylamine; In dichloromethane; at 5 - 20℃;
4-[(Ethylsulfonyl)amino]butyl ethanesulfonate 4-Amino-1-butanol (commercially available, for example, from Aldrich) (0.97 g, 11 mmol) was dissolved in DCM (50 ml) together with triethylamine (9.0 ml, 65 mmol), and the stirred solution was cooled to approximately 5 C. in an external ice-water bath under a nitrogen atmosphere. <strong>[594-44-5]Ethanesulfonyl chloride</strong> (commercially available, for example, from Aldrich) (4.09 g, 31.8 mmol), dissolved in DCM (30 ml), was added dropwise, using further DCM (20 ml) to wash in. The reaction mixture was stirred under nitrogen and allowed to warm gradually to room temperature over 4 h. The mixture was diluted with further DCM (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (100 ml). The aqueous layer was extracted with further DCM (100 ml,*2). The combined organic solutions were dried (MgSO4) and concentrated in vacuo to give the crude product, which was used without further purification in the reaction below (3.11 g): LCMS RT=2.06 min, ES+ve m/z 274 (M+H)+, 291 (M+NH4)+.
CDI (4.07 g, 25 mmol) was added to a solution of 4-pyridin-2-yl- benzoic acid (5.0 g, 25 mmol) in dichloromethane and the reaction mixture stirred for 4 hours. 4-aminobutanol (3.0 mL, 30 mmol) was added and the reaction mixture stirred for 4 hours after which the solution was washed with a saturated solution of Na2CO3. The organic layer was separated, dried over MgSO4, filtered and the solvent removed under reduced pressure. The product was purified by column chromatography (dichloromethane, dichloromethane/MeOH 1%) to give 2.4 g of the title alcool. LC Rt = 0.98 min (5 min run) (M+l=271) 1H NMR (400 MHz, DMSO): 8.71-8.66 (lH,m), 8.53-8.46 (IH, m), 8.78 (2H,d, 8.1 Hz), 8.12 (IH, d, 8.3 Hz), 7.94 (2H, d, 8.1 Hz), 7.92-7.83 (IH, m), 7.46-7.36 (IH, m), 4.38 (IH, t, 6.6 Hz), 3.42 (2H, dd, 6.6 Hz, 12.0 Hz), 3.35-3.25 (2H5 m), 1.60-1.42 (4H,m).
N,N'-bis(4-hydroxybutyl)pyrido[2,3-d]pyrimidine-2,4-diamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With triethylamine; In ethanol; at 70℃; for 5h;
General procedure: A mixture of 5 (5.0 mmol), the respective amine (12 mmol), equimolecular amounts of triethylamine, and ethanol (15 mL) was heated at 70 C for 5 h with stirring. The solvent was removed under vacuum and the residue was dissolved in water (30 mL); the mixture was extracted with chloroform (3 × 25 mL) and the organic extracts were dried over anhydrous sodium sulfate and the solvent was removed in vacuum. For compounds 6t-y the resulting solid was purified by recrystallization as indicated in Table 1. For compounds 6z-ai the residual material isolated after removal of the solvent was washed with 5% HCl (25 mL) and the resulting solid was isolated and purified as indicated in Table 1.
Stage #1: 4-(((benzyloxy)carbonyl)amino)benzoic acid With triethylamine; methyl chloroformate In dichloromethane at 0 - 20℃;
Stage #2: 4-Aminobutanol In dichloromethane at 0 - 20℃;
4.1.7.1. Benzyl (4-((4-hydroxybutyl)carbamoyl)phenyl)carbamate (36)
To a solution of the known acid 35 (1 g, 3.69 mmol) in CH2Cl2 (10 mL) at 0 °C was added triethylamine (1.03 mL, 7.38 mmol) and methyl chloroformate (0.57 mL, 7.38 mmol) dropwise. The resulting solution was allowed to warm to rt and stirred for 2 h before cooling to 0 °C and 4-aminobutanol (0.68 mL, 7.38 mmol) added dropwise and the mixture stirred at rt for 6 h. The solvent was removed in vacuo and water added (20 mL). The resulting white precipitate was filtered to afford 36 as a white solid (0.9 g, 2.66 mmol, 72%). Mp 164-165 °C; νmax cm-1 (KBr) 3567, 3381, 3294, 3030, 2952, 2866, 2741, 1792, 1699, 1667, 1628, 1611, 1587, 1524, 1411, 1312, 1245, 1061, 736, 696; 1H NMR (400 MHz, CDCl3) δ 8.10 (1H, s, NH), 7.49 (2H, d, J = 8.8 Hz, ArH), 7.44-7.32 (7H, m, ArH), 6.85 (1H, s, NH), 5.21 (1H, s, NH), 2.58 (1H, s, OH), 2.44-2.37 (4H, m, (CH2)2), 1.79 (2H, app. quintet, J = 7.5 Hz, CH2), 1.60 (2H, app. quintet, J = 7.2 Hz, CH2); 13C NMR (75 MHz, CDCl3) δ 164.3, 154.2, 143.1, 134.6, 130.4, 128.3, 128.1, 119.5, 66.1, 58.7, 38.3, 26.1, 22.9; LRMS (m/z): [M]- 341.29 [M-H]-.
4-(tert-butyloxycarbonylamino)butylamine hydrochloride The 4-(tert-butyloxycarbonylamino)butylamine hydrochloride was obtained from 4-aminobutan-1-ol in accordance with procedures described in literature (Mattingly, P. G., Synthesis, 1990, 1990, 366-368). m.p. 156-158 C.
2-[6-fluoro-3-(4-methanesulfinyl-benzylidene)-2-methyl-3H-inden-1-yl]-N-(4-hydroxy-butyl)-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;
Step 3.1 Synthesis of 2-[6-fluoro-3-(4-methanesulfinyl-benzylidene)-2-methyl-3H-inden-1-yl]-N-(4-hydroxy-butyl)-acetamide (139) <strong>[38194-50-2]Sulindac</strong> (138) (0.356 g, 1 mmol), 4-amino-1-butanol (0.138 ml, 1.5 mmol) and HBTU (0.57 g, 1.5 mmol) were dissolved in 5 ml of DMF further containing DIPEA (0.17 ml, 1 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC. The remnant was dissolved in ethyl acetate, and then washed with 1 M HCl, saturated NaHCO3 solution, distilled water, brine, and dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was purified by flash column chromatography to give 139 as a white solid in 95% yield.
General procedure: General synthetic procedure: To a solution of 1,8-dihydroxyanthracene-9,10-dione (1) (0.2g; 0.82mmol) in pyridine (5mL) was added the copper (II) salt (1.6mmol). The aminoalcohol (16mmol) was then added, or dissolved in pyridine (2mL) and then added, dropwise under stirring at room temperature, and the mixture was stirred at 80C for 5-10h, until no starting material could be detected by TLC (20% EtOAc in DCM). The reaction mixture was subsequently transferred into a large vessel and deionised water (20mL) was added. The resulting low viscosity mixture was acidified with hydrochloric acid (2M) to pH 2 under constant stirring. The mixture was partitioned between water and dichloromethane and the product extracted into the organic phase. The extract was dried (MgSO4), concentrated under reduced pressure, and applied to a silica gel flash chromatography column. Elution with ethyl acetate in dichloromethane and a gradient between 5 and 60% gave the title compound as a chromatographically homogeneous orange-yellow solid.
With 4-amino-2,3-dimethyl-1-phenylpyrazolin-5-one; N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline sodium salt dihydrate; oxygen In aq. phosphate buffer Enzymatic reaction;
To a stirred solution of 9 (4.31 g, 48.4 mmol) in EtOH (50 mL) was added ethylformate (5.86 mL, 75.5 mmol) and the mixture was stirred at reflux for 18 hrs under N2. The solution was evaporated under reduced pressure, and the crude product was used for the next step without further purification. The crude reaction mixture was dissolved in THF (25 mL) and added to a suspension of LiAlH4 (5.50 g, 145 mmol) in THF (50 mL) dropwise under a drying tube while stirring. The reaction mixture was brought to reflux and monitored by TLC (20% EtOH/80% CHC13) and JH NMR (CDC13). After 2 hours, the starting material was consumed, and 0 (4.16 mL) was added to the cooled reaction mixture, followed by 4 M NaOH (4.16 mL) and 0 (12.5 mL) while stirring vigorously. The precipitate was then removed by filtration, and the filtrate concentrated in vacuo. The residue was re-dissolved in CHCI3, dried over Na2S04, filtered and concentrated under reduced pressure to give 20 as a colorless oil (2.76 g, 56%); JH NMR (CDC13) delta 3.74 (br, 2H), 3.57 (t, 2H), 2.62 (t, 2H), 2.43 (s, 3H), 1.50-1.75 (m, 4H).18
General procedure: The amino alcohol 21 (1.0 equiv) was dissolved in MeOH ([21] = 0.5 mol/L), then benzaldehyde [24] (1.3 equiv) was added and the mixture was allowed to stir for 10 min at room temperature. Subsequently, the reaction was cooled in an ice bath, NaBH4 (1.3 equiv) was added portionwise, the mixture was stirred for 0.25 h at 0 C and 2 h at ambient temperature. Next, the reaction suspension was cooled again to 0 C, conc. HCl-solution in water (3.0 equiv) was added dropwise and MeOH was removed under reduced pressure ( 100 mbar). The residue was diluted with water (1 mL/1 mmol 21) and Et2O (H2O/Et2O 2:1; pH of the mixture ? 0), the phases were separated and the aqueous phase was washed with further Et2O (2x, H2O/Et2O 2:1). In the following,the aqueous phase was cooled in an ice bath, KOH (2.5 equiv) was added and dissolved under stirring, whereby an oil separated. The basic mixture was extracted with Et2O (3x, H2O/Et2O 2:1), the combined extraction phases were dried over MgSO4 and concentrated under reduced pressure. The crude benzylamine 12 was dissolved in 1 mL of chloroform and concentrated under reduced pressure (2x) to remove residual Et2O and dried in high vacuum for 0.5 h under stirring (until the gas evolution ceased).
Stage #1: 4-Aminobutanol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere;
Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;
3 Example 3: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazoiinamine)(MS1)·dimethy)sulfonate
Example 3: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazoiinamine)(MS1)·dimethy)sulfonate [0060] N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69g, 12mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100ml), and 4-hydroxy-1-butylamine (2.22g, 25mmol) was added. The mixture was stirred under nitrogen at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12h. To the mixture was added saturated aqueous solution of sodium carbonate (50 ml), and the mixture was stirred for 15 min and then layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS1. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and then a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After addition, the mixture was stirred at room temperature for 12h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70°C under vacuum to afford a yellow solid (7.51g, 88.0%), i.e. the dimethanesolfonate of the compound of Number MS1. m.p.: 257.9-260 °C ; 1H NMR(DMSO-d6) 1H NMR(DMSO-d6)δ: 8.49(s, 1H), 8.22(1H), 8.06(1H),8.05(1H), 7.43(1H), 7.36(1H), 7.24(d, 1H), 7.17(1H), 6.90(m, 1H), 6.7(2H), 6.28(1H), 5.16(2H), 4.0(1H), 3.66(2H), 3.65(1H), 3.50(2H), 3.29(6H), 2.55(2H), 2.0(3H), 1.53(2H), 1.38(2H); ESI-MS m/z: 547[M+H]+. N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((3-phenylpropyl)amino)methyl)-2-fury 1)-4-quinazolinamine can be prepared by the same method, m.p.: 156-160°C;
Stage #1: 4-Aminobutanol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere;
Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;
3
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69 g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), and 4-hydroxy-1-butylamine (2.22 g, 25 mmol) was added. The mixture was stirred under nitrogen at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12 h. To the mixture was added saturated aqueous solution of sodium carbonate (50 ml), and the mixture was stirred for 15 min and then layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS1. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and then a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70° C. under vacuum to afford a yellow solid (7.51 g, 88.0%), i.e. the dimethanesolfonate of the compound of Number MS1. m.p.: 257.9-260° C.; 1H NMR (DMSO-d6) 1H NMR (DMSO-d6) δ: 8.49 (s, 1H), 8.22 (1H), 8.06 (1H), 8.05 (1H), 7.43 (1H), 7.36 (1H), 7.24 (d, 1H), 7.17 (1H), 6.90 (m, 1H), 6.7 (2H), 6.28 (1H), 5.16 (2H), 4.0 (1H), 3.66 (2H), 3.65 (1H), 3.50 (2H), 3.29 (6H), 2.55 (2H), 2.0 (3H), 1.53 (2H), 1.38 (2H); ESI-MS m/z: 547[M+H]+
4-((6-aminopyridazin-3-yl)amino)butan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium phosphate; copper(l) iodide; 4R-4-hydroxyproline; In dimethyl sulfoxide; at 50℃; for 24h;Inert atmosphere;
General procedure: A 10 mL round-bottomed flask containing a magnetic stirbar was charged with CuI (0.1 mmol) followed by L-hydroxyproline (0.2 mmol),<strong>[187973-60-0]6-iodopyridazin-3-amine</strong> (1.3 mmol) and K3PO4 (3.0 mmol). The flask wasflushed with N2 and a solution of the appropriate amine (1.0 mmol) inanhydrous DMSO (1.5 mL) was then added. The mixture was stirred under N2at 50 C for 24 h. MeOH (5 mL) and H2O (5 mL) were added and the stirredmixture was neutralised by dropwise addition of AcOH. The resultant solidswere allowed to settle out and the supernatant solution added to the top of astrong cation exchange (SCX) column. The remaining solid was washed withfurther MeOH (5 mL), and the washings also added to the SCX column. Thesolution was allowed to elute slowly through the column, which was thenflushed with further MeOH. These MeOH washings were discarded. A 1 Msolution of NH3 in MeOH was flushed through until elution of the product wascomplete and the solvent was evaporated under reduced pressure to yield acrude material. Purification was done by flash silica chromatography, elutiongradient typically 0-10% MeOH in CH2Cl2. Relevant fractions were evaporatedto dryness to afford the desired product.
2-(2-aminoethyl)-ethanol (2.10 g, 19.94 mmol) and phthalic anhydride (2.95 g, 19.94 mmol) were dissolved in 90 mL toluene and the resulting solution was then heated under reflux for 6 h with Dean-Stark apparatus. The reaction mixture was allowed to cool, dried over MgSO4, filtered, and concentrated under diminished pressure afforded compound 128 as a white solid: yield 4.67 g (99%); silica gel TLC Rf 0.35 (1:2 hexanes-ethyl acetate); ‘H NMR (CDC13) ö 3.61 (m, 2H), 3.69 (m, 2H), 3.75 (t, 2H, J = 5.3Hz), 3.91 (t, 2H, J = 5.3Hz), 7.73 (m, 2H), 7.85 (m, 2H, m).
4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4-hydroxybutyl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In tetrahydrofuran; at 20℃;Inert atmosphere;
General procedure: To a suspension of the appropriate quinolonecarboxylic acid (1mmol) in 6mL of dry THF at 25C, HOBt (1.5mmol), WSC (1.5mmol) and the appropriate aminoalcohol (1.5mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen, then the solvent was evaporated, water was added and the solid formed filtered. The crude product was purified by flash chromatography.
4-((4-hydroxybutyl)amino)quinazolin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With triethylamine; In isopropyl alcohol; for 1.0h;Cooling with ice; Reflux;
[0205] To a solution of <strong>[848438-50-6]4-chloroquinazolin-6-ol</strong> (1.0 g, 5.56 mmol) and 4-aminobutan-1- ol (1.0 g, 11.1 mmol) in isopropanol (20 mL) was added Et3N (1.7 g, 16.8 mmol) at ice- water. The reaction mixture was stirred at reflux for 1 hour. The resulting mixture was evaporated and the residue was purified by column chromatography on silica gel (DCM/MeOH from 100:1 to 20:1, v/v) to afford 4-((4-hydroxybutyl)amino)quinazolin-6-ol (0.8 g, 62% yield) as a white solid.
General procedure: 4,7-Dichloroquinoline (2g, 10mmol) was heated with stirring in neat aminoethanol (10mL) at 130C for 5h. The mixture was then allowed to cool at room temperature and poured into cold water during which the compound precipitated. The precipitate was filtered using a Buchner funnel dried under vacuum to get 2-((7-chloroquinolin-4-yl)amino)ethan-1-ol (2a) as a white solid in 95% yield.
4-(7-(Trifluoromethyl)quinolin-4-ylamino)butan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In neat (no solvent); at 130℃;
General procedure: 4,7-Dichloroquinoline (2g, 10mmol) was heated with stirring in neat aminoethanol (10mL) at 130C for 5h. The mixture was then allowed to cool at room temperature and poured into cold water during which the compound precipitated. The precipitate was filtered using a Buchner funnel dried under vacuum to get 2-((7-chloroquinolin-4-yl)amino)ethan-1-ol (2a) as a white solid in 95% yield.
Stage #1: malonic acid With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.5h;
Stage #2: 2-(n-butyl)octanol In dichloromethane at 20℃;
Stage #3: 1 ,6-dibromohexane; 4-amino-1-butanol Further stages;
26 Example 26: Synthesis of Compound 26
Malonic acid (1.0eq) was dissolved in an appropriate amount of dichloromethane, stirred, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0eq), 4- Dimethylaminopyridine (1.0eq) and triethylamine (3.0eq) were stirred at room temperature for 0.5h, 2-butyl-1-octanol (3.0eq) was added, and the reaction was carried out at room temperature overnight. TLC confirmed that the reaction was complete, and added saturated brine and dichloromethane for extraction. The organic phase was washed twice with water, the organic phase was concentrated, and a colorless transparent liquid was obtained by column chromatography.The colorless transparent liquid (1.0eq) obtained above was dissolved in an appropriate amount of anhydrous tetrahydrofuran, sodium hydride (1.0eq) was added in an ice bath, and after stirring for 20min, 1,6-dibromohexane (1.0eq) was added dropwise. After slowly returning to room temperature, the reaction was continued for 5 hours. TLC monitored the completion of the reaction. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed twice with water, dried and concentrated. color transparent liquid.The colorless and transparent liquid (2.5eq) obtained above was dissolved in an appropriate amount of N,N-dimethylformamide, 4-amino-1-butanol (1.0eq) and potassium carbonate (3.0eq) were added, and the solution was heated to a high temperature. The reaction was carried out in a pressure-resistant bottle at 100 °C for 30 hours, the spot plate reaction was completed, and after slowly returning to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, dried, concentrated, and column chromatography to obtain compound 26 .
Stage #1: malonic acid With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.5h;
Stage #2: 7-Hydroxymethylpentadecane In dichloromethane at 20℃;
Stage #3: 1 ,6-dibromohexane; 4-amino-1-butanol Further stages;
25 Example 25: Synthesis of Compound 25
Malonic acid (1.0eq) was dissolved in an appropriate amount of dichloromethane, stirred, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0eq), 4- Dimethylaminopyridine (1.0eq) and triethylamine (3.0eq) were stirred at room temperature for 0.5h, 2-hexyl-1-decanol (3.0eq) was added, and the mixture was reacted at room temperature overnight. TLC confirmed that the reaction was complete, and added saturated brine and dichloromethane for extraction. The organic phase was washed twice with water, the organic phase was concentrated, and a colorless transparent liquid was obtained by column chromatography.The colorless transparent liquid (1.0eq) obtained above was dissolved in an appropriate amount of anhydrous tetrahydrofuran, sodium hydride (1.0eq) was added in an ice bath, and after stirring for 20min, 1,6-dibromohexane (1.0eq) was added dropwise. After slowly returning to room temperature, the reaction was continued for 5 hours. TLC monitored the completion of the reaction. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed twice with water, dried and concentrated. color transparent liquid.The colorless and transparent liquid (2.5eq) obtained above was dissolved in an appropriate amount of N,N-dimethylformamide, 4-amino-1-butanol (1.0eq) and potassium carbonate (3.0eq) were added, and the solution was heated to a high temperature. The reaction was carried out at 100°C for 30 hours in a pressure-resistant bottle, the spot plate reaction was completed, and after slowly returning to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, dried, concentrated, and subjected to column chromatography to obtain compound 25 .
Stage #1: malonic acid With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.5h;
Stage #2: 7-Hydroxymethylpentadecane In dichloromethane at 20℃;
Stage #3: 4-amino-1-butanol; 1,9-Dibromononane Further stages;
27 Example 27: Synthesis of Compound 27
Malonic acid (1.0eq) was dissolved in an appropriate amount of dichloromethane, stirred, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0eq), 4- Dimethylaminopyridine (1.0eq) and triethylamine (3.0eq) were stirred at room temperature for 0.5h, 2-hexyl-1-decanol (3.0eq) was added, and the mixture was reacted at room temperature overnight. TLC confirmed that the reaction was complete, and added saturated brine and dichloromethane for extraction. The organic phase was washed twice with water, the organic phase was concentrated, and a colorless transparent liquid was obtained by column chromatography.The colorless transparent liquid (1.0eq) obtained above was dissolved in an appropriate amount of anhydrous tetrahydrofuran, sodium hydride (1.0eq) was added in an ice bath, and after stirring for 20min, 1,9-dibromononane (1.0eq) was added dropwise. After slowly returning to room temperature, the reaction was continued for 5 hours. TLC monitored the completion of the reaction. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed twice with water, dried and concentrated. color transparent liquid.The colorless and transparent liquid (2.5eq) obtained above was dissolved in an appropriate amount of N,N-dimethylformamide, 4-amino-1-butanol (1.0eq) and potassium carbonate (3.0eq) were added, and the solution was heated to a high temperature. The reaction was carried out in a pressure-resistant bottle at 100°C for 30 hours, the spot plate reaction was completed, and after slowly returning to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, dried, concentrated, and subjected to column chromatography to obtain compound 27 .