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Structure of 821-48-7 * 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.
Stage #1: at 150℃; for 5 h; Inert atmosphere Stage #2: With sodium carbonate In waterSaturated solution
1-(3-Chlorophenyl)piperazine: Under an atmosphere of dry nitrogen, a mixture of 3-chloroaniline (10.0 g, 78.38 mmol), bis (2-chloroethyl)amine hydrochloride (13.9 g, 78.38 mmol) and diethylene glycol monomethyl ether (19.5 mL) was heated at about 150° C. for about 5 hours. The reaction mixture was cooled to ambient temperature, dissolved in methanol (20 mL) and diluted with ether (500 mL). The obtained precipitate was filtered and washed with ether to yield the hydrochloride salt, which was converted to the free amine by basification with saturated sodium carbonate solution. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (3percent methanol in chloroform) to yield the title product as a pale yellow liquid (5.5 g, 36percent). 1H NMR (400 MHz, CDCl3) δ 2.99-3.04 (m, 4H), 3.10-3.18 (m, 4H), 6.75-6.82 (m, 2H), 6.87 (s, 1H), 7.16 (t, J=8.1 Hz, 1H); IR (film) ν 3294, 2946, 2826, 1592, 1485, 1449, 1239 cm-1; MS 197, 199 [(M+1), (M+3)].
Reference：
[1] Patent: US2009/209550, 2009, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6766 - 6769,4
[3] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
2
[ 821-48-7 ]
[ 75-04-7 ]
[ 5308-25-8 ]
Reference：
[1] DRP/DRBP Org.Chem.,
3
[ 504-29-0 ]
[ 821-48-7 ]
[ 34803-66-2 ]
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
4
[ 109-12-6 ]
[ 821-48-7 ]
[ 20980-22-7 ]
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
5
[ 821-48-7 ]
[ 99-09-2 ]
[ 54054-85-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3116 - 3135
[2] ChemMedChem, 2011, vol. 6, # 4, p. 654 - 666
[3] Journal of Medicinal Chemistry, 1989, vol. 32, # 5, p. 1052 - 1056
[4] Patent: US5852019, 1998, A,
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 18, p. 5443 - 5448
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6766 - 6769,4
6
[ 821-48-7 ]
[ 100-01-6 ]
[ 6269-89-2 ]
Yield
Reaction Conditions
Operation in experiment
14%
With potassium carbonate In butan-1-ol
PREPARATION 6 1-(4-Nitrophenyl)Piperazine This compound was prepared according to the procedure of Preparation 1. A mixture of 100.0 g (0.56 mol) of bis(2-chloroethyl)amine hydrochloride, 77.3 g (0.56 mol) of p-nitroaniline and 160.0 g (1.2 mol) of solid potassium carbonate in a total volume of 1 L of n-butanol gave an oil that solidified upon trituration with ethyl acetate. The hydrochloric acid salt was converted to the base which solidified. The solid was triturated with ethyl ether/methanol to give 16.1 g (14percent) of the product. Concentration of the ethyl ether/methanol mixture gave 1.3 g as a light yellow solid, mp 121°-123° C. Anal. Calculated for C10 H13 N3 O2: C, 57.96; H, 6.32; N, 20.28. Found: C, 57.84; H, 6.29; N, 20.37.
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 46, p. 7921 - 7922
[2] Patent: US5086055, 1992, A,
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6766 - 6769,4
[4] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
7
[ 821-48-7 ]
[ 91-00-9 ]
[ 841-77-0 ]
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1531 - 1536
12
[ 821-48-7 ]
[ 98-59-9 ]
[ 42137-88-2 ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridine In dichloromethane at 0 - 20℃; for 4 h;
bis(2-Chloroethyl)amine hydrochloride (Tokyo Chemical Industry CO., LTD., 25.2 g) was suspended in methylene chloride (280 ml), and the suspension was cooled to 0°C. Pyridine (24 ml) and p-toluenesulfonyl chloride (28.3 g) were added, and the mixture was stirred at room temperature for 4 hr. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with methylene chloride. The organic layer was washed with 1N aqueous hydrochloric acid and water and dried. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (15:1-5:1)) to give N,N-bis(2-chloroethyl)-4-methylbenzenesulfoneamide (30.0 g, yield 71percent). 1H-NMR(300MHz,DMSO-d6)δ(ppm): 2.41(3H,s), 3.45(4H,t,J=6.9Hz), 3.72(4H,t,J=6.9Hz), 7.44(2H,d,J=8.2Hz), 7.75(2H,d,J=8.2Hz).
Stage #1: at 0℃; for 0.166667 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
To a suspension of bis(2-chloroethyl)amine hydrochloride salt (5 g, 0.028 mole) in 30 ml dry dichloro-methane, with cooling (ice water) and stirring, benzyl chloroformate (5.1 g, 0.03 mole) was added dropwise. The addition was complete within 10 min and was followed by addition of triethylamine (6.46 g, 0.063 mole) during 1 h. The mixture was further stirred at room temperature for 1 hour. Water (10 ml) was added, and the mixture was stirred for 15 min. Separated dichchloromethane layer was washed with HCl 1M (10 ml), brine (10 ml), dried and concentrated in vacuo to give an oily product (7 g, 95.5percent yield, 80percent pur).
70%
With triethylamine In dichloromethane at 0 - 20℃; for 6.5 h;
To a solution of 1 (10.4 g, 56.5 mmol) and TEA (11.4 g, 113 mmol) in DCM (60 mE) was added dropwiseCbzCl (10 g, 56.5 mmol) over 30 mins at 00 C. Then the mixture was stirred at room temperature (tt.) for 6 hrs. H20(50 ml) was added, the organic layer was washed with aqueous NaC1, dried by anhydrous Na2504, concentrated in vacuo and the residue was purified by silica gel chromatography (PE/EA=20: 1) to afford compound 2 as a white solid (11.6 g, yield: 70percent).
70%
With triethylamine In dichloromethane at 0 - 20℃; for 6.5 h;
Step 1: To a solution of 1 (10.4 g, 56.5 mmol) and TEA (11.4 g, 113 mmol) in DCM(60 mL) was added dropwise CbzCl (benzyl chloroformate, 10 g, 56.5 mmol) over 30 mins at 0 C. Then the mixture was stirred at room temperature (r.t.) for 6 hrs. H2O(50 ml) was added, the organic layer was washed with aqueous NaCl, dried by anhydrous Na2S04, concentrated in vacuo and the residue was purified by silica gel chromatography (PE/EA = 20:1) to afford compound 2 as a white solid (11.6 g, yield: 70percent).
51.3%
With triethylamine In dichloromethane at 0 - 20℃; for 18 h;
bis(2-chloroethyl)amine hydrochloride (16.000 g, 89.646 mmol) and triethylamine (31.237 mL, 224.115 mmol) was dissolved in dichloromethane (300 mL) at 0 °C then benzyl chloroformate (13.437 mL, 94.128 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hour and further stirred at room temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0percent to 40percent) and concentrated to give the title compound (12.700 g, 51.3percent) as a white solid.
26%
With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 16.5833 h;
10.1: Benzyl bis(2-chloroethyl)carbamate; 13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a solution, cooled to 0° C., of 15 g (84 mmol) of bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 20 g of crude residue are obtained and purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 6 g (26percent) of benzyl bis(2-chloroethyl)carbamate are thus obtained.
26%
With triethylamine In tetrahydrofuran; dichloromethane at 0 - 20℃; for 18.25 h;
13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a solution, cooled to 0° C., of 15 g (84 mmol) of bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and evaporated. 20 g of crude residue are obtained and purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 6 g (26percent) of benzyl bis(2-chloroethyl)carbamate are thus obtained.
28 g
With sodium hydroxide In water at 0℃; for 3 h;
To an aqueous solution (200 mL) of 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (19.3 g) and benzyl chloroformate (15.44 mL) was added dropwise 2M aqueous sodium hydroxide solution (108 mL) at 0° C., and the mixture was stirred at 0° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (28 g). 1H NMR (300 MHz, DMSO-d6) δ 3.53-3.66 (4H, m), 3.68-3.83 (4H, m), 5.11 (2H, s), 7.21-7.55 (5H, m).
Reference：
[1] Organic Letters, 2009, vol. 11, # 2, p. 449 - 452
[2] Patent: US2009/143582, 2009, A1, . Location in patent: Page/Page column 8
[3] Patent: US2015/105384, 2015, A1, . Location in patent: Paragraph 0174; 0175
[4] Patent: WO2016/57779, 2016, A2, . Location in patent: Page/Page column 63
[5] Patent: KR2017/43091, 2017, A, . Location in patent: Paragraph 0693-0696
[6] Patent: US2012/323006, 2012, A1, . Location in patent: Page/Page column 17
[7] Patent: US2014/275108, 2014, A1, . Location in patent: Paragraph 0251
[8] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1979, vol. 33, p. 584 - 586
[9] Patent: US2018/155333, 2018, A1, . Location in patent: Paragraph 1903; 1904
14
[ 111-42-2 ]
[ 821-48-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With thionyl chloride In 1,2-dichloro-ethane at 50℃; for 3 h;
Into a 1 L flask, equipped a refluxing condenser, is added 31.5 g (0.30 mole) of diethanolamine and 300 mL of dichloroethane, then 51.0 mL of thionyl chloride. Solid suspension formed immediately after the addition of thionyl chloride and then dissolved upon warming to 50° C. During refluxing, the solid suspension is dissolved and then the crystalline solid appears. The crystalline suspension is refluxed while being stirred for 3 hrs. The reaction is quenched by adding 20 mL of methanol and the solvents are removed under vacuum. A white crystalline material, bis(2-chloroethyl)amine hydrochloride, weighted 53.0 g, is obtained in a quantitative yield.
100%
With thionyl chloride In dichloromethane for 24 h;
In frst step the starting materials were prepared formdiethanolamine 1 which was reacted with thionyl chloride andafter crystallization gives diethanolamine hydrochloride 2 inquantitative yield. Next, salt 2 was reacted with sodium azide and after extraction and chromatographic purifcation led to corresponding bis-azide derivative 3 in 65percent.
98.8%
With thionyl chloride In chloroform at 50℃; for 4 h;
1) 500 g of diethanolamine was added to the reaction flask equipped with a thermometer and a reflux condenser, Chloroform 9000g, After stirring slowly, add 1500 g of thionyl chloride, The system was then warmed to a reflux reaction at 50 ° C, TLC tracking, 4h reaction is complete, After the second washing, Drying the organic phase, Concentrated to remove chloroform, Followed by addition of 1800 g of ethyl acetate, Filtered, Dried to give bis(2-chloroethyl)amine hydrochloride as a white solid (Formula 4) 839g, Yield 98.8percent
97.8%
With thionyl chloride In chloroform at 0 - 70℃;
1) A first mixed solution was prepared by diluting diethanolamine using chloroform. A second mixed solution was prepared by mixing chlorinated sulfoxid with chloroform. The first mixed solution was dropped to the second mixed solution while stirring after the second mixed solution was cooled to a temperature approximately 0°C, a molar ratio between chlorinated sulfoxid and diethanolamine was controlled at 1:4. Thereafter, a resulting mixture was stirring for reaction for between 2 and 5 h. The temperature was then increased to between 30 and 70°C for allowing the mixture to react at the temperature therein for 2 h. After the reaction, anhydrous ethanol was added. The mixture was then cooled and suction filtrated to obtain a solid. The solid was then washed by ethanol and ether, respectively, and desiccated to obtain bis (2-dichloro ethyl) amine nicotinate having a yield of 97.8percent and an mp of 205.1-207.0°C.
89%
With thionyl chloride In chloroform at 20 - 70℃;
The thionyl chloride (128 ml, 1 . 76mol) by adding 80 ml chloroform, stirring, for 1h slowly dropping in 68 ml chlorofrom dilution of diethanolamine (40 ml, 0 . 417mol). the drop finishes, room temperature reaction 2-5h rear, slow heating to 70 °C, reflux 0.5-1h after the reaction. Cooling, filtering, the filter cake is washed with methylene chloride twice washing, drying, the white solid obtained 66g, yield 89percent,
72%
With thionyl chloride In chloroform for 3 h; Reflux
To a mechanically stirred solution of 63.7 g diethanolamine (0.60 mol) in anyhydrous chloroform (250 mL), 221.0 g thionyl chloride (1.85 mol) were added dropwise at room temperature. The reaction mixture was later heated to reflux, followed by vigorous stirring. Then, 3 h later, the reaction mixture was cooled to 0 °C. The precipitate was then filtered, washed with diethyl ether, and dried under an infrared lamp to obtain 78.1 g white solid bis(2-chloroethyl)amine hydrochloride with a yield of 72percent. 1H NMR (500 MHz, CD3OD): δ 4.91 (2H, s,-NH2), 3.96 (4H, t, –N–CH2), 3.54 (4H, t, –CH2–Cl). An amount of 17.8 g bis(2-chloroethyl)amine hydrochloride (0.10 mol) was added to 200 mL dichloromethane to form a suspension. Later, 120 mL aqueous solution of sodium hydroxide (1 moL/L) were added and stirred at room temperature for 6 h. The dichlormethane layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was distilled under reduced pressure to acquire the pure bis(2-chloroethyl)amine, with a yield of 70percent. 1H NMR (500 MHz, CDCl3): δ 3.60 (4H, t, J = 4.40 Hz, –CH2–Cl), 2.94 (4H, t, –N–CH2), 1.88 (1H, s, -NH).
51.24%
With sodium In chloroformCooling with ice
The 250 ml round-bottom flask by three, the mechanical stirring and the top of the device with drying tube and poisonous gas processing device of the condensation tube, adding 22.00g after sodium wire of diethanolamine treated with 30 ml of chloroform, is stirred and mixed under ice bath. The constant voltage dropping funnel for slowly dropped into 20 ml thionyl chloride with 20 ml chcl mixed solution, a white solid is generated immediately, about 1h completion of the dropping, to 40 °C constant temperature, and to continue stirring 3h. Decompression evaporate solvent and excess of thionyl chloride, to get the yellow solid, in ethanol and acetone recrystallization in a mixture, the white solid obtained 19.24g, yield 51.72percent. Melting point m.p. 216 °C (216 °C fire).
50%
With thionyl chloride In chloroform for 6 h; Cooling
To a stirred chloroform solution of diethanol amine (0.20 mol, 21.01 g), the chloroform solution of SOCl2 was added dropwise under ice-bath. The mixture was stirred for 6 h and evaporated undervacuum and white solid was obtained, and then recrystallized in absolute alcohol, white needle solidwas obtained and dried under vacuum. Yield (50percent). m.p. 215~216 °C. C4H10NCl3 (178.5), MS(ESI)m/z: [M - HCl + H]+ = 142.0.
Reference：
[1] Patent: US2015/299113, 2015, A1, . Location in patent: Paragraph 0043
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2017, vol. 192, # 2, p. 231 - 234
[3] Patent: CN106397356, 2017, A, . Location in patent: Paragraph 0045; 0060; 0066; 0074; 0082; 0090; 0098
[4] Patent: EP2682390, 2014, A1, . Location in patent: Paragraph 0018; 0080
[5] Synthesis, 2010, # 16, p. 2705 - 2707
[6] Inorganic Chemistry, 2014, vol. 53, # 5, p. 2460 - 2470
[7] Organic and Biomolecular Chemistry, 2008, vol. 6, # 23, p. 4323 - 4332
[8] Patent: CN105294685, 2016, A, . Location in patent: Paragraph 0047; 0048
[9] Chemical Biology and Drug Design, 2018, vol. 92, # 3, p. 1597 - 1609
[10] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 20, p. 3444 - 3450
[11] Oriental Journal of Chemistry, 2010, vol. 26, # 4, p. 1401 - 1406
[12] Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1831 - 1840
[13] Journal of Chemical Research, 2011, vol. 35, # 1, p. 43 - 46
[14] Chemistry Letters, 2004, vol. 33, # 9, p. 1212 - 1213
[15] Research on Chemical Intermediates, 2018, vol. 44, # 9, p. 5091 - 5105
[16] New Journal of Chemistry, 2016, vol. 40, # 2, p. 1817 - 1824
[17] Luminescence, 2011, vol. 26, # 6, p. 523 - 530
[18] Asian Journal of Chemistry, 2013, vol. 25, # 15, p. 8292 - 8296
[19] Patent: CN105254631, 2016, A, . Location in patent: Paragraph 0059; 0060; 0061
[20] Molecules, 2018, vol. 23, # 8,
[21] Tetrahedron Letters, 1996, vol. 37, # 32, p. 5805 - 5808
[22] Synthesis, 2005, # 14, p. 2345 - 2348
[23] Biomacromolecules, 2010, vol. 11, # 11, p. 3102 - 3111
[24] Tetrahedron, 2013, vol. 69, # 1, p. 15 - 21
[25] Medicinal Chemistry Research, 2013, vol. 22, # 12, p. 5901 - 5911
[26] Journal of Chemical Research, 2014, vol. 38, # 2, p. 108 - 110
[27] Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, vol. 31, # 2, p. 219 - 228
[28] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1811 - 1818
[29] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1589 - 1597
15
[ 15567-79-0 ]
[ 821-48-7 ]
Reference：
[1] Letters in Drug Design and Discovery, 2015, vol. 11, # 9, p. 1096 - 1106
16
[ 50-18-0 ]
[ 821-48-7 ]
Reference：
[1] Phosphorus, Sulfur and Silicon and Related Elements, 1996, vol. 109, # 1-4, p. 473 - 476
17
[ 50-00-0 ]
[ 821-48-7 ]
[ 55-86-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 100 - 120℃; for 3.33333 h;
Formic acid (10.0 g; 0.2 mol) and 37percent formaldehyde (20 ml) were mixed in a 250 ml round-bottom flask equipped with reflux condenser. 1,5-Dichloro-3-azapentane, hydrochloride (17.0 g; 0.1 mol) was added and the solution was heated with magnetic stirring at 100° C. After 3 h the temperature was increased to 120° C. for 20 min and finally allowed to cool to room temperature before the solvent was evaporated in vacuo to afford 3 as white solid in quantitative yield. 1HNMR (CD3OD, 400 MHz) δ 3.0 (s, 3H); 3.45 (br s, 2H); 3.62 (br s, 2H); 4.07 (br s, 4H).
100%
With formic acid In water at 100 - 120℃; for 3.33333 h; Heating / reflux
Formic acid (10.0 g; 0.2 mol) and 37percent formaldehyde (20 ml) were mixed in a 250 ml round-bottom flask equipped with reflux condenser. 1,5-Dichloro-3-azapentane, hydrochloride (17.0 g; 0.1 mol) was added and the solution was heated with magnetic stirring at 100° C. After 3 h the temperature was increased to 120° C. for 20 min and finally allowed to cool to room temperature before the solvent was evaporated in vacuo to afford 8 as white solid in quantitative yield. 1HNMR (CD3OD, 400 MHz) δ 3.0 (s, 3H); 3.45 (br s, 2H); 3.62 (br s, 2H); 4.07 (br s, 4H).
100%
With formic acid In water at 100 - 120℃; for 3.33333 h;
1,5-Dichloro-3-methyl-3-azapentane hydrochloride 3; Formic acid (10.0 g; 0.2 mol) and 37percent formaldehyde (20 ml) were mixed in a 250 ml round-bottom flask equipped with reflux condenser. 1,5-Dichloro-3-azapentane, hydrochloride (17.0 g; 0.1 mol) was added and the solution was heated with magnetic stirring at 100 C. After 3 h the temperature was increased to 120 C for 20 min and finally allowed to cool to room temperature before the solvent was evaporated in vacuo to afford 3 as white solid in quantitative yield. 1HNMR (CD3OD, 400 MHz) δ 3.0 (s, 3H); 3.45 (br s, 2H); 3.62 (br s, 2H); 4.07 (br s, 4H).
1,5-Dichloroazapentane hydrochloride (1.0 g, 5.6 mmol) was taken in formic acid (0.43 mL, 11.2 mmol). A formaldehyde solution (1.2 mL, 37percent in water) was added and the reaction mixture was heated to 100 °C for 4 h and then to 120 °C for 0.5 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude mixture was washed with hexane to afford 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.0 g, yield 92percent) as a white solid. 1H NMR (300MHz, DMSO-d6) δ 11.21 (br s, 1 H), 4.04 - 4.00 (t, J = 6.8 Hz, 4H), 3.54 - 3.48 (m, 4H), 2.82 (s, 3H).
Reference：
[1] Magnetic Resonance in Chemistry, 2005, vol. 43, # 10, p. 869 - 872
21
[ 821-48-7 ]
[ 90-04-0 ]
[ 5464-78-8 ]
Yield
Reaction Conditions
Operation in experiment
74%
at 150℃; for 12 h;
General procedure: A mixture of 2-methoxyaniline (369.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethyleneglycol monomethyl ether (0.75 mL) was heated at 150 °C for about 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4 mL), followed by the addition of diethyl ether (150 mL). The precipitate formed was recovered byfiltration and washed with diethyl ether to obtain 7c as an HCl salt(510 mg, 74percent). The HCl salt was used for the next reaction without further purification.
74%
at 150℃; for 12 h;
General procedure: A mixture of aniline 30l (279.4mg, 3mmol), bis(2-chloroethyl)amine hydrochloride (535.5mg, 3mmol) and diethylene glycol monomethyl ether (0.75mL) was heated at 150°C for about 12h. The reaction mixture was cooled to room temperature and dissolved in methanol (4mL), followed by the addition of diethyl ether (150mL). The precipitate formed was recovered by filtration and washed with diethyl ether to obtain 31l as an HCl salt (530mg, 89percent). The HCl salt was used for the next reaction without further purification.
74%
at 150℃;
General procedure: A mixture of aniline 44a (279.4mg, 3mmol), bis(2-chloroethyl)amine hydrochloride (535.5mg, 3mmol), and diethylene glycol monomethyl ether (0.75mL) was heated at 150°C for approximately 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4mL), followed by the addition of diethyl ether (150mL). The precipitate formed was recovered by filtration and washed with diethyl ether to obtain 45a as an HCl salt (530 mg, 89percent). The HCl salt was used without further purification for the next reaction.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5546 - 5555
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4127 - 4135
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5538 - 5546
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2137 - 2145
22
[ 821-48-7 ]
[ 108-42-9 ]
[ 13078-15-4 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 150℃; for 14 h;
General procedure: General procedure for synthesis of 1-arylpiperazine hydrochlorides The following procedure for the synthesis of 1-(2,3-dichlorophenyl)piperazine hydrochloride (3a) is illustrative. A 20L round bottom flask connected to scrubber was charged with 2,3-dichloroaniline (1a) (1.0kg, 6.17mol) and bis(2-chloroethyl)amine hydrochloride (2) (1.43kg, 8.02mol) and 3.0L of sulfolane. The heterogeneous mixture was heated to 150°C to give a homogeneous solution which was stirred at 150°C for 14h, by which the time the reaction was completed as monitored by HPLC (see below Table 4). The reaction mixture was cooled to 45°C and diluted with 5.0L of acetone and further cooled to 0°C. The mixture was maintained at 0°C for 1 more hour to precipitate the desired product. This was filtered under nitrogen atmosphere and washed with 1L of chilled acetone and dried at 60°C under vacuum for 8h to yield
70%
at 150℃; for 12 h;
General procedure: A mixture of 2-methoxyaniline (369.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethyleneglycol monomethyl ether (0.75 mL) was heated at 150 °C for about 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4 mL), followed by the addition of diethyl ether (150 mL). The precipitate formed was recovered byfiltration and washed with diethyl ether to obtain 7c as an HCl salt(510 mg, 74percent). The HCl salt was used for the next reaction without further purification.
70%
at 150℃; for 12 h;
The procedure described for the preparation of 23a was usedwith compound 22c (321.5 mg, 3 mmol), bis(2-chloroethyl)aminehydrochloride (535.5 mg, 3 mmol) and diethylene glycol monomethylether (0.75 mL) to obtain 23c as an HCl salt (490 mg,70percent). The HCl salt was used for next reaction without further purification.
70%
at 150℃;
General procedure: A mixture of aniline 44a (279.4mg, 3mmol), bis(2-chloroethyl)amine hydrochloride (535.5mg, 3mmol), and diethylene glycol monomethyl ether (0.75mL) was heated at 150°C for approximately 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4mL), followed by the addition of diethyl ether (150mL). The precipitate formed was recovered by filtration and washed with diethyl ether to obtain 45a as an HCl salt (530 mg, 89percent). The HCl salt was used without further purification for the next reaction.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 30, p. 4541 - 4544
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5546 - 5555
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2266 - 2276
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5538 - 5546
[5] MedChemComm, 2018, vol. 9, # 9, p. 1457 - 1465
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2137 - 2145
23
[ 821-48-7 ]
[ 371-40-4 ]
[ 64090-19-3 ]
Reference：
[1] Magnetic Resonance in Chemistry, 2005, vol. 43, # 10, p. 869 - 872
24
[ 821-48-7 ]
[ 536-90-3 ]
[ 16015-70-6 ]
Reference：
[1] Chemical Biology and Drug Design, 2018, vol. 92, # 3, p. 1597 - 1609
25
[ 821-48-7 ]
[ 106-47-8 ]
[ 13078-12-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 150℃; for 12 h;
General procedure: A mixture of 2-methoxyaniline (369.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethyleneglycol monomethyl ether (0.75 mL) was heated at 150 °C for about 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4 mL), followed by the addition of diethyl ether (150 mL). The precipitate formed was recovered byfiltration and washed with diethyl ether to obtain 7c as an HCl salt(510 mg, 74percent). The HCl salt was used for the next reaction without further purification.
90%
at 150℃; for 12 h;
The procedure described for the preparation of 23a was used with compound 22d (321.4 mg, 3 mmol), bis(2-chloroethyl)aminehydrochloride (535.5 mg, 3 mmol) and diethylene glycol monomethylether (0.75 mL) to obtain 23d as an HCl salt (630 mg,90percent). The HCl salt was used for next reaction without purification.
90%
at 150℃; for 12 h;
General procedure: A mixture of aniline 30l (279.4mg, 3mmol), bis(2-chloroethyl)amine hydrochloride (535.5mg, 3mmol) and diethylene glycol monomethyl ether (0.75mL) was heated at 150°C for about 12h. The reaction mixture was cooled to room temperature and dissolved in methanol (4mL), followed by the addition of diethyl ether (150mL). The precipitate formed was recovered by filtration and washed with diethyl ether to obtain 31l as an HCl salt (530mg, 89percent). The HCl salt was used for the next reaction without further purification.
90%
at 150℃;
General procedure: A mixture of aniline 44a (279.4mg, 3mmol), bis(2-chloroethyl)amine hydrochloride (535.5mg, 3mmol), and diethylene glycol monomethyl ether (0.75mL) was heated at 150°C for approximately 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4mL), followed by the addition of diethyl ether (150mL). The precipitate formed was recovered by filtration and washed with diethyl ether to obtain 45a as an HCl salt (530 mg, 89percent). The HCl salt was used without further purification for the next reaction.
89%
at 150℃; for 14 h;
General procedure: General procedure for synthesis of 1-arylpiperazine hydrochlorides The following procedure for the synthesis of 1-(2,3-dichlorophenyl)piperazine hydrochloride (3a) is illustrative. A 20L round bottom flask connected to scrubber was charged with 2,3-dichloroaniline (1a) (1.0kg, 6.17mol) and bis(2-chloroethyl)amine hydrochloride (2) (1.43kg, 8.02mol) and 3.0L of sulfolane. The heterogeneous mixture was heated to 150°C to give a homogeneous solution which was stirred at 150°C for 14h, by which the time the reaction was completed as monitored by HPLC (see below Table 4). The reaction mixture was cooled to 45°C and diluted with 5.0L of acetone and further cooled to 0°C. The mixture was maintained at 0°C for 1 more hour to precipitate the desired product. This was filtered under nitrogen atmosphere and washed with 1L of chilled acetone and dried at 60°C under vacuum for 8h to yield
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5546 - 5555
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2266 - 2276
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4127 - 4135
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5538 - 5546
[5] Tetrahedron Letters, 2015, vol. 56, # 30, p. 4541 - 4544
[6] Chemical Biology and Drug Design, 2018, vol. 92, # 3, p. 1597 - 1609
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 9, p. 2137 - 2145
26
[ 821-48-7 ]
[ 95-51-2 ]
[ 41202-32-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 150℃; for 14 h;
General procedure: General procedure for synthesis of 1-arylpiperazine hydrochlorides The following procedure for the synthesis of 1-(2,3-dichlorophenyl)piperazine hydrochloride (3a) is illustrative. A 20L round bottom flask connected to scrubber was charged with 2,3-dichloroaniline (1a) (1.0kg, 6.17mol) and bis(2-chloroethyl)amine hydrochloride (2) (1.43kg, 8.02mol) and 3.0L of sulfolane. The heterogeneous mixture was heated to 150°C to give a homogeneous solution which was stirred at 150°C for 14h, by which the time the reaction was completed as monitored by HPLC (see below Table 4). The reaction mixture was cooled to 45°C and diluted with 5.0L of acetone and further cooled to 0°C. The mixture was maintained at 0°C for 1 more hour to precipitate the desired product. This was filtered under nitrogen atmosphere and washed with 1L of chilled acetone and dried at 60°C under vacuum for 8h to yield
85%
at 150℃; for 12 h;
General procedure: A mixture of 2-methoxyaniline (369.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethyleneglycol monomethyl ether (0.75 mL) was heated at 150 °C for about 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4 mL), followed by the addition of diethyl ether (150 mL). The precipitate formed was recovered byfiltration and washed with diethyl ether to obtain 7c as an HCl salt(510 mg, 74percent). The HCl salt was used for the next reaction without further purification.
85%
at 150℃; for 12 h;
The procedure described for the preparation of 23a was used with compound 22b (321.5 mg, 3 mmol), bis(2-chloroethyl)aminehydrochloride (535.5 mg, 3 mmol) and diethylene glycol monomethylether (0.75 mL) to obtain 23b as an HCl salt (595 mg,85percent). The HCl salt was used for next reaction without further purification.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 30, p. 4541 - 4544
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5546 - 5555
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2266 - 2276
27
[ 24424-99-5 ]
[ 821-48-7 ]
[ 118753-70-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydroxide In dichloromethane at 20℃; for 18.5 h;
A suspension of 6/s-(2-chloro-ethyl)-amine hydrochloride (5 g, 0.028 mol) in dichloromethane (42 ml) was rapidly stirred with 10percent aqueous sodium hydroxide (28 ml) in an ice bath, to which di-tert-butyl dicarbonate (6.11 g, 0.028 mol) in dichloromethane (28 ml) was added. After stirring at room temperature for 18.5 hours, dichloromethane (30 ml) was added to the reaction mixture and the two phases were separated. The aqueous phase was further extracted with dichloromethane (30 ml). The combined organic layers were dried (Mg2SO4), filtered and concentrated to give 6/s-(2-chloro-ethyl)-carbamic acid tert-butyl ester (6.74 g, 0.028 mol, 100percent). 1H NMR (250 MHz, CDCl3): 1.48 (9H, s), 3.62-3.68 (8H, m).
100%
With sodium hydroxide In dichloromethane; water at 0 - 20℃; for 18.5 h;
EXAMPLE 42[4-(4-Chloro-phenyl)-1-(7H-pyrrolor2.3-cηpyrimidin-4-yl)-piperidin-4-ylmethyll-methyl-amine <n="143"/>42A. 5/s-(2-chloro-ethvπ-carbamic acid tert-butyl esterA suspension of /s-(2-chloro-ethyl)-amine hydrochloride (5 g, 0.028 mol) in dichloromethane (42 ml) was rapidly stirred with 10percent aqueous sodium hydroxide (28 ml) in an ice bath, to which di-terf-butyl dicarbonate (6.11 g, 0.028 mol) in dichloromethane (28 ml) was added. After stirring at room temperature for 18.5 hours, dichloromethane (30 ml) was added to the reaction mixture and the two phases were separated. The aqueous phase was further extracted with dichloromethane (30 ml). The combined organic layers were dried (Mg2SO4), filtered and concentrated to give 6/s-(2-chloro-ethyl)-carbamic acid tert-butyl ester (6.74 g, 0.028 mol, 100percent). 1H NMR (250 MHz, CDCI3): 1.48 (9H, s), 3.62- 3.68 (8H, m).
99%
With triethylamine In dichloromethane at 0 - 20℃;
To a suspension of 33 (10.05 g, 56.3 mmol) and Boc2O (13.6 g, 62.3 mmol) in CH2C12 (70 mL), cooled by ice/water, was added triethylamine (9.5 mL, 68.2 mmol). After 45 min, the cooling bath was removed, and the reaction mixture was stirred at ambient temperature overnight. Water (50 mL) was added, and the mixture was extracted with ethenhexanes 1:1 (3x100 mL). The combined organic layers were washed with water (2x) and brine, dried over MgSO4 and concentrated to give a pale yellow liquid, which was a 1:1 mixture of 34 and Boc2O. The reaction was therefore repeated with this materil twice, first with 5.89 g (33.0 mmol) of 33 and 4.8 mL of NEt3 (34 mmol) and then with 2.5 g (14 mmol) of 33 and 2.3 mL of NEt3 (17 mmol). This gave 14.887 g (61.5 mmol, 99percent) of the known amine 34 as pale yellow liquid, pure by AH NMR and TLC. *H NMR (CDC13, 200 MHz): 6=1.47 (s, 9H), 3.55-3.70 (brm, 8H).
98%
With triethylamine In dichloromethane
In 500 mL three-necked flask add 100gDi (2-chloroethyl) amine hydrochloride (IV) and dissolved in 300 mL of methylene chloride,Then add 113g triethylamine, stirring constantly dropping 147gBoc anhydride, the reaction 4 ~ 6h.Add 200 mL of purified water, liquid separation, then add 200 mL of saturated saline to wash,Dried over anhydrous sodium sulfate, dried,133 g of t-butyl N, N-bis (2-chloroethyl) carbamate (V) was obtained in an oil yield of 98percent.
97%
With sodium hydroxide In dichloromethane; water at 20℃; for 18.5 h;
Bis (2-chloroethyl) amino hydrochloride (starting material e) (10g, 56mmol) in dichloromethane 40ml was added,The ice bath was then added under stirring state mass fraction of 10percent aqueous sodium hydroxide 56ml,Di-tert-butyl dicarbonate (12 g, 56 mmol) was dissolved in 30 ml of dichloromethane,Was added to the above solution of bis (2-chloroethyl) ammonium hydrochloride,Stirred at room temperature for 18.5 h,A solution of 50 ml of methylene chloride was added,Two separate,The aqueous phase is then extracted once again with methylene chloride solution,The organic phase was dried over magnesium sulfate,filter,The solvent was distilled off under reduced pressure,(2-chloroethyl) carbamate (Intermediate f).Tert-butyl bis (2-chloroethyl) carbamate (Intermediate f) as a white solid,Yield: 97percent .
95%
With sodium hydroxide In dichloromethane at 0℃; for 0.166667 h;
To a solution of 6 (28.0mmol) in dichloromethane (150mL), 10percent sodium hydroxide solution (33.6mmol) was added. This was followed by addition of di-tert-butyl dicarbonate (33.6mmol) over a period of 10minat 0°C. After completion of the reaction, the organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography with petroleum ether/ethylacetate (8: 1) to yield 7 as a pale yellow oil. Yield: 95percent, 1H NMR (600MHz, DMSO) δ (ppm): 3.71–3.67 (m, 4H), 3.52 (t, J=1.8Hz, 4H), 1.40 (s, 9H). MS (ESI) m/z: 242 [M+H]+.
88%
With sodium hydroxide In dichloromethane at 20℃; for 6 h;
Toa rapidly stirred suspension of Bis(2-chloroethyl)aminehydrochloride 5 (1 g, 5.60 mmol)dissolved in DCM (300mL), 10percent sodium hydroxide solution (6 ml, 5.60 mmol) wasadded. This was followed by addition of di-tert-butyldicarbonate (1.416 ml, 6.16 mmol) over a period of 10 min at room temperature.After completion of addition, the reaction mixture was stirred for 6 h at roomtemperature. Completion of the reaction was monitored by LCMS. After completionof the reaction, the organic layer was separated, washed with water, dried overNa2SO4 and evaporated under reduced pressure to get 1.2g of tert-butylbis(2-chloroethyl)carbamate 6in 88 percent yield. The product was used in next step without furtherpurification. ESMS calcd. 242.1; Found: 185.9; 187.8 (M- tBu, chloro pattern observed).
87%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere
Example 39A1tert-butyl bis(2-chloroethyl)carbamateTo a mixture of bis(2-chloroethyl)amine hydrogen chloride (1 1 g, 62 mmol) and di-tert-butyl dicarbonate (14.8 g, 68.2 mmol) in dichloromethane (90 mL) was added triethylamine (7.5 g, 74.4 mmol) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred overnight. The solid was filtered off and the cake was washed with dichloromethane. The filtrate was washed with IN HCl, saturated NaHC(¾ and brine. The organics was dried over Na2S04, filtered and concentrated to afford 39A1 (13 g, 87percent) as colorless oil.
84%
With triethylamine In dichloromethane at 20℃; for 3 h;
To a suspension of bis [(2-CHLOROETHYL)] amine hydrochloride (55g, 0.31 mol, 1.09 equiv. ) and (BOC) 20 (62g, 0.28 [MMOL,] 1 equiv. ) in 380 mL CH2CI2, was added dropwise Et3N (48 mL, 0.345 mol, 1.22 equiv. ). After stirring at room temperature for 3 hours, TLC (Hexane [CH2CI2=90/10)] indicated the reaction was complete. The suspension was filtered through a sintered glass funnel. The filtrate was diluted with 300 mL [CH2CI2,] and then washed with 1 M [NAOH] (200 mL). The aqueous layer was extracted with another 300 mL [CH2CI2.] The combined organic layer was washed with saturated [NAHC03] (100 mL) and brine (100 mL), then dried over [NA2SO4,] filtered and concentrated to give a liquid as crude. The reaction mixture was purified through a silica gel plug eluting with (CH2CI2/Hexane=3/2) to give 28 as a liquid (57.18 g, yield 84percent). MS: 188 (M-56+1).
71%
With triethylamine In dichloromethane at 20℃; for 4 h;
To a solution of 10.0 g (56.0 mmol) bis(2-chloroethyl)amine hydrochloride and 14.7 g (67.2 mmol) di-tert-butyl dicarbonate in 60 ml dichloromethane were added dropwise 9.37 ml (67.2 mmol) triethylamine at room temperature. After stirring for 4 h the solvent was evaporated. The residual oil was redissolved in 300 ml tert-butyl methyl ether and washed with saturated aqueous ammonium chloride solution (1*100 ml) and water (1*100 ml). The combined aqueous layers were extracted with tert-butyl methyl ether (1*200 ml). The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (9.6 g, 71percent) as a colourless oil. MS m/e (percent): 186 (M-C4H8+H+, 100).
61%
With potassium carbonate In diethyl ether; water at 20℃; for 5 h;
bis(2-Chloroethyl)amine hydrochloride (Tokyo Chemical Industry CO., LTD., 1.0 g) was added to a mixture of diethyl ether (15 ml) and water (15 ml). Potassium carbonate (0.85 g) and di-tert-butyl bicarbonate (1.6 g) were added, and the mixture was stirred at room temperature for 5 hr. After completion of the reaction, the organic layer was separated. The aqueous layer was extracted with diethyl ether. The organic layers were combined and dried. The solvent was evaporated under reduced pressure to give tert-butyl bis(2-chloroethyl)carbamate (0.83 g, yield 61percent). 1H-NMR(300MHz,DMSO-d6)δ(ppm): 1.48(9H,s), 3.57-3.62(4H,m), 3.74-3.78(4H,m).
55%
With triethylamine In dichloromethane at 20℃; for 16 h; Inert atmosphere
To a solution of bis(2-chloroethyl)amine hydrochloride (2.0 g, 11 mmol; CASNo. 821-48-7), TEA (1.9 ml_, 13 mmol) in DCM (50 ml_) was added di-terf-butyl dicarbonate (2.9 g,. 13 mmol) and allowed to stir 16 h at room temperature under an atmosphere of argon. The reaction mixture was diluted with water and the organic layer separated. The organic layer was extracted with 1 N aq. HCI, saturated aq. NaHCO3, dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified on silica gel column eluted with 3:2 hexanes/EtOAc to yield bis(2-chloroethyl)carbamic acid tert-butyl ester (1.5 g, 55percent).
21%
With N-ethyl-N,N-diisopropylamine In dichloromethane
Step 1: Bis-(2-chloroethyl)-carbamic Acid Tert-Butyl Ester To a solution of bis-(2-chloroethyl)-amine hydrochloride (7.12 g, 40 mmol) in dichloromethane (65 ml) was added N,N-diisopropylethylamine (34.8 ml, 200 mmol) and catalytic amount of 4-dimethylaminopyridine, followed by portionwise addition of di-tert-butyl dicarbonate (8.72 g, 40 mmol). The solution was stirred at room temperature for 72 hours. The reaction mixture was concentrated and triturated with ether (70 ml). The solid was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluding with hexane-ethyl acetate (9:1) to give the title compound (2.02 g, 21percent). 1H-NMR (CDCl3) δ: 1.5 (9H, s), 3.5-3.6 (8H, m).
21%
With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 72 h;
Step 1 Bis-(2-chloroethyl)-carbamic acid tert-butyl ester To a solution of bis-(2-chloroethyl)-amine hydrochloride (7.12 g, 40 mmol) in dichloromethane (65 ml) was added N,N-diisopropylethylamine (34.8 ml, 200 mmol) and catalytic amount of 4-dimethylaminopyridine, followed by portionwise addition of di-tert-butyl dicarbonate (8.72 g, 40 mmol). The solution was stirred at room temperature for 72 hours. The reaction mixture was concentrated and triturated with ether (70 ml). The solid was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with hexane-ethyl acetate (9:1) to give the title compound (2.02 g, 21percent). 1H-NMR (CDCl3) ∂: 1.5 (9H, s), 3.5-3.6 (8H, m).
8.3 g
With triethylamine In dichloromethane at 20℃; for 1.5 h;
Step A - Preparation of Int 12-1 Int 12-1 Bis(2-chloroethyl)amine hydrochloride (8.72 g, 48.8 mmol, leq) was dispersed in 150 mL DCM, then 3eq Et3N (about 15 mL) was added to the stirring mixture. Excess (Boc^O was added to the stirring mixture in ice bath and then the mixture was stirred at room temperature for 1.5 h. The mixture was washed by water, dilute citric acid solution, saturated a2C03 solution in turn. The organic layer was dried over Na2S04, filtrated and purified by column to afford 8.3 g oil residue. H NMR (CDC13) δ 3.67-3.58 (m, 8H), 1.46 (s, 9H).
8.3 g
With triethylamine In dichloromethane at 20℃; for 1.5 h; Cooling with ice
Bis(2-chloroethyl)amine hydrochloride (8.72 g, 48.8 mmol, leq) was dispersed in 150 mL DCM, then 3eq Et3N (about 15 mL) was added to the stirring mixture. Excess (Boc)20 was added tothe stirring mixture in ice bath and then the mixture was stirred at room temperature for 1.5 h. The mixture was washed by water, dilute citric acid solution, saturated Na2CO3 solution in turn. The organic layer was dried over Na2SO4, filtrated and purified by column to afford 8.3 g oil residue. ‘H NMR (CDC13) ö 3.673.58 (m, 8H), 1.46 (s, 9H).
25 g
With triethylamine In dichloromethane at 25 - 30℃;
oilStep-2: N-Hoc bis (2-chloroethyl) amine: To a stirred mixture of bis (2-chloroethyl) amine hydrochloride (20 g) and methylene dichioride (MDC) (100 ml) was added triethyl amine (i2.45g) in one lot followed by boc anhydrideover a period of 30 minutes at 25-30° C. The resulted reaction mass was stirred for a period of about 12 to about18 hours at 25-30° C. Water was added to the above reaction mass and the MDC layer separated, dried over anhydrous sodium sulphate and concentrated to get 25 g of light yellow‘H NMR (300 MHz, CDC13) ö 1.47 (s, 9H), 3.65 (m, 8H). APCI-MS (mlz) 243.43(M+H).
Reference：
[1] Tetrahedron, 2004, vol. 60, # 22, p. 4875 - 4878
[2] Patent: US2003/187020, 2003, A1,
[3] Patent: WO2006/46024, 2006, A1, . Location in patent: Page/Page column 146
[4] Patent: WO2007/125321, 2007, A2, . Location in patent: Page/Page column 140-141
[5] Patent: US2003/229067, 2003, A1, . Location in patent: Page 26
[6] Patent: CN107501209, 2017, A, . Location in patent: Paragraph 0020
[7] Patent: CN104876934, 2017, B, . Location in patent: Paragraph 0062-0064
[8] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 543 - 551
[9] Polyhedron, 2012, vol. 43, # 1, p. 104 - 113
[10] Journal of Medicinal Chemistry, 1992, vol. 35, # 11, p. 2033 - 2039
[11] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3234 - 3245
[12] Patent: WO2013/10453, 2013, A1, . Location in patent: Page/Page column 125; 126
[13] Patent: WO2004/4722, 2004, A1, . Location in patent: Page/Page column 50-51
[14] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 20, p. 3444 - 3450
[15] Patent: US2007/27173, 2007, A1, . Location in patent: Page/Page column 115
[16] Patent: EP1714961, 2006, A1, . Location in patent: Page/Page column 18
[17] Patent: WO2009/67202, 2009, A1, . Location in patent: Page/Page column 196
[18] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 21, p. 7213 - 7230
[19] Patent: US2005/70549, 2005, A1,
[20] Patent: US2016/31908, 2016, A1, . Location in patent: Paragraph 1202; 1203
[21] Journal of Medicinal Chemistry, 1992, vol. 35, # 21, p. 3919 - 3927
[22] Patent: US2005/176722, 2005, A1, . Location in patent: Page/Page column 11
[23] Patent: US5635510, 1997, A,
[24] Patent: US5824690, 1998, A,
[25] Patent: US2007/142349, 2007, A1, . Location in patent: Page/Page column 25
[26] Patent: US2005/54628, 2005, A1, . Location in patent: Page/Page column 30
[27] Patent: WO2009/51715, 2009, A1, . Location in patent: Page/Page column 31-32
[28] Patent: WO2009/61681, 2009, A2, . Location in patent: Page/Page column 64-65
[29] Patent: US2007/21609, 2007, A1, . Location in patent: Page/Page column 9
[30] Patent: WO2011/46771, 2011, A1, . Location in patent: Page/Page column 136
[31] New Journal of Chemistry, 2013, vol. 37, # 4, p. 1174 - 1179
[32] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9275 - 9295
[33] Patent: WO2015/73310, 2015, A1, . Location in patent: Page/Page column 43; 44
[34] Patent: WO2015/70367, 2015, A1, . Location in patent: Page/Page column 42; 43
[35] Patent: US9518048, 2016, B2, . Location in patent: Page/Page column 26
[36] MedChemComm, 2018, vol. 9, # 8, p. 1340 - 1350
[37] Patent: WO2008/152149, 2008, A1, . Location in patent: Page/Page column 59
[38] Patent: US6339090, 2002, B1, . Location in patent: Example 3
28
[ 24424-99-5 ]
[ 821-48-7 ]
[ 473735-52-3 ]
[ 118753-70-1 ]
Yield
Reaction Conditions
Operation in experiment
42%
With triethanolamine In dichloromethane
EXAMPLE 1 4-Aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester: To a solution of bis-(2-chloro-ethyl)amine hydrochloride (50 g, 280 mmol) in CH2Cl2 (400 mL) was added (Boc)2O (61.14 g, 280 mmol). The mixture was cooled to 0° C. and TEA (78 mL, 256 mmol, 2 eq.) was added in 5 portions. The resulting thick slurry was diluted with CH2Cl2 (100 mL) then stirred and warmed to room temperature for 4 h. The mixture was filtered and the solids were washed with hexane. The filtrate was concentrated by rotary evaporation and the resulting slurry was purified by flash column chromatography by eluding with 30percent CH2Cl2/hexanes to afford bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester as a clear oil (28 g, 42percent). 1H NMR (300 MHz, CDCl3): δ 3.72 (br. m, 8H), 1.58 (s, 9H).
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
31
[ 5192-23-4 ]
[ 821-48-7 ]
[ 84807-09-0 ]
Yield
Reaction Conditions
Operation in experiment
90.8%
With potassium carbonate In isopropyl alcohol at 90℃; for 48 h;
4-aminoindole (2g, 15.2mmol), bis(2-chloroethyl)amine hydrochloride (3.2g, 18.2mmol) and potassium carbonate (4.2g, 30.4mmol) was added to isopropanol (30 mL) after the reaction solution was reacted at 90 °C for 48 hours, and thereto was added dichloromethane (50mL) and methanol (50mL). The reaction mixture was filtered and the filtrate under reduced pressure to spin dry, the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)= 10/1) by to give the title compound as a brown solid (2.78g, 90.8percent).
Reference：
[1] Patent: CN105367472, 2016, A, . Location in patent: Paragraph 0179; 0180; 0181; 0182
[2] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 19-20
A mixture of 5-aminoindazole (2.53 g, 19.0 mmol), bis (2- chloroethyl) amine hydrochloride (3.60 g, 20.1 mmol) and ethanol (30 mL) was heated at reflux overnight. The mixture was allowed to cool to room temperature. Na2C03 (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate evaporated in vacuo.-The residue was dissolved in 1 N HC1 (100 mL) and extracted with DCM (2 x 50 mL). The aqueous phase was made basic with 4 N NaOH (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (20: 1 DCM/MeOH to 20: 1: 0.5 DCM/MeOH/Et3N) to 5-Piperazin-l-yl-lH-indazole (1.26 g, 33percent) as a brown solid. 1H NMR (DMSO-d6, 400 MHz) 8 12.80 (s, 1H), 7.89 (s, 1H), 7.40 (d, J= 8.8 Hz, 1H), 7.16 (dd, J= 8. 8 Hz, J= 2. 0 Hz, 1H), 7.07 (s, 1H), 3.17 (s, 1H), 2.99 (m, 4H), 2. 89 (m, 4H). LCMS (APCI+) m/z 203 [M+H] + ; Rt = 1. 33 minutes.
[1769] The product from Example 242B (3.5 g, 23.2 mmol) was added slowly to bis-2-chloroethylaime hydrochloride (4.96 g, 27.78 mmol) at room temperature and refluxed for 48 hours. The reaction was cooled to room temperature and sodium carbonate added (9 g) and refluxed for another 48 hours. The mixture was cooled to room temperature, filtered and the white solid partitioned between dichloromethane and 3N sodium hydroxide. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 3.2 g (63%) pink oil. 1H NMR (300 MHz, CDCl3) delta1.4 (d, 6H, J=6 Hz), 1.5-1.6 (m, 4H), 2.45-2.65 (m, 4H), 3.43 (m, 1H), 6.6-6.8 (m, 2H), 6.81-6.91 (m, 2H); MS (DCI/NH3) m/e 221 (M+H)+.
To a suspension of bis(2-chloroethyl)amine hydrochloride salt (5 g, 0.028 mole) in 30 ml dry dichloro-methane, with cooling (ice water) and stirring, benzyl chloroformate (5.1 g, 0.03 mole) was added dropwise. The addition was complete within 10 min and was followed by addition of triethylamine (6.46 g, 0.063 mole) during 1 h. The mixture was further stirred at room temperature for 1 hour. Water (10 ml) was added, and the mixture was stirred for 15 min. Separated dichchloromethane layer was washed with HCl 1M (10 ml), brine (10 ml), dried and concentrated in vacuo to give an oily product (7 g, 95.5% yield, 80% pur).
70%
With triethylamine; In dichloromethane; at 0 - 20℃; for 6.5h;
To a solution of 1 (10.4 g, 56.5 mmol) and TEA (11.4 g, 113 mmol) in DCM (60 mE) was added dropwiseCbzCl (10 g, 56.5 mmol) over 30 mins at 00 C. Then the mixture was stirred at room temperature (tt.) for 6 hrs. H20(50 ml) was added, the organic layer was washed with aqueous NaC1, dried by anhydrous Na2504, concentrated in vacuo and the residue was purified by silica gel chromatography (PE/EA=20: 1) to afford compound 2 as a white solid (11.6 g, yield: 70%).
70%
With triethylamine; In dichloromethane; at 0 - 20℃; for 6.5h;
Step 1: To a solution of 1 (10.4 g, 56.5 mmol) and TEA (11.4 g, 113 mmol) in DCM(60 mL) was added dropwise CbzCl (benzyl chloroformate, 10 g, 56.5 mmol) over 30 mins at 0 C. Then the mixture was stirred at room temperature (r.t.) for 6 hrs. H2O(50 ml) was added, the organic layer was washed with aqueous NaCl, dried by anhydrous Na2S04, concentrated in vacuo and the residue was purified by silica gel chromatography (PE/EA = 20:1) to afford compound 2 as a white solid (11.6 g, yield: 70%).
51.3%
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;
bis(2-chloroethyl)amine hydrochloride (16.000 g, 89.646 mmol) and triethylamine (31.237 mL, 224.115 mmol) was dissolved in dichloromethane (300 mL) at 0 C then benzyl chloroformate (13.437 mL, 94.128 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hour and further stirred at room temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 40%) and concentrated to give the title compound (12.700 g, 51.3%) as a white solid.
26%
With triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 16.5833h;
10.1: Benzyl bis(2-chloroethyl)carbamate; 13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a solution, cooled to 0 C., of 15 g (84 mmol) of bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 20 g of crude residue are obtained and purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 6 g (26%) of benzyl bis(2-chloroethyl)carbamate are thus obtained.
26%
With triethylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 18.25h;
13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a solution, cooled to 0 C., of 15 g (84 mmol) of bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and evaporated. 20 g of crude residue are obtained and purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 6 g (26%) of benzyl bis(2-chloroethyl)carbamate are thus obtained.
28 g
With sodium hydroxide; In water; at 0℃; for 3h;
To an aqueous solution (200 mL) of 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (19.3 g) and benzyl chloroformate (15.44 mL) was added dropwise 2M aqueous sodium hydroxide solution (108 mL) at 0 C., and the mixture was stirred at 0 C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (28 g). 1H NMR (300 MHz, DMSO-d6) delta 3.53-3.66 (4H, m), 3.68-3.83 (4H, m), 5.11 (2H, s), 7.21-7.55 (5H, m).
7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone (1-2) A solution of <strong>[66491-03-0]7-amino-3,4-dihydro-1(1H)-isoquinolone</strong> (1-1)(Girard et al, J. Org. Chem., 1983, vol. 48, p. 3220; 5.0 g, 30.8 mmol) and bis(2-chloroethyl)amine hydrochloride (6.3 g, 33.9 mmol) in n-butanol (250 mL) was stirred at 110 C. for 3 days. The precipitate was removed by filtration to provide the starting amine as the HCl salt (3.6 g). Evaporation of the n-butanol under reduced pressure afforded a dark oil which was purified by column chromatography (silica gel; EtOH/H2 O/NH4 OH 10:0.5:0.5) to give 1-2. 1 H NMR (CD3 OD); delta2.86 (2H, t), 3.10 (4H, m), 3.22 (4H, m), 3.44 (2H, t), 7.18 (2H, m), 7.55 (1H, m).
With sodium carbonate; In butan-1-ol; for 67h;Heating / reflux;
To a solution of <strong>[3964-52-1]4-amino-2-chlorophenol</strong> (1.0 g, 6.97 mmol) in n-butanol (2 mL) was added bis(2-chloroethyl)amine hydrochloride (1.2 g, 6.97 mmol). After completion of addition the reaction mixture was heated at reflux for 6Oh. Solid Na2CO3 (740 mg, 6.97 mmol) was added to the hot reaction mixture in one portion and the reaction mixture continued stirring at reflux. After 7h the reaction mixture was cooled to RT and 2-chloro-4-(piperazin-l-yl)phenol was collected via filtration. The purple solid was washed with heptanes before proceeding to the next step without further purification (554 mg, 37% yield). 1H NMR (300 MHz, DMSO-d6): delta 6.95 (dd, IH, J= 2.8, 1.9 Hz), 6.91 (s, IH), 6.81 (m, IH), 3.21 (m, 4H), 3.16 (m, 4H).
With potassium carbonate; In diethylene glycol dimethyl ether; for 24.0h;Heating / reflux;
To a solution of <strong>[870606-29-4]5-chloro-3-iodo-2-methylaniline</strong> (1.32 g, 4.9 mmol) in diglyme (5 mL) was added potassium carbonate (677 mg, 4.9 mmol) and bis(2-chloroethyl)amine hydrochloride (875 mg, 4.9 mmol). The mixture was refluxed for 24 h and then cooled to room temperature. Water and ethyl acetate were added. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. Column chromatography on silica (dichloromethane:methanol 4:1) provided 1-(5-chloro-3-iodo-2- methylphenyl) piperazine as a white solid (660 mg, 40% yield). IH NMR (400 MHz, CDC13) 8 7.56 (d, 1H), 6.97 (d, 1H), 3.03 (m, 4H), 2.83 (m, 4H), 2.39 (s, 3H), 1.73 (br s, 1H); MS (ESI) for C11H14ClIN2: 337 (MH+).
[00296] A mixture of <strong>[90-52-8]8-amino-6-methoxyquinoline</strong> (150.0 g, 0.862 mol) and bis(2- chloroethyl)amine (219 g, 1.23 mol,) in 6 parts (volume of hexanol vs weight of 8-amino- 6-methoxyquinoline) of 1 -hexanol (900 mL) was heated to 1450C and stirred for 21 hours. Upon completion, the reaction mixture was cooled 50 - 6O0C, and 507 g of aqueous NaOH solution was added slowly. The reaction mixture was cooled to 25 - 3O0C and isopropyl acetate (750 mL) was added. The mixture was clarified through a celite pad. The aqueous phase was then split off. The organic solution was treated with a slurry of adipic acid (126 g, 0.862 mol) in isopropyl acetate (250 ml). The resulting mixture was stirred for 16 hours to form 6-methoxy-8-(l-piperazinyl)quinoline adipate salt. The- 100 -USl DOCS 6425925vl <n="103"/>Docket No. AM 102651 (361 19.379WO 1 )adipate salt was filtered and washed with isopropyl acetate (2x150 ml) and dried by nitrogen flow to give adipate of 6-Methoxy-8-rhoiperazin-l-yl-quinoline (186 g, 55% yield) with -97% HPLC area, 88% strength purity in 51% yield.|00297] The salt can be recrystallized from a mixture of methanol and isopropyl acetate if further purification is required. To purify the adipate salt, 580 g of the crude adipate salt and 2.8 liter of methanol were mixed and heated to 65 0C and a dark solution was obtained. To this solution was charged slowly 1.1 liter of isopropyl acetate over 40 min at about 63 0C. The mixture was stirred at about 63 0C for about 1 h and cooled to 0- 5C. After stirring at 0-5 0C for 2 hours, the mixture was filtered and washed with 300 ml of isopropyl acetate and dried with airflow. Yield, 395 g, 68.1% recovery yield.[00298] To liberate 6-methoxy-8-(l-piperazinyl)quinoline from its adipate salt, 100 g (0.257 mol) of the adipate salt was added into a 2-L reactor followed by the addition of 500 ml of dichloromethane. To this mixture was added 100 g of water followed by the slow (in about 15 min) addition of 41 g of 50% sodium hydroxide solution to maintain the pH in the 13-14 range, adding sodium hydroxide solution as necessary if the pH is below 10. The organic bottom layer was separated and filtered through a pad of activated basic aluminum oxide (100 g, 6.5 cm diameter x 3 cm depth). The pad was washed with 100 ml of isopropyl acetate twice. The dichloromethane was replaced by toluene by distillation under vacuum (450 to 500 mm Hg) while 3x150 ml of toluene was added into the reactor until the final volume was about 135 ml. Some white solid precipitated after distillation, the solid was removed by filtration, the filter cake was washed with 50 ml of toluene. Final volume, 185 ml, purity 97.56%, solution strength 27.4%)
6-Methoxy, 8-amino-quinoline (8.2 g) and bis(chloroethyl)amine hydrohloride (9.0g) were taken in 70 mL chlorobenzene and heated at about 135C with vigorous stirring for 3 days. The reaction never went to completion. The mixture was cooled. Water was added and extracted with ether. The aqueous phase was basified with sodium carbonate and extracted with ethyl acetate, dried and the solvent removed. The crude product was filtered through 300 mL of silica gel using 10% MeOH/CH2Cl2, 20% MeOH/ CH2Cl2, then 1% NH4OH / 80% MeOH / 19% CH2Cl2, to give 1.5 g of the desired product. MS (ES) m/z (relative intensity): 244 (M+H+, 100).
With potassium carbonate; potassium iodide; In butan-1-ol; for 72h;Heating / reflux;
A mixture of 0.16 g (1 mmol) of <strong>[452-84-6]2-fluoro-5-methylaniline</strong>, 0.18 g (1 mmol) of bis-(2-chloroethyl)-amine hydrochloride, 0.14 g (1 mmol) of potassium carbonate, 0.08 g (0.5 mmol) of potassium iodide and 5 ml of n-butyl alcohol was stirred at reflux for 72 hours. After cooling to room temperature, the solvent was evaporated and the residue treated with water (20 ml) and extracted with dichloromethane. The purification was carried out by flash chromatography eluding with dichloromethane:2N-methanolic-ammonia 96:4 to give 0.17 g of the title compound. Yield 86%. 1H-NMR (CDCl3, delta): 2.17 (s, 1H, NH), 2.31 (s, 3H, CH3), 3.21-3.37 (m, 8H, piperazine CHs), 6.69-6.82 (m, 2H, phenyl CHs), 6.84-6.97 (m, 1H, phenyl CH).
In 1,2-dichloro-benzene; hexan-1-ol; for 7.5h;Heating / reflux;
A mixture of 0.74 g (5mmol) of <strong>[367-34-0]2,4,5-trifluoroaniline</strong>, 0.91 g (5 mmol) of bis-(2-chloroethyl)amine hydrochloride, 2.5 ml of o-dichlorobenzene, and 0.25 ml of n-hexanol was stirred at reflux temperature for 7.5 hours. After cooling to room temperature, the mixture was treated with 2N NaOH (10 ml) and extracted with diethyl ether (3 x 20 ml). Purification was carried out by flash chromatography eluding with dichloromethane:2N methanolic ammonia gradient from 100:5 to 100:10 to give 0.65 g of the title compound. Yield: 60percent. 1H-NMR (CDCl3, delta): 2.97-3.18 (m, 8H, piperazine CHs), 3.32 (s, 1H, NH); 6.68-7.00 (m, 2H, phenyl CHs).
With sodium hydroxide; sodium carbonate; In methanol; hexane; chloroform; butan-1-ol;
EXAMPLE 4 (2,4,5-Trifluorophenyl)piperazine (Compound 4) A mixture of <strong>[367-34-0]2,4,5-trifluoroaniline</strong> (2.94 g, 20 mmol) and bis(2-chloroethyl)amine hydrochloride (3.56 g, 20 mmol) in butanol (10 mL) was heated at reflux for 24 hours. The mixture was cooled to room temperature, sodium carbonate (2.33 g, 22 mmol) was added, and the mixture was heated again at reflux. After 2 days, the mixture was cooled to room temperature, hexane (15 mL) and 3 N NaOH (25 mL) were added, and the resulting layers were separated. The aqueous layer was extracted with chloroform (3*25 mL) and the combined organic fractions were flashed over a column of silica gel. The silica gel was further eluted with a gradient of chloroform to chloroform/methanol (4:1). The solvent was removed from the combined fractions with Rf=0.20 [silica gel, chloroform/methanol (4:1)], giving the title compound as a yellow oil (1.028 g, 4.76 mmol, 24percent). ESI-MS m/z 217 (MH+).
In 1,2-dichloro-benzene; hexan-1-ol; for 11h;Heating / reflux;
A mixture of 1 g (6.87 mmol) of <strong>[2106-05-0]5-chloro-2-fluoroaniline</strong>, 1.35 g (7.55 mmol) of bis-(2-chloroethyl)-amine hydrochloride, 3 ml of o-dichlorobenzene and 0.3 ml of n-hexanol was stirred at reflux temperature for 11 h. After cooling to room temperature, the mixture was treated with 10 ml of 2 N NaOH and extracted with CH2Cl2 (3x20 ml). The combined organic layers were washed with H2O, dried (Na2SO4) and evaporated to dryness in vacuo. The purification was carried out by flash chromatography eluding with CH2Cl2: 2 N methanolic ammonia 97:3 to give 1.13 g (76.6%) of the title compound. 1H-NMR (CDCl3, delta): 2.06 (bs, 1H, NH), 3.01-3.12 (m, 8H, piperazine CHs), 6.86-7.03 (m, 3H, phenyl CHs).
Reference Example 9b 2-chloro-5-piperazin-1-yl benzonitrile 3-Cyano-4-chloroaniline (10.1 g, 66 mmol), as prepared in Reference Example 9a, was dissolved in n-butanol (300 mL) bis-(2-chloroethyl)amine hydrochloride (23.2 g, 130 mmol) and potassium iodide (50 mg, catalytic) were added. The mixture was heated at reflux for three days, then cooled in a refrigerator overnight. A solid precipitate was collected by filtration, washed with cold n-butanol and dried. The crude product was distributed between methylene chloride and 2N ammonium hydroxide. The organic layer was separated, dried (Na2SO4) and concentrated to yield a light yellow solid (9.1 g, 59%) which gave a single peak by GC and TLC analysis.
59%
With potassium iodide; In butan-1-ol;
REFERENCE EXAMPLE 9b 2-chloro-5-piperazin-1-yl benzonitrile. 3-Cyano-4-chloroaniline (10.1 g, 66 mmol), as prepared in Reference Example 9a, was dissolved in n-butanol (300 mL) bis-(2-chloroethyl)amine hydrochloride (23.2 g, 130 mmol) and potassium iodide (50 mg, catalytic) were added. The mixture was heated at reflux for three days, then cooled in a refrigerator overnight. A solid precipitate was collected by filtration, washed with cold n-butanol and dried. The crude product was distributed between methylene chloride and 2N ammonium hydroxide. The organic layer was separated, dried (Na2SO4) and concentrated to yield a light yellow solid (9.1 g, 59%) which gave a single peak by GC and TLC analysis.
59%
With potassium iodide; In butan-1-ol;
Reference Example 9b 2-chloro-5-piperazin-1-yl Benzonitrile 3-Cyano-4-chloroaniline (10.1 g, 66 mmol), as prepared in Reference Example 9a, was dissolved in n-butanol (300 mL) bis-(2-chloroethyl)amine hydrochloride (23.2 g, 130 mmol) and potassium iodide (50 mg, catalytic) were added. The mixture was heated at reflux for three days, then cooled in a refrigerator overnight. A solid precipitate was collected by filtration, washed with cold n-butanol and dried. The crude product was distributed between methylene chloride and 2N ammonium hydroxide. The organic layer was separated, dried (Na2SO4) and concentrated to yield a light yellow solid (9.1 g, 59%) which gave a single peak by GC and TLC analysis.
With hydrogenchloride; sodium hydroxide; potassium iodide; potassium carbonate; In diethyl ether; chloroform; water; acetic acid; butan-1-ol;
a) 1-(2-Methoxy-5-trifluoromethylphenyl)piperazine (Compound 17A) A mixture of 6.65 g of 2-methoxy-5-trifluoromethylaniline, 6.21 g of bis-(2-chloroethyl)amine hydrochloride, 4.71 g of anhydrous potassium carbonate and 0.34 g of anhydrous potassium iodide in 70 mL of n-butanol was refluxed for 50 hours. The solvent was removed at reduced pressure and the residue was taken up in 400 mL of diethyl ether. The suspension was acidified with 3N anhydrous hydrogen chloride in diethyl ether and stirred at room temperature for 3 hours. The solid was collected by filtration and dissolved in 50 mL of water. The solution was acidified with 36% hydrochloric acid, washed with 3*50 mL of diethyl ether, alkalinised with excess 36% sodium hydroxide and extracted with 2*70 mL of diethyl ether. The organic layer was dried over sodium sulphate and evaporated to dryness at reduced pressure to give a residue which was purified twice by flash chromatography, first using chloroform/3N methanolic ammonia 100:3 and subsequently using the upper layer of a 4:5:1 mixture of water, n-butanol and glacial acetic acid. The solvents were removed by evaporation in vacuo to give a residue which was dissolved in water. The mixture was alkalinised with 2N sodium hydroxide and extracted with chloroform; the organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure to afford 1.42 g (16%) of Compound 17A as an oil.
With sodium hydroxide; potassium iodide; potassium carbonate; In chloroform; water; butan-1-ol;
c) 1-(5-Cyano-2-methoxyphenyl)piperazine. 0.25 H2O (Compound 18C) A mixture of 6.38 g of Compound 18B, 7.1 g of potassium iodide, 5.95 g of anhydrous potassium carbonate and 7.68 g of 98% bis-(2-chloroethyl)amine hydrochloride in 150 mL of n-butanol was refluxed for 43 hours under nitrogen. After this time, an additional 3.4 g of 98% bis-(2-chloroethyl)amine hydrochloride and 3 g (21 mmol) of anhydrous potassium carbonate were added and reflux was continued for a further 14 hours. The solvent was removed under reduced pressure. The residue was taken up in 100 mL of water, acidified with 37% hydrochloric acid, then alkalinised with 35% sodium hydroxide and extracted with 3*100 mL of ethyl acetate. The organic layer was washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was purified twice by flash chromatography (chloroform/2.7N methanolic ammonia gradient from 100:1 to 100:5; then chloroform: 2.7N methanolic ammonia gradient from 100:5 to 80:20) to afford 2.76 g (29%) of the title compound as an ivory solid. M.p. (78) 100-106 C.
1-(2,4,6-trifluorophenyl)piperazine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; sodium carbonate; In water;
(1) Synthesis of 1-(2,4,6-Trifluorophenyl)piperazine Dihydrochloride To a solution of <strong>[363-81-5]2,4,6-trifluoroaniline</strong> (4.4 g) an bis(2-chloroethyl)amine hydrochloride (6.4 g) in water (4.2 ml) was added dropwise a solution of sodium carbonate (3.8 g) in water (8.9 ml) over 40 min under reflux under heating and the mixture was further refluxed under heating for 5.5 hr. To the reaction mixture was added an aqueous solution (8.9 ml) of sodium hydroxide (3.6 g) and the mixture was further refluxed under heating for 2.5 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a dark brown oil. The oil was subjected to silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (0.61 g) as a pale-brown solid. 1H-NMR(DMSO-d6)delta: 2.86(2H, br.s), 3.03(2H, br.s), 4.07(4H, br.s), 7.13(2H, t, J=9.5 Hz). IR(KBr): 3205, 2954, 2846, 1633, 1594 cm-1; MS(EI): 216(M+).
1-(2,5-Difluorophenyl)piperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In water; butan-1-ol;
(1) 1-(2,5-Difluorophenyl)piperazine hydrochloride 7.0 g of bis(2-chloroethyl)amine hydrochloride was suspended in 60 ml of butanol and 5 g of <strong>[367-30-6]2,5-difluoroaniline</strong> was added thereto at room temperature. After heating under reflux for 72 hours, the reaction mixture was cooled and 4.1 g of sodium carbonate was added. After heating under reflux for additional 24 hours, the precipitate was taken up by filtration, dissolved in water and extracted with chloroform. Then the extract was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in a small amount of chloroform, converted into hydrochloride by adding a 4N hydrochloric acid/dioxane solution and filtered to thereby give 2.39 g mg of the title compound.
E. 1-(2,5-Difluorophenyl)piperazine hydrochloride 0.03 Mol of <strong>[367-30-6]2,5-difluoroaniline</strong> and 0.03 mol of bis-(2-chloroethyl)amine hydrochloride are suspended in 50 mL of xylene and 15 mL of NMP. The mixture is heated at 130 C. for 25 h while stirring, then cooled to RT and the solvents are evaporated. The residue is dissolved in water and 1 equivalent of 2N aqueous sodium hydroxide (NaOH) is added. The mixture is extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous MgSO4, filtered and evaporated to dryness in vacuo. The residue is dissolved in acetone and 1 equivalent of HCL in diethyl ether (Et2O) is added. The precipitated product is collected by filtration and recrystallized from isopropanol to afford 1-(2,5-difluorophenyl)piperazine hydrochloride: m.p. 195 C. LC/MS (M+1=199.1). 1H NMR (DMSO-d6, 400 MHz) delta 3.22 (m, 4H), 3.28 (m, 4H), 6.83 (m, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 9.46 (br s, NH).
With potassium carbonate; In 2-bytoxyethanol; at 180℃; for 24h;
A suspension of 2-(4-aminophenyl)-1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (1.0g), his-(2- chloroethyl)amine hydrochloride (0.69g) and potassium carbonate (0.53g) in 2- butoxyethanol (5ml), was heated at 180° for 24 hours. Diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. Organic layer dried and evaporated to give crude product. Chromatography on silica gel gave, after elution with 0-20percent methanol in DCM, the desired product as a brown solid (0.54g). LC/MS (ESI) found 329 (M+H).
With pyridine; In dichloromethane; at 0 - 20℃; for 4h;
bis(2-Chloroethyl)amine hydrochloride (Tokyo Chemical Industry CO., LTD., 25.2 g) was suspended in methylene chloride (280 ml), and the suspension was cooled to 0C. Pyridine (24 ml) and p-toluenesulfonyl chloride (28.3 g) were added, and the mixture was stirred at room temperature for 4 hr. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with methylene chloride. The organic layer was washed with 1N aqueous hydrochloric acid and water and dried. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (15:1-5:1)) to give N,N-bis(2-chloroethyl)-4-methylbenzenesulfoneamide (30.0 g, yield 71%). 1H-NMR(300MHz,DMSO-d6)delta(ppm): 2.41(3H,s), 3.45(4H,t,J=6.9Hz), 3.72(4H,t,J=6.9Hz), 7.44(2H,d,J=8.2Hz), 7.75(2H,d,J=8.2Hz).
To a reaction flask, 100 g. of bis(2-chloroethyl)amine hydrochloride and 500 ml. of MDC were added and stirred. To the reaction mass was added Triethyl amine as a base and again stirred for 15 minutes at room temperature, p-toluene sulfonylchloride solution (in MDC) was added to the reaction mass and heated to 40 C and maintained for 6 hours. TLC was checked for completion of reaction and treated with 250 ml of water and organic layer was separated. To this reaction mass, was added 250 ml of 10% HC1 solution and stirred. The organic layer was separated, treated with sodium sulfate and washed thrice with MDC as the solvent was removed under vacuum. To this mass hexane was added and again removed under vacuum twice. Once again Hexane was added and reaction mass stirred for two hours and cooled which afforded the product N,N-bis(2-chloroethyl)-4-methylbenzene sulfonamide which was filtered, washed with hexane and dried.
To a reaction flask, 100 g. of bis(2-chloroethyl)amine hydrochloride and 500 ml. of MDC were added and stirred. To the reaction mass was added triethyl amine as a base and again stirred for 15 minutes at room temperature. p-Toluene sulfonylchloride solution (in MDC) was added to the reaction mass and heated to 40 C. and maintained for 6 hours. TLC was checked for completion of reaction and treated with 250 ml of water and organic layer was separated. To this reaction mass, was added 250 ml of 10% HCl solution and stirred. The organic layer was separated, treated with sodium sulfate and washed thrice with MDC as the solvent was removed under vacuum. To this mass hexane was added and again removed under vacuum twice. Once again Hexane was added and reaction mass stirred for two hours and cooled which afforded the product N,N-bis(2-chloroethyl)-4-methylbenzene sulfonamide which was filtered, washed with hexane and dried.
In a sealed pressure flask a phenyl amine (1.0 equiv.), bis(2-chloroethyl)amine hydrochloride (1.5 equiv.), and potassium carbonate (1.5 equiv.) were suspended in diglyme. The resulting mixture was allowed to stir at 22O0C for 3.5 hours. The mixture was cooled to room temperature over two hours and further cooled to O0C. It was then partitioned between EPO <DP n="82"/>dichloromethane and distilled water. The pH of the water layer was adjusted to basic pH (9- 10) with 5% aqueous sodium hydroxide. The water phase was extracted thrice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and the solvent removed in vacuo. The product was purified by column chromatography in 2M ammonium/methanol and dichloromethane mixtures.; l-(4-Chloro-2-methoxy-phenyl)-piperazine was synthesized from 4-Chloro-2-methoxy- phenylamine (1.15 g, 7.30 mmol), bis(2-chloroethyl)amine hydrochloride (1.95 g, 10.95 mmol), and potassium carbonate (1.51 g, 10.95 mmol) in diglyme. Column chromatography 2.5% 2M ammonia/methanol in dichloromethane provided the product as a brown solid EPO <DP n="83"/>(187.9 mg, 11%). 1H NMR (300 MHz, CDCl3): delta(ppm) 6.93(d, IH), 6.84(m, 2H), 3.87(s, 3H), 3.12( broad m, 4H), 2.88(broad t, 4H).
Step (b): Preparation of 1-(4-fluoro-2-methoxyphenyl)piperazine Reaction of bis(2-chloroethyl)amine hydrochloride (0.11 mol) with <strong>[1978-39-8]5-fluoro-2-methoxyaniline</strong> (0.01 mol) according to Step (c) of Example XII, provided 19.5 g (95% yield) of the piperazine intermediate used without further purification.
Step (c): Preparation of 1-(3-fluoro-6-methoxyphenyl)piperazine <strong>[1978-39-8]5-fluoro-2-methoxyaniline</strong> (0.092 mol) and bis(2-chloroethyl)aminehydrochloride (0.1 mol) in xylene (300 ml) was refluxed with stirring for a period of 20 hrs. Water was added to the reaction and the organic layer discarded. The aqueous layer was basified with sodium hydroxide and extracted with methylene chloride (2*100 ml). The methylene chloride extract was dried (sodium carbonate), filtered, and concentrated. Residual material was distilled to provide 8.8 g (45% yield) of piperazine product, b.p. 111-114 C. 0.15 mmHg:
With potassium carbonate; In ethyl acetate; butan-1-ol;
EXAMPLE 7 1-(3,5-Dichloro-4-methoxyphenyl) piperazine 3,5-Dichloro-4-methoxyaniline, m.p. 77-79, was prepared by the catalytic hydrogenation (10% Pd-C) of <strong>[17742-69-7]2,6-dichloro-4-nitro-anisole</strong> in ethyl acetate at ambient temperature and atmospheric pressure. A mixture of 3,5-dichloro-4-methoxyaniline (16.0g) and bis-(2-chloroethyl)amine hydrochloride (14.77g) in n-butanol (100 ml) was stirred under reflux for 48 hr. Anhydrous potassium carbonate (11.45g) was added and the resulting mixture was stirred under reflux for a further 24 hr., then filtered hot.
Example 25; 2-Butoxy-7,8-dihydro-9-[2-{4-(3-methoxycarbonylmethylphenyl)piperazin-1-yl}ethyl] -8-oxoadenine; [Show Image] Step (i); N-(3-Methoxycarbonylmethylphenyl)piperazine; [Show Image] 3-Methoxycarbonylmethylaniline 100mg (0.61mmol) was dissolved in butanol 6ml. To the solution was added bis(2-chloroethyl)amine hydrochloride 324mg (1.82mmol) and the mixture was stirred at 140C for 22 hours. After removal of the solvent by distillation, thereto was added aqueous saturated sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the subtitled compound 65mg as a pink oil. Yield 46% 1H NMR (DMSO-d6) delta 8.43 (1H, bs), 7.18 (1H, dd, J= 7.6 Hz), 6.87 (1H, s), 6.86 (1H, d, J= 7.6, 7.6 Hz), 6.73 (1H, d, J= 7.6 Hz), 4.02 (2H, t, J= 6.6 Hz), 3.59 (2H, s), 3.30-3.25 (4H, m), 3.15-3.11 (4H, m), 1.57-1.49 (2H, m), 1.33-1.24 (2H, m), 0.86 (3H, t, J= 7.4 Hz).
With sodium carbonate; In butan-1-ol; for 67h;Heating / reflux;
To a solution of the <strong>[16750-67-7]4-amino-2-bromophenol</strong> (1.0 g, 5.32 mmol) in n- butanol (5 mL) was added bis(2-chloroethyl)amine hydrochloride (949 mg, 5.32 mmol). After completion of addition, the reaction mixture was heated at reflux for <n="57"/>6Oh. Solid Na2CO3 (564 mg, 5.32 mmol) was added to the hot reaction mixture in one portion and the reaction mixture continued stirring at reflux. After 7h the reaction mixture was cooled to RT and 2-bromo-4-(piperazin- 1 -yl)phenol was collected via filtration. The purple solid was washed with heptanes before proceeding to the next step without further purification.[0113] To a solution of 2-bromo-4-(piperazin-l-yl)phenol (500 mg, 1.95 mmol) and diisopropylethylamine (373 muL, 2.14 mmol) in DMF (6 mL) was added the tert- butyl (lH-pyrazol-l-yl)methanediylidenedicarbamate (664 mg, 2.14 mmol). After stirring at room temperature for 45 min. the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x 5OmL). The organic layers were separated and washed with brine, dried over Na2SO4, and concentrated to yield a crude oil. Purification of the crude material using silica gel chromatography (gradient of 0% to 100% EtOAc in hexanes) afforded tert-butyl (4-(3-bromo-4- hydroxyphenyl)piperazin-l-yl)methanediylidenedicarbamate was obtained as a white foam (171 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6): delta 9.64, (br s, IH), 9.60 (s, IH), 7.05 (br s, IH), 6.84 (br s, 2H), 3.49 (dd, 4H, J= 5.0, 4.4 Hz), 2.99 (dd, 4H, J = 4.5, 4.3 Hz), 1.44 - 1.37 (m, 18H); 13C (75.5 MHz, DMSO-d6): delta 159.5, 151.2, 150.8, 147.7, 144.7, 120.8, 117.5, 116.6, 109.5, 80.1, 77.1, 49.3, 45.3, 27.9 (2C); Minor rotomeric population is also visible; HRMS calcd for C2IH3IBrN4Os: 499.15506 found 499.15446.
(-) -1- [ (4-chlorophenyl)phenylmethyl] -4-piperazineCharge 300 mL of N-ethyldiisopropylamine, 30 g of -(-)-4- chlorobenzhydryamine (Clemo, J. Chem. Soc. (1939) 1958-1969; Ingold, J. Chem. Soc. (1933) 1493-1505) and 42 g of bis (2- chloroethyl) amine hydrochloride in a reaction vessel, stir and heat to reflux for 3 hours. Cool to 60 0C, add 24 mL of dieth- ylamine, then heat the mixture again reflux temperature for another 5 hours. After reaction is completed evaporate the solvent in vacuum, add a mixture of water and ethyl acetate (1:1), adjust aqueous phase pH value to 10-11 with 30% sodium hydroxide solution. Separate organic phase and extract aqueous phase with ethyl acetate. Wash combined organic phase with purified water, decolorize organic phase with activated carbon, and evaporate the filtrate in vacuum. Separate impurities by of silica gel chromatography by eluting with ethyl ace- tate/ethanol (7:1) and/or then with ethyl ace- tate/ethanol/ammonia (7:1:0.25). Collect the eluate and evaporate the solvent in vacuum to obtain the oily residue which is further dissolved in hexane, treated with activated carbon heated and filtered. Cool the filtrate to 10 0C for 1 hour, collect a precipitate and dry at 40-450C in vacuum for 5-8 hours to afford a product. HPLC (area) 98-99 %.
300 ml of N-ethyldiisopropylamine, 30 g of -(-)-4- chlorobenzhydryamine (Clemo, J. Chem. Soc. (1939) 1958-1969; Ingold, J. Chem. Soc. (1933) 1493-1505) and 42 g of bis (2- chloroethyl) amine hydrochloride were charged in a reaction vessel, stirred and heated to reflux for 3 hours. It was cooled to 600C, 24 ml of diethylamine were added, then the mixture was heated again to reflux temperature for another 5 hours. After the reaction was completed the solvent was evaporated in vacuum, a mixture of water and ethyl acetate (1:1) was added, the pH value of the aqueous phase was adjusted to 10-11 with 30% sodium hydroxide solution. The organic phase and extract aqueous phase were separated with ethyl acetate. The combined organic phases were washed with purified water, the organic phase was decolorized with activated carbon, and the filtrate was evaporated in vacuum. The impurities were separated by use of silica gel chromatography by eluting with ethyl acetate/ethanol (7:1) and/or then with ethyl ace- tate/ethanol/ammonia (7:1:0.25) . The eluate was collected and the solvent was evaporated in vacuum to obtain the oily residue which was further dissolved in hexane, treated with activated carbon, heated and filtered. The filtrate was cooled to 100C for 1 hour, a precipitate was collected and dried at 40- 45 C in vacuum for 5-8 hours to afford a product. HPLC (area) 98-99 %.
A mixture of 5-aminoindazole (2.53 g, 19.0 mmol), bis (2- chloroethyl) amine hydrochloride (3.60 g, 20.1 mmol) and ethanol (30 mL) was heated at reflux overnight. The mixture was allowed to cool to room temperature. Na2C03 (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate evaporated in vacuo.-The residue was dissolved in 1 N HC1 (100 mL) and extracted with DCM (2 x 50 mL). The aqueous phase was made basic with 4 N NaOH (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (20: 1 DCM/MeOH to 20: 1: 0.5 DCM/MeOH/Et3N) to 5-Piperazin-l-yl-lH-indazole (1.26 g, 33%) as a brown solid. 1H NMR (DMSO-d6, 400 MHz) 8 12.80 (s, 1H), 7.89 (s, 1H), 7.40 (d, J= 8.8 Hz, 1H), 7.16 (dd, J= 8. 8 Hz, J= 2. 0 Hz, 1H), 7.07 (s, 1H), 3.17 (s, 1H), 2.99 (m, 4H), 2. 89 (m, 4H). LCMS (APCI+) m/z 203 [M+H] + ; Rt = 1. 33 minutes.
With potassium carbonate; In isopropyl alcohol; at 90℃; for 48.0h;
4-aminoindole (2g, 15.2mmol), bis(2-chloroethyl)amine hydrochloride (3.2g, 18.2mmol) and potassium carbonate (4.2g, 30.4mmol) was added to isopropanol (30 mL) after the reaction solution was reacted at 90 °C for 48 hours, and thereto was added dichloromethane (50mL) and methanol (50mL). The reaction mixture was filtered and the filtrate under reduced pressure to spin dry, the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)= 10/1) by to give the title compound as a brown solid (2.78g, 90.8percent).
With sodium carbonate; In isopropyl alcohol;Heating / reflux;
Into a 1000 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1H-indol-4-ylamine (2.8 g, 21.05 mmol, 1.00 equiv) in i-PrOH (800 mL). To this was added bis(2-chloroethyl)amine hydrochloride (4.5 g, 25.21 mmol, 1.20 equiv). To the mixture was added Na2CO3 (8.9 g, 83.96 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This results in 4.3 g (crude) of 4-piperazin-1-yl-1H-indole as a red oil.
To a suspension of bis(2-chloroethyl)amine hydrochloride salt (4.78 g, 0.026 mole) in 45 ml dry dichloro-methane, with cooling (ice water) and stirring, <strong>[7693-41-6]4-methoxyphenyl chloroformate</strong> (5 g, 0.026 mole) was added dropwise. The addition was complete within 20 min. and was followed by addition of triethylamine (5.95 g, 0.05 mole) during 55 min. The mixture was further stirred at room temperature for 1 hour. Water (12 ml) was added, and the mixture was stirred for 10 min. Separated dichchloromethane layer was washed with HCl 1M (12 ml), brine (10 ml), dried and concentrated in vacuo to give an oily product (7 g, ~89.7% yield).
In methanol; sodium hydroxide; diethyl ether; 2-(2-methoxyethoxy)ethyl alcohol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Example 1 Synthesis of 1-(3,5-di-tert-butylphenyl)piperazine 3,5-di-tert-Butylaniline (9 g, 43.8 mmol, 1 eq.) was combined with bis(2-chloroethyl)amine hydrochloride (7.82 g, 43.8 mmol, 1 eq.) in diethylene glycol monomethyl ether (11.7 mL). The reaction was heated at 140 C. for 16 hours. The homogeneous reaction was cooled and dissolved into an aqueous solution of NaOH (2N, 50 mL). The aqueous solution was extracted with ethyl acetate (4*100 mL). The pooled organic extracts were dried (Na2SO4) and concentrated to yield a gummy solid. The resulting crude was dissolved in diethyl ether (100 mL) and acidified with HCl in diethyl ether (2M, 100 mL). The excess solvent was removed in vacuo. The crude HCl salt was stirred in 1:1 hexanes:diethyl ether (300 mL) for 2 hours and then filtered by vacuum filtration to yield a beige precipitate. The beige precipitate was dissolved in an aqueous NaOH solution (2N, 50 mL) which was extracted with EtOAc (4*150 mL). The pooled organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was purified by silica gel chromatography on a Biotage flash chromatography system (Rf 0.4 in 18:1:1 DCM:MeOH:Et3N) to yield the desired product as a tan solid (6.4 g, 53% yield).
Preparation Example 18 : l-(3-chloro-2-methylphenyI)piperazine; To a stirred solution of 3-chloro-2-methylaniline (21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81 %) as white solid. MH+ 21 1
81%
To a stirred solution of 3-chloro-2-methylaniline (compound 26, 21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (compound 27, 30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81 %) as a white solid.MH+ 211.
81%
To a stirred solution of 3-chloro-2-methylaniline (21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81%) as white solid.MH+ 211.
1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.60%
Bis(2-chloroethyl)amine hydrochloride (1.79 g, 10.03 mmol) and 4-fluoro-2-methylaniline (1.26 g, 10.07 mmol) were dissolved in 2-propanol (Volume: 10 mL) and stirred in a closed vial at 100 C. overnight. The reaction mixture was diluted with i-PrOH (10 mL) and cooled to 10 C. The resulting precipitate was filtered and purified using HPLC (10-80% ACN in water, TFA-buffered). The fractions were concentrated in vacuo, suspended in ether (3 mL) and treated with 4N HCl in dioxane (1 mL). The precipitate was filtered and dried in vacuum to afford 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (150 mg, 0.561 mmol, 5.60% yield). ESI-MS:m/z 195 (M+H)+.
ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.3%
Example-3: preparation of ethyl 5-(l-piperazinyl)-benzofuran-2-carboxylate dihydrochloride. ethyl-5 -amino- l-benzofuran-2-carboxylate obtained in above step was dissolved in o-Xylene (1500ml) and then Bis (2-chloroethyl) amine hydrochloride (1 13.8g), Potassium carbonate powder (108.6g) and TBAB (5.0g) at 20-30C was added in the reaction mixture. The reaction mixture was maintained for 32 hrs at 135-140C. After completion of the reaction solid was filtered and washed it with o-Xylene [100ml *3], suck it dry. The wet cake was charged in the saturated brine solution under stirring and ammonia solution (100ml) was added in the reaction mixture at 10- 15C under stirring. The product was extracted in MDC (1000ml) and washed subsequently with dilute acetic acid and water. Cone. HC1 (100.5g) was charged in MDC layer and then MDC was removed atmospherically up-to 50C. Ethanol (700ml) was charged to the residue and raise the temperature of the suspension to 55-60C. The reaction mass was cooled for 1-2 hours at 20-30C and filtered the solid, washed it with Ethanol [100ml x3]. Dried at 55-60C for 12 hours. Yield: 81.3%
81.3%
<strong>[174775-48-5]ethyl-5-amino-1-benzofuran-2-carboxylate</strong> obtained in above step was dissolved in o-Xylene (1500 ml) and then Bis(2-chloroethyl) amine hydrochloride (113.8 g), Potassium carbonate powder (108.6 g) and TBAB (5.0 g) at 20-30 C. was added in the reaction mixture. The reaction mixture was maintained for 32 hrs at 135-140 C. After completion of the reaction solid was filtered and washed it with o-Xylene [100 ml*3], suck it dry. The wet cake was charged in the saturated brine solution under stirring and ammonia solution (100 ml) was added in the reaction mixture at 10-15 C. under stirring. The product was extracted in MDC (1000 ml) and washed subsequently with dilute acetic acid and water. Conc. HCl (100.5 g) was charged in MDC layer and then MDC was removed atmospherically up-to 50 C. Ethanol (700 ml) was charged to the residue and raise the temperature of the suspension to 55-60 C.The reaction mass was cooled for 1-2 hours at 20-30 C. and filtered the solid, washed it with Ethanol [100 ml×3]. Dried at 55-60 C. for 12 hours. Yield: 81.3%
Example-4: preparation of ethyl 5-(l-piperazinyl)-benzofuran-2-carboxylate hydrobromide. ethyl-5 -amino- l-benzofuran-2-carboxylate obtained in above step was dissolved in o-Xylene (1500ml) and then Bis (2-chloroethyl) amine hydrochloride (1 13.8g), Potassium carbonate powder (108.6g) and TBAB (5.0g) at 20-30C was added in the reaction mixture. The reaction mixture was maintained for 32 hrs at 135-140C. After completion of the reaction solid was filtered and washed it with o-Xylene [100ml *3], suck it dry. The wet cake was charged in the saturated brine solution under stirring and ammonia solution (100ml) was added in the reaction mixture at 10- 15C under stirring. The product was extracted in MDC (1000ml) and washed subsequently with dilute acetic acid and water. Aqueous HBr was charged in MDC layer and then MDC was removed atmospherically up-to 50C. Ethanol (700ml) was charged to the residue and raise the temperature of the suspension to 55-60C. The reaction mass was cooled for 1-2 hours at 20-30C and filtered the solid, washed it with Ethanol [100ml x3]. Dried at 55-60C for 12 hours. Yield: 81.3%
General procedure: In an atmosphere of dry N2, a mixture of 5a (10.0 mmol), bis(2-chloroethyl)aminehydrochloride (10.0 mmol), and diethylene glycol monomethyl ether (20 mL) washeated at 150 0C for 8 h. After being cooled to room temperature,the mixture was dissolved in MeOH (5 mL) followed by addition of Et2O(100 mL). The precipitate was filtered off and washed with Et2O toprovide HCl salt. The HCl salt was further converted to free amine by treatmentwith Na2CO3 solution and extracted with EtOAc (2 × 50ml). The combined organic layers were dried over Na2SO4, andconcentrated in vacuo to provide 6a(1.2 g, 67.0%) for next step.
5-piperazinylbenzofuran-2-carboxylic acid ethyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
210 g
In 1,2-dichloro-benzene; at 20 - 180℃;
Step B: Preparation of ethyl-5-(piperazine-1-yl)-1-benzofuran-2-carboxylate hydrochlorideEthyl-5-amino-1-benzofuran-2-carboxylate prepared in step A (82 g) was added toN, N-Bis-2-chloroethylamine hydrochloride (91.14 g) and 1, 2-dichlorobenzene (500 mL)at 20C to 3 0C. The temperature of the reaction mixture was increased to 180C and the reaction mixture was further heated for 2 hours to 4 hours. The reaction mixture was cooled to 20C to 30C and filtered. The solid obtained was washed with dichloromethane (400 mL) at 20C to 30C to obtain the title compound.Yield (Wet): 210 g
With potassium carbonate; potassium iodide; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux;
A mixture of 3-amino-2,2'-bipyridile (0.12 g, 0.7 mmol), bis(2-chloroethyl)amine hydrochloride (0.13 g, 0.7 mmol), K2CO3 (0.1 g, 0.7 mmol) and KI (0.12 g, 0.7 mmol) in xylene (20 mL) was refluxed for 48 h. After cooling, the solvent was distilled off in vacuo and the residue was partitioned between AcOEt (30 mL) and 5% aqueous NaOH solution (30 mL). The organic phase was separated and, then, washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was chromatographed (CHCl3/MeOH, 9:1, as eluent) to give the desired compound as a brown oil (0.07 g, 21% yield). 1H NMR (CDCl3): delta 1.79 (s, 1H, D2O exchanged), 2.78-2.81 (m, 4H), 3.01-3.04 (m, 4H), 7.02-7.19 (m, 2H), 7.20-7.24 (m, 1H), 7.78-7.81 (m, 1H), 8.06 (dd, 1H, J = 1.5 and 4.0 Hz), 8.48-8.58 (m, 2H). GC/MS m/z 241 (M+ + 1, 3), 240 (M+, 20), 210 (43), 184 (100), 156 (64).
In 1-methyl-pyrrolidin-2-one; at 120 - 130℃; for 48h;
Charged 30 mL of N-methyl-2-pyrrolidone (NMP) in a flask followed by the addition of 2-((2,4-dimethylphenyl)thio)aniline (II) (10 g) and Bis(2-chloroethyl)amine hydrochloride (III) (15.6 g). The reaction mixture was heated at a temperature of 120-130 C. for 2 days. The reaction mixture was cooled to the temperature of 25-30 C., followed by the addition of water (100 mL). The obtained solid was filtered and dried under vacuum as Vortioxetine Hydrochloride [Yield 70%; Purity: 99.5% (HPLC)].
58.77%
With potassium iodide; In 1-methyl-pyrrolidin-2-one; at 110 - 120℃; for 48h;
Charged 360 mL of N-Methyl-2-pyrrolidone (NMP) in a flask followed by the addition of 2 ((2,4-dimethylphenyl)thio)aniline (120 g), Bis(2-chloroethyl)amine hydrochloride (374 g) and catalytic amount of potassium iodide. The reaction mixture was heated at a temperature of 110-120 C for 2 days. The reaction mixture was cooled to the temperature of 25-30C, followed by the addition of water (1440 mL) and Toluene (360 mL). The reaction mixture was cooled to 0-5 C temperature and the obtained solid ^as filtered. The wet cake ^as suspended in acetone (1200 mL). The solid obtained w'as filtered and dried under vacuum as Vortioxetine Hydrochloride (Form-P) [Yield: 103 g (58.77%); Purity: 99.7 % (HPLC)].
53%
In diethylene glycol dimethyl ether; at 130℃; for 72h;
A mixture of 2-((2,4-dimethylphenyl)thio)aniline IV (5.0 g, 21 .8 mmol), bis(2- chloroethyl)amine hydrochloride (3.89 g, 21 .8 mmol) and diethylene glycol methyl ether (10 mL) was stirred at 130C for 3 days. Reaction mixture was then cooled to 25C, water (20 mL) was added, and the mixture then further cooled to 10C while stirring. Precipitate was then filtered off, washed with water (10 mL), and dried. The solid was then washed with acetone (3 x 10 mL) and dried to afford vortioxetine hydrochloride as white powder (m = 3.87 g, 53% yield). A mixture of vortioxetine hydrochloride (3.5 g, 10.5 mmol), MeTHF (20 mL) and 1 M NaOH (20 mL) was stirred at room temperature for 1 h. Organic layer was then separated and water layer was extracted with MeTHF (2 x 20 mL). Combined organic layers were dried over Na2S04, and solvent was evaporated to give brownish oil, which crystalized upon standing to give vortioxetine (V) as colorless crystals (m = 2.84 g, 91 % yield): DSC: Onset 1 15.69C, Peak 1 16.71 C; 1H NMR (CDCI3, 500 MHz) delta 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J = 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]+.
53.8%
Thesolution of 2-[(2,4-dimethylphenyl)thiojaniline (100 g; 0.4347 moles) and bis(2-chloroethyl)amine hydrochloride (77.6 g; 0.4347 moles) in n-butanol (500mL) was heated to reflux temperature for 24 h, cool the reaction mass to 70±2C, anhydrous potassium carbonate (30 g; 0.2170 moles) was added and again heated the reaction mass to reflux temperature and maintained for 42 h, reaction mixture was filtered to remove undissolved solid, filtrate was evaporated to give syrup. The obtained syrup crystallized in acetone (500mL) at room temperature, solid was filtered and washed with acetone (lOOmL) to obtain white to off white coloredcrystalline solid of 1 -[2-(2,4-dimethyl-phenylsuIfanyl)-phenyl] -p iperazinehydrochloride (vortioxetine hydrochloride).[Yield: 70.0 g (53.8%); Purity (HPLC) = 99.0%]
In toluene; for 36h;Reflux;
70 g of 2-(2,4-dimethylphenylthio)aniline and 55 g of bis(2-chloroethyl)amine hydrochloride were added to 500 mLInto toluene, the reaction was heated to reflux for 36 hours. After cooling, 800 mL of water and 500 mL of ethyl acetate were added and the mixture was separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was added dropwise with dilute hydrochloric acid to adjust the pH to 2, stirring, precipitation of solids. After filtration, the filter cake was washed with ethyl acetate and dried to obtain 43 g of hydrochloric acid.
ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.3%
<strong>[174775-48-5]ethyl-5-amino-1-benzofuran-2-carboxylate</strong> obtained in above step was dissolved in o-Xylene (1500 ml) and then Bis(2-chloroethyl) amine hydrochloride (113.8 g), Potassium carbonate powder (108.6 g) and TBAB (5.0 g) at 20-30 C. was added in the reaction mixture. The reaction mixture was maintained for 32 hrs at 135-140 C. After completion of the reaction solid was filtered and washed it with o-Xylene [100 ml*3], suck it dry. The wet cake was charged in the saturated brine solution under stirring and ammonia solution (100 ml) was added in the reaction mixture at 10-15 C. under stirring. The product was extracted in MDC (1000 ml) and washed subsequently with dilute acetic acid and water.Aqueous HBr was charged in MDC layer and then MDC was removed atmospherically up-to 50 C. Ethanol (700 ml) was charged to the residue and raise the temperature of the suspension to 55-60 C. The reaction mass was cooled for 1-2 hours at 20-30 C. and filtered the solid, washed it with Ethanol [100 ml×3]. Dried at 55-60 C. for 12 hours. Yield: 81.3%
With sodium carbonate; In ethanol; at 80℃; for 25h;
Add 28.5 g (0.16 mo1) of bis (2-chloroethyl) amine hydrochloride and 200 ml of ethanol to a 500 ml three-necked flask, heat to 80 C, stir for 1 h, and add 21.7 g (0.17 mo1) of 2-chloroaniline , 7.4g of anhydrous sodium carbonate (0.07mo1), continue to heat and stir for 25h, cool to room temperature, suction filter, concentrate the filtrate to dryness, add 100ml of acetonitrile to crystallize, and obtain 35.8g of white crystals, yield 96%.
90%
In sulfolane; at 150℃; for 14h;
General procedure: General procedure for synthesis of 1-arylpiperazine hydrochlorides The following procedure for the synthesis of 1-(2,3-dichlorophenyl)piperazine hydrochloride (3a) is illustrative. A 20L round bottom flask connected to scrubber was charged with 2,3-dichloroaniline (1a) (1.0kg, 6.17mol) and bis(2-chloroethyl)amine hydrochloride (2) (1.43kg, 8.02mol) and 3.0L of sulfolane. The heterogeneous mixture was heated to 150C to give a homogeneous solution which was stirred at 150C for 14h, by which the time the reaction was completed as monitored by HPLC (see below Table 4). The reaction mixture was cooled to 45C and diluted with 5.0L of acetone and further cooled to 0C. The mixture was maintained at 0C for 1 more hour to precipitate the desired product. This was filtered under nitrogen atmosphere and washed with 1L of chilled acetone and dried at 60C under vacuum for 8h to yield
85%
With 2-(2-methoxyethoxy)ethyl alcohol; at 150℃; for 12h;
General procedure: A mixture of 2-methoxyaniline (369.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethyleneglycol monomethyl ether (0.75 mL) was heated at 150 C for about 12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4 mL), followed by the addition of diethyl ether (150 mL). The precipitate formed was recovered byfiltration and washed with diethyl ether to obtain 7c as an HCl salt(510 mg, 74%). The HCl salt was used for the next reaction without further purification.
85%
With 2-(2-methoxyethoxy)ethyl alcohol; at 150℃; for 12h;
The procedure described for the preparation of 23a was used with compound 22b (321.5 mg, 3 mmol), bis(2-chloroethyl)aminehydrochloride (535.5 mg, 3 mmol) and diethylene glycol monomethylether (0.75 mL) to obtain 23b as an HCl salt (595 mg,85%). The HCl salt was used for next reaction without further purification.
1-(3-methanesulfonylphenyl)piperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
In sulfolane; at 150℃; for 14h;
General procedure: General procedure for synthesis of 1-arylpiperazine hydrochlorides The following procedure for the synthesis of 1-(2,3-dichlorophenyl)piperazine hydrochloride (3a) is illustrative. A 20L round bottom flask connected to scrubber was charged with 2,3-dichloroaniline (1a) (1.0kg, 6.17mol) and bis(2-chloroethyl)amine hydrochloride (2) (1.43kg, 8.02mol) and 3.0L of sulfolane. The heterogeneous mixture was heated to 150C to give a homogeneous solution which was stirred at 150C for 14h, by which the time the reaction was completed as monitored by HPLC (see below Table 4). The reaction mixture was cooled to 45C and diluted with 5.0L of acetone and further cooled to 0C. The mixture was maintained at 0C for 1 more hour to precipitate the desired product. This was filtered under nitrogen atmosphere and washed with 1L of chilled acetone and dried at 60C under vacuum for 8h to yield
With N-ethyl-N,N-diisopropylamine;Inert atmosphere; Reflux;
In a 1 L two-necked flask, intermediate (IV) (68 g, 0.297 mol) was added. bis-(2-chloroethyl)amine hydrochloride (58 g, 0.325 mol) and N,N-diisopropylethylamine (70 ml) were added. Under nitrogen protection. Heated to reflux. The reaction was performed for 6 to 8 hours (TLC endpoint: petroleum ether: ethyl acetate = 10: 1). Stop heating. Cooled to room temperature. Ethyl acetate (70 ml). Cooled to 0C. Precipitation of a large number of khaki solids. Filtration. Methanol washing. The filter cake was dried by suction filtration to obtain 78.7 g of a earth yellow solid (VI), yield: 79%.
78%
With potassium carbonate; potassium iodide; In acetonitrile; for 24h;Reflux;
Compound II (<strong>[1019453-85-0]2-(2,4-dimethylphenylsulfanyl)-phenylamine</strong>) (45.87 g, 0.2 mol), bis(2-chloroethyl)amine hydrochloride (46.4 g, 0.26 mol) Potassium carbonate (55.0g, 0.4mol), Potassium iodide (33 mg, 0.2 mmol) was added to acetonitrile (500 ml), and the mixture was heated and refluxed for 24 h, filtered while hot, and the filtrate was stirred at room temperature, and then filtered. The filter cake was dried under vacuum at 40 C for 10 h. Compound I (white solid, 46.57 g) was obtained. The molar yield was 78%.
With 1,3-dimethyl-2-imidazolidinone; potassium carbonate; In toluene; at 170 - 180℃; for 12h;
1,0 g (4.36 millimoles) of <strong>[1019453-85-0]2-[(2,4-dimethyl-phenyl)-sulfanyl]-aniline</strong>, 0.91 g (5.0 millimoles) of bis-(2-chloroethyl-amine)-hydrochloride and 0.72 g (5.2 millimoles) of potassium carbonate are suspended in a mixture of 10 ml of toluene and 10 ml of DM1. The suspension is placed in a hermetically closed Teflon vessel and heated in an oil bath at 170-180C for 12 hours under stirring.. The reaction mixture is cooled every 3 hours, whereupon bis-(2- chloroethyl)-amine hydrochloride and potassium carbonate are added in an amount disclosed above. Heating is continued. The reaction having been completed the suspension is filtered, the inorganic salt mixture is washed successively with 5 ml of toluene and three times with 5 ml of dichioro methane each. The united filtrates are poured in a mixture of 100 g of ice and 5 ml of ammonium hydroxide, then evaporated dichloro methane and toluene free. The precipitated resin is solidified by rubbing. The solid substance is filtered, washed with water until neutral and dried. Thus about 0.94 g (72 %) of sticky crystals are obtained from which a 0.3 g (about 1.0 millimole) portion is suspended in 6 ml of acetone. The suspension is warmed to 60C whereupon at this temperature a solution of 0.15 g (1.0 millimole) of L-(+)-mandelic acid and 2 ml of acetone is added dropwise. After some minutes the precipitation of crystals begins. The precipitated salt is filtered, washed three times whit 2 ml of cold acetone each and dried. Thus 0.35 g (78%) of the desired compound is obtained. Mp.: 155-158C, HPLC purity 99.9 %.IR(KBr):2736,2517, 1716, 1594, 1471, 1370, 1232, 1187 cm1.?H-NMR (CDCI3, 400 MHz): oe 7.50 (m, 2H), 7.36 (d, J=7.8 Hz, IH), 7.32 (m, 2H), 7.21 (m, 1H), 7.19 (s, IH), 7.09 (m, 1H), 7.05 (m, IH), 6.92 (m, lH), 6.91 (m, lH), 6.52 (m, 1H), 4.95 (s, 1H), 3.06 (m, 2H), 3.02 (m, 4H), 2.95 (m, 2H), 2.38 (s, 3H), 2.31 (s, 3H) ppm.
In o-xylene; at 110 - 130℃;
A mixture of bis(dibenzyldieneacetone) palladium (0.16712 g, 0.00029 mol), (±)-2,2?- bis(diphenylphosphino)- 1,1? -binaphtalene(0. 180 g, 0.00029 mol), and o-xylene(50 mL)were combined in a flask. The reaction mass was stirred at 25C under nitrogen atmosphere and 2- bromoaniline (formula-XIII, 5 g, 0.029 mol) and 2,4-dimethylthiophenol (formula-IV, 4.42 g, 0.03 194 mol) were added. The reaction mass was stined for 15 minutes at 25-35C before adding potassium tert-butoxide (4.9 g, 0.0436 mol). Thetemperature of the reaction mass was raised to 110-120 C and stined for 2-3 hours. After completion of the reaction, the reaction mass was cooled to 25-30C. Bis(2-chloroethyl)amine hydrochloride (formula-XIV, 10.36 g, 0.058 mol) was then added and the reaction mass was stined for 15-30 minutes. The reaction temperature was raised to 110-130C and stined for 15-20 hours. After completion of the reaction, the reaction mass was cooled to 5-10C and water (50 mL) was added. The reaction mass was stined for 15 minutes before filtering and separating the organic and aqueous layers. The organic layer was adjusted to a pH of 9-10 with a 10% sodium hydroxide solution,stined for 15 minutes, and the organic and aqueous layers were separated. The organic layer was concentrated by distillation at 60-65 C under vacuum and the resulting residue was dissolved in toluene. The solution was heated to 60 C and aqueous hydrobromic acid (48%, 5 mL)was slowly added. The reaction mass was maintained for 30 minutes at 60, then cooled to room temperature and stirred for 60 minutes.The reaction mass was filtered and the resulting solid was washed with toluene to yield vortioxetine hydrobromide.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 4h;Reflux;
Compound 4 (18 g, 78 mmol) was dissolved in 150 mL of acetonitrile.Dichloroethylamine hydrochloride (14.3 g, 80 mmol) was added.And DIEA (32g, 4eq),Reflux for 4 hours,Concentrated, diluted with water, extracted with ethyl acetate, dried,The crude product obtained was used in the next step without purification.
In 1-methyl-pyrrolidin-2-one; at 130℃;
Add 4.51g of 2-(2,4-dimethylphenylthio)aniline, 5.24g of bis(2-chloroethyl)amine hydrochloride, and 30mL of NMP to a 100mL reaction flask. The temperature is raised to 130, and the temperature is kept stirring. 22-24h.Reduce to room temperature, add 200 mL of water and 80 mL of dichloromethane for extraction, combine the organic phases and wash with 150 mL of saturated brine, dry with anhydrous magnesium sulfate, spin dry in vacuo, add 50 mL of ethyl acetate, filter, and add to the filter cake with stirring 2M sodium hydroxide aqueous solution 35mL, ethyl acetate 80mL extraction, the organic phase was washed with 100mL water, dried with anhydrous magnesium sulfate, 0.3g activated carbon was added, the temperature was raised to 55-60, the temperature was kept and stirred for 1-2h, and the diatomaceous earth Filtered on a Buchner funnel, and the filtrate was spin-dried in vacuo to obtain 1.97 g of crude yellow solid vortioxetine with a yield of 38%.
1-[2-(2,4-dimethylphenylsulphanyl)phenyl]piperazine 4-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
2-(2,4-Dimethylphenylsulphanyl)nitrobenzene of formula X, (14.63 g; 56.43 mmol) is placed into an autoclave, 125 ml of methanol and 2.2 g of Ra-Ni are added. The mixture is hydrogenated at pressure of 2000 kPa and temperature of 60C for 2 hours. The reaction mixture is cooled down to 20C, the catalyst is filtered off, and the filtration cake is washed with methanol. Methanol is evaporated and the oily product is co-distilled 3 x with toluene.The obtained 2-(2,4-dimethylphenylthio)benzeneamine of formula Xl is dissolved in 68 ml of toluene, bis-(2-chloroethyl)amine hydrochloride of formula Xllaa (10.95 g; 61.35 mmol) and KI (7.03 g; 42.325 mmol) are added, and the reaction mixture is refluxed in the nitrogen atmosphere for 30 hours. 90 ml of brine and 18 ml of 30% NaOl-l are then added at 35C, the mixture is stirred at this temperature for 20 minutes, and then it is left standing at 35Covernight. The phases are separated and the aqueous layer is shaken with 2 x 45 ml of toluene at 35C. The combined organic phases are washed with 2 x 30 ml of sodium thiosulphate and 2 x 30 ml of water. 8.44 g of 4-chlorobenzoic acid is then added, the mixture is heated up to reflux, gradually cooled down to 20C, and left in a refrigerator overnight. The separated vortioxetine 4-chlorobenzoate (LPCB) is washed with toluene, recrystallized fromtoluene, and subsequently from ethanol. 12.8 g of white crystals are obtained (50%); HPLC purity 99.8%.
General procedure: In a flask charged with diethylene glycol monomethyl ether (8 mL)added equimolar quantities (25 mmol) of appropriate amine (1a-w)and bis(2-chloroethyl)amine hydrochloride (2). The resulting mixturewas heated for 150 C for 16-48 h under N2 atmosphere in the presenceof catalytic amount of KI (3 mol%). The progress of the reaction wasmonitored using TLC with the mobile phase toluene: acetone (8:2).After the completion of the reaction, the mixture was cooled to roomtemperature and dissolved in methanol (25 mL), and ethyl acetate(100 mL) was added. The precipitate thus obtained were filtered,washed with ethyl acetate and the resulting salt was then convertedto free amines upon treating with Na2CO3 and extracted with ethyl acetate(2 × 25 mL). The combined organic phase was dried over MgSO4and evaporated to give analytically pure piperazine derivatives 3a-win reasonably good yields.
Example 10 Synthesis of Vortioxetine hydrobromide 2-(2,4-dimethyl-phenylthio) aniline (13.7g, 0.06mol), bis(2-chloroethyl)amine hydrochloride (11.0g, 0.06mol) was added 250mL reaction flask, toluene was added (80mL), protection of nitrogen, the reaction was heated at reflux with stirring overnight. And cooled to 60C, the solvent was evaporated, the residue was added water (80mL), ethyl acetate (80mL) extraction separation, the organic layer was separated (20 mL) and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decolorized with charcoal, filter, the filtrate was added dropwise 48% hydrogen bromide (approximately 10mL) was adjusted to pH1~2, stirred, precipitated solids. Filter, drying, give white solid 17.8g, yield 78.3%, Purity 99.3%
1-(benzo[b]thiophen-4-yl)piperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With toluene-4-sulfonamide; In 5,5-dimethyl-1,3-cyclohexadiene; at 120 - 150℃; for 16h;
4-Aminobenzo [b] thiophene 14. 92 g(100 mmol) was added to the reaction flask with di (2-chloroethyl) amine hydrochloride and 85 g (5 mmol) of p-toluenesulfonamide and 225 mL of xylene were added at 120 to 150 ° C C under stirring for 16 hours. And then naturally dropped to room temperature, and then reduced to 0 ° C for 2 hours, filtered to obtain white solid crystal 21. 66g, the yield of 85. 0percent, 98percent purity.
84%
With potassium carbonate; In butan-1-ol; for 24h;Reflux;
Intermediate IV 74. 6g (0 · 5mol), n-butanol 1300ml, bis (2-chloroethyl) amine hydrochloride 71. 5g (0 · 5mol), and potassium carbonate 35g (0. 25mol), stirred suspension of and heated to reflux, the reaction 24h, the reaction end point TLC (developing solvent: ethyl acetate - methanol = 9: 1), completion of the reaction, cooled to room temperature, the supernatant was decanted, filtered, and the filtrates were combined The supernatant was concentrated to dryness and the crude product was recrystallized from methanol to give a white solid intermediate V (107g, 0 42mol.), a yield of 84percent, Murho: 214~217. . .
A mixture of <strong>[74586-53-1]3-bromo-5-methyl-aniline</strong> (5 g, 26.87 mmol) and 2-chloro-N-(2-chloroethyl)ethanamine (Hydrochloric Acid (1)) (5.28 g, 29.56 mmol) in butan-1-ol (100 mL) was refluxed at 125 C for 16h. After filtration, the solids were collected, washed with n-butanol and dried. The solid was dissolved in EtOAc (200 mL) and treated with sat. Na2CO3 (40 mL). The organic layer was collected, then excess solvent was removed in vacuo. ISCO purification (40 g silica; 0 % to 10% to 30% of MeOH in DCM) gave 1-(3-bromo-5-methyl- phenyl)piperazine YL-19a (2.7 g, 39.4%). ?H NMR (300 MHz, CDC13) oe 6.86 (d, J = 1.9 Hz, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 3.50 (s, 1H), 3.14 (dd, J = 6.3, 3.6 Hz, 4H), 3.02 (dd, J = 6.2, 3.6 Hz, 4H), 2.29 (d, J = 0.4 Hz, 3H) ppm. ESI-MS m/z calc. 254.04, found 255.32 (M+1)+; Retention time: 0.64 minutes.
General procedure: 20% KOH solution in hydrazine hydrate and the calculated amount of diorganyl dichalcogenide R2Y2 (R2Y2 : KOH = 1 : 5) was stirred for 4 h at 85-90C. the reaction mass was cooled to 60C, 1 equivalent of chlorex 1a or salt 1b was added, the mixture was stirred for 5 h at 60-70C, cooled to 25C, the product was extracted with ether (2x50 mL), the extract was dried over MgSO4, the solvent was removed. Compounds 2g, 2j were distilled in a vacuum, compounds 2h, 2i were analyzed without distillation.
<strong>[1019453-85-0]2-[(2,4-dimethylphenyl)sulfanyl]aniline</strong> (20 g), o-Xylene (60 ml), Bis(2-chloroethyl)amine hydrochloride (15.59 g) and PTSA (0.5 g) was added into round bottom flask. The reaction mixture was heated at 140±7 C. Reaction mixture was stirred for 30 hr at reflux temperature. Reaction mixture was cooled to 30±5 C. and then, o-Xylene (200 ml) and water (160 ml) was added to the reaction mixture at 30±5 C. Resulting reaction mixture was basified with 10% NaOH (pH >7.0) at 30±5 C. Organic layer was separated out and into resulting organic layer, adipic acid solution (12.8 g) in Acetone (306 ml) was added at 40 C. Resulting reaction mixture was stirred for 2 hr at 30±5 C. Reaction mixture was filtered and solid mass was washed with acetone (20 ml) and dried it under vacuum for 6-8 hrs at 55±5 C. Resulting crude Vortioxetine adipate salt was added in THF (500 ml) at 30±5 C. Resulting reaction mixture was heated to reflux temperature for 5-10 mins. Resulting reaction mixture was cooled to 30±5 C. and stirred it for 1 hr at 30±5 C. and pure Vortioxetine adipate salt was collected by filtration.
1-(2'-fluoro-[1,1'-biphenyl]-2-yl)piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With potassium carbonate; potassium iodide; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 48h;
General procedure: A mixture of biphenyl amine 27 (90 mmol), Bis(2-chloroethyl)amine hydrochloride 28 (90 mmol), K2CO3 (90 mmol) and KI(90 mmol) in xylene (450 mL) was stirred at 140 C for 48 h. Aftercooling to room temperature, the solvent was evaporated, thenDCM (150 mL) was added. The mixture was washed with water andbrine, dried over anhydrous Na2SO4, filtered and concentrated. Theresiduewas purified by column chromatography on silica gel (DCM/MeOH = 20/1, V/V) to give compound 20. 4.1.20.1. 1-(2'-fluoro-[1,1'-biphenyl]-2-yl)piperazine (20a).Yield (22%) as a yellow solid. Mp: 63-64 C. MS (ESI) m/z: 257.23[MH]. 1H NMR (400 MHz, CDCl3) delta 7.47 (td, J = 7.5, 1.8 Hz, 1H),7.36-7.31 (m, 1H), 7.31-7.23 (m, 2H), 7.19-7.13 (m, 1H), 7.13-7.06(m, 3H), 2.80-2.77 (m, 4H), 2.71-2.68 (m, 4H).
5-(piperazin-1-yl)benzofuran-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium carbonate; In isopropyl alcohol; at 50 - 60℃; for 4h;
20.0 g of <strong>[174775-48-5]ethyl <strong>[174775-48-5]5-aminobenzofuran-2-carboxylate</strong></strong>, 20.0 g of bis (2-chloroethyl) amine hydrochloride, 20 g of sodium carbonate and 300 ml of isopropanol were charged into a reaction flask as in Example 3 The mixture was stirred for 4 hours under heating at 50 to 60 C. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to remove most of the solvent. Water (200 ml) and dichloromethane (200 ml) were stirred and extracted. The filtrate was concentrated under reduced pressure and the filtrate was filtered, the solid was transferred to a vacuum oven 40 to 50 C for 8 hours to obtain the finished productAbout 22.7 g of ethyl 5- (1-piperazinyl) -2-benzofuran-2-carboxylate was obtained, yield 85%, purity 98.9%
83.1%
With sodium carbonate; In ethanol; at 50 - 60℃; for 4h;
Ethyl <strong>[174775-48-5]5-aminobenzofuran-2-carboxylate</strong> (20.5 g), bis(2-chloroethyl)amine hydrochloride (18.0 g), sodium carbonate (20 g), and ethanol (300 ml) were added to the reaction flask as in Example 5.The reaction was heated at 50 to 60 C. for 4 hours. The insoluble material was filtered off. The filtrate was concentrated under reduced pressure to remove most of the solvent. 200 ml of water was added, and 200 ml of dichloromethane was stirred and extracted.The filtrate was concentrated under reduced pressure and the slurry was filtered. The solid was transferred to a vacuum oven 40 and dried at 50 DEG C. for 8 hours to obtain the final product, about 22.8 g of ethyl 5-(1-piperazinyl)-2-benzofuran-2-carboxylate.,Yield 83.1%, purity 99.5%,
methyl 2-[2-methyl-5-(piperazin-1-yl)phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
In methanol; at 100℃; for 72.0h;Sealed tube;
Step 4: a mixture of <strong>[850449-93-3]methyl 2-(5-amino-2-methylphenyl)acetate</strong> Ex.4c (2.00 g, 11.16 mmol), bis-(2-chloroethyl)amine hydrochloride (1.99 g, 11.16 mmol) in MeOH (20 mL) was heated at 100C in a sealed tube and stirred for 72h. LCMS showed the formation of the expected product as the main peak. After cooling, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 solution and brine. The organic layer was dried, filtered and the solution was concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography eluting with CH2CI2/MeOH to afford methyl 2-[2- methyl-5-(piperazin-1-yl)phenyl]acetate (0.82 g, 30%).
methyl 2,4-difluoro-5-(piperazin-1-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29.9%
at 170℃; for 2.5h;
A mixture of methyl 5-amino-2,4-difluoro-benzoate (2, 3.0 g, 0.016 mol) and 2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (3.719 g, 0.021 mol) in diethylene glycol monomethyl ether (12 mL) was heated to 170C for 2.5h. Progress of the reaction was monitored by TLC. Water was added to the reaction mixture and extracted with ethyl acetate. The organic part was discarded. Then pH of the aqueous part was adjusted with sodium bicarbonate and extracted with ethyl acetate. Combined organic part was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography to afford the product (1.5 g, 29.9%). LCMS (ESI positive ion) m/z: calculated: 256.25; Observed; 257.0 (M+l).
3-fluoro-4-(piperazin-1-yl)phenol hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In sulfolane; at 150℃; for 16h;
To a stirred solution of <strong>[399-95-1]4-amino-3-fluorophenol</strong> (2, 6.9 g, 0.054 mol) in sulfolane (15 mL), bis(2- chloroethyl)amine hydrochloride (13.56 g, 0.076 mol) was added. The reaction mixture was heated at 150°C for 16h. After the completion of the reaction, the reaction mixture was cooled to RT. About 30 mL of cold acetone was added and stirred at 0°C for 0.5h. The solid formed was filtered, and dried to afford the 3-fluoro-4-(piperazin-l-yl)phenol hydrochloride as black colored solid (10 g, 98percent). LCMS (ESI positive ion); m/z: calculated: 196.23; Observed; 197.1 (M+l).
2,4-difluoro-5-(piperazin-1-yl)phenol hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.3%
In sulfolane; at 150℃; for 16h;Inert atmosphere;
To a stirred solution of <strong>[113512-71-3]5-amino-2,4-difluorophenol</strong> (2, 20 g, 0.131 mol) in sulfolane (30 mL) bis(2-chloroethyl) amine hydrogen chloride (31 g, 0.170 mol) was added. The resulting mixture was stirred at 150 C under nitrogen atmosphere for 16 h. It was cooled to RT and acetone was added to the crude reaction mixture and stirred at 0 C for 1 h. After 1 h, the precipitated solid was filtered and washed with chilled acetone under nitrogen atmosphere. The solid material was dried under vacuum to afford 2,4-difluoro-5-(piperazin-l-yl)phenol (3) as off white solid (23 g, 80.3%); LCMS (ESI positive ion) m/z: calculated: 214.09; observed: 215.1 (M+l).
With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 1,4-dioxane; at 80℃; for 9h;Inert atmosphere;
Add 125 ml of dioxane to a 250 ml four-necked flask.<strong>[56961-77-4]2,3-dichlorobromobenzene</strong> (22.59 g, 0.1 mol),Bis(dichloroethylamine) hydrochloride (21.42 g, 0.12 mol),Sodium tert-butoxide (20.18 g, 0.21 mol),Bis(dibenzylideneacetone)palladium (2.875 g, 50 mmol),Under the protection of nitrogen, the temperature was raised to 80 C for 9 h.TLC monitored the complete conversion of <strong>[56961-77-4]2,3-dichlorobromobenzene</strong>.The reaction solution is cooled to room temperature, and the catalyst is recovered by filtration.The filtrate was reduced in oxime to recover dioxane, and the intermediate was 27.13 g.The yield was 94.5% and the HPLC purity was 97.9%.The recovered catalyst and solvent can continue to be applied.
1) Preparation of 1-[3-Fluoro-5-(trifluoromethyl)phenyl]-piperazine To 60 ml of n-butanol were added 5.0 g of <strong>[454-67-1]3-fluoro-5-(trifluoromethyl)aniline</strong> and 5.0 g of bis(2-chloroethyl)amine hydrochloride, and the mixture was heated under reflux for 47 hours. To the reaction mixture was added 3.85 g of potassium carbonate, followed by heating under reflux for 24 hours. After cooling to room temperature, the solvent was removed by evaporation. The residue was dissolved in an 1N sodium hydroxide aqueous solution and extracted with chloroform-methanol (19:1 by volume). The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 9:1 (by volume) mixed solvent of chloroform and methanol as a developing solvent. The fraction containing the desired compound was concentrated to yield 2.1 g of the title compound. 1H-NMR (CDCl3) delta: 3.02 (m, 4H), 3.20 (m, 4H), 6.71 (dm, 1H, J=12 Hz), 6.74 (dm, 1H, J=10 Hz), 6.89 (brs, 1H).
1-benzo[b]thiophen-4-ylpiperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14.92 g of <strong>[17402-83-4]4-aminobenzothiophene</strong>, 17.85 g of bis(2-chloroethyl)amine hydrochloride and 11.13 g of sodium carbonate were dissolved in 120 mL of n-butanol.The reaction was refluxed for 6 h, and cooled to give benzo[b]thiophen-4-ylpiperazine hydrochloride. The benzo[b]thiophen-4-ylpiperazine hydrochloride was dissolved in water, adjusted to pH 12 with 2 mol/L NaOH, and extracted with ethyl acetate.The ethyl acetate extract was washed successively with saturated sodium chloride solution and deionized water until neutral.Drying with anhydrous sodium sulfate, removing the solvent to obtain benzo[b]thiophen-4-ylpiperazine;
1-(5-bromo-2,4-difluorophenyl)piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
In sulfolane; at 150℃; for 16h;Inert atmosphere;
To a stirred solution of <strong>[452-92-6]5-bromo-2,4-difluoroaniline</strong> (1) (2.0 g, 0.01 mol) in sulfolane was added bis(2-chloroethyl)amine hydrochloride (2.23 g, 0.012 mol). The resulting mixture was stirred at 150 C. under nitrogen atmosphere for 16 h. At RT, acetone (10 mL) was added to the reaction mixture and stirred at 0 C. After 1 h, the precipitated solid was filtered and washed with cold acetone (5 mL) under nitrogen atmosphere. The solid was dried under vacuum to afford the title compound as off a white solid. Yield: (1.6 g; 59%); LCMS (ESI positive ion) m/z: calculated: 277.1; observed: 279.5 (M+2).
Chemistry
Pharmaceutical Intermediates
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Material Science
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110K+ Compounds
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