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Chemical Structure| 821-48-7
Chemical Structure| 821-48-7
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Product Details of [ 821-48-7 ]

CAS No. :821-48-7 MDL No. :MFCD00012515
Formula : C4H10Cl3N Boiling Point : -
Linear Structure Formula :- InChI Key :YMDZDFSUDFLGMX-UHFFFAOYSA-N
M.W :178.49 Pubchem ID :522769
Synonyms :

Calculated chemistry of [ 821-48-7 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 4
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 40.7
TPSA : 12.03 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.12 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.78
Log Po/w (WLOGP) : 1.86
Log Po/w (MLOGP) : 1.89
Log Po/w (SILICOS-IT) : 1.59
Consensus Log Po/w : 1.42

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.8
Solubility : 2.8 mg/ml ; 0.0157 mol/l
Class : Very soluble
Log S (Ali) : -1.65
Solubility : 3.99 mg/ml ; 0.0223 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.76
Solubility : 0.312 mg/ml ; 0.00175 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.61

Safety of [ 821-48-7 ]

Signal Word:Danger Class:8
Precautionary Statements:P234-P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P390-P405-P406-P501 UN#:3261
Hazard Statements:H290-H302-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 821-48-7 ]

* 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.

  • Upstream synthesis route of [ 821-48-7 ]
  • Downstream synthetic route of [ 821-48-7 ]

[ 821-48-7 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 821-48-7 ]
  • [ 108-42-9 ]
  • [ 6640-24-0 ]
YieldReaction ConditionsOperation in experiment
36%
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 ]
YieldReaction ConditionsOperation 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
  • 8
  • [ 821-48-7 ]
  • [ 140-53-4 ]
  • [ 91721-16-3 ]
Reference: [1] Patent: US2007/88036, 2007, A1, . Location in patent: Page/Page column 16
  • 9
  • [ 455-14-1 ]
  • [ 821-48-7 ]
  • [ 30459-17-7 ]
Reference: [1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
  • 10
  • [ 821-48-7 ]
  • [ 98-16-8 ]
  • [ 15532-75-9 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 46, p. 7921 - 7922
  • 11
  • [ 821-48-7 ]
  • [ 873-74-5 ]
  • [ 68104-63-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1531 - 1536
  • 12
  • [ 821-48-7 ]
  • [ 98-59-9 ]
  • [ 42137-88-2 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Journal of Molecular Structure, 2009, vol. 923, # 1-3, p. 132 - 140
[2] Patent: EP1714961, 2006, A1, . Location in patent: Page/Page column 18
[3] Patent: WO2013/175499, 2013, A2, . Location in patent: Page/Page column 23
[4] Patent: US2014/179713, 2014, A1, . Location in patent: Paragraph 0085
[5] RSC Advances, 2015, vol. 5, # 118, p. 97205 - 97211
  • 13
  • [ 821-48-7 ]
  • [ 501-53-1 ]
  • [ 72791-76-5 ]
YieldReaction ConditionsOperation in experiment
95.5%
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 ]
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YieldReaction ConditionsOperation 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.

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[4] Patent: EP2682390, 2014, A1, . Location in patent: Paragraph 0018; 0080
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Reference: [1] Letters in Drug Design and Discovery, 2015, vol. 11, # 9, p. 1096 - 1106
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Reference: [1] Phosphorus, Sulfur and Silicon and Related Elements, 1996, vol. 109, # 1-4, p. 473 - 476
  • 17
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  • [ 55-86-7 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Patent: US2008/139553, 2008, A1, . Location in patent: Page/Page column 24
[2] Patent: US2008/153861, 2008, A1, . Location in patent: Page/Page column 19-20
[3] Patent: US2008/161304, 2008, A1, . Location in patent: Page/Page column 14
[4] Journal of Organic Chemistry, 1993, vol. 58, # 6, p. 1359 - 1366
  • 18
  • [ 64-18-6 ]
  • [ 821-48-7 ]
  • [ 55-86-7 ]
YieldReaction ConditionsOperation in experiment
92% at 100 - 120℃; 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] Patent: EP2533783, 2015, B1, . Location in patent: Paragraph 0395-0396
  • 19
  • [ 50-00-0 ]
  • [ 64-18-6 ]
  • [ 821-48-7 ]
  • [ 55-86-7 ]
Reference: [1] Dalton Transactions, 2014, vol. 43, # 1, p. 290 - 299
  • 20
  • [ 821-48-7 ]
  • [ 104-94-9 ]
  • [ 38869-47-5 ]
Reference: [1] Magnetic Resonance in Chemistry, 2005, vol. 43, # 10, p. 869 - 872
  • 21
  • [ 821-48-7 ]
  • [ 90-04-0 ]
  • [ 5464-78-8 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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] Patent: US2003/13720, 2003, A1,
  • 29
  • [ 821-48-7 ]
  • [ 118753-70-1 ]
Reference: [1] Patent: WO2006/51290, 2006, A2, . Location in patent: Page/Page column 120-121; 133
[2] Patent: WO2006/136829, 2006, A2, . Location in patent: Page/Page column 119
  • 30
  • [ 367-25-9 ]
  • [ 821-48-7 ]
  • [ 115761-79-0 ]
Reference: [1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
  • 31
  • [ 5192-23-4 ]
  • [ 821-48-7 ]
  • [ 84807-09-0 ]
YieldReaction ConditionsOperation 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
  • 32
  • [ 19335-11-6 ]
  • [ 821-48-7 ]
  • [ 478827-33-7 ]
YieldReaction ConditionsOperation in experiment
33%
Stage #1: Heating / reflux
Stage #2: for 8 h; Heating / reflux
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.
Reference: [1] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 76-77
[2] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 76-77
  • 33
  • [ 6967-12-0 ]
  • [ 821-48-7 ]
  • [ 763910-07-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 21, p. 7639 - 7646
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