* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With methyllithium; lithium bromide In diethyl ether at -78℃; for 0.5 h;
General procedure: To a cooled (–78°C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi–LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides.
Reference：
[1] Chemical Communications, 2013, vol. 49, # 75, p. 8383 - 8385
[2] Synthesis (Germany), 2014, vol. 46, # 21, p. 2897 - 2909
2
[ 79-04-9 ]
[ 87-62-7 ]
[ 1131-01-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium carbonate In ethyl acetate at 20℃; Cooling with ice
Example 1Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide1.1: Preparation of 2-chloro-N-(2,6-dimethylphenyl)-acetamide[0027][0028]30.5 g (0.252 mol) of 2,6-xylidine, 100 ml of ethyl acetate, 26.5 g (0.25 mol) of sodium carbonate were successively added into a 250 ml of 3-neck flask and placed in an ice-water bath. 36.5 g (0.323 mol) of chloroacetyl chloride was dissolved in 50 ml of ethyl acetate and then the mixture was dropwise added into the 3-neck flask till completion. The ice-water bath was removed and the reaction was carried out for 3 h at the room temperature. The reaction product was slowly added 100 ml of water in an ice-water bath, stirred for 10 min and filtered. The filter cake as white needle solid was washed and dried under vacuum to get 46.3 g of 2-chloro-N-(2,6-dimethylphenyl)-acetamide having a yield of 93percent.
92%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 5℃; for 5 h;
Example 1; 2,6-Dimethylaniline (1.0 kg) in tetrahydrofuran (1.2 /) was added to a solution of sodium bicarbonate (1.20 kg in 10.80 / water) and the reaction mass was cooled to 0 to 50C. To the reaction mass, chloroacetyl chloride (1.06 kg) was added at 0 to 50C was and stirred for further 5 hours at same temperature. After completion of reaction (monitored by thin layer chromatography), the solid obtained was filtered, washed with demineralized water. The wet product was slurry washed with hexane and dried at 60-700C to afford I 50 kg of the title compound.Yield-92percent; Example 5; 2,6-Dimethylaniline (10 Kg) and tetrahydrofuran (12 L) were added to a solution of sodium bicarbonate (12 Kg in 108 L water) and the reaction mass was cooled to 0 to 5°C. To the reaction mass, chloroacetyl chloride (10.6 Kg) was added at 0 to 50C was and stirred for further 5 hours at same temperature. After completion of reaction (monitored by thin layer chromatography), the solid obtained was filtered, washed with demineralized water (5.0 L). The wet product was slurry washed with hexane (2.0 L) and dried at 60-700C to afford 14.7 Kg of the title compound having purity 98.96 percent by HPLC.
87.59%
With triethylamine In dichloromethane at 0 - 20℃; for 6 h;
General procedure: 2-chloroacetyl chloride (1.5 mmol) was added dropwise to a mixture of amine (1 mmol) and triethylamine (3 mmol) in 20 mL dichloromethane originally at 0 °C with stirring. Then the resulting mixture was cooled to ambient temperature and stirred for 6 h. After removal of dichloromethane solvents on a rotary evaporator, water was added and extract with ethyl acetate (3 × 30 mL). The organic layer was combined and dried with sodium sulfate. The solution was evaporated to give the crude product, which was purified by Silica gel column chromatography with ethyl acetate–petroleum ether as eluent.
86.12%
at 0 - 20℃;
Procedure: Adding drop wise to a solution of 2,6 xylidine 1 (50.0 g, 41.26 mmol; 1.0 eq) in 1.0 L of Dichloromethane, chloroacetyl chloride (51.26 g, 45.38 mmol; 1.0 eq) for 30 min at 0° C. to make a mixture. The temperature of the mixture is brought to room temperature and left for stirring overnight to obtain a reaction mixture. On completion of the reaction (monitored by TLC), the reaction mixture was washed with water (1.0 L), followed by brine solution (0.5 L) to separate organic layer and inorganic layer. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get product 2 which was recrystallized in hexane (1 L) and the solid filtered to yield 70 g (86.12percent) of compound 2 as a white solid.
83%
at 0 - 20℃; for 3.5 h;
To a stirred solution of 2,6-dimethyl aniline(30.O g, 0.24 mole; 1.0 eq) in DCM (600 mL; LR grade) was added Chioroacetyl chloride at 0 °C over 30 mm and the reaction mixture was stirred for 3 h at room temperature. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (200 mL) and washed with water (2 x 250 mL) followed by saturated aqueous NaHCO3 solution (2 x 250 mL). The combined organic layer was washed with brine solution (1 x 100 mL) and dried over anhydrous Na2SO4. Evaporate organic layer under reduced pressure to get solid mass, which was triturated with hexane (250 mL) and filtered to get 40.8 g of compound as a white solid (Yield = 83percent)
82%
at -5 - 0℃; for 3 h;
Step 2: Preparation of 2-chloro-yV-(2,6-dimethyIphenvI)acetamide; 2,6-Dimethylaniline (100 g) was added to a solution of sodium bicarbonate (91 g in 1.0 / water) and reaction mass was cooled to 0 to -5°C. To the reaction mass, chloroacetyl chloride (106 g) was added slowly at 0 to -5°C. The reaction mass was stirred for 3 hours at 0 to -5°C. After completion of reaction (monitored by thin layer chromatography), the solid obtained was filtered and washed with demineralized water to afford 142 g of the title compound having purity 98.97percent by high performance liquid chromatography.Yield-87percent; Step 2: Preparation of 2-chloro-./V-(2,,6-dimethylphenvDacetamide; 2,6-Dimethylaniline (100 g) was added to a solution of sodium bicarbonate (91 g in 1.0 / water) and reaction mass was cooled to 0 to -5°C. To the reaction mass, chloroacetyl chloride (106 g) was added slowly at 0 to -5°C. The reaction mass was stirred for 3 hours at 0 to -5°C. After reaction completion (monitored by thin layer chromatography), the solid obtained was filtered and washed with demineralized water to afford 135 g of the title compound having purity 98.72percent by high performance liquid chromatography.Yield-82percent
78%
With triethylamine In dichloromethane at 0℃; for 14 h;
At about 0° C., Chloroacetyl chloride (3.2 mL, 40.6 mmol) was slowly added to a solution of 2,6-dimethylaniline (4.9 mL, 40 mmol) and triethylamine (6.5 mL) in dichloromethane (50 mL). The mixture was maintained at about 0° C. for about 14 hours, and then washed with 1N hydrochloric acid (60 mL). The organic phase was concentrated in vacuo, and hexane (100 mL) was added to precipitate the title product (6.21 g, 78percent). 1H NMR (300 MHz, CDCl3) δ 7.82 (br. s, 1H), 7.15-7.09 (m, 3H), 4.27 (s, 2H), 2.25 (s, 6H), 2.90, 2.63-2.46 (m, 6H); LC-MS: m/z=198 (MH)+.
95%
With sodium carbonate In water; toluene
EXAMPLE 1 Preparation of 2-Chloro-N-(2,6-dimethylphenyl)acetamide In 3 l of toluene was dissolved 182 g of 2,6-xylidine, and in 1.5 l of water was dissolved 159 g of sodium carbonate. The two solutions were combined, and 203 g of chloroacetyl chloride was added thereto dropwise over 1.5 hours at an inner temperature of from 20° to 35° C., followed by stirring at that temperature for 1.5 hours. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 282 g (95percent) of the titled compound. Melting point: 148°-148.5° C. 1 H-NMR (CDCl3): 2.24 (6H, s), 4.24 (2H, s), 7.16 (3H, s), 7.9 (1H, br s)
95%
With sodium hydroxide In trans-1,2-dichloroethylene
EXAMPLE 2 Preparation of 2-Chloro-N-(2,6-dimethylphenyl)acetamide In 4 l of 1,2-dichloroethylene was dissolved 182 g of 2,6-xylidine, and 1.6 l of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring. To the mixture was added dropwise 203 g of chloroacetyl chloride over 1.5 hours at an inner temperature between 20 and 35° C. The mixture was stirred at that temperature for 1.5 hours. The reaction mixture was separated into two layers, and the organic layer was concentrated under reduced pressure. The precipitate was collected by filtration and dried under reduced pressure to obtain 282 g (95percent) of the titled compound. Melting point: 148°-148.5° C. 1 H-NMR data agreed with those of Example 1.
150 g
With sodium carbonate In dichloromethane at 10 - 15℃;
2,6-dimethylaniline 1 (100 g) and dichloromethane (500 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. Sodium carbonate (43.8 g) was added and the mixture was cooled to 10-15° C. Chloroacetyl chloride 2 (79 mL) was slowly added at 10-15° C. and the mixture was maintained at 10-15° C. for 60-90 minutes. The temperature was raised to 25-35° C. and water (1000 mL) was added. The organic solvent was evaporated completely at 40-45° C. under reduced pressure. The residue was cooled to 25-35° C. and maintained for 45-60 minutes. The obtained solid was filtered and washed with water (200 mL), then the solid was dried at 70° C., to afford 150 g of the compound 3
95 mg
With potassium carbonate In water; acetone at 0 - 5℃; for 3 h;
To 0.74 kg of potassium carbonate and 2.5 lml of water, was added. 500 gm of 2,6-Dimethyl aniline in 1.25 L of Acetone at 0-5 °C. 650 gm of Chloroacetyl chloride was added to the reaction mixture below 5 °C and stirred for 3 hrs. 2500 ml of water was added, stirred for 1 hr, filtered the product, washed with water and dried at 75 °C to get [(2,6- Dimethylphenyl)-amino carbonyl methyljchloride (6). Yield: 95percent; purity >98percent
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 748 - 754
[2] RSC Advances, 2016, vol. 6, # 54, p. 49150 - 49157
[3] Acta Poloniae Pharmaceutica - Drug Research, 2010, vol. 67, # 2, p. 119 - 127
[4] Patent: US2013/90475, 2013, A1, . Location in patent: Paragraph 0027; 0028
[5] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 16; 17
[6] Chemistry - A European Journal, 2015, vol. 21, # 30, p. 10660 - 10665
[7] Green Chemistry, 2013, vol. 15, # 3, p. 756 - 767
[8] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 11, p. 1218 - 1222
[9] European Journal of Medicinal Chemistry, 2013, vol. 62, p. 301 - 310
[10] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 1885 - 1892
[11] Patent: US2012/22147, 2012, A1, . Location in patent: Page/Page column 4
[12] Patent: WO2017/85733, 2017, A2, . Location in patent: Paragraph 00042; 00043; 00056
[13] Pharmaceutical Chemistry Journal, 1991, vol. 25, # 2, p. 79 - 83[14] Khimiko-Farmatsevticheskii Zhurnal, 1991, vol. 25, # 2, p. 13 - 15
[15] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 12; 14
[16] Patent: US2008/312247, 2008, A1, . Location in patent: Page/Page column 31
[17] Farmaco, 2004, vol. 59, # 8, p. 595 - 600
[18] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 5, p. 965 - 970
[19] Patent: US6337423, 2002, B1, . Location in patent: Example 5
[20] Arkiv foer Kemi, 1946, vol. 22A, # 18, p. 11
[21] Journal of Medicinal Chemistry, 1965, vol. 8, p. 62 - 73
[22] Archiv der Pharmazie, 2004, vol. 337, # 2, p. 105 - 111
[23] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3712 - 3715
[24] Patent: US2001/44541, 2001, A1,
[25] Patent: US5461157, 1995, A,
[26] Patent: US5461157, 1995, A,
[27] Patent: US5071876, 1991, A,
[28] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 1162 - 1166
[29] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 16
[30] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 17
[31] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 16
[32] Journal of Molecular Structure, 2008, vol. 886, # 1-3, p. 187 - 196
[33] Patent: WO2010/23687, 2010, A2, . Location in patent: Page/Page column 15
[34] Patent: WO2010/25370, 2010, A2, . Location in patent: Page/Page column 50
[35] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2705 - 2708
[36] Patent: WO2010/97805, 2010, A1, . Location in patent: Page/Page column 8
[37] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1538 - 1548
[38] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 401 - 414
[39] Patent: US2015/148352, 2015, A1, . Location in patent: Paragraph 0126; 0127; 0128
[40] RSC Advances, 2015, vol. 5, # 60, p. 48368 - 48381
[41] Combinatorial Chemistry and High Throughput Screening, 2016, vol. 19, # 6, p. 507 - 512
[42] Patent: WO2016/142819, 2016, A2, . Location in patent: Page/Page column 16
[43] Arkivoc, 2017, vol. 2017, # 3, p. 316 - 325
[44] Green Chemistry, 2018, vol. 20, # 8, p. 1748 - 1753
[45] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1765 - 1774
3
[ 87-62-7 ]
[ 1131-01-7 ]
Reference：
[1] Patent: US2004/29887, 2004, A1,
4
[ 87-62-7 ]
[ 541-88-8 ]
[ 1131-01-7 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 3, p. 756 - 767
[2] Synthesis, 2006, # 19, p. 3316 - 3340
Reference：
[1] Bulletin des Societes Chimiques Belges, 1989, vol. 98, # 5, p. 319 - 326
8
[ 67129-08-2 ]
[ 288-13-1 ]
[ 4073-98-7 ]
[ 1131-01-7 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1989, vol. 98, # 5, p. 319 - 326
9
[ 110-85-0 ]
[ 1131-01-7 ]
[ 5294-61-1 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 748 - 754
[2] Patent: WO2005/25498, 2005, A2, . Location in patent: Page/Page column 48
[3] Organic Process Research and Development, 2003, vol. 7, # 6, p. 939 - 941
[4] Organic Process Research and Development, 2003, vol. 7, # 6, p. 939 - 941
[5] Patent: WO2005/25498, 2005, A2, . Location in patent: Page/Page column 48
10
[ 110-85-0 ]
[ 1131-01-7 ]
[ 5294-61-1 ]
Yield
Reaction Conditions
Operation in experiment
77%
at 80℃; for 3 h;
Step 3: Preparation of λr-(2,6-dimethyl phenvD-l-piperazine acetamide; 2-Chloro-N-(2,6-dimethylphenyl) acetamide (100 g) and piperazine (182 g) was taken in ethanol (300 ml) and the reaction mass was refluxed for 3 hours at 8O0C. The reaction completion was monitored on thin layer chromatography. After reaction completion, the reaction mass was cooled to 25-300C and demineralized water (800 ml) was added. The reaction mass was cooled to 5-100C and stirred for 30 minutes. The reaction mass was filtered through hyflo bed and washed with demineralized water (200 ml). Reaction mass was extracted <n="14"/>with methylene dichloride and organic layer so obtained was washed with sodium hydroxide solution (20 g sodium hydroxide in 340 ml demineralized water). Organic layer was washed again with demineralized water (100 ml) and then with sodium chloride solution. The solvent was distilled out under vacuum and n-hexane (300 ml) was added to the oil obtained and stirred at room temperature for 5 hours. The solid so obtained was filtered and washed with n-hcxane (100 ml) at ambient temperature to afford 96 g of the title compound having purity 99.08 percent by high performance liquid chromatography.Yield- 77percent; Step 3: Preparation of./V-(2,6-dimethyl phenvD-1-piperazine acetamide; 2-Chloro-N-(2,6-dimethylphenyl) acetamide (125 g) and piperazine (223 g) was taken in ethanol (325 ml) and the reaction mass was refluxed for 3 hours at 800C. The reaction \\completion was monitored on thin layer chromatography. After reaction completion, the reaction mass was cooled to 25-300C and demineralized water (1.0 /). The reaction mass was cooled to 5-100C and stirred for 30 minutes. The reaction mass was filtered through hyflo bed and washed with demineralized water (250 ml). Reaction mass was extracted with methylene dichloride and organic layer so obtained was washed with sodium hydroxide solution (25 g <n="16"/>sodium hydroxide in 425 ml demineralized water). Organic layer was washed again with demineralized water (125 ml) and then with sodium chloride solution. The solvent was distilled out under vacuum and n-hexane (500 ml) was added to the oil obtained and stirred at room temperature for 5 hours. The solid so obtained was filtered and washed with n-hexane (125 ml) at ambient temperature to afford 123 g of the title compound having purity 98.31 percent by high performance liquid chromatography.Yield- 78percent -
Reference：
[1] Green Chemistry, 2013, vol. 15, # 3, p. 756 - 767
[2] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 12-15
[3] Organic Process Research and Development, 2012, vol. 16, # 5, p. 748 - 754
[4] RSC Advances, 2016, vol. 6, # 54, p. 49150 - 49157
[5] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 11, p. 1218 - 1222
[6] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[7] Patent: WO2010/23687, 2010, A2, . Location in patent: Page/Page column 16
[8] Patent: WO2010/25370, 2010, A2, . Location in patent: Page/Page column 51
[9] Patent: WO2010/97805, 2010, A1, . Location in patent: Page/Page column 9
[10] Patent: US2015/148352, 2015, A1, . Location in patent: Paragraph 0126; 129; 0130
Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide 58.3 g (0.3 mol) of piperazine hexahydrate was dissolved in 230 ml of ethanol and 50.0 g (0.25 mol) of 2-chloro-N-(2,6-dimethylphenyl)-acetamide was subsquently added. The mixture was heated under reflux for 3 h till completion. The reaction product was cooled to room temperature and filtered. The filter was concentrated under reduced pressure and 80 ml of water was added. The mixture was extracted with dichloromethane and the organic layer was concentrated under vacuum at 60° C. to get 39.4 g of N-(2,6-dimethylphenyl)-1-piperazinylacetamide having a yield of 63percent. 1HNMR (CDCl3): 2.23˜2.27,s, 6H, 2.67,s, 4H, 2.96˜2.98,t, 4H, 3.19˜3.21,s, 2H, 7.08˜7.26,m, 3H, 8.69,s, 1H.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1989, vol. 98, # 5, p. 319 - 326
17
[ 616-45-5 ]
[ 1131-01-7 ]
[ 77191-36-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium methylate In water; toluene
EXAMPLE 6 Preparation of N-(2,6-Dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide In 5 l of toluene was suspended 203 g of sodium methylate, and 511 g of 2-pyrrolidinone was added thereto. The mixture was slowly heated up to 100° to 110° C., at which it was allowed to react for 3 hours. During the reaction, about 300 ml of toluene was distilled off. After allowing to cool, 296 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 300 ml of hot water of about 70° to 85° C., followed by allowing to cool with stirring. The crystals formed in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 332 g (90percent) of the titled compound. Melting point: 152.5°-153° C.
Reference：
[1] Patent: US5461157, 1995, A,
[2] Patent: US5461157, 1995, A,
[3] Patent: US5461157, 1995, A,
[4] Patent: US5461157, 1995, A,
18
[ 162712-35-8 ]
[ 1131-01-7 ]
[ 95635-55-5 ]
Yield
Reaction Conditions
Operation in experiment
34%
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 30 - 35℃; for 18 h;
N-(2,6-Dimethyl-phenyl)-2-{4-[2-hydroxy-3-(2-methoxy-phenoxy)-propyl]-piperazin-1-yl}-acetamide: A mixture of 1-(2-methoxy-phenoxy)-3-piperazin-1-yl-propan-2-ol (2 g, 7.52 mmol), 2-chloro-N-(2,6-dimethyl-phenyl)-acetamide (1.84 g, 9.34 mmol), anhydrous potassium carbonate (2 g, 14.5 mmol) and sodium iodide (74 mg, 0.5 mmol) in dimethylformamide (5 mL) was maintained at 30-35° C. for about 18 hours. The mixture was quenched with water and standard extractive work up afforded a crude residue which was purified by flash column chromatography on silica gel (2*16 cm, dichloromethane/methanol/triethylamine=100/2/1 elution) to afford the title compound (1.1 g, 34percent). 1H NMR (300 MHz, CDCl3) δ 7.11 (s, 3H), 6.98-6.90 (m, 4H), 4.19 (br. s, 1H), 4.05 (d, 2H, J=5.4 Hz), 3.87 (s, 3H), 3.30-3.24 (m, 2H), 2.76-2.63 (m, 10H), 2.25 (s, 6H); LC-MS: m/z=428 (MH)+; HPLC: 99percent (Purity).
Reference：
[1] Patent: US2008/312247, 2008, A1, . Location in patent: Page/Page column 31-32
[2] Patent: WO2006/8753, 2006, A1, . Location in patent: Page/Page column 7; 8
[3] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
With triethylamine In N,N-dimethyl-formamide at 99℃; Flow reactor;
97%
at 40℃; for 6h;
6.2; 7.2; 8.2; 9.2; 10.2 (2) Preparation of lidocaine from α-chloroacetyl-2,6-dimethylaniline
At normal temperature, add the α-chloroacetyl-2,6-dimethylaniline (7.51g, 38mmol) and diethylamine (5.56g, 76mmol) prepared in step (1) to the reactor, and heat to 40°C Reaction, after the completion of the TLC tracking reaction, the reaction is ended (the corresponding reaction time is 6h),A solution containing lidocaine was obtained.The mixture containing lidocaine is filtered, and the resulting filtrate is distilled under reduced pressure, and then water is added to cause lidocaine to form a precipitate. The crude lidocaine is filtered, and then washed and dried to obtain the productLidocaine(8.64g, 37mmol), white powder,The separation yield was 97%, and its purity was 99.8% measured by liquid chromatography.
95.05%
With potassium carbonate In acetone at 50 - 57℃; for 10h; Inert atmosphere;
2.i-2.ii; 7-11
i, inert gas (nitrogen) protection, add 24kg (about 121.5mol) chloroacetyl-2,6-dimethylaniline (above-mentioned gained), 17.76kg (about 242.8mol) diethylamine, 13.43kg ( About 97.2mol) potassium carbonate and 120L acetone, stir and react at 5057 for 10h, HPLC (high performance liquid chromatography) or TLC monitoring reaction is basically complete (the remaining amount of chloroacetyl-2,6-dimethylaniline≤2wt %) to end;ii, the reaction solution in the reactor is cooled to 2030 , suction filtration, filter cake is rinsed twice with acetone (5kg × 2), obtain filtrate, underpressure distillation (vacuum degree≤-0.09MPa, temperature 40 45°C) until almost no distillate was produced, add 96kg of purified water, stir at 15-35°C for 5 hours, centrifuge, and blow dry (40-50°C) to obtain lidocaine, white powdery solid, yield 95.05% (calculated as chloroacetyl-2,6-dimethylaniline).
91.1%
In hexane at 60℃; Reflux;
1.3; 2.3; 3.3; 4-6 (3) Preparation of lidocaine
Weigh 29.7g of chloroacetyl-2,6-dimethylaniline, 30g of n-hexane, and 33g of diethylamine, add it to the reaction bottle, and react at 60 ° C under reflux to complete. After washing with purified water, the organic phase is cooled and crystallized, filtered with suction, and dried , 31.7g lidocaine was obtained, the yield was 91.1%, and the HPLC purity was 99.68%.
87%
With triethylamine In N,N-dimethyl-formamide at 60℃; for 0.190278h;
83%
In benzene for 6h; Reflux;
80.3%
In acetone for 8h; Reflux;
1-3; 1.2 (2) Preparation of lidocaine
In a 500 mL three-necked flask, add 40 g (202.4 mmol) of the intermediate chloroacetyl-2,6-dimethylaniline, and use 200 mL of acetone as a solvent. After dissolution, 56 g (405.2 mmol) of potassium carbonate was added, and 30 g (410.2 mmol) of diethylamine was added. The reaction was refluxed for 8 hours; after the reaction was completed, suction filtration was performed, and the filtrate was removed under reduced pressure at 40 ° C. It was then recrystallized with 75 mL of petroleum ether, filtered with suction, it was vacuum-dried at 40 °C for 6h to obtain 38.1g of white powder. That is lidocaine, with a yield of 80.3% and a content of 98.25%;
With benzene
In water; toluene Heating;
With triethylamine In 1,4-dioxane for 120h; Reflux;
2.2.2. Preparation of Lidocaine (I) and Benzothiazolederivatives (II-VI)
General procedure: 2-aminobenzothiazole and its derivatives (R-H, 0.1 mol),N-(2,6-dimethylphenyl) chloroacetamide (0.1 mol) andtriethylamine in 25 ml of dried dioxane were refluxed during5 days. After observing by TLC, the reaction mixture wascooled, extracted with potassium carbonate solution, filteredand re-crystallized with ethanol to yield I-VI) (Schemes 1and 2).
0.37 g
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 90℃; Flow reactor; Ionic liquid; Green chemistry;
With potassium carbonate In acetone at 50 - 57℃; for 10h; Inert atmosphere; Large scale;
1.2; 7-11 Preparation of lidocaine
i, inert gas (nitrogen) protection, to the reactor added 24kg (about 121.5mol) chloroacetyl-2,6-dimethylaniline (obtained in the previous process), 17.76kg (about 242.8mol) diethylamine, 13.43kg (about 97.2mol) potassium carbonate and 120L acetone, stirred at 50 ~ 57 °C for 10h, HPLC (high performance liquid chromatography) or TLC monitoring reaction is basically complete ( chloroacetyl-2,6- The remaining amount of dimethylaniline ends after ≤2wt%);Ii, the reaction liquid in the reactor cooled to 20 ~ 30 °C, filtering, filter cake with acetone leaching twice (5kg×2), to obtain filtrate, vacuum distillation (vacuum degree ≤-0.09MPa, temperature 40 ~ 45 ° C) to basically no fraction, add 96kg of purified water, stirred at 15 ~ 35 ° C for 5h, centrifugal, blast drying (40 ~ 50 ° C), to obtain lidocaine, white powder solid, yield of 95.05% (in chloracetyl-2,6-dimethylaniline meter).
97.8 %
In toluene at 90 - 100℃;
4-6 Example 5
20.0 g of 2-chloro-N-(2,6-xylyl)acetamide obtained in Example 2,Put 22.2g of diethylamine and 100mL of toluene into a 500mL reaction flask,React at 90-100°C for 3 hours, add 100mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid,The toluene layer was extracted once again with 50 mL of water, and the aqueous phases were combined,Use 30% NaOH solution to adjust the pH to 11-12, add 60mL n-hexane for extraction,The aqueous phase was extracted once with 20 mL of n-hexane, and the n-hexane layers were combined.Dry, filter, and concentrate to dryness under reduced pressure to obtain 23.2 g of lidocaine,
48 %
With triethylamine In 1,4-dioxane Sealed tube; Reflux;
48 %
With triethylamine In 1,4-dioxane Reflux;
In toluene Reflux;
1 Revised procedure: 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide (lidocaine)
The amide is placed in a 50-mL round-bottom flask containing diethylamine (7.5 mL, 5.29 g, 72.5 mmol) and 25 mL of toluene and refluxed for one hour. The reaction mixture is cooled to room temperature and transferred to a separatory funnel, where it is washed 4× with 50 mL portions of water to remove diethylamine hydrochloride and excess diethylamine. The organic layer is extracted with one 20-mL portion of 3 M hydrochloric acid and extracted[1] once with 20 mL of water. The combined aqueous extracts are placed in a 125 mL Erlenmeyer flask, cooled to 10° C. in an ice bath, and neutralized by addition of 3 M sodium hydroxide in portions with stirring while maintaining the temperature below 20° C. The product separates as a granular white solid and is isolated by vacuum filtration. It is washed with cold water, pressed dry, and air-dried as long as possible.
11
N- (2, 6-Dimethyl-phenyl)-2-ethylamino-acetamide 2-Chloro-2', 6'-acetoxylidide (3.953g, 20 mmol) was treated with 2M ethylamine in THF (50mL, 100mmol) and resulting mixture was stirred at room temperature in a tightly sealed flask for 3 days. The precipitate formed (hydrochloride of the amine) was filtered off, the solid was washed with diethyl ether and the combined filtrate was evaporated to give residue, which was recrystallized from diethyl ether/hexane to yield 3.028g of product (73%).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 30 - 35℃; for 18.0h;
N-(2,6-Dimethyl-phenyl)-2-{4-[2-hydroxy-3-(2-methoxy-phenoxy)-propyl]-piperazin-1-yl}-acetamide: A mixture of 1-(2-methoxy-phenoxy)-3-piperazin-1-yl-propan-2-ol (2 g, 7.52 mmol), 2-chloro-N-(2,6-dimethyl-phenyl)-acetamide (1.84 g, 9.34 mmol), anhydrous potassium carbonate (2 g, 14.5 mmol) and sodium iodide (74 mg, 0.5 mmol) in dimethylformamide (5 mL) was maintained at 30-35 C. for about 18 hours. The mixture was quenched with water and standard extractive work up afforded a crude residue which was purified by flash column chromatography on silica gel (2*16 cm, dichloromethane/methanol/triethylamine=100/2/1 elution) to afford the title compound (1.1 g, 34%). 1H NMR (300 MHz, CDCl3) delta 7.11 (s, 3H), 6.98-6.90 (m, 4H), 4.19 (br. s, 1H), 4.05 (d, 2H, J=5.4 Hz), 3.87 (s, 3H), 3.30-3.24 (m, 2H), 2.76-2.63 (m, 10H), 2.25 (s, 6H); LC-MS: m/z=428 (MH)+; HPLC: 99% (Purity).
With potassium carbonate;sodium iodide; In N,N-dimethyl-formamide; at 30 - 35℃; for 18.0h;
Preparation of crude (+)-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride; A mixture of 90 gms l-[3-(2-Memoxyphenoxy)-2-hydroxypropyl ] piperazine, 85 gms [(2,6-dtmetliylphenyl) aminocarbonyl methyl)chloride, 120 gms anhydrous potassium carbonate and 3.6 gms sodium iodide in 260 ml dimethyl fonnamide is stirred at room temperature (30-35 C) for 18 Hrs. The reaction mixture is quenched in 1600 ml water and extracted thrice with 300 ml methylene dichloride each time . Combined methylene dichloride layer is treated with a mixture of 1100 ml aqueous hydrochloric acid (35 %) & 900 ml water. Acidic aqueous layer is basified with ammonia, extracted with methylene dichloride and solvent is evaporated to get Ranolazine base. Yield = 140 gms ,The above Ranolazine base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic. The precipitated dihydrochloride compound is filtered, is washed with acetone to give the Ranolazine dihydrochloride Yield = 144 gm.
cis-N-(2-Chlorophenyl)-2-(3,5-dimethylpiperazin-1-yl)acetamide[ No CAS ]
[ 109-07-9 ]
[ 1131-01-7 ]
[ 97617-15-7 ]
Yield
Reaction Conditions
Operation in experiment
i (+-)-N-(2,6-Dimethylphenyl)-2-(3-methylpiperazin-1-yl)acetamide The subtitle compound was prepared from 2-chloro-N-(2,6-dimethylphenyl)acetamide (7 g) and (+-)-2-methyl-piperazine (3.55 g) by the method of Example 15 step (ii) as a white solid. Yield 7 g. MS: ES(+ve) 262(M+1, 100%)
Part B. Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5). To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added compound 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 dichloromethane: methanol) to afford compound 5.
Part B. Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5). To a solution of compound 3 in 100 mL EtOH (5 g, 25.2 mmol) was added compound 4 (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to afford compound 5..
With N-ethyl-N,N-diisopropylamine; In ethanol;
Part B. Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5). To a solution of compound 3 in 100 mL EtOH (5 g, 25.2 mmol) was added compound 4 (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to afford compound 5..
EXAMPLE 3 Preparation of N-(2,6-Dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide In 300 ml of toluene was suspended 9.2 g of 60% sodium hydride in a nitrogen stream, and 21.3 g of 2pyrrolidinone was slowly added dropwise to the suspension at an inner temperature controlled at 40 C. or lower. After stirring the mixture for 2 hours, 19.7 g of 2-chloro-N(2,6-dimethylphenyl)acetamide was added thereto, and the mixture was allowed to react at 60 to 70 C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70 to 85 C., followed by allowing to cool with stirring. The precipitated crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 22.2 g (90%) of the titled compound. Melting point: 153-153.5 C. 1 H-NMR (CDCl3): 1.9-2.6 (4H, m), 2.18 (6H, s), 3.57 (2H, t, J=6.8Hz), 4.07 (2H, s), 7.06 (3H, s), 7.9 (1H, br s)
332 g (90%)
With sodium methylate; In water; toluene;
EXAMPLE 6 Preparation of N-(2,6-Dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide In 5 l of toluene was suspended 203 g of sodium methylate, and 511 g of 2-pyrrolidinone was added thereto. The mixture was slowly heated up to 100 to 110 C., at which it was allowed to react for 3 hours. During the reaction, about 300 ml of toluene was distilled off. After allowing to cool, 296 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto to react at 60 to 70 C. for 2 hours. To the reaction mixture was added 300 ml of hot water of about 70 to 85 C., followed by allowing to cool with stirring. The crystals formed in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 332 g (90%) of the titled compound. Melting point: 152.5-153 C.
22.4 g (91%)
In nitrogen; water; toluene;
EXAMPLE 5 Preparation of N-(2,6-Dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide In 300 ml of toluene was suspended 9.0 g of sodium amide in a nitrogen stream, and 21.3 g of 2-pyrrolidinone was slowly added thereto dropwise. After stirring the mixture at 60 to 70 C. for 2 hours, 19.7 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by allowing to react at 60 to 70 C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70 to 85 C., and the mixture was allowed to cool with stirring. The precipitated crystals in the aqueous layer were recovered by filtration and dried under reduced pressure to obtain 22.4 g (91%) of the titled compound. Melting point: 152-152.5 C.
2.19 g (89%)
In tert-butyl methyl ether; nitrogen; water;
EXAMPLE 4 Preparation of N-(2,6-Dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl]acetamide In 30 ml of t-butyl methyl ether was suspended 897 mg of sodium amide in a nitrogen stream, and 2.13 g of 2-pyrrolidinone was slowly added thereto dropwise, followed by refluxing for 2 hours. After allowing to cool, 1.97 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by refluxing for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70 to 85 C., and the mixture was allowed to cool with stirring. The thus formed crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 2.19 g (89%) of the titled compound. Melting point: 151-152.5 C.
V.A A.
A. 2-Ethyl-1-[(2,6-dimethylphenyl)carbamoylmethyl]-2-imidazoline In a manner similar to Ex. IA react 47.7 gm. (0.486 M) of 2-ethyl-2-imidazoline and 19.21 gm. (0.097 M) of 2-chloro-2',6'-acetoxylidide in 200 ml. of nitromethane, to obtain the title compound.
1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-3-[N-(2,6-xylyl)carbamoylmethyl]-imidazolium chloride hydrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1-[2,4-dichloro-beta-(2,4-dichlorobenzyloxy)phenethyl]-3-[N-(2,6-xylyl)carbamoylmethyl]-imidazolium chloride hydrate, m.p. 143°-150° C., by the reaction of 1-[2,4-dichloro-beta-(2,4-dichlorobenzyloxy)phenethyl]imidazole and 2-chloroaceto-2',6'-xylidide.
In ethanol; at 80℃; for 3.0h;Product distribution / selectivity;
Step 3: Preparation of lambdar-(2,6-dimethyl phenvD-l-piperazine acetamide; 2-Chloro-N-(2,6-dimethylphenyl) acetamide (100 g) and piperazine (182 g) was taken in ethanol (300 ml) and the reaction mass was refluxed for 3 hours at 8O0C. The reaction completion was monitored on thin layer chromatography. After reaction completion, the reaction mass was cooled to 25-300C and demineralized water (800 ml) was added. The reaction mass was cooled to 5-100C and stirred for 30 minutes. The reaction mass was filtered through hyflo bed and washed with demineralized water (200 ml). Reaction mass was extracted <n="14"/>with methylene dichloride and organic layer so obtained was washed with sodium hydroxide solution (20 g sodium hydroxide in 340 ml demineralized water). Organic layer was washed again with demineralized water (100 ml) and then with sodium chloride solution. The solvent was distilled out under vacuum and n-hexane (300 ml) was added to the oil obtained and stirred at room temperature for 5 hours. The solid so obtained was filtered and washed with n-hcxane (100 ml) at ambient temperature to afford 96 g of the title compound having purity 99.08 % by high performance liquid chromatography.Yield- 77%; Step 3: Preparation of./V-(2,6-dimethyl phenvD-1-piperazine acetamide; 2-Chloro-N-(2,6-dimethylphenyl) acetamide (125 g) and piperazine (223 g) was taken in ethanol (325 ml) and the reaction mass was refluxed for 3 hours at 800C. The reaction completion was monitored on thin layer chromatography. After reaction completion, the reaction mass was cooled to 25-300C and demineralized water (1.0 /). The reaction mass was cooled to 5-100C and stirred for 30 minutes. The reaction mass was filtered through hyflo bed and washed with demineralized water (250 ml). Reaction mass was extracted with methylene dichloride and organic layer so obtained was washed with sodium hydroxide solution (25 g <n="16"/>sodium hydroxide in 425 ml demineralized water). Organic layer was washed again with demineralized water (125 ml) and then with sodium chloride solution. The solvent was distilled out under vacuum and n-hexane (500 ml) was added to the oil obtained and stirred at room temperature for 5 hours. The solid so obtained was filtered and washed with n-hexane (125 ml) at ambient temperature to afford 123 g of the title compound having purity 98.31 % by high performance liquid chromatography.Yield- 78% -
In methanol; at 25 - 30℃;Reflux;
25 gm of 2-chloro-N-(2,6-dimethyl phenyl) acetamide, 45 gm of piperazine was charged in a flask containing 150 ml of methanol and heated to reflux. The reaction mixture was stirred at reflux for about 4 hours and then cooled to 25-300C. 150 ml of water was charged to the reaction mixture, cooled to 0-5 0C and maintained for 30 minutes. The reaction mixture was filtered through hyflow bed and washed with water (50 ml). The filtrate was extracted with dichloromethane (250 ml) and the organic layer was washed with water (5 X 50 ml). The final organic layer was washed with 10 % aqueous sodium chloride solution (50 ml). The organic layer was concentrated under vacuum at below 45C to remove about 90 % of the solvent. 75 ml of cyclohexane was added to the concentrated organic layer and stirred at room temperature for 2 hours. The solid was filtered and washed with cyclohexane (10 ml) and dried to give 20.5 gm of the title compound. Melting range: 114C - 1500C
In methanol;Reflux;Product distribution / selectivity;
2-chloro-N-(2,6-dimethylphenyl) acetamide (100 g), piperazine (182 g) and methanol (300 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture is heated to reflux temperature and maintained for 2-3 hours. The mixture is cooled to 25-35C and water (800 mL) is added. The mixture is stirred for 15-30 minutes, then filtered to remove unwanted solid, and the filter is washed with water (200 mL). Dichloromethane (400 mL) is added to the filtrate and the mixture is stirred for 15-30 minutes. The layers are separated and the aqueous layer is extracted with dichloromethane (400 mL). The combined organic layer is washed with a solution of sodium hydroxide (20 g) in water (350 mL) and the solvent is evaporated at 40-450C. 500 mL of n-hexane is added to the residue at 25-35C and the mixture is maintained for 30-45 minutes. The solid is filtered under reduced pressure, washed with n-hexane (100 mL), and dried at 400C, to afford 88.5 of the title compound.Purity by HPLC: 99.61%.
Step 2: Preparation of Piperazine acetamide (II); 100 gm of chloro acetamide (VIII) and 172 gm of anhydrous piperazine was dissolved in 1000 ml of isopropyl alcohol. The reaction mixture was stirred for 1 hour at reflux temperature. The reaction mass was concentrated to get thick slurry and water (1000 ml) was charged to the slurry. 350 ml of 50% aqueous acetic acid solution was added to adjust pH between 5.0-5.50. The reaction mass was extracted with dichloromethane (3 x 500 ml). The aqueous layer was basified with 720 ml of 5N NaOH solution and extracted with dichloromethane (3 x 500 ml). The combined organic layer was washed with 20% brine solution. The organic layer was separated and concentrated under reduced pressure to get oily mass. Cyclohexane (300 ml) was charged to the oily mass. Stirred for 30 minutes at 45- 5O0C. Cooled to 25-3O0C and stirred for 1 hour. The solid was filtered, washed with 100 ml of cyclohexane and dried under reduced pressure to give 105 gm of white solid.
In methanol;Reflux;
2-chloro-N-(2,6-dimethylphenyl) acetamide 3 (100 g), piperazine 4 (182 g) and methanol (300 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture was heated to reflux temperature and maintained for 2-3 hours. The mixture was cooled to 25-35 C. and water (800 mL) was added. The mixture was stirred for 15-30 minutes, then filtered to remove unwanted solid, and the filter was washed with water (200 mL). Dichloromethane (400 mL) was added to the filtrate and the mixture was stirred for 15-30 minutes. The layers are separated and the aqueous layer was extracted with dichloromethane (400 mL). The combined organic layer was washed with a solution of sodium hydroxide (20 g) in water (350 mL) and the solvent was evaporated at 40-45 C. 500 mL of n-hexane was added to the residue at 25-35 C. and the mixture was maintained for 30-45 minutes. The solid was filtered under reduced pressure, washed with n-hexane (100 mL), and dried at 40 C., to afford 88.5 of the intermediate compound 5.
2,2'-(piperazine-1,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide)[ No CAS ]
[ 5294-61-1 ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In tetrahydrofuran; at 20℃; for 72.0h;
2, 6-DIMETHYLCHLOROACETANILIDE (1. 977 g, 10 mmol) was dissolved in anhydrous THF (10 mL) and finely powdered anhydrous sodium carbonate (1.5 g) was added with stirring followed by piperazine (0.431 g, 5 mmol). Reaction mixture was stirred at room temperature for 3 days. Solid material was filtered off, washed with ethyl acetate, triturated with IN HC1 and filtered. The aqueous filtrate was brought to basic pH by addition of solid KOH and resulting solution was extracted 3 times with dichloromethane. Organic extracts were dried with magnesium sulfate, decanted and evaporated. Residue was subjected to chromatography using dichloromethane/methanol (95: 5) as a solvent system separating compounds A and B.
A solution of 5.2 g (26.5 mmol) of 2,6-dimethylchloroacetanilide 1 and N-methyl homopiperazine (4.54 g, 39.5 mmol) in 100 mL of dry tetrahydrofuran (THF) was allowed to stir at room temperature for 3 days. TLC [30: 70: 1, ethyl acetate: hexane: triethylamine (TEA) ] showed complete reaction. Solvents were removed by rotoevaporation and the residue redissolved in chloroform, washed with dilute KOH, water, and dried (MGS04). Evaporation of solvents afforded crude amine in good yield. Recrystallization from ethyl acetate/hexane AT-20 C gave the title compound as a white solid
N-(2,6-dimethylphenyl)-l-piperazine acetamide (20 gm), l-(2-methoxy phenoxy)-2,3-epoxy propane (16 gm) and methanol (150 ml) were charged in a flask and heated to reflux. The reaction mixture was stirred at reflux for about 5 hours and carbon treatment given to methanol layer. Taken methanol layer and distilled off completely under vacuum. 48 ml of methanol was added to the residue and stirred at 25-30C for about 1-2 hours. The reaction mixture was cooled to about 0-5C and stirred for about 1 hour. The solid was filtered and washed with methanol (6 ml) . The wet solid was dried at 50-600C to get 28 gm of the title compound. Purity by HPLC: 99.89 % w/w
Stage #1: CVT-2513; 2-chloro-N-(2,6-dimethylphenyl)acetamide In N,N-dimethyl-formamide at 90 - 95℃;
Stage #2: With hydrogenchloride In isopropyl alcohol; acetone at 0 - 65℃;
7
2-chloro-N-(2,6-dimethylphenyl) acetamide (25.8 g), 1 -[3-(2- methoxyphenoxy)-2-hydroxypropyl]piperazine (30 g), and dimethylformamide (200 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture is heated to 90-95°C and maintained for 4-5 hours. The mixture is cooled to 25-35°C and is added to water (300 mL). The mixture is acidified with HCI (10 mL), washed with toluene (2x100 mL), and the aqueous layer is made basic with aqueous ammonia (40 mL). The aqueous layer is extracted with dichloromethane (3x180 mL) and the solvent from the combined organic layer is distilled completely under reduced pressure at 40-55°C. The residue is cooled to 25- 35°C. Isopropanol, HCI [10-13%] (100 mL), and acetone (300 mL) are added to the residue and stirred for 5-10 minutes. The mixture is heated to 60-650C and maintained for 15-30 minutes. The mixture is cooled to 0-50C and maintained for 45-60 minutes. The formed solid is filtered and washed with a mixture of isopropanol, HCI, and acetone (15 mL; 1 :1 ). The solid is dried at 40-450C, to afford 33.7 g of the title compound.
Preparation of N-(2,6-dimethylphenyl)-1-piperazinylacetamide 58.3 g (0.3 mol) of piperazine hexahydrate was dissolved in 230 ml of ethanol and 50.0 g (0.25 mol) of 2-chloro-N-(2,6-dimethylphenyl)-acetamide was subsquently added. The mixture was heated under reflux for 3 h till completion. The reaction product was cooled to room temperature and filtered. The filter was concentrated under reduced pressure and 80 ml of water was added. The mixture was extracted with dichloromethane and the organic layer was concentrated under vacuum at 60 C. to get 39.4 g of N-(2,6-dimethylphenyl)-1-piperazinylacetamide having a yield of 63%. 1HNMR (CDCl3): 2.23?2.27,s, 6H, 2.67,s, 4H, 2.96?2.98,t, 4H, 3.19?3.21,s, 2H, 7.08?7.26,m, 3H, 8.69,s, 1H.
With methyllithium lithium bromide In diethyl ether at -78℃;
97%
With methyllithium; lithium bromide In diethyl ether at -78℃; for 0.5h; chemoselective reaction;
Chemoselective Addition of Lithium Carbenoids to Isocyanates; General Procedure 1 (GP1)
General procedure: To a cooled (-78°C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi-LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides.
2-(4-methylbenzo[d]thiazol-2-ylamino)-N-(2,6-dimethylphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With triethylamine In 1,4-dioxane for 120h; Reflux;
2.2.2. Preparation of Lidocaine (I) and Benzothiazolederivatives (II-VI)
General procedure: 2-aminobenzothiazole and its derivatives (R-H, 0.1 mol),N-(2,6-dimethylphenyl) chloroacetamide (0.1 mol) andtriethylamine in 25 ml of dried dioxane were refluxed during5 days. After observing by TLC, the reaction mixture wascooled, extracted with potassium carbonate solution, filteredand re-crystallized with ethanol to yield I-VI) (Schemes 1and 2).
Added 1000 ml of water to R.B Flask. 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with 0-phosphoric acid. After stirring for 1-2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride to obtained compound of formula (7).
Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with 0-phosphoric acid. After stirring for 1- 2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of 1-(2- Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature, added 500 ml water, cooled to 0C and filtered the product to get cmde Ranolazine. Yield: 80%; purity >99%.
Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with 0-phosphoric acid, 100 gms of [(2,6- Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30C and adjusted pH to 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of 1-(2-Methoxy phenoxy)-2, 3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature and added 500 ml water and cooled to 0C. Filtered the product to get cmde Ranolazine. Yield: 80%; purity >99%.
In acetonitrile at 80℃; for 12h; Inert atmosphere; Schlenk technique;
Synthesis of Ligand (1F-1G):
General procedure: Under nitrogen atmosphere, a schlenk tubewas charged with a strring bar, 1.00 mmol of 2-chloro-N-arylacetamide, 1.5 mmol of 1-(4-Methoxyphenyl)-1H-imidazole, and 2mL of dry acetonitrile. The reaction mixture was stirred for 12 h at 80 °C temperature. Subsequently, the reaction mixture was cooled and diethyl ether was added in it and during stirring precipitate of product was formed. The precipitate was isolated by decanting off the solvent, and washed with acetone (2 X 5 mL) and Hexane (2 X 5 mL), and dried in a vacuum. Ligand 1F: white solid, Yield: 97%,1H NMR (400 MHz, DMSOd6): δ 10.29 (s, 1H), 9.93 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.70 (d,J 8.8 Hz, 2H), 7.16 (d, J 8.8 Hz, 2H), 7.04 (s, 3H), 5.38 (s, 2H), 3.80(s, 3H), 2.16 (s, 6H). 13C NMR (101 MHz, DMSO-d6): δ 163.7, 160.4,136.8, 135.5, 134.5, 128.1, 128.1, 127.2, 125.0, 123.8, 121.3, 115.6, 56.1,51.3, 18.6. Anal. Calcd for C20H22ClN3O2: C, 64.60; H, 5.96; N, 11.30.Found: C, 64.53; H, 5.78; N, 11.42.
Compound IV (17 g, 0.086 mol) prepared in the first step was added to a 250 mL three-necked flask, followed by N,N-diethylpropanolamine (Compound V, 11.3 g, 0.086 mol). Finally, absolute ethanol (20 g) was added, and mechanical stirring and reflux condenser were placed, and the reaction was carried out at 110 C for 8 h. Ethyl acetate was added to dissolve, disperse, and then naturally cooled to precipitate a white solid. Filtration and drying gave the product (Compound VI) 23.5 g, yield 83%.
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