* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 5700
[2] Journal of the Chemical Society, 1936, p. 691,694
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 932
4
[ 62662-74-2 ]
[ 87-63-8 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 20, p. 5537 - 5540
[2] Journal of Organic Chemistry, 1993, vol. 58, # 20, p. 5537 - 5540
5
[ 95-51-2 ]
[ 87-63-8 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 20, p. 5537 - 5540
[2] Journal of Organic Chemistry, 1993, vol. 58, # 20, p. 5537 - 5540
6
[ 150545-04-3 ]
[ 87-63-8 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 20, p. 5537 - 5540
7
[ 31656-92-5 ]
[ 87-63-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1921, vol. 424, p. 300[2] Justus Liebigs Annalen der Chemie, 1925, vol. 441, p. 303
8
[ 611-22-3 ]
[ 87-63-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1921, vol. 424, p. 300[2] Justus Liebigs Annalen der Chemie, 1925, vol. 441, p. 303
9
[ 611-22-3 ]
[ 2835-99-6 ]
[ 95-53-4 ]
[ 87-63-8 ]
[ 95-69-2 ]
Reference：
[1] Canadian Journal of Chemistry, 1996, vol. 74, # 7, p. 1321 - 1328
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6061 - 6066
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6061 - 6066
[3] Patent: CN106749223, 2017, A,
22
[ 6191-99-7 ]
[ 87-63-8 ]
[ 863127-76-8 ]
Yield
Reaction Conditions
Operation in experiment
73.6%
With pyridine In tetrahydrofuran at 0 - 20℃; for 2 h;
To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5°C. The mixture was then warmed and stirred for 2 h. at 20°C. Hydrochloric acid (1N, 115 mL) was added at 0-10°C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22°C then 1 h. at 0°C. The solid was collected by vacuum filtration, washed with water (2 x 75 mL) and dried to give 74.1 g (73.6 percent yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). lH NMR (400 Hz, DMSO-d6) 8 1. 26 (t, 3H, J= 7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J= 7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7. 27 (m, 2H, J=7.5 Hz), 7.27-7. 37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz), 9. 28 (s, 1H) ; l3c NMR (100MHz, CDC13) b : 14. 57, 18.96, 67.17, 97.99, 126. 80, 127. 44, 129. 07, 131.32, 132.89, 138. 25,161. 09,165. 36.
300 g
With pyridine In tetrahydrofuran at 10 - 30℃; for 4 h;
Ethyl vinyl ether compound of formula-5 (500 gm) was slowly added to oxalyl chloride compound of formula-4 (670 ml) at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 12 hours at the same temperature. Heated the reaction mixture to 120- 125°C and stirred for 90 minutes at the same temperature. Cooled the reaction mixture to 30-35 °C and (E)-3-ethoxyacryloyl chloride compound of formula-7 was collected by fractional distillation. Added tetrahydrofuran (1160 ml) to the obtained compound of formula-7 and cooled the reaction mixture to 10-15°C. Slowly added a solution of 2-methyl-6-chloroaniline compound of formula-9 (290 gm), pyridine (248ml) & tetrahydrofuran (1160 ml) to the reaction mixture at same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 4 hours at the same temperature. Cooled the reaction mixture to 5-10°C and acidified the reaction mixture using aqueous HC1 solution. Water and ethyl acetate were added to the reaction mixture and stirred for 10 minutes. Separated the both aqueous & organic layers and extracted the aqueous layer with ethyl acetate. Washed the total organic layer with aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate was added to the obtained compound at 25-30°C and cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled ethyl acetate and dried the material to get the title compound. Yield: 300 gm; M.R.: 160-164°C; HPLC Purity: 99.66percent.
Reference：
[1] Archiv der Pharmazie, 2011, vol. 344, # 7, p. 451 - 458
[2] Patent: WO2005/77945, 2005, A2, . Location in patent: Page/Page column 50-51
[3] Arkivoc, 2010, vol. 2010, # 6, p. 32 - 38
[4] Patent: WO2017/2131, 2017, A1, . Location in patent: Page/Page column 17; 18
To a solution of 2-chloro-6-methyl-aniline (28) (25.0 g, 176.6 mmol) in CH2Cl2 (200 mL) was added pyridine (28.6 mL, 353 mmol) at -10 C. After 10 mins, chloroacetyl chloride (3a) (21.1 mL, 265 mmol) was added. The reaction mixture was allowed to warm to room temperature over a period of 2 h. A solution of 1 N HCl (500 mL) was added and the mixture was stirred for 10 mins. The organic phase was separated and the aqueous layer was extracted with CH2Cl2 (2×300 mL). The combined organic extracts were washed with 1 N HCl solution (400 mL), H2O (400 mL) and brine (400 mL). It was dried over MgSO4, filtered and concentrated in vacuo to give the product 29a as a white solid (37.8 g, 98% yield). 1H NMR (500 MHz, CDCl3) delta 2.28 (s, 3H), 4.25 (s, 2H), 7.14-7.18 (m, 2H), 7.26-7.31 (m, 1H), 8.02 (bs, 1H).
87.6%
at 0 - 25℃; for 2.5h;
General procedure: To a solution of 4a-j (0.11 mol) in AcOH (30 mL) was added dropwise chloroacetyl chloride (9.5 mL, 0.12 mol) at 0C. The mixture was allowed to react at 0C for 0.5 h, and at room temperature for 2 h. AcONa solution was added to the reaction, and the precipitated white solid was collected and dried to afford 5a-j.
With sodium acetate; acetic acid; In water; at 20℃;
Compound A1 (14.2 g, 100 mmol) was dissolved in acetic acid (100 mL) and saturated aqueous solution of sodium acetate (80 mL). Chloroacetyl chloride (17.0 g, 150 mmol) was added dropwise under ice-bath and turbidity quickly appeared. The reaction mixture was slowly warmed to room temperature and stirred overnight. Water (100 ml) was added, the precipitated solid was filtered by vacuum, washed with water and dried to obtain compound A2 as a white solid. Yield: 12.7 g, 58.0%. The crude product was used in the next step without purification.
With sodium hydroxide; In dichloromethane; at 23℃; for 2h;
General procedure: The respective amine (1) was stirred in 2N sodium hydroxide solution (1.5 ml per millimole of (1)) at 23?C, chloroacetyl chloride (2) (2.5% molar excess) in dichloromethane (DCM) (1.5 ml per millimole of aniline) was added gradually with vigorous stirring. The reaction mixture was stirred at room temperature for 2 hours, transferred to a separating funnel and the layers separated. The aqueous layer was further extracted with DCM (x2) and the combined organics washed with IN HC1 (x2), water (x2) and saturated brine (x2). After drying over MgSQ* the DCM solution was evaporated to dryness and the isolated product (3) dried thoroughly under vacuum.
[0499] Experimental Details: To a solution of compound 1 (14 g, 0.1 mol) in aqueous HBr (30 mL) was added a solution OfNaNO2 (8.3 g 0.15 mol) in H2O (10 mL) at 0 0C over a period of 30 min. After stirring for 60 min, the reaction mixture was added to a solution of CuBr (14 g, 0.1 mol) in aqueous HBr (16 mL) at 80 C. After complete addition, the reaction mixture was stirred at the same temperature for 2 h. After cooling to room temperature, the reaction mixture was extracted with EA (100 mL * 3). The combined organic layer were washed with brine and dried over Na2SO4. After filtrating off the Na2SO4, the filtrate was concentrated to dryness. The residue was purified by column to give the product 2.
Example 23 Experimental Details: To a solution of compound 1 (14 g, 0.1 mol) in aqueous HBr (30 mL) was added a solution of NaNO2 (8.3 g 0.15 mol) in H2O (10 mL) at 0 C. over a period of 30 min. After stirring for 60 min, the reaction mixture was added to a solution of CuBr (14 g, 0.1 mol) in aqueous HBr (16 mL) at 80 C. After complete addition, the reaction mixture was stirred at the same temperature for 2 h. After cooling to room temperature, the reaction mixture was extracted with EA (100 mL×3). The combined organic layer were washed with brine and dried over Na2SO4. After filtrating off the Na2SO4, the filtrate was concentrated to dryness. The residue was purified by column to give the product 2.
tert-butyl 6-((2-chloro-6-methylphenyl)carbamoyl)benzo[d]thiazol-2-yl-carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 30℃; for 25.5h;
Into a clean and dry 3L 4-neck round bottom flask connected to a mechanical stirrer,condenser and thermometer socket is charged with <strong>[302964-20-1]2-tert-butoxycarbonylamino-thiazole-5-carboxylic acid chloride</strong> (4) crude (27.5 g) and dichloromethane (750 mL) under stirring. Cooled the reaction mass to 0-5 C and add 2-chloro-6-methylaniline (22.2 g) to the reaction mass at 0-5 C within 30-45 min period. Added DiPEA to the reaction mass at 0-5 C in 30-45 min period, raised the reaction mass temperature to 25-30 C and stirred the reaction mass at 25-30 C for 24 h. After TLC compliance distilled-off the solvent completely under plant vacuum at the temperature not crossing 50 C and Charge 2 N HCl (250 mL) to the reaction mass, Stirred for 15-30 min. Transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum. The wet cake is washed with 500mL of water and dried the above-wet material in the dryer at temperature 60-65 C for 10-12 h. Purification: Into a clean and dry 3.0 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charging with 2-tert-butoxy-carbonyl-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide crude, methanol and isopropyl ether under stirring at 25- 30 C. Raised the reaction mass temperature to 60-65 C and stirred the reaction mass at 60-65 C for 45-60 min. Cooled the reaction mass temperature to 25-30 C and transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum. Washed the wet cake with 20.0 mL of methanol and dried the wet material in dryer at 60-65 C for 4-6 h to furnish 16.0 g of the title compound with purity above 95 %. Cream colour solid; Elemental analysis C16H18N3O3SClcalcd (found) %: C 52.24 (52.12), H 4.93 (5.05), N 11.42 (11.31),O 13.05 (13.25), S 8.72 (8.83). IR (KBr, numax, cm-1): 3423.42-3276.87, 3162.67, 2928.46, 1724.90, 1632.68-1566, 1522.80,775.21; 1H NMR (400 MHz, DMSO-d6): delta1.504 (s, 9H, -3CH3),2.225 (s, 3H, -CH3), 7.262-7.301 (t, 2H, ArH), 7.389-7.412(m, 1H, ArH), 8.204 (s, 1H, ArH), 10.017 (s, 1H, -NH), 11.847(s, 1H, -NH); 13C NMR (100 MHz, DMSO-d6): delta163.220, 159.74,152.91, 141.27, 139.02, 133.31, 132.57, 129.34, 128.64, 127.28,126.62, 82.33, 28.06, 18.45; ESI-MS (m/z): 368.21 (M+1),370.18 (M+3)
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
[00106] Compound 8 was made using by adapfing the synthesisdsdosed n J.Med.Chem. 2006, 6819. Synthesis of amde 5 was accomphshedn two steps, starting from compound 1. Compound I was converted to acidchorde 2 using oxay chorde n dchoromethane (DCM). Formafion of theacd chorde was confirmed by quenching an aquot n methano (MeOH);LCMS anayss ndcated the presence of the corresponding methy? ester 3 n>90%. Add Won of 2 to a mixture of excess anWne 4 and dsopropy ethyamne(DPEA) gave good conversion to amine 5. After fHtehng the sohds off thisafforded 1.15 g (40%) amde 5 n high purIty. Remova of the Boc-group using tr[fluoroacefic acid (TFA) gave good conversion to amine 6. Amine 6 was converted to compound 8 n the presence of compound 7 and sodium t-butoxde (NaOBu-t).
16.0 g
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 30℃;
Into a clean and dry 3.0.L 4-neck RB flask charged 2- tert-Butoxycarbonylamino- thiazole-5-carboxylic acid chloride crude (28 gm) and methylene chloride (750 (0089) ml) under stirring, cooled the reaction mass to temperature to 0-5C. Added 2- Chloro-6-methyl aniline (23gm) to the reaction mass at temperature 0- 5C within 30-45 min period. Diisopropyl ethylamine (55 gm) was added to the reaction mass at temperature 0-5 C in 30-45 min period, reaction mass temperature was raised to 25-30C and maintained for 24 hrs, after completion of the reaction, distilled off the solvent completely under plant vacuum at temperature not crossing 50C. (0090) charged 2 HC1 to the reaction mass and stirred for 15-30 min, transferred the (0091) reaction mass into a buchner funnel and flask kept under plant Vacuum. Wet cake was washed with 250.0 ml of water and suck dried thoroughly for 30-45 min, wet material was transferred into a clean and dry petridish. Dried the above wet (0092) material in drier at temperature 60-65 C forlO-12 hrs. (0093) Weight: 20gm f) purification of 2-tert-butoxy- carbonyl amino-N-(2-chloro-6- methylphenyl)-5-thiazolecarboxamide (0095) Into a clean and dry 3.0.L 4-neck RB flask charged 2-tert-butoxy- carbonyl (0096) amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide crude(20gm) , (0097) methanol (250ml, Lot-1) and (0098) Isopropyl ether(200ml) under stirring at temperature 25- 30C, reaction mass (0099) temperature was raised to 60-65C and maintained for 45-60 min. cooled the (0100) reaction mass temperature to 25-30C and transferred the reaction mass into a (0101) buchner funnel and flask kept under plant vacuum. Washed the wet cake with (0102) 20.0 ml of methanol (LOT-II)and suck dried for 10-15min, and dried the (0103) compound in drier at temperature 60-65 C for 4-6 hrs. (0104) Weight: 16.0 g
N-(2-Chloro-6-methylphenyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To <strong>[87-63-8]2-chloro-6-methylaniline</strong> (12.46 mg, 0.088 mmol) in THF (0.4 mL) was added sodium hexamethyldisilazide (0.22 mL, 0.22 mmol, 1M in THF) and the reaction was heated to reflux for 0.5 h. The reaction was cooled to room temperature and 1C (18 mg, 0.088 mmol) was added in THF (0.8 mL). The mixture was heated to reflux for 0.5 h then cooled to room temperature and quenched with acetic acid. The reaction was concentrated in vacuo followed by addition of water and saturated sodium bicarbonate. The solid product was isolated by filtration with water and hexane rinses, then dried in vacuo to give the desired product 1D. HPLC: 3.255 min (YMC ODS-A C18 S-5 column, 4.6x50mm, 4 min gradient from 0 to 100% B with 2 min hold at 100% B. Solvent A: 90%H2O-10%MeOH-0.2%H3PO4; Solvent B: 10%H2O-90%MeOH-0.2%H3PO4).
With sodium t-butanolate;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In toluene; at 90℃; for 3h;
Example 1e N-(2'-Chloro-6'-methylphenyl)-4-ethylaniline To a solution of 5.2 g (37 mmol) of <strong>[87-63-8]2-chloro-6-methylaniline</strong> and 6.95 g (37.6 mmol) of 4-ethyl bromobenzene in 50 ml of toluene is added 6.5 g (68 mmol) sodium tert-butoxide, 180 mg (0.89 mmol) tri-tert-butylphosphine (dissolved in 2 ml of toluene) and 300 mg (0.52 mmol) of bis-dibenzylideneacetone palladium(0). The mixture is heated under nitrogen to 90 C. for 3 hours and then cooled to room temperature. Hyflo (1 g), water (30 ml) and conc. hydrochloric acid (10 ml) are added and after stirring for 30 minutes the mixture is filtered. The organic phase washed with water (30 ml) twice and evaporated. The is subjected to flash-chromatography on silica (75 g) eluding with hept to afford 5.3 g (21.6 mmol. 58%) of N-2'-chloro-6'-methylphenyl)-4-ethylaniline as an almost colourless liquid. 1H-NMR (300 MHz, CDCl3): 1.10 (t, 3H, CH3-CH2-); 2.10 [s, 3H, CH3-C (6')]; 2.50 (q, 2H, CH3-CH2-); 5.54 (s, br, 1H, NH); 6.48 [d, 2H, HC (2, 6)]; 6.93 [t, 1H, H (C4')]; 6.95 [d, 2H, HC (3, 5)]; 7.05 [d, 1H, HC (5')]; 7.22 [d, 1H, HC (3')].
2,6-diacetylpyridinebis(2-chloro-6-methylphenylimine)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.2%
With formic acid; In methanol; at 20℃;Heating / reflux;
Experiment 12,6-Diacetylpyridinebis(2-chloro-6-methylphenylimine) In a 200 mL round bottom flask, 2.0 g of 2,6-diacetylpyridine (FW 163.18, 0.0122 mole) and 50 mL of methanol were placed. Next, 3.45 g of <strong>[87-63-8]2-chloro-6-methylaniline</strong> (FW 141.60, 0.0245 mole) was added followed by three drops of formic acid and the solution was stirred at RT under nitrogen for four d, at which time no precipitate had formed. The reaction was then refluxed for 24 h. GC analysis indicated that reaction was incomplete. Refluxing was continued for a total of 1 week. Solvent was stripped from the reaction mixture via rotovap. Flash chromatography through a basic alumina column (eluted with hexane/ethyl acetate 20:1) lead to isolation of an oil. The oil was then crystallized from methanol/methylene chloride. Collected 0.21 g (4.2% yield) of pale yellow crystals. 1H-NMR (ppm, CDCl3): 2.12(s, 6H), 2.32(s, 6H), 6.95(t, 2H), 7.13(d, 2H), 7.30(d, 2H), 7.92(t, 1H), 8.5(d, 2H).
With pyridine; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5C. The mixture was then warmed and stirred for 2 h. at 20C. Hydrochloric acid (1N, 115 mL) was added at 0-10C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22C then 1 h. at 0C. The solid was collected by vacuum filtration, washed with water (2 x 75 mL) and dried to give 74.1 g (73.6 % yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). lH NMR (400 Hz, DMSO-d6) 8 1. 26 (t, 3H, J= 7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J= 7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7. 27 (m, 2H, J=7.5 Hz), 7.27-7. 37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz), 9. 28 (s, 1H) ; l3c NMR (100MHz, CDC13) b : 14. 57, 18.96, 67.17, 97.99, 126. 80, 127. 44, 129. 07, 131.32, 132.89, 138. 25,161. 09,165. 36.
300 g
With pyridine; In tetrahydrofuran; at 10 - 30℃; for 4h;
Ethyl vinyl ether compound of formula-5 (500 gm) was slowly added to oxalyl chloride compound of formula-4 (670 ml) at 10-15C. Raised the temperature of the reaction mixture to 25-30C and stirred for 12 hours at the same temperature. Heated the reaction mixture to 120- 125C and stirred for 90 minutes at the same temperature. Cooled the reaction mixture to 30-35 C and (E)-3-ethoxyacryloyl chloride compound of formula-7 was collected by fractional distillation. Added tetrahydrofuran (1160 ml) to the obtained compound of formula-7 and cooled the reaction mixture to 10-15C. Slowly added a solution of 2-methyl-6-chloroaniline compound of formula-9 (290 gm), pyridine (248ml) & tetrahydrofuran (1160 ml) to the reaction mixture at same temperature. Raised the temperature of the reaction mixture to 25-30C and stirred the reaction mixture for 4 hours at the same temperature. Cooled the reaction mixture to 5-10C and acidified the reaction mixture using aqueous HC1 solution. Water and ethyl acetate were added to the reaction mixture and stirred for 10 minutes. Separated the both aqueous & organic layers and extracted the aqueous layer with ethyl acetate. Washed the total organic layer with aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate was added to the obtained compound at 25-30C and cooled the reaction mixture to 0-5C. Stirred the reaction mixture for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled ethyl acetate and dried the material to get the title compound. Yield: 300 gm; M.R.: 160-164C; HPLC Purity: 99.66%.
2-Tert-butoxycarbonyloxyamino-thiazole-5-carboxylic Acid[ No CAS ]
[ 1101105-53-6 ]
[ 87-63-8 ]
[ 302964-06-3 ]
Yield
Reaction Conditions
Operation in experiment
48%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane
C C.
C. [5-[[(2-Chloro-6-methylphenyl)amino]carbonyl]-2-thiazolyl]carbamic Acid,1,1-dimethylethyl Ester A 2 M solution of oxalyl chloride in dichloromethane (1 mL, 2 mmol) was added dropwise to a stirred solution of 2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid (234 mg, 1 mmol) in THF (10 mL) and N,N-dimethyl formamide (few drops). The solution was stirred at rt for 4 h. The solvent was evaporated under reduced pressure, and in vacuo to obtain the crude acid chloride. 2-Chloro-6-methyl aniline (212 mg, 1.5 mmol) was added dropwise to a stirred solution of crude 2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid chloride (1 mmol) in dichloromethane (10 mL) at 0° C. Diisopropylethylamine (516 mg, 4 mmol) was added. The solution was allowed to warm to rt and stirred for 24 h, diluted with dichloromethane (60 mL) and washed with 2 N aq. HCl solution (15 mL). The organic extract was dried (MgSO4), filtered and concentrated. The residue was diluted with EtOAc-ether (25 mL, 1:4) and the solid was filtered and washed with ether (5 mL, 4*), and dried in vacuo to obtain the title compound (175 mg, 48%) as a tan solid.
[0168] 2-Chloro-6-methyl-phenylamine (5.00g, 35.3mmol) was dissolved in methanol (15mL) and acetic acid was added (5mL). The solution was chilled in an ice bath and a solution of bromine (1.8mL) in acetic acid (15mL) was added dropwise. After complete addition MeOH (5mL) was added to dissolve the precipitated solid. The solvents were removed under reduced pressure and the residue was triturated with hexanes to provide the title compound as an off white solid (10.49g, 99%). *H NMR (300 MHz, MeOD): 5 7.42 (s, 1H), 7.28 (s, 1H), 2.42 (s, 3H).
With potassium carbonate; In N-methyl-acetamide; water;
EXAMPLE 4 A solution of 250 g of potassium isobutyl xanthate (about 90% pure) in 400 ml of dimethylformamide is added dropwise to a mixture of 141.5 g of 2-chloro-6-methylaniline and 276 g of potassium carbonate in 1 liter of dimethylformamide at 150 C. in the course of one hour, under a nitrogen atmosphere. The reaction mixture is stirred for about a further 26 hours, whilst cooling intensively. The batch is cooled, freed from salt and then concentrated to dryness. The residue is taken up in 400 ml of water and the mixture is acidified. The 4-methyl-2-mercaptobenzothiazole which precipitates is filtered off, washed with water and dried. 172 g (95% of theory) of 4-methyl-2-mercaptobenzothiazole of melting point 188-190 C. are obtained.
trimethylammonium 4-chloro-2-methylphenyl dithiocarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.5%
With carbon disulfide; In acetone;
EXAMPLE 2 Preparation of trimethylammonium 4-chloro-2-methylphenyldithiocarbamate from mixed chlorinated 2-methylanilines To a 250-ml round-bottom flask equipped with a stirrer, thermometer and addition funnel is added at 25C. 68.2 g. (0.23 mole) of 20.8% aqueous trimethylamine, 28 ml. of acetone, and 28.3 g. of crude chlorinated 2-methylaniline, which by analysis contains 1.5% o-toluidine, 10.4% 6-chloro-2-methylaniline, 75.1% 4-chloro-2-methylaniline, 6.4% 4,6-dichloro-2-methylaniline and 0.7% unknown material. To the reaction mixture is added dropwise 16.7 g. (0.21 mole) of carbon disulfide and the temperature is allowed to rise to a maximum of 35C. Following the addition of the carbon disulfide, the addition funnel is rinsed with 10 ml. of acetone and the acetone rinsing is added to the reaction mixture. The reaction mixture is then stirred for 2 hours at ambient temperature and then cooled to 20C. The precipitate is then separated by filtration and washed with 75 ml. of acetone to obtain 37.10 g. of product which is identified by thin-layer chromatography as 95.5% pure trimethylammonium 4-chloro-2-methylphenyldithiocarbamate.
With sodium hydroxide; trichlorophosphate; In dichloromethane;
EXAMPLE 24 14.1 g of 2-chloro-6-methyl-aniline, 14.09 g of 1-acetyl-imidazolidin-2-one and 146 ml of POCl3 are stirred for 70 hours at 50C and evaporated in vacuo, methylene chloride is added to the residue, and the whole is shaken with 100 g of ice for 30 minutes. The mixture is then rendered alkaline with 40% strength sodium hydroxide solution and extracted three times with methylene chloride (a total of 700 ml), and the methylene chloride solution is washed with water until neutral, dried over sodium sulphate and evaporated. The residue is dissolved in 250 ml of warm ether and insoluble matter is filtered off. The ether solution is extracted with three times 70 ml and twice 40 ml of 2% strength acetic acid and is then rendered alkaline with 4 N NaOH and cooled, and the resulting crystals are filtered off, washed with water and dried. Yield: 15.6 g of the acetyl derivative of 2-(2'-chloro-6'-methylphenylamino)-2-imidazoline, that is to say 62.1% of theory. For analysis, the material is recrystallized from a little isopropanol and dried over silica gel at 80 and 0.01 mm Hg. Analysis: (C12 H14 N3 OCl; 251.715); calculated: C 57.26; H 5.61; N 16.68; O 6.37; Cl 14.08; found: C 57.6; H 5.7; N 16.7; O 6.1; Cl 14.1 5.04 g of the acetyl compound, in methanol, are boiled under reflux for 10 hours and the crystalline residue is recrystallized from i-propanol. Yield: 3.29 g of 2-(2'-chloro-6'-methylphenylamino)-2-imidazoline, that is to say 78.9% of theory. Melting point: 143-146C. Analysis: (C10 H12 N3 Cl); calculated: C 57.33; H 5.77; N 20.00; Cl 16.90; found: C 57.1; H 5.9; N 19.8; Cl 16.9
α-chloro-β-(3-chloro-o-tolyl)2,3-epoxypropyl propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With acetic acid; sodium nitrite;copper(l) chloride; In hydrogenchloride; water; acetone;
EXAMPLE 16 Preparation of alpha-chloro-beta-(3-chloro-o-tolyl)2,3-epoxypropyl propionate. 141.5 g of 6-chloro-o-toluidine are slowly added with agitation to a mixture of 200 ml of concentrated HCl and 2.0 ml of acetic acid in a 3-liter reactor. The hydrochloride solution thus formed is cooled to 0 C., and 150 ml of an aqueous solution containing 74 g of NaNO2 are added drop by drop over a period of 15 minutes. After filtering the 6-chlorotoluene-2-diazonium chloride solution is added to a mixture of 170 ml of glycidyl acrylate and 240 ml of acetone; whereafter a solution of 6 g of CuCl in 60 ml of HCl is added at a temperature of 25 C. over a period of 2 hours. The evolution of nitrogen ceases completely after 2 hours reaction time at 25 C. The alpha-chloro-beta-(3-chloro-o-tolyl)propionate of 2,3-epoxypropyl is extracted in ether and the ethereal extract is washed in water. After drying on CaCl2 and removal of the solvent the residue is distilled at low pressure. 200 g, corresponding to a 70% yield, of an oil distilling between 195 and 200 C. at 0.1 mm Hg are obtained. Analysis: % Cl found: 28 % Cl calculated: 27
1-{4-[3-(2-methoxy-5-methylphenyl)-ureido]-phenyl}-piperidine-4-carboxylic acid[ No CAS ]
[ 87-63-8 ]
1-{4-[3-(2-methoxy-5-methyl-phenyl)-ureido]-phenyl}-piperidine-4-carboxylic acid (2-chloro-6-methyl-phenyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
A solution of 1-{4-[3-(2-methoxy-5-methylphenyl)-ureido]-phenyl}-piperidine-4-carboxylic acid (103 mg) obtained in Example (196d), <strong>[87-63-8]2-chloro-6-methylaniline</strong> (42 mg), 1-propanephosphonic acid cyclic anhydride (50% ethyl acetate solution, 0.32 mL) and triethylamine (0.11 mL) in dimethylacetamide (5 mL) was stirred at room temperature for 17 hours, and then heated at 80C for nine hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated sodium hydrogen carbonate aqueous solution and saturated brine and dried over sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate 2:1 ? 0:1 and dichloromethane/methanol 5:1) and 26 mg (19%) of the title compound was obtained as a light brown solid. 1H-NMR spectrum (400MHz,DMSO-d6):delta(ppm)=9.51(1H, s), 9.06(1H, s), 8.05(1H, s), 7.99(1H, s), 7.37-7.27(2H, m), 7.31(1H, d, J=9.0Hz), 7.26-7.18(m, 2H), 6.92(2H, d, J=8.6Hz), 6.88(1H, d, J=8.2Hz), 6.72(1H, d, J=10.9Hz), 3.84(3H, s), 3.66(2H, d, J=11.4Hz), 3.34-3.27(1H, m), 2.73-2.63(2H, m), 2.23(3H, s), 2.18(3H, s), 1.97-1.89(2H, m), 1.87-1.75(2H, m). MS(FAB) m/z:507 (M + H)+. Melting point: >250C (dec).
N,N-bis-p-tolyl-2-chloro-6-methylaniline[ No CAS ]
[ 332903-62-5 ]
Yield
Reaction Conditions
Operation in experiment
With sodium t-butanolate;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In toluene; at 60 - 90℃;
Example 1d N-(2'-Chloro-6'-methylphenyl)-4-methylaniline 1.02 g (7.2 mmol) of <strong>[87-63-8]2-chloro-6-methylaniline</strong>, 1.23 g (7.2 mmol) 4-bromotoluene, 1.15 g (12 mmol) sodium tert-butoxide, 160 mg (0.7 mmol) tri-tert-butylphosphine and 130 mg (0.23 mmol) bis-dibenzylideneacetone-paladium(0) are reacted in 50 ml toluene under nitrogen at 90 C. for 20 minutes and at 60 C. over night. Aqueous workup (3N HCl, with hyflo, washing the organic phase with water) and flash-chromatography on silica using heptan/toluene (4:1) as the eluent affords 1.49 g of N-(2'-chloro-6'-methylphenyl)-4-methylaniline. 1H-NMR (400 MHz, CDCl3): 2.21 (s, 3H, C-6'-CH3); 2.29 (s, 3H, C4-CH3); 5.61 (s, br, 1H, NH); 6.57 [d, 2H, HC (2, 6)]; 7.04 [d, 2H, HC (3, 5)]; 7.07 [t under signal at 7.04, 1H, HC (4')]; 7.16 [d, 2H, H (C5')]; 7.33 [d, 1H, H(C3')]. N,N-Bis-p-tolyl-<strong>[87-63-8]2-chloro-6-methylaniline</strong> (9 mg) is isolated as a byproduct.
Example 1; [0163] A mixture of ethyl beta-ethoxyacrylate (26.50 g, 183 rnmol) and 2 N sodium hydroxide(110 mL, 220 mrnol) was refluxed for 2 h and cooled to 0C , water was removed under vacc, and the yellow solids were triturated with toluene and evaporated to give the sodium beta- ethoxyacrylate (25 g, 97%). The mixture of sodium beta-thoxyacrylate (10.26 g, 74.29 mrnol) and thionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporated, to give the beta- ethoxyacryloyl chloride crude product, which was used without purification, To a cold stirring solution of 3-ethoxyacryloyl chloride in THF (100 mL) was added 2-chloro-6-methylaniline (6.2 mL, 50,35 mmol) and pyridine (9 ml, 1 1 1 mmol) The mixture was then wanned and stirred overnight at room temperature. Water was added at 0-10C, extracted with EtOAc, The organic layer was washed with CuSO4 (3x50 mL) and the resulting solution was passed a pad of silica gel, concentrated under vacuum to give solids, The solids was diluted with toluene and kept, at 0C, The solid was collected by vacuum filtration, washed with water and dried to give 5,2 g (43% yield) of compound 1 , (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (500 Hz1 CDCl3) delta 1 ,26 (t, 3H1 J=7 Hz), 2, 15 (s, 3H), 3 94 (q, 2H, J=7 Hz), 5,58 (d, IH, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7,27-7.37 (d, IH, J=7.5 Hz), 7,45(d, 1Hf J=12.4 Hz); ESI-MS: calcd for (Cl 2H14C1NO2) 239, found 240 MH+),
With pyridine; In tetrahydrofuran; at 20℃;
Example 1[0156] A mixture of ethyl beta-ethoxyacrylate (26.50 g, 183 mmol) and 2 N sodium hydroxide (110 mL, 220 mmol) was refluxed for 2 h and cooled to 0 C water was removed under vacc, and the yellow solids were triturated with toluene and evaporated to give the sodium beta-ethoxyacrylate (25 g, 97%). The mixture of sodium beta-thoxyacrylate (10.26 g, 74.29 mmol) and thionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporated, to give the beta-ethoxyacryloyl chloride crude product, which was used without purification. To a cold stirring solution of 3-ethoxyacryloyl chloride in THF (100 mL) was added 2-chloro-6- methylaniline (6.2 mL, 50.35 mmol) and pyridine (9 ml, 111 mmol). The mixture was then warmed and stirred overnight at room temperature. Water was added at 0-10 C, extracted with EtOAc. The organic layer was washed with CuSO4 (3x50 mL) and the resulting solution was passed a pad of silica gel, concentrated under vacuum to give solids. The solids was diluted with toluene and kept, at O0C. The solid was collected by vacuum filtration, washed with water and dried to give 5.2 g (43% yield) of compound 1, (E)-N-(2-chloro-6- methylphenyl)-3-ethoxyacrylamide). 1H NMR (500 Hz, CDCl3) delta 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, IH, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27- 7.37 (d, IH, J=7.5 Hz), 7.45(d, IH, J=12.4 Hz); ESI-MS: calcd for (C12Hi4ClNO2) 239, found 240 MH+).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
[0327] Experimental Details: The mixture of compound 2 (0.3 g, 1.0 eq), 2-chloro- 6-methyl-phenylamine (0.26 g, 1.0 eq), EDC (0.53 g, 1.5 eq), HOBt (25 mg, 0.1 eq) in 10 mL of dichloromethane was stirred at r.t. overnight. The mixture was washed with 1 N NaOH <n="205"/>solution, water, and extracted with dichloromethane. The organic layer was dried over Na2SO4, concentrated to dryness, purified by column chromatography to give compound 3.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
Example 5 Experimental Details: The mixture of compound 2 (0.3 g, 1.0 eq), 2-chloro-6-methyl-phenylamine (0.26 g, 1.0 eq), EDC (0.53 g, 1.5 eq), HOBt (25 mg, 0.1 eq) in 10 mL of dichloromethane was stirred at r.t. overnight. The mixture was washed with 1 N NaOH solution, water, and extracted with dichloromethane. The organic layer was dried over Na2SO4, concentrated to dryness, purified by column chromatography to give compound 3.
[0608] To a cooled (0 C.) THF solution of 2-chloro-6-methyl aniline (2.86 mL, 23.3 mmol, 1.10 equiv) was added dropwise a 1.0 M solution of lithium bis(trimethylsilyl)amide (42.2 mL, 42.2 mmol, 2.00 equiv) via syringe. The homogeneous solution was allowed to stir for 5 minutes, and then a THF solution of <strong>[41731-83-3]ethyl 2-bromo-5-thiazolecarboxylate</strong> (5.00 g, 21.1 mmol, 1.00 equiv, prepared in a manner analogous to compound 319A) was added via cannula. The solution was allowed to stir for 15 minutes until TLC analysis showed no remaining starting material. To the reaction was then added 4-methoxybenzyl chloride (7.15 mL, 52.7 mmol, 2.5 equiv), followed by a catalytic amount of tetrabutylammonium iodide (1.56 g, 4.22 mmol, 0.20 equiv). The homogeneous mixture was allowed to stir overnight at ambient temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic extracts were washed with brine and dried over Na2SO4. After filtration and removal of solvent, the product was purified by flash chromatography (10-20% ethyl acetate in hexanes) to afford the title compound as a tan solid (47%).
With Dichlorophenylphosphine; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -5 - 20℃; for 14h;
tert-butyl The 10m1 dichloromethane adding 50m1 three flasks, and then balance weighing 1g of Cape - 3 is added to the three flasks; the reaction container is transferred to the low-temperature constant in the responds the bath, regulating the temperature to -5 C, batch by adding phenyl phosphate dichloride (1.036g) and 2 - chloro -6 - methylaniline (0.754g); then, dropping N, N - diisopropyl ethylamine 1.6g; raising the temperature to room temperature, stirring reaction 14h. The pressure of the reaction solution after the organic solvent, adding 5m1 ethanol, stirring beating 30min; finally, adding 10m1 tap water, stirring crystallization, filtered, get 1.43g Cape - 3 yellow solid, yield 95%. The total reaction equation is as follows: Nuclear magnetic with the mass spectrometry data:
48%
[0407] A 2 M solution of oxalyl chloride in dichloromethane (1 mL, 2 mmol) was added dropwise to a stirred solution of <strong>[302964-02-9]2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid</strong> (234 mg, 1 mmol) in THF (10 mL) and N,N-dimethyl formamide (few drops).The solution was stirred at rt for 4 h. The solvent was evaporated under reduced pressure, and in vacuo to obtain the crude acid chloride. 2-Chloro-6-methyl aniline (212 mg, 1.5 mmol) was added dropwise to a stirred solution of crude <strong>[302964-02-9]2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid</strong> chloride (1 mmol) in dichloromethane (10 mL) at 0 C. Diisopropylethylamine (516 mg, 4 mmol) was added. The solution was allowed to warm to rt and stirred for 24 h, diluted with dichloromethane (60 mL) and washed with 2 N aq. HCl solution (15 mL). The organic extract was dried (MgSO4), filtered and concentrated. The residue was diluted with EtOAc-ether (25 mL, 1:4) and the solid was filtered and washed with ether (5 mL, 4×), and dried in vacuo to obtain the title compound (175 mg, 48%) as a tan solid.
Example 100[0255] To compound 97 (700mg, 4.96mMol) in 7mL of DMF at O0C was added pyridine (883 muL, 863mg, 10.9ImMoI) followed by careful, dropwise addition of pentafluorophenyl trifluoroacetate (1.68mL, 2.78g, 9.92mMol). Reaction mixture was stirred at 0 C for 10 minutes and 90 minutes at room temperature. 2-chloro-6-methylaniline (1.22mL, 1.4g, 9.92mMol) was added and reaction mixture was stirred overnight at room temperature. Reaction was poured into 5OmL of IN HCl, organic layer was separated. Aqueous layer was extracted with EtOAc. Organic fractions were combined, washed with brine, dried over Na2SO4, filtered and solvent was evaporated to give 1.79g (quant.) of crude product 100 that was used in the next step without purification.
Example 3 [0148] A solution of oxalyl chloride in dichloromethane (2M, 4.28 ml, 8.56 mmole) was added dropwise to a stirred suspension of compound 2 (1.36 g, 5.71 mmole) and DMF (ca. ~ 0.3 mL) in anhydrous dichloromethane at 0 C. After the addition was complete, the reaction mixture was stirred at -room temperature for 4 h. The solvents were removed under reduced pressure and the residue was co-evaporated with toluene twice. Anhydrous dichloromethane was added to the reaction flask and pyridine (0.66 ml, 8.50 mmol) was added, followed by addition of 2-chloro-6-methylaniline (0.85 ml, 6.85 mmol) at 0 C. The mixture was stirred at room temperature overnight. Water was added and the the mixture was extracted byethyl acetate (3x100 mL). The combined organic was washed by brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluting solvents: 0-50% ethyl acetate in hexanes. After removal of solvents, the title compound was obtained as white solids (1.00 g, 49%). IH NMR (500 MHz, DMSO-d6) delta 10.22 (s, IH), 10.07 (s, IH), 8.87 (s, IH), 8.29 (d, J = 9.0 Hz, IH), 7.94(d, J = 9.0 Hz, IH), 7.40 (d, J = 7.5 Hz, IH), 7.30-7.26 (m, 2H), 2.22 (s, 3H), 1.49 (s, 9H); ESI-MS: calcd for (Ci8H2OClN3O3) 361, found 360 ([M-H]-).
Example 19 [0165] Thionyl chloride (20 mL) was added to a flask charged with compound 18 (300 mg, 1.96 mmol)) at room temperature and the mixture was stirred at 80 C for 2 hours. Thionyl chloride was removed under reduced pressure. The residue was dissolved into THF (50 mL) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (0.70 ml, 5.68 mmol) was added, followed by addition of pyridine (0.20 ml, 2.50 mmol) at 0 C. The mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted by ethyl acetate. The combined organic was washed by brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluting solvents: 0-5% 7N NH3 in methanol /100-95% dichloromethane). After removal of solvents, the title compound was obtained as white solids (100 mg, 18% yield). IH NMR (500 MHz, DMSO-d6) delta 9.73 (s, IH), 8.49 (s, IH), 7.37 (d, J = 8.0 Hz, IH), 7.28-7.23 (m, 2H), 7.05 (br, 2H), 2.43 (s, 3H), 2.25 (s, IH); ESI-MS: calcd for (C13H13ClN4O) 276, found 277 (MH+).
Method B: Thionyl chloride (15 mL) was added to a flask charged with 6- aminonicotic acid (100 mg) at room temperature and the mixture was stirred at 85-90 C for 3 hours. Thionyl chloride was removed under reduced pressure. The residue was dissolved into dichloromethane (5 mL) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (0.18 ml, 1.46 mmol) was added, followed by addition of pyridine (0.12 ml, 1.50 mmol) at 0 C. The mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted by dichloromethane (3x10 mL). The combined organic was washed by brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluting solvents: 0-5% methanol in dichloromethane. After removal of solvents, the title compound was obtained as white solids (80 mg, 42% yield). The IH NMR and Mass spectra are the same as that obtained by method A.
With O-phenyl phosphorodichloridate; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;Product distribution / selectivity;
Method C:; Under nitrogen atmosphere, 2-(6-bromo-2-methylpyrimidin-4-ylamino) thiazole-5-formic acid (Compound 12) (15.8g, 0.05mol), PDCP (9.0mL, 0.06mol) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8)) (7.4mL, 0.06mol) were added into methylene dichloride (650mL) by stirring and cooling, and then triethylamine (20.4mL, 0.15mol) was added by droplets at 0C. When finish adding, it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 15 mins and then filtrated. The cake was taken up and added in DMSO (80mL) and heated to 60C-70C when stirring. After dissolving, the mixture of water and ethanol (1:1, 320mL) was added in thermal insulation. Crystals precipitated by stirring and then cooled down to 0C to grow the grain for 1h. After air pump filtration the cake was rinsed by water and then by the mixture of water and ethanol (1:1), and dried by air pump. With phosphorus pentoxide as an auxiliary desiccant, the cake was dried by vacuum (-0.095MPa) at about 50C to give Compound 14 (17.0g, yield: 77.5%).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 10 - 30℃;
Example 8: Synthesis of 2-(6-bromo-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl) thiazole-5-formamide (Compound 14); Method A; 2-(6-bromo-2-methylpyrimidin-4-ylamino) thiazole-5-formic acid (Compound 12) (31.5g, 0.1mol THF (315mL) and DMF (3mL) were mixed in reaction flask, and a solution of oxalyl chloride (25.4g, 0.2mol) in methylene dichloride (100mL) was added by droplet when the temperature is controlled between 10C and 20C. After adding, the mixture reacted by stirring at room temperature for 5h and then was condensed to dry by vacuum to yield 2-(6-bromo-2-methylpyrimidin-4-ylamino) thiazole-5-formyl chloride (Compound 13), which was transferred by acetonitrile (500mL) into reaction flask. a solution of <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (21.2g, 0.15mol) in acetonitrile (500mL) was added by droplet and stirred when the temperature is controlled between 10C and 15C. After adding, DIPEA (56g, 0.4mol) was added and reacted overnight when the temperature is controlled at 30C. When Cooled down to 0-5C, hydrochloric acid (1N, 1000mL) was added and stirred for 1h. After filtration, the cake was washed by water and then dried to give target Compound 14 (23.3g, yield: 53.2%). Element analysis: C16H13BrCN5OS, Calculated: C, 43.80; H, 2.99; N, 15.96; Found: C, 43.83; H, 2.96; N, 15.97.
23.3 g
2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 12) (31.5 g, 0.1 mol), THF (315 mL) and DMF (3 mL) were mixed in reaction flask, and a solution of oxalyl chloride (25.4 g, 0.2 mol) in methylene dichloride (100 mL) was added by droplet when the temperature is controlled between 10 C. and 20 C. After adding, the mixture reacted by stirring at room temperature for 5 h and then was condensed to dry by vacuum to yield 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formyl chloride (Compound 13), which was transferred by acetonitrile (500 mL) into reaction flask. a solution of <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (21.2 g, 0.15 mol) in acetonitrile (500 mL) was added by droplet and stirred when the temperature is controlled between 10 C. and 15 C. After adding, DIPEA (56 g, 0.4 mol) was added and reacted overnight when the temperature is controlled at 30 C. When Cooled down to 0-5 C., hydrochloric acid (1N, 1000 mL) was added and stirred for 1 h. After filtration, the cake was washed by water and then dried to give target Compound 14 (23.3 g, yield: 53.2%).[0201]Element analysis: C16H13BrClN5OS, Calculated: C, 43.80; H, 2.99; N, 15.96. Found: C, 43.83; H, 2.96; N, 15.97
With O-phenyl phosphorodichloridate; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Example 17: Synthesis of Dasatinib (Compound 1); Under nitrogen atmosphere, methyl 2-(6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formate (Compound 6) (0.5g, 1.3mmol), PDCP (0.2mL, 1.5mmol) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (0.18mL, 1.5mmol) were into methylene dichloride (10mL) by stirring and then triethylamine (0.55mL, 4mmol) was added by droplets when cooling to 0C. When finish adding it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 10 mins and then filtrated. The cake was dried to constant weight by blast at 60C to give Dasatinib (Compound 1) (0.2g, yield: 32.0%) 1H-NMR (300MHz, DMSO-d6): delta (ppm) 2.238(s, 3H), 2.406-2.431(d, 5H), 2.497-2.502(d, 4H), 3.398-3.524(q, 6H), 4.335-4.457(q, 1H), 6.049(s, 1H), 7.254-7.305(t, 2H), 7.386-7.410(d, 1H), 8.218(s, 1H), 9.876(s, 1H), 11.469(s, 1H). ESI(M+1): 490.33.
32%
With O-phenyl phosphorodichloridate; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Under nitrogen atmosphere, methyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate (Compound 6) (0.5 g, 1.3 mmol), PDCP (0.2 mL, 1.5 mmol) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (0.18 mL, 1.5 mmol) were into methylene dichloride (10 mL) by stirring and then triethylamine (0.55 mL, 4 mmol) was added by droplets when cooling to 0 C. When finish adding it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 10 mins and then filtrated. The cake was dried to constant weight by blast at 60 C. to give Dasatinib (Compound 1) (0.2 g, yield: 32.0%)[0283]1H-NMR (300 MHz, DMSO-d6): delta (ppm) 2.238 (s, 3H), 2.406-2.431 (d, 5H), 2.497-2.502 (d, 4H), 3.398-3.524 (q, 6H), 4.335-4.457 (q, 1H), 6.049 (s, 1H), 7.254-7.305 (t, 2H), 7.386-7.410 (d, 1H), 8.218 (s, 1H), 9.876 (s, 1H), 11.469 (s, 1H).[0284]ESI (M+1): 490.33.
With O-phenyl phosphorodichloridate; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
4.C
Method C: Synthesis of Dasatinib (Compound 1); Under nitrogen atmosphere, 2-(6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formic acid (Compound 7) (7.3g, 0.02mol), PDCP (3.4mL, 0.023mol) and 2-chloro-6-methylaniline (Compound 8)) (2.8mL, 0.023mol) were added into methylene dichloride (35mL) by stirring and cooling, and then triethylamine (8.4mL, 0.062mol) was added by droplets at 0°C. When finish adding it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate solution was added and stirred for 15 min and then filtrated to give crude Dasatinib (Compound 1) (yield: 97.2%). The cake was added in DMSO (36mL) and heated to 60°C-70°C by stirring. After dissolving the mixture of water and ethanol (1:1, 145mL) was added in thermal insulation. Crystals precipitated by stirring and then cooled down to 0°C to grow the grain for 10 min. After air pump filtration the cake was rinsed by water and then by the mixture of water and ethanol (1:1), and dried by air pump. With phosphorus pentoxide as an auxiliary desiccant, the cake was dried by vacuum (-0.095MPa) at about 50°C to give Dasatinib (Compound 1) (7.9g, yield: 80.9%, purity: 99.95%, See Fig. 1); 1H-NMR(500MHz, DMSO-d6): δ(ppm) 2.245(s, 3H), 2.413-2.446(s, 5H), 2.491-2.509(m, 4H), 3.521-3.557(q, 6H), 4.46(s, 1H), 6.05(s, 1H), 7.248-7.305(m, 3H), 8.226(s, 1H), 9.883(s, 1H), 11.476(s, 1H). 1H-NMR(500MHz, DMSO-d6, D2O): δ(ppm 2.233(s, 3H), 2.403-2.435, (s, 5H), 2.473-2.507(d, 4H), 6.047(s, 1H), 7.238-7.292(m, 2H), 7.386-7.400(d, 1H), 8.218(s, 1H). 13C-NMR(500MHz, DMSO-d6): δ(ppm) 18.756, 26.034, 44.098, 53.186, 58.997, 60.658, 83.098, 126.157, 127.458, 128.612, 129.474, 132.910, 134.002, 139.285, 141.286, 157.410, 160.393, 162.964, 165.629. ESI (M+1): 490.27
80.9%
With O-phenyl phosphorodichloridate; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
4.C Method C: Synthesis of Dasatinib (Compound 1)
Under nitrogen atmosphere, 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 7) (7.3 g, 0.02 mol), PDCP (3.4 mL, 0.023 mol) and 2-chloro-6-methylaniline (Compound 8)) (2.8 mL, 0.023 mol) were added into methylene dichloride (35 mL) by stirring and cooling, and then triethylamine (8.4 mL, 0.062 mol) was added by droplets at 0° C. When finish adding it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate solution was added and stirred for 15 min and then filtrated to give crude Dasatinib (Compound 1) (yield: 97.2%).[0171]The cake was added in DMSO (36 mL) and heated to 60° C.-70° C. by stirring. After dissolving the mixture of water and ethanol (1:1, 145 mL) was added in thermal insulation. Crystals precipitated by stirring and then cooled down to 0° C. to grow the grain for 10 min. After air pump filtration the cake was rinsed by water and then by the mixture of water and ethanol (1:1), and dried by air pump. With phosphorus pentoxide as an auxiliary desiccant, the cake was dried by vacuum (-0.095 MPa) at about 50° C. to give Dasatinib (Compound 1) (7.9 g, yield: 80.9%, purity: 99.95%, See FIG. 1) 1H-NMR (500 MHz, DMSO-d6): δ(ppm) 2.245 (s, 3H), 2.413-2.446 (s, 5H), 2.491-2.509 (m, 4H), 3.521-3.557 (q, 6H), 4.46 (s, 1H), 6.05 (s, 1H), 7.248-7.305 (m, 3H), 8.226 (s, 1H), 9.883 (s, 1H), 11.476 (s, 1H).[0173]1H-NMR (500 MHz, DMSO-d6, D2O): δ(ppm) 2.233 (s, 3H), 2.403-2.435, (s, 5H), 2.473-2.507 (d, 4H), 6.047 (s, 1H), 7.238-7.292 (m, 2H), 7.386-7.400 (d, 1H), 8.218 (s, 1H).[0174]13C-NMR (500 MHz, DMSO-d6): δ(ppm) 18.756, 26.034, 44.098, 53.186, 58.997, 60.658, 83.098, 126.157, 127.458, 128.612, 129.474, 132.910, 134.002, 139.285, 141.286, 157.410, 160.393, 162.964, 165.629.[0175]ESI (M+1): 490.27
350 g of 1,2-dichloroethane was placed in a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser, and a 35% aqueous solution of sodium hydroxide. 40.6 g (0.1 mol) of 2-[[6-[4-(2-acetoxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxylic acid (VI), 23.8 g (0.2 mol) of thionyl chloride,the reaction was stirred at 55-60 C for 4 hours.Cooled to 30 C, changed to a vacuum distillation unit, distilled under reduced pressure to recover 1,2-dichloroethane and excess thionyl chloride (after analysis of the content for the next batch of reaction), after distillation, cooled to 20- The residue (intermediate product) obtained was dissolved in 150 g of 1,2-dichloroethane at 25 C, and transferred to a constant pressure dropping funnel for use. Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a distillation apparatus, 200 g of 1,2-dichloroethane and 15.0 g of triethylamine were added. 15.6 g (0.11 mol) of <strong>[87-63-8]2-chloro-6-methylaniline</strong>, and the above obtained intermediate solution was added dropwise while maintaining the internal temperature of 40-50 C, and the dropwise addition was completed in 1 hour, after which the reaction was stirred at 45-50 C. After an hour, the mixture was filtered while hot, and the filter cake was washed twice with 1,2-dichloroethane, 40 g each time, and the filtrate was combined. The filtrate was evaporated under reduced pressure to recover the solvent. The residue was crystallized from isopropyl alcohol, filtered and dried. 50.6 g of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-acetoxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (VII), yield 95.6%, liquid phase purity 99.9%.
71.7%
With O-phenyl phosphorodichloridate; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Method B:; Under nitrogen atmosphere, 2-(6-(4-(2-acetyloxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formic acid (Compound 17, Pg is acetyl) (8.5g, 0.021mol), PDCP (3.4mL, 0.023mol) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (2.8mL, 0.023mol) were added into methylene dichloride (34mL) by stirring, and then when cooling down to 0C triethylamine (8.4mL, 0.062mol) was added by droplets. After adding, it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 10 mins and then filtrated. The cake was dried to constant weight by blast at 60C to give light yellow to off-white solid target Compound 19 (Pg is acetyl) (7.98g, yield: 71.7%). Melting Point: 295.5 C Element analysis: C24H28ClN7O3S, Calculated: C, 54.38; H, 5.32; N, 18.50; Found: C, 54.32; H, 5.38; N, 18.57.
71.7%
With O-phenyl phosphorodichloridate; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Under nitrogen atmosphere, 2-(6-(4-(2-acetyloxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 17, Pg is acetyl) (8.5 g, 0.021 mol), PDCP (3.4 mL, 0.023 mol) and <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (2.8 mL, 0.023 mol) were added into methylene dichloride (34 mL) by stirring, and then when cooling down to 0 C. triethylamine (8.4 mL, 0.062 mol) was added by droplets. After adding, it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 10 mins and then filtrated. The cake was dried to constant weight by blast at 60 C. to give light yellow to off-white solid target Compound 19 (Pg is acetyl) (7.98 g, yield: 71.7%).[0273]Melting Point: 295.5 C.[0274]Element analysis: C24H28ClN7O3S, Calculated: C, 54.38; H, 5.32; N, 18.50. Found: C, 54.32; H, 5.38; N, 18.57.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;
Example 15: Synthesis of Dasatinib protected by acetyl (Compound 19, Pg is acetyl); Method A:; 2-(6-(4-(2-acetoxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formic acid (Compound 17, Pg is acetyl) (30g, 0.074mol), methylene dichloride (270mL) and DMF (3mL) were mixed in a four-necked flask and cooled down. Then a solution of oxalyl chloride (12.7mL) in methylene dichloride (30mL) was added by droplet when the temperature is controlled between 0C and 5C. After adding, the mixture was heated and reacted at room temperature for 3h. Filtrated and the cake was mixed with methylene dichloride (300mL) in reaction flask, and cooled down to 0C by stirring. <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (13.6mL, 0.11mol) was added, as well as a solution of DIPEA (21mL, 0.12mol) in methylene dichloride (30mL) was added by droplet. After adding, it reacted at room temperature for 2h. After reaction saturated sodium bicarbonate solution was added and stirred for 30 mins. Filtrated and the cake was dried to constant weight at 60C by blast to give target Compound 19 (Pg is acetyl) (yield: 40.8%). Melting Point: 295.2C Purity: 98.5% (HPLC, normalization method); Element analysis: C24H28ClN7O3S, Calculated: C, 54.38; H, 5.32; N, 18.50; Found: C, 54.42; H, 5.40; N, 18.55. 1H-NMR(500MHz, DMSO-d6): delta(ppm) 2.030(s, 3H), 2.245(s, 3H), 2.372-2.414(d, 3H), 2.584-2.605(t, 6H), 3.517(s, 4H), 4.133-4.155(t, 2H), 6.056(s, 1H), 7.248-7.305(m, 2H), 7.400-7.414(t, 1H), 8.226(s, 1H), 9.883(s, 1H), 11.845(s, 1H). 1H-NMR(500MHz, DMSO-d6,D2O): delta(ppm) 2.020-2.055(d, 3H), 2.240-2.278(d, 3H), 2.367-2.441(t, 3H), 2.491-2.501(d, 4H), 2.546-2.592(q, 2H), 3.423(s, 1H), 3.514(s, 1H), 4.122-4.144(t, 1H), 6.054(s, 1H), 7.240-7.296(m, 2H), 7.391-7.406(d, 1H), 8.230(m, 1H). 13C-NMR (500MHz, DMSO-d6): delta(ppm) 18.759, 21.237, 26.034, 44.053, 52.866, 56.480, 61.695, 83.198, 126.080, 127.458, 128.594, 129.473, 132.921, 134.036, 139.297, 141.320, 157.532, 160.411, 163.001, 165.617, 170.780. ESI: (M)531.29
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;
2-(6-(4-(2-acetoxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 17, Pg is acetyl) (30 g, 0.074 mol), methylene dichloride (270 mL) and DMF (3 mL) were mixed in a four-necked flask and cooled down. Then a solution of oxalyl chloride (12.7 mL) in methylene dichloride (30 mL) was added by droplet when the temperature is controlled between 0 C. and 5 C. After adding, the mixture was heated and reacted at room temperature for 3 h. Filtrated and the cake was mixed with methylene dichloride (300 mL) in reaction flask, and cooled down to 0 C. by stirring. <strong>[87-63-8]2-chloro-6-methylaniline</strong> (Compound 8) (13.6 mL, 0.11 mol) was added, as well as a solution of DIPEA (21 mL, 0.12 mol) in methylene dichloride (30 mL) was added by droplet. After adding, it reacted at room temperature for 2 h. After reaction saturated sodium bicarbonate solution was added and stirred for 30 mins. Filtrated and the cake was dried to constant weight at 60 C. by blast to give target Compound 19 (Pg is acetyl) (yield: 40.8%).[0262]Melting Point: 295.2 C.[0263]Purity: 98.5% (HPLC, normalization method)[TABLE-US-00006] HPLC Test Conditions Mobile Phasemethanol/0.05M potassium dihydrogen phosphate pH = 2.5 (55/45) Detection 300 nm Wavelength (lambda) Retention Time12.315 min (TR) [0264]Element analysis: C24H28ClN7O3S, Calculated: C, 54.38; H, 5.32; N, 18.50. Found: C, 54.42; H, 5.40; N, 18.55.[0265]1H-NMR (500 MHz, DMSO-d6): delta(ppm) 2.030 (s, 3H), 2.245 (s, 3H), 2.372-2.414 (d, 3H), 2.584-2.605 (t, 6H), 3.517 (s, 4H), 4.133-4.155 (t, 2H), 6.056 (s, 1H), 7.248-7.305 (m, 2H), 7.400-7.414 (t, 1H), 8.226 (s, 1H), 9.883 (s, 1H), 11.845 (s, 1H).[0266]1H-NMR (500 MHz, DMSO-d6, D2O): delta(ppm) 2.020-2.055 (d, 3H), 2.240-2.278 (d, 3H), 2.367-2.441 (t, 3H), 2.491-2.501 (d, 4H), 2.546-2.592 (q, 2H), 3.423 (s, 1H), 3.514 (s, 1H), 4.122-4.144 (t, 1H), 6.054 (s, 1H), 7.240-7.296 (m, 2H), 7.391-7.406 (d, 1H), 8.230 (m, 1H).[0267]13C-NMR (500 MHz, DMSO-d6): delta(ppm) 18.759, 21.237, 26.034, 44.053, 52.866, 56.480, 61.695, 83.198, 126.080, 127.458, 128.594, 129.473, 132.921, 134.036, 139.297, 141.320, 157.532, 160.411, 163.001, 165.617, 170.780.[0268]ESI: (M) 531.29
With O-phenyl phosphorodichloridate; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Employing the above-mentioned synthetic method: Prepared from 2-(6-(4-(2-benzoyloxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formic acid (Compound 17, Pg is benzoyl): Dasatinib protected by benzoyl group was yielded: Compound 19 (Pg is benzoyl) (yield: 76.3%). Element analysis: C29H30ClN7O3S, Calculated: C, 58.83; H, 5.11; N, 16.56; Found: C, 58.87; H, 5.19; N, 16.61.
With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 160℃; for 3h;Inert atmosphere; Microwave irradiation;
General procedure: NaOt-Bu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g, 0.025 mmol) and [HPt-Bu3][BF4] (0.010 g, 0.035 mmol) were suspended in toluene (3 ml) in a 5 ml microwave vial. The appropriate 2-chloroaniline (0.50 mmol) and aryl bromide (0.50 mmol) were then added and the vial sealed. The reaction was then heated in the microwave reactor at 160 C for 3 h, allowed to cool, and then quenched by addition of aqueous HCl (2 M, 3 ml). The organic phase was extracted with CH2Cl2 (2×20 ml), dried (MgSO4), then filtered and the solvent removed under reduced pressure. The crude product mixture was then subjected to column chromatography (SiO2).
With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 160℃; for 3h;Inert atmosphere; Microwave irradiation;
General procedure: NaOt-Bu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g, 0.025 mmol) and [HPt-Bu3][BF4] (0.010 g, 0.035 mmol) were suspended in toluene (3 ml) in a 5 ml microwave vial. The appropriate 2-chloroaniline (0.50 mmol) and aryl bromide (0.50 mmol) were then added and the vial sealed. The reaction was then heated in the microwave reactor at 160 C for 3 h, allowed to cool, and then quenched by addition of aqueous HCl (2 M, 3 ml). The organic phase was extracted with CH2Cl2 (2×20 ml), dried (MgSO4), then filtered and the solvent removed under reduced pressure. The crude product mixture was then subjected to column chromatography (SiO2).
With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 160℃; for 3h;Inert atmosphere; Microwave irradiation;
General procedure: NaOt-Bu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g, 0.025 mmol) and [HPt-Bu3][BF4] (0.010 g, 0.035 mmol) were suspended in toluene (3 ml) in a 5 ml microwave vial. The appropriate 2-chloroaniline (0.50 mmol) and aryl bromide (0.50 mmol) were then added and the vial sealed. The reaction was then heated in the microwave reactor at 160 C for 3 h, allowed to cool, and then quenched by addition of aqueous HCl (2 M, 3 ml). The organic phase was extracted with CH2Cl2 (2×20 ml), dried (MgSO4), then filtered and the solvent removed under reduced pressure. The crude product mixture was then subjected to column chromatography (SiO2).
With triethylamine; In dichloromethane; at 0 - 20℃;
[0100] At 0C, compound (2-4) (0.91 g, 5 mmol) dissolved in dichloromethane (20 mL) is added into a solution of 2-chloro-6-methyl aniline (0.79 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (100 mL), and is stirredat room temperature overnight. The resulting solution is partitioned between dichloromethane and water. The organiclayer is dried through anhydrous sodium sulfate and concentrated to give compound (2-5) (0.86 g, 60%).
60%
With triethylamine; In dichloromethane; at 0 - 20℃;
[0109] At 0 C., compound (2-4) (0.91 g, 5 mmol) dissolved in dichloromethane (20 mL) is added into a solution of 2-chloro-6-methyl aniline (0.79 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (100 mL), and is stirred at room temperature overnight. The resulting solution is partitioned between dichloromethane and water, The organic layer is dried through anhydrous sodium sulfate and concentrated to give compound (2-5) (0.86 g, 60%).
With triethylamine; trichlorophosphate; In acetonitrile; for 2h;Reflux;
General procedure: Compound 4 (0.1mmol), 4-(trifluoromethoxy) aniline (0.1mmol), and triethylamine (0.1mmol) were dissolved in CH3CN (15mL) with stirring, and POCl3 (0.1mmol) was dissolved in CH3CN (5mL) and then added dropwise. After stirring and refluxing for 2h, CH3CN was removed in vacuo. The mixture was washed with saturated sodium bicarbonate solution. The solution was filtered to obtain a crude product, which was recrystallized with ethanol to obtain the title compound 5a
With zinc trifluoromethanesulfonate; In neat (no solvent); at 20℃; for 0.25h;
General procedure: Zn(OTf)2 (0.05 mmol) was added into a mixture of primary amines(1 mmol) and the 1,3-dicarbonyl compounds (1.1 mmol) in a 50 mLround bottomed flask and it was kept stirring at room temperature.The completion of the reaction was monitored by TLC. The productwas dissolved in ethyl acetate (50 mL) and filtered. The pure productwas obtained by directly passing through a silica gel (200-300 mesh)column using petroleum ether/ethyl acetate and identified by IR, 1HNMR, 13C NMR, MS, and HRMS.
With zinc trifluoromethanesulfonate; In neat (no solvent); at 20℃; for 0.2h;
General procedure: Zn(OTf)2 (0.05 mmol) was added into a mixture of primary amines(1 mmol) and the 1,3-dicarbonyl compounds (1.1 mmol) in a 50 mLround bottomed flask and it was kept stirring at room temperature.The completion of the reaction was monitored by TLC. The productwas dissolved in ethyl acetate (50 mL) and filtered. The pure productwas obtained by directly passing through a silica gel (200-300 mesh)column using petroleum ether/ethyl acetate and identified by IR, 1HNMR, 13C NMR, MS, and HRMS.
Stage #1: 2-chloro-6-methylaniline With ethyl bromide; iodine; magnesium In tetrahydrofuran at 0 - 25℃;
Stage #2: ethyl 2-[(tert-butoxycarbonyl)amino]-1.3-thiazole-5-carboxylate In tetrahydrofuran for 3.5h;
1 Example 1 : Preparation of ferf-butyl {5-[(2-chloro-6-methylphenyl)carbamoyl]-1.3- thiazol-2-yl } carbamate
Tetrahydrofuran (15 mL) was added to the flask. A solution of ethyl bromide (16 g in 60 mL tetrahydrofuran) was prepared and 10 mL of this solution was slowly charged to the round bottom flask. Iodine (30 mg) was added to the reaction mixture and stirred at 25°C to 32°C for 5 minutes. The reaction mixture was warmed to 27°C and the remaining amount of ethyl bromide was added slowly over 30 minutes. The reaction mixture was heated to gentle reflux for 30 minutes and was then cooled to 0°C. 2-Chloro-6- methylaniline (22.86 g) was added drop-wise at 0°C and the temperature of the reaction mixture was slowly raised to 20°C to 25 °C. Ethyl 2-[(teri-butoxycarbonyl)amino]-l,3- thiazole-5-carboxylate (10 g) dissolved in tetrahydrofuran (60 mL) was slowly added to the reaction mixture over 30 minutes. The reaction mixture was stirred for 3 hours. The reaction mixture was poured slowly into 25% ammonium chloride solution (200 mL) with stirring. Ethyl acetate (200 mL) was added and stirred for 30 minutes, filtered, suck dried, and dried under vacuum at 40°C to 45°C to obtain the title compound.
4-chloro--N-(2-chloro-6-methylphenyl)-2-(methylthio)pyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Amberlyst A21; In ethyl acetate; at 40℃;
To a solution of 4-chloro-2-(methylthio)pyrimidine-5- carbonyl chloride (24.81 g, 111 mmol) in ethyl acetate (250 mL), Amberlyst A21 (7 g, 106 mmol) was added and the reaction mixture heated to 40C. A solution of 2-chloro-6-methylaniline (15 g, 106 mmol) in ethyl acetate (250mL) was then added and the reaction was stirred at 40 C overnight. A white precipitate formed. It was filtered then taken up in dry THF (1 L) and heated at 60 C for 15 mm, then filtered again. The filtrate was concentratedin vacuo. The residue was slurried in DCM (200 mL) then filtered and dried. It was suspended in THF (1 L) and methylamine (2 M in THF, 50 mL) was added at 0 C. After stirring for 1 h at room temperature, the solution was filtered. The filtrate was concentrated in vacuo. Theresulting oil was triturated in acetonitrile until formation of a white precipitate which was collected and dried at ambient temperature to give the title compound (3.5 g, 11%) . LCMS (Method A) : = 1.43 mm, m/z = 323 [M+H] +
2-[2-methyl-4-(4-methylpiperazine-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carbonyl chloride[ No CAS ]
[ 87-63-8 ]
N-(2-chloro-6-methyl-phenyl)-2-[2-methyl-4-(4methylpiperazine-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With dmap; In acetonitrile; at 50℃;
Exampe 2N-(2-chloro-6-methyl-phenyl)-2-[2-methyl-4-(4methylpiperazine-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamideTo a suspension of 2-[2-methyl-4-(4-methylpiperazin-1 -yI)anilmno]-56- dihydropyrimido[45-e]indolizine-7-carbonyl chloride (ntermedate 2, 52 mg, 0.07 mmol theor.)in acetonitril (2 mL) was added 2-chloro-6methylaniline (15 iiL, 012 mmol) and a catalytic amount of 4-DMAP. The reaction mixture was stirred at 50 C 0/n. After evaporation of the solvent, the crude product was purified by preparative HPLC. Fractions containing product were collected and concentrated in vacuo. The residue was partitioned between dichioromethane and 5% NaHCO3-solution. The organic phase was separated over a PE-filterand evaporated to afford 28 mg of the title compound (74% yield). Data: LCMS (B) Rt: 9.852 mm; m/z 542.2/544.2 (M+H ) (chloride-pattern).
(2-chloro-6-methylphenyl)hydrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With hydrogenchloride; tin(ll) chloride; sodium nitrite; In water; at 0 - 20℃; for 6h;
To a 1000 mL 3 -necked round-bottom flask was added <strong>[87-63-8]2-chloro-6-methylaniline</strong> 8a (10 g, 70.62 mmol, 1.00 equiv.), a 4M hydrogen chloride aqueous solution (60 mL), and water (45 mL). The mixture was cooled to 0C, and added slowly with NaNO2 (4.9 g, 71.01 mmol, 1.00 equiv.), followed by SnCl2 (19 g, 100.20 mmol, 1.40 equiv.). The resulting mixture was stirred at room temperature for 6h. Solids were collected by filtration. The crude product was purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, MeCN:H2O=0: 100; Detector, UV 254 nm. Removal of solvents afforded (2- chloro-6-methylphenyl)hydrazine hydrochloride 8b (3.0, 22%) as a light yellow solid.
a vinyl ether as a starting material, after the reaction with oxalylchloride, acid chloride is heated in the vacuum distillation, acidchloride with 2-chloro-6-methyl anilines amides, the sulfur and then with NBSurea cyclization reaction
Compounds 19 (425 mg, 3.00 mmol), NaNO2 (414 mg, 6.00 mmol) and 5 mL H2O were added to a round bottom flask at 0 C. While stirring slowly, 3N hydrochloric acid (3 mL, 9.00 mmol) was added dropwise and the mixture was stirred for 1 h. NaN3 (214.5 mg, 3.30 mmol) was weighed and dissolved in 2 mL H2O. The mixture was slowly added dropwise to the flask. The mixture was stirred for 1.5 h. TLC was detected and the starting material had disappeared and the reaction was complete. The reaction mixture was extracted with methylene chloride, the organic phases were combined, the partially removed solvent was removed by rotation, adding acetonitrile solution, continue to dry the methylene chloride to get 20 mixture, the product dissolved in acetonitrile, directly cast the next step;
Compound 8 (424.8 mg, 3 mmol), NaNO2 (414 mg, 6 mmol) and 5ml H2O were all added to the flask, the resulting mixture was stirred at 0 C and hydrochloric acid (3 ml, 9 mmol) was dropwise added to the mixture through a constant pressure drop funnel slowly. The mixture was stirred at this temperature for 1 h. NaN3 (214.5 mg, 3.3 mmol) dissolved in 2 ml H2O was also dropwise added to the mixture through a constant pressure drop funnel slowly. The mixture was stirred at this temperature for 1.5 h. The reaction mixture was extracted with CH2Cl2 (3 × 10 ml) and the organic layers were combined and concentrated to remove part of the solvent. Acetonitrile was added to carry off the reside CH2Cl2 to give the acetonitrile solution of compound 9.
ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate[ No CAS ]
[ 87-63-8 ]
N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
To a solution of 200 mg (0.454 mmol [calculation value with the purity defined as 100%]) of ethyl 5-(chloro- carbonyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido] -5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)- carboxylate synthesized in the same way as in Reference Example 4 in 3 ml of 1,4-dioxane, 0.39 ml (2.3 mmol) of DIPEAand 0.16 ml (1.4 mmol) of <strong>[87-63-8]2-chloro-6-methylaniline</strong> were added at room temperature in an argon atmosphere, reacted at 120 C. for 0.5 hours in a microwave reaction apparatus, and then reacted at 1500 C. for 2 hours. Subsequently, 0.21 ml (2.3 mmol) of N,N-dimethylethane-1,2- diamine was added thereto at room temperature and then reacted at room temperature for 2 hours with stirring.10683] After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The whole organic layer thus obtained was washed with saturated saline, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to preparative colunm chromatography (apparatus 1, DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30-50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative colunm chromatography (apparatus 1, silica gel, elution solvent: 1,2- dichloroethane:methanol=99: 1 -92: 8 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 3, ODS silica gel, elution solvent: acetonitrile:1 mM aqueous potassium dihydrogen phosphate solution=50: 50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure, followed by the distilling oil of acetonitrile. The obtained concentrate was subjected to extraction with ethyl acetate, and subsequently, the whole organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by the addition of ethyl acetate, then n-hexane was added thereto, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 23.6 mg of the title compound (yield: 11% [calculation value with the purity of the starting material defined as 100%]) as a white solid.10684] Mass spectrum (CI, mlz): 474 [M+1].10685] ?H-NMR spectrum (400 MHz, DMSO-d5) oe: 12.26& 11.73 (br s, total 1H), 9.58 (s, 1H), 7.81 (br s, 1H), 7.30(dd, J=1.3, 7.8 Hz, 1H), 7.23-7.11 (m, 2H), 4.61 (br s, 2H),2.56-2.41 (m, 2H), 2.27-2.12 (m, 5H), 1.90-1.73 (m, 2H),1.64 (s, 6H), 0.09 (s, 9H).
5-chloro-7-((2-chloro-6-methylphenyl)amino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium bicarbonate
11.a (11a)
(11a) Synthesis of 5-chloro-7-((2-chloro-6-methylphenyl)amino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester A solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (CAS No. 1232224-62-2) (2.9 g) and 2-chloro-6-methylaniline (CAS No. 87-63-8) (1.6 g) in NMP (1.1 mL) was stirred at 140° C. for 4 hours. The reaction mixture was cooled, subsequently diluted with ethyl acetate, the precipitate was collected by filtration and washed with diethyl ether. A saturated aqueous solution of sodium hydrogen carbonate was added to the filtrate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate system), to obtain the title compound (3.44 g). 1H-NMR (400 MHz, CDCl3) δ: 1.47 (t, J=7 Hz, 3H), 2.33 (s, 3H), 4.51 (q, J=7 Hz, 2H), 5.65 (s, 1H), 7.02 (s, 1H), 7.30 (dd, J=8, 2 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H), 7.98 (br.s, 1H).
Ethyl 3-oxopropionate 30 mmol, 37.5 mmol sodium methoxide was dissolved in 80 mL of tetrahydrofuran and stirred at room temperature for 10 min.Then, 27 mmol of 2-chloro-6-methylaniline was added, and the mixture was heated under reflux for 45 min. After the reaction was completed, it was cooled to room temperature, and 60 mL of the solution was added.81 mmol of copper bromide in tetrahydrofuran, heated to reflux for 1 h, filtered while hot, the filtrate was taken, and 42 mmol of thiourea was added to the filtrate.4.5mmol [Bmim]Br, stir the reaction at 20 ~ 25 C for 30min, TLC monitoring reaction (tracking reaction to disappearance of raw materials), antiAfter completion, pour into ice water, extract with dichloromethane, concentrate the organic phase, wash with water, add 50 mL of diethyl ether, stir and crystallize for 20 min, suction filtrationAfter drying, 6.68 g of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide was obtained in a yield of 92.31%, purity.99.91%.
90.94%
The 3 - oxo ethyl propionate 30 mmol, 39 mmol sodium methoxide dissolved in 80 ml in tetrahydrofuran, room temperature stirring 10 min after, adding 2 - chloro -6 - methylaniline 27 mmol, elevate temperature the backflow to 45 min, after the reaction, by adding 60 ml dissolved with the 84 mmol [...] tetrahydrofuran, heating reflux 1 h, filtered while hot, and the air of the filtrate, the filtrate is added in 42 mmol thiourea, 2.4 mmol H18N3O43PW12, For 20 - 25 C stirring for 15 min, TLC monitoring reaction (tracking response to the disappearance of the raw material), after the reaction, the catalyst is filtered, the filtrate is decompressed and evaporate the solvent, adding 50 ml ethyl ether stirring crystallization 20 min, filtered and dried to obtain 2 - amino - N - (2 - chloro -6 - methyl phenyl) thiazole -5 - carboxamide 6.59 g, yield 91.07%, purity 99.86%.
Ethyl 3-oxopropionate 30 mmol, 36 mmol sodium methoxide was dissolved in 80 mL of tetrahydrofuran.After stirring at room temperature for 10 min, 27 mmol of <strong>[87-63-8]2-chloro-6-methylaniline</strong> was added, and the mixture was refluxed for 1 h.After completion of the reaction, the mixture was cooled to room temperature, and 60 mL of tetrahydrofuran in which 78 mmol of copper bromide was dissolved was added thereto, and the mixture was heated to reflux for 2 hours, and filtered while hot, and the filter cake was washed with 50 ml of hot tetrahydrofuran.The filtrate is combined with the washing liquid, washed with water until neutral, and the solvent is distilled off under reduced pressure.The residue was poured into 50 mL of ice water, stirred for 0.5 h, and filtered under reduced pressure.The filter cake was washed with ice water and dried to give 7.19 g of Compound 2.The yield was 91.60%, and the purity was 99.92%.
91.6%
30 mmol of ethyl 3-oxopropionate, 36 mmol of sodium methoxide was dissolved in 80 mL of tetrahydrofuran, and stirred at room temperature for 10 min. Add 27 mmol of <strong>[87-63-8]2-chloro-6-methylaniline</strong> and reflux at reflux for 1 h. After cooling to room temperature, 60 mL of tetrahydrofuran dissolved in 78 mmol of copper bromide was added. It was heated to reflux for 2 h, filtered while hot, and the filter cake was washed with 50 mL of hot THF. The filtrate is combined with the washing liquid, washed with water until neutral, and the solvent is distilled off under reduced pressure. The residue was poured into 50 mL of ice water, stirred for 0.5 h, and filtered under reduced pressure. The filter cake was washed with ice water and dried to give 7.19 g of Compound 3. The yield was 91.60%, and the purity was 99.92%.
91.6%
30 mmol of ethyl 3-oxopropionate,37.5mmol sodium methoxide is solubleIn 80 mL of tetrahydrofuran,After stirring at room temperature for 10 min,<strong>[87-63-8]2-chloro-6-methylaniline</strong> 27mmol,The temperature was refluxed for 1 h, and after the reaction was completed, it was cooled to room temperature.60 mL of tetrahydrofuran dissolved in 81 mmol of copper bromide was added.Heated to reflux for 2 h, filtered while hot.The filter cake was washed with 50 mL of hot tetrahydrofuran, the filtrate was combined with a washing solution, washed with water until neutral, and the solvent was evaporated under reduced pressure.The residue was poured into 50 mL of ice water, stirred for 0.5 h, filtered under reduced pressure, and the filter cake was washed with ice water and dried.7.19 g of Compound 3 was obtained in a yield of 91.60% and a purity of 99.92%.
N-(2-chloro-6-methylphenyl)-4-hydroxy-2-(methylthio)pyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With phosphorus trichloride; In toluene; at 100.0℃; for 72h;
To a stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-(methylthio)pyrimidine-5-carboxylic acid</strong> (5 g, 26.88 mmol, 1.0 eq) in 24 toluene (100 mL) were added 279 2-chloro-6-methylaniline (3.8 g, 26.88 mmol, 1 eq) and 91 PCl3 (25 mL). The reaction mixture was allowed to stir at 100 C. for 72 h. Progress of reaction was monitored by LCMS. After consumption of starting material, solvent was removed under reduced pressure, residue was diluted with diethyl ether (100 mL) and MeOH (10 mL) stirred at rt for 10 min then filtered off and dried under vacuum to obtain 280 N-(2-chloro-6-methylphenyl)-4-hydroxy-2-(methylthio)pyrimidine-5-carboxamide (4 g, 48%). (0405) LCMS: 310 [M+1]+
5-bromo-N-(2-chloro-6-methylphenyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
655 mg
In tetrahydrofuran; at 0 - 90℃;
General procedure: Compound 9b (2.16 g, 10 mmol) and thionyl chloride (10 mL) were placed in 30 mL of toluene, and reacted at 110 C for 2 h, then The reaction mixture was concentrated under reduced pressure, and then the remaining solid compound was dissolved in THF (40 mL), 2-chloro-6-methylaniline (3.186 g, 22.6 mmol) was slowly added in an ice bath, and the reaction was held at 90 C for 6 h. After cooling to room temperature, 20 mL of a saturated aqueous solution of potassium carbonate was added, and then the mixture was extracted with EtOAc. Then, it was extracted with EA three times, and the EA layer was combined, washed with brine, dried over anhydrous sodium sulfate and filtered. The crude material was separated and purified by silica gel column chromatography (PE/EA = 8:1) and then recrystallized to afford the compound 10b.
30 mmol of ethyl 3-oxopropionate and 37.5 mmol of sodium methoxide were dissolved in 80 mL of tetrahydrofuran, and stirred at room temperature for 10 min. Then, 27 mmol of <strong>[87-63-8]2-chloro-6-methylaniline</strong> was added, and the mixture was heated to reflux for 1 h. After completion of the reaction, the mixture was cooled to room temperature. The reaction solution was concentrated to remove tetrahydrofuran, and the residue was poured into 100 mL of ice water, and the pH was adjusted to 6-7 with 3N hydrochloric acid, and solids were precipitated, filtered, and the filter cake was iced.The water was washed and dried to give 5.56 g of Compound 3, yield 97.30%, purity 99.94%.
With allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium(II); barium(II) hydroxide; In isopropyl alcohol; at 80℃; for 4h;
Fully dried 200mL three-neck eggplant flask(Condenser with 3-way cock, magnetic stirrer included)2-methyphenylboronic acid7.2 g (47.1 mmol), 5.20 g (36.7 mmol) of 2-chloro-6-methylalanine,1,3-bis- (2,6-diisopropylphenyl) imidazolium- (allyl) -palladium (II) -chloride59.6 mg (0.092 mmol),After adding 12.8 g (40.4 mmol) of barium hydroxide octahydrate and dissolving in 73 mL of isopropyl alcohol,The reaction was carried out at 80 C. for 4 hours. After cooling the reaction solution to room temperature,Remove solid residue by filtration,The solvent was distilled off under reduced pressure to obtain a crude product.Crude product is silica gel column chromatograph(Eluent: hexane / ethyl acetate = 95/5)6.23 g (80%, light brown liquid) was obtained.
Multi-step reaction with 3 steps
1: sodium hydroxide / water / 2 h / 50 °C
2: acetic acid; hydrogenchloride; dihydrogen peroxide / water / 40 - 50 °C
3: hydrogenchloride / water; sulfolane / 26 h / 120 °C
With hydrogenchloride; In sulfolane; water; at 120℃; for 26h;
In a three-necked flask equipped with a stirrer thermometer, 115 g of 2-chloro-4-acetamido-3-methylbenzenesulfonic acid, 434 g of sulfolane and 106 g of concentrated hydrochloric acid were added, and the mixture was heated to 120 C for 26 hours, and the reaction was completed, and cooled to 25 C. Add 575g of water, adjust ph=7 with 30% sodium hydroxide, stratify statically, extract the aqueous phase once with dichloromethane, dry with anhydrous sodium sulfate 20g, suction filtration, add filtrate to 30% hydrochloric acid ethanol (58g), stir 2h, cooling to -5 C for 1h, suction filtration, filter cake added 0.6 times water dilution, add 30% sodium hydroxide to adjust ph = 7 to add 100g of dichloromethane, activated carbon 3g stirred for 0.5h, suction filtration, the filtrate is static Layer, the aqueous phase is extracted once with dichloromethane, combined with dichloromethane, dried over anhydrous sodium sulfate, and the filtrate is firstly pumped at a water temperature of 25-30 C with a first-order Roots pump (Note: high concentration temperature will cause the product to darken), concentrated Then, adjust to the third stage, and measure the GC until the dichloromethane disappears.The wine red liquid was obtained: 37 g, and the product yield was 60%. The test results are shown in Fig. 1, and the product purity was 99.7%.
5-[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-ylamino][1,3,4]oxadiazole-2-carboxylic acid ethyl ester[ No CAS ]
[ 87-63-8 ]
C20H23ClN8O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With trimethylaluminum; In toluene; at 100℃; for 24h;Inert atmosphere;
Add 2c (173.5 mg, 0.5 mmol), <strong>[87-63-8]2-chloro-6-methylaniline</strong> (70.5mg, 0.5mmol),Toluene (5mL) and trimethylaluminum solution (1mL, 1mmol), under the protection of argon,The reaction flask was placed in an oil bath at 100 C. for 24 hours for amidation reaction, and then cooled to room temperature. Methanol (20 mL) was added to the reaction flask, followed by filtration,The filtrate was concentrated under reduced pressure and separated with a silica gel column to obtain the corresponding product 3d (102 mg).White solid, melting point: 260 C, yield 46%, purity 95%.
5-[6-(4-acetylpiperazin-1-yl)-2-methylpyrimidin-4-ylamino][1,3,4]oxadiazole-2-carboxylic acid ethyl ester[ No CAS ]
[ 87-63-8 ]
C21H23ClN8O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With trimethylaluminum; In toluene; at 100℃; for 24h;Inert atmosphere;
Add 2d (187.5mg, 0.5mmol), <strong>[87-63-8]2-chloro-6-methylaniline</strong> (70.5mg, 0.5mmol), toluene (5mL) and trimethylaluminum solution (1mL, 1mmol), under the protection of argon, The reaction flask was placed in an oil bath at 100 C. for 24 hours for amidation reaction, and then cooled to room temperature. Methanol (20 mL) was added to the reaction flask, followed by filtration,The filtrate was concentrated under reduced pressure and separated on a silica gel column to obtain the corresponding product 3f (80 mg).White solid, melting point: 187 C, yield 34%, purity 95%.
5-{6-[4-(2-hydroxy-ethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester[ No CAS ]
[ 87-63-8 ]
C21H25ClN8O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With trimethylaluminum; In toluene; at 100℃; for 24h;Inert atmosphere;
Add 2e (188.5mg, 0.5mmol),2-Chloro-6-methylaniline (70.5mg, 0.5mmol), toluene (5mL) and trimethylaluminum solution (1mL, 1mmol), under the protection of argon,The reaction flask was placed in an oil bath at 100 C. for 24 hours for amidation reaction, and then cooled to room temperature. Methanol (20 mL) was added to the reaction flask, followed by filtration,The filtrate was concentrated under reduced pressure and separated on a silica gel column to obtain the corresponding product 3h (85mg).White solid, melting point: 153 C, yield 36%, purity 95%.
2,4-dichloro-N-(2-chloro-6-methylphenyl)pyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
In tetrahydrofuran; at 20℃;
2,4- dichloropyrimidine-5-carbonyl chloride (100 mg, 0.47 mmol) was dissolved in THF (1 mL). At it, a solution of 2-chloro-6-methylaniline (67 mg, 0.47 mmol) in THF (1 mL) was then added and a white precipitate quickly formed. The mixture was stirred overnight before the solvent was removed and the crude solid purified by silica gel chromatography to obtain the title compound as a white solid (119 mg, 0.38 mmol, 80%). LC/MS: m/z calculated for (0336) [M+H]+ 315.97, found 316.07.
2-chloro-N-(2-chloro-6-methylphenyl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.8%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 80℃; for 0.5h;
General procedure: To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid (n,0.50 g, 1.65 mmol) in EtOAc (10 mL) was added substituted aromaticamine (2.15 mmol). The mixture was heated to 80 C andpropylphosphonic anhydride (T3P, 1.5 g, 4.70 mmol) was add to thesolution. The mixture was stirred for 0.5 h at 80 C. Thereafter, themixture was cooled to room temperature and poured into water, andthe mixture was extracted with EAOAc (25 × 3 mL) and washed withwater(25 × 3 mL) and saturated aqueous solution of NaCl (50 × 3 mL)[29]. The organic layer was concentrated to dryness to afford producto1-o9.
1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-chloro-6-methylphenyl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.5%
With acetic acid; In ethanol; at 80℃; for 3h;
General procedure: To asolution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (e, 1.0 g 3.52 mmol) in ethanol (20 mL) was addedsubstituted aromatic amine (3.52 mmol) and acetic acid (1 drop). Themixture was refluxed for 3 h. Thereafter, the mixture was cooled toroom temperature, the precipitate was formed and filtered, washedwith ethanol and dried under reduced pressure to afford product l1-l14
In N,N-dimethyl acetamide; at 150℃; for 0.0833333h;Microwave irradiation;
General procedure: In a 20mL microwave reaction vial (Biotage), a mixture of substituted 2-halogeno-aniline (1 equiv, 500 mg), O-isopropylxanthic acid potassium salt (PIX) (2 equiv), and DMAC (8 mL) was added. The vial was irradiated at 150 C for 5 min in a Biotage microwave reactor. The mixture was cooled to room temperature. Then it was poured into cold H2O and adjusted to pH 3 by HCl 1N. The precipitate was filtered and washed (5 times) with H2O to afford products without additional purification.
With N-ethyl-N,N-diisopropylamine at -5 - 20℃; for 8h;
3 Preparation of intermediate compound C:
First, add compound B (10mmol, 2.44g) into a 100mL three-necked flask,Then, 2-chloro-6-methylaniline (13mmol, 1.84g) was added dropwise under an ice-salt bath at -5°C,Poly(dichlorophosphazene) (12mmol, 2.53g), N,N-diisopropylethylamine (20mmol, 2.58g).After the dropwise addition was completed, the reaction was carried out at room temperature for 8 hours, monitored by TCL (developing solvent: EA/PE=1:3) until the reaction was completed.After the reaction is completed, the solvent is removed by spinning off, and finally a yellow solid (compound C) is obtained by column chromatography.
2-tert-butylcarbonylaminothiazole-5-carboxylic acid[ No CAS ]
[ 87-63-8 ]
[ 302964-06-3 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: 2-tert-butylcarbonylaminothiazole-5-carboxylic acid With thionyl chloride; N,N-dimethyl-formamide In chlorobenzene at 40℃; for 1h;
Stage #2: 2-chloro-6-methylaniline With pyridine In chlorobenzene at 90 - 100℃;
2.1 (Step 1) Synthesis of 2-tertbutylcarbonylamino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide
2-tertbutylcarbonylamino-aminothiazole-5-carboxylic acid (50g), chlorobenzene (1000ml), DMF (1.5g), and SOCl2 (48g) were added to the reactor, and the temperature of the reactant was heated to 40°C, followed by reaction for 1 hour. When the reaction was completed, the reaction was concentrated under reduced pressure at 55-65° C. so that the total amount of the reaction product was about 250 ml. In another reactor, put 2-chloro-6-methylaniline (24g), chlorobenzene (150ml), and pyridine (81g), heat the reactant to a temperature of 90~100, and slowly add the concentrated reactant over 30 minutes 3 time reacted. When the reaction was completed, the in-situ coupling compound was cooled to 0-5° C. and stirred for 2 hours. After filtering the precipitated solid, the obtained off-white solid was put into a reactor, methanol (250ml) and 10% K2CO3 solution (100ml) were added, followed by stirring at room temperature for 3 hours. Filtration, washing with methanol (50ml) twice, vacuum drying at 45-50 for 10-12 hours, and 2-tertbutylcarbonylamino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5- carboxamide as a white solid (55 g, yield = 73%) was obtained.
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