* 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 Chemical Society, 1932, p. 1806,1809
2
[ 627-01-0 ]
[ 24424-99-5 ]
[ 149794-10-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium carbonate In 1,2-dimethoxyethane; water for 4 h;
2-[(tert-butoxy)-N-ethylcarbonylamino]acetic Acid A solution of di-tert-butyl dicarbonate (2.18 g, 12.5 mmol) in dimethoxyethane (30 mL) was added to a stirred solution of 2-(ethylamino)acetic acid in Na2CO3 (1.04 g, 10 mmol in water, 30 mL). Stirring was continued for 4 h, then the reaction mixture was acidified with hydrochloric acid (1 N, 30 mL) and extracted with ethyl acetate (3.x.30 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-[(tert-butoxy)-N-ethylcarbonylamino]acetic acid as a colorless oil with quantitative yield. 1H NMR (CDCl3), δ 3.95 (m, 2H), 3.30 (m, 2H), 1.45 (m, 9H), 1.12 (t, J=7.2 Hz, 3H).
100%
With sodium carbonate In 1,2-dimethoxyethane; water for 4 h;
A solution of di-tert-butyl dicarbonate (2.18 g, 12.5 mmol) in dimethoxyethane (30 mL) was added to a stirred solution of 2-(ethylamino)acetic acid in Na2CO3 (1.04 g, 10 mmol in water, 30 mL). Stirring was continued for 4 h, then the reaction mixture was acidified with hydrochloric acid (1 N, 30 mL) and extracted with ethyl acetate (3.x.30 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-[(tert-butoxy)-N-ethylcarbonylamino]acetic acid as a colorless oil in quantitative yield. 1H NMR (CDCl3), δ 3.95 (m, 2H), 3.30 (m, 2H), 1.45 (m, 9H), 1.12 (t, J=7.2 Hz, 3H).
Reference:
[1] Patent: US2006/79522, 2006, A1, . Location in patent: Page/Page column 12
[2] Patent: US2006/79524, 2006, A1, . Location in patent: Page/Page column 13
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 3, p. 681 - 695
With sodium carbonate; In 1,2-dimethoxyethane; water; for 4h;
2-[(tert-butoxy)-N-ethylcarbonylamino]acetic Acid A solution of di-tert-butyl dicarbonate (2.18 g, 12.5 mmol) in dimethoxyethane (30 mL) was added to a stirred solution of 2-(ethylamino)acetic acid in Na2CO3 (1.04 g, 10 mmol in water, 30 mL). Stirring was continued for 4 h, then the reaction mixture was acidified with hydrochloric acid (1 N, 30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-[(tert-butoxy)-N-ethylcarbonylamino]acetic acid as a colorless oil with quantitative yield. 1H NMR (CDCl3), delta 3.95 (m, 2H), 3.30 (m, 2H), 1.45 (m, 9H), 1.12 (t, J=7.2 Hz, 3H).
100%
With sodium carbonate; In 1,2-dimethoxyethane; water; for 4h;
A solution of di-tert-butyl dicarbonate (2.18 g, 12.5 mmol) in dimethoxyethane (30 mL) was added to a stirred solution of 2-(ethylamino)acetic acid in Na2CO3 (1.04 g, 10 mmol in water, 30 mL). Stirring was continued for 4 h, then the reaction mixture was acidified with hydrochloric acid (1 N, 30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 2-[(tert-butoxy)-N-ethylcarbonylamino]acetic acid as a colorless oil in quantitative yield. 1H NMR (CDCl3), delta 3.95 (m, 2H), 3.30 (m, 2H), 1.45 (m, 9H), 1.12 (t, J=7.2 Hz, 3H).
1-Ethyl-3-(2-ethyl-6-methylphenyl)-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With triethylamine In chloroform for 18h; Heating;
With triethylamine In hexane; chloroform; ethyl acetate
11 1-Ethyl-3-(2-ethyl-6-methylphenyl)-2-thioxo-imidazolidin-4-one
EXAMPLE 11 1-Ethyl-3-(2-ethyl-6-methylphenyl)-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 10 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20% ethyl acetate in hexane). The title compound was obtained (8.6 g) as a light peach solid, m.p. 82°-84° C. Anal. Calcd. for. C14 H18 N2 OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M.+) m/z 262.
3-(2-chloro-6-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With triethylamine In chloroform for 18h; Heating;
With triethylamine In dichloromethane
27 3-(2-Chloro-6-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 27 3-(2-Chloro-6-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 9.1 g of 2-chloro-6-methylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (5.4 g) as a creamy solid, m.p. 124°-126° C. Anal. Calcd. for. C12 H13 Cl N2 O S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (El, M.+) m/z 268/270.
With triethylamine In dichloromethane
6 3-(2-Chloro-6-methylphenyl)-1 -ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 6 3-(2-Chloro-6-methylphenyl)-1 -ethyl-2-thioxo-imidazolidin-4-one A mixture of the crude N-ethyl glycine (9.2 g), 2-chloro-6-methylphenyl-isothiocyanate (9.1 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3.5 hours. The solvent was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (5.4 g) as a creamy solid, m.p. 124°-126° C. Anal. Calcd. for. C12 H13 Cl N2 O S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (EI, M.+) m/z 268/270.
3-(5-chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With triethylamine In chloroform for 18h; Heating;
With triethylamine In dichloromethane
19 3-(5-Chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 19 3-(5-Chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one A mixture N-ethyl glycine (9.2 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10 g), triethylamine (10.1 g), methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. The residue collected, washed with hot ethanol and dried. Title compound (7.6 g) was obtained as a creamy solid, m.p. 171°-174° C. Anal. Calcd. for. C12 H13 Cl N2 O2 S: C, 50.61; H, 4.60; N, 9.84. Found: C, 50.33; H, 4.50; N, 9.69. Mass spectrum (El, M.+) m/z 284/286.
1-ethyl-3-(2-methylsulfanylphenyl)-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With triethylamine In chloroform for 18h; Heating;
With triethylamine In dichloromethane
58 1-Ethyl-3-(2-methylsulfanylphenyl)-2-thioxo-imidazolidin-4-one
EXAMPLE 58 1-Ethyl-3-(2-methylsulfanylphenyl)-2-thioxo-imidazolidin-4-one A mixture of N-ethyl glycine (9.23 g), 2-(methylthio)-phenyl-isothiocyanate (9.1 g), triethylamine (10.1 g) and methylene chloride (150 mL) was heated at reflux for 3 hours. The mixture was evaporated to dryness. The residue was recrystallized from ethanol to give the title compound (6.5 g) as a creamy solid, m.p. 128°-131° C. Anal. Calcd. for. C12 H14 N2 S2 O: C, 52.11; H, 5.30; N, 10.52. Found: C, 52.28; H, 5.26; N, 10.54. Mass spectrum (EI, M.+) m/z 266.
With triethylamine In dichloromethane
12 1-Ethyl-3-(2-methylsulfanylphenyl)-2-thioxo-imidazolidin-4-one
EXAMPLE 12 1-Ethyl-3-(2-methylsulfanylphenyl)-2-thioxo-imidazolidin-4-one A mixture of N-ethyl glycine (9.23 g), 2-(methylthio)-phenyl-isothiocyanate (9.1 g), triethylamine (10.1 g) and methylene chloride (150 mL) was heated at reflux for 3 hours. The mixture was evaporated to dryness. The residue was recrystallized from ethanol to give the title compound (6.5 g) as a creamy solid, m.p. 128°-131° C. Anal. Calcd. for. C12 H14 N2 S2 O: C, 52.11; H, 5.30; N, 10.52. Found: C, 52.28; H, 5.26; N, 10.54. Mass spectrum (EI, M.+) m/z 266.
1-ethyl-3-(5-fluoro-2-methylphenyl)-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In diethyl ether; ethanol; chloroform; ethyl acetate;
EXAMPLE 28 1-Ethyl-3-(5-fluoro-2-methylphenyl)-2-thioxo-imidazolidin-4-one A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenylisothiocyanate (10.42 g), triethylamine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98-100 C. Anal. Calcd. for. C12 H13 F N2 O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252.
With triethylamine; In diethyl ether; ethanol; chloroform; ethyl acetate;
EXAMPLE 7 1-Ethyl-3-(5-fluoro-2-methylphenyl)-2-thioxo-imidazolidin-4-one A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenyl-isothiocyanate (10.42 g), triethyl amine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98-100 C. Anal. Calcd. for. C12 H13 F N2 O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252.
3-(2,6-dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With triethylamine In chloroform for 18h; Heating;
With triethylamine In dichloromethane
21 3-(2.6-Dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 21 3-(2.6-Dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-dimethylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128°-131° C. Anal. Calcd. for. C13 H16 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
3-(2,6-Dichlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine In chloroform for 18h; Heating;
With triethylamine In chloroform
17 3-(2,6-Dichlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 17 3-(2,6-Dichlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 16 using 10.2 g of 2,6-dichlorophenyl-isothiocyanate, 7.4 g of N-ethyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The title compound (6.5 g) was obtained as a tan solid, m.p. 170°-172° C. Anal. Calcd. for. C11 H10 C12 N2 O S: C, 45.69; H, 3.48; N, 9.69. Found: C, 45.53; H, 3.19; N, 9.62. Mass spectrum (El, M.+) m/z 288/290/292.
3-(2,6-dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane
7 3-(2,6-Dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 7 3-(2,6-Dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one 2-Chloro acetic acid (27.5 g) was added portionwise while stirring to a 70% aqueous ethyl amine solution (500 mL). The addition was carried over a period of 30 minutes. The mixture was stirred at ambient temperature for 18 hours. The mixture was then evaporated to a viscous oily residue (55 g). The crude product consisted of a 1:1 mixture of N-ethyl glycine and ethyl amine hydrochloride. This product mixture was used in the next paragraph without further purification. A mixture of N-ethyl glycine (9.2 g), 2,6-dimethylphenyl-isothiocyanate (8.2 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128°-131° C. Anal. Calcd. for. C13 H16 N2 OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
1-ethyl-3-(4-fluorobenzyl)-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane
22 1-Ethyl-3-(4-fluorobenzyl)-2-thioxo-imidazolidin-4-one
EXAMPLE 22 1-Ethyl-3-(4-fluorobenzyl)-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Title compound (4.85 g) was obtained as a white solid, m.p. 73°-76° C. Anal. Calcd. for. C12 H13 F N2 O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H,5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
With triethylamine In dichloromethane
6 1-Ethyl-3-(4-fluorobenzyl)-2-thioxo-imidazolidin-4-one
EXAMPLE 6 1-Ethyl-3-(4-fluorobenzyl)-2-thioxo-imidazolidin-4-one The title compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Title compound (4.85 g) was obtained as a white solid, m.p. 73°-76° C. Anal. Calcd. for. C12 H13 F N2 O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H,5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
3-(5-chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane
4 3-(5-Chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one
EXAMPLE 4 3-(5-Chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one 2-Chloro acetic acid (27.5 g) was added portionwise while stirring to a 70% aqueous ethyl amine solution (500 mL). The addition was carried over a period of 30 minutes. The mixture was stirred at ambient temperature for 18 hours. The mixture was then evaporated to a viscous oily residue (55 g). The crude product consisted of a 1:1 mixture of N-ethyl glycine and ethyl amine hydrochloride. This product mixture was used without further purification. A mixture N-ethyl glycine (9.2 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10 g), triethylamine (10.1 g), methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. The residue collected, washed with hot ethanol and dried. Title compound (7.6 g) was obtained as a creamy solid, m.p. 171°-174° C. Anal. Calcd. for. C12 H13 Cl N2 O2 S: C, 50.61; H, 4.60; N, 9.84. Found: C, 50.33; H, 4.50; N, 9.69. Mass spectrum (EI, M.+) m/z 284/286.
General procedure: 6-Methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (20.8 g, 108 mmol) was suspended in DMSO (55 mL). The mixture was then placed on a preheated mantle (157 C). The mixture was stirred until dissolved. Sarcosine (32.0 g, 108 mmol) was added portionwise. Almost immediately effervescence was observed. The mixture was heated for 2 h then cooled to ca. 70 C then poured into water (300 mL). A suspension of a white powder formed which was collected by filtration and dried in vacuo (13.9 g, 59%).