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Structure of 10191-60-3 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With potassium hydroxide In water at 20℃; for 0.75 h; Stage #2: at 40℃; for 2 h; Stage #3: at 20℃;
Dimethyl cyanodithioimidocarbonate was obtained according to the publishedmethod in literature. Cyanamide (0.02 mol;50percent aqueous solution) was dissolved of water in 80 mL. Potassium hydroxide (0.04 mol) was added and the solution was stirred for 45 min at room temperature. Carbon disulfide wasadded. The reaction was heated at 40°C. When all carbon disulfide was dissolved (2 h is required), methyl iodide (0.04 mol)was added and the reaction was stirred at room temperature overnight. The precipitate was filtered and the solid was washed with water, dried at room temperature under vacuum until constant weight, and purified by recrystallization in EtOH. Dimethyl cyanodithioimidocarbonate (1c) Yield: 71percent. M.p. = 58–60°C. IR (FT-IR 200 V, ν (cm−1)): 1678,2176 cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 2.90 ppm (s,6H, 2 × SCH3). 13C NMR (75 MHz, CDCl3) δ: 18.8, 115.3, and 186.8 ppm.
Reference：
[1] Tetrahedron, 2008, vol. 64, # 39, p. 9309 - 9314
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 5, p. 759 - 764
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2309 - 2314
[4] Synthetic Communications, 2004, vol. 34, # 5, p. 805 - 815
[5] Synthetic Communications, 2006, vol. 36, # 6, p. 743 - 753
[6] Bulletin of the Chemical Society of Japan, 2005, vol. 78, # 5, p. 873 - 876
[7] Nucleosides, Nucleotides and Nucleic Acids, 2017, vol. 36, # 3, p. 213 - 223
2
[ 13145-41-0 ]
[ 77-78-1 ]
[ 10191-60-3 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 20℃;
To a mixture of potassium cyanocarbonimidodithioate (19.4 g, 0.1 mmol) in 100 mL of methanol and 150 mL of water was added dropwise dimethyl sulfate (15.1 g, 0.12 mol). The mixture was left to stand overnight at rt. The precipitate was separated and recrystallized from IPA-isopropyether to give dimethyl cyanocarbonimidodithioate (H g, 75percent).
Reference：
[1] Patent: WO2007/70201, 2007, A1, . Location in patent: Example 15
[2] Arzneimittel-Forschung/Drug Research, 1984, vol. 34, # 7, p. 751 - 754
3
[ 74-87-3 ]
[ 35042-86-5 ]
[ 10191-60-3 ]
Reference：
[1] Organic Preparations and Procedures International, 1998, vol. 30, # 4, p. 473 - 476
4
[ 74-87-3 ]
[ 108-04-3 ]
[ 10191-60-3 ]
Reference：
[1] Organic Preparations and Procedures International, 1998, vol. 30, # 4, p. 473 - 476
5
[ 10191-61-4 ]
[ 74-88-4 ]
[ 10191-60-3 ]
Reference：
[1] Journal of Organic Chemistry, 1967, vol. 32, p. 1566 - 1572
6
[ 108-04-3 ]
[ 74-88-4 ]
[ 10191-60-3 ]
Reference：
[1] Asian Journal of Chemistry, 2013, vol. 25, # 16, p. 9233 - 9236
With sodium carbonate In water at 10 - 20℃; for 2 h;
Example 1Into a solution of 26.5 g of sodium carbonate in 150 ml of water are metered, at room temperature, 28.8 g of cysteamine hydrochloride. The reaction mixture is cooled to 100C and 37.1 g of dimethyl N-cyanocarbonimidodithiocarbonate are metered in. After the end of the metered addition, the mixture is stirred at 1O0C for a further 2 hours and then heated to 200C. At 200C, 37 g of 20percent hydrochloric acid are added dropwise. The mixture is then filtered and the solids are washed with 100 ml of water. After drying under reduced pressure, 30.3 g of cyanimino-l,3-thiazolidine are obtained (corresponds to a yield of 94.7percent).Example 2Into a solution of 26.5 g of sodium carbonate in 150 ml of water are metered, at room temperature, 28.8 g of cysteamine hydrochloride. The reaction mixture is cooled to 100C and 37.1 g of dimethyl N-cyanocarbonimidodithiocarbonate are metered in. After the end of the metered addition, the mixture is stirred at 1O0C for a further 2 hours and then heated to 200C. The mixture is subsequently filtered and the solids are washed with 2 x 100 ml of water. After drying under reduced pressure, 29.8 g of cyanimino-l,3-thiazolidine are obtained (corresponds to a yield of 93 percent).
92%
With sodium hydrogencarbonate In water at 10 - 20℃; for 3 h;
Example 3Into a solution of 23.8 g of sodium hydrogencarbonate in 200 ml of water are metered, at room temperature, 28.8 g of cysteamine hydrochloride. The reaction mixture is cooled to 100C and 37.1 g of dimethyl N-cyanocarbonimidodithiocarbonate are metered in. After the end of the metered addition, the mixture is stirred at 100C for a further 3 hours and then heated to 200C. The mixture is then filtered and the solids are washed with 100 ml of water. After drying under reduced pressure, 29.4 g of cyanimino-l,3-thiazolidine are obtained (corresponds to a yield of 92percent).
87.5%
With sodium hydroxide In water at 0 - 10℃; for 0.666667 h;
Add 300 ml of water to the three-necked bottle, then add 16.4 g of sodium hydroxide, stir and dissolve,Cool down to below 10 °C,Rapid addition of cysteamine hydrochloride 56g (0.50 mol),After stirring and dissolving,The temperature was lowered to 0 to 5 ° C, and then a compound HRB-1365-0 (cyanimide dimethyl ester molecular formula: C4H6N2S2) 61 g (0.41 mol) was added, and after stirring for 40 minutes, the reaction was completed and filtered.The filter cake was washed with 200 ml of water, the filter cake was white solid, and the wet product was 57 g.Drying under reduced pressure at 60-65 ° C gave a white crystalline solid 46 g.That is, the compound HRB-1365-2 (2-cyanoimido-1,3-thiazolidine molecular formula: C4H5N3S),The yield was 87.5percent, and the HPLC (High Performance Liquid Chromatograph) content was ≥99percent.
85.8%
Stage #1: With sodium methylate In methanolInert atmosphere Stage #2: at 0 - 5℃; Inert atmosphere Stage #3: With hydrogenchloride In methanol; water at 20 - 40℃; Inert atmosphere
EXAMPLE 3; A 1 litre four-necked flask provided with a thermometer and stirrer is charged with 9Og of methanol (2.815 moles) and 36g of sodium methoxide (0.667 moles, 1.3 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in <n="16"/>methanol, then 63.5g of 2-aminoethane thiol hydrochloride (0.564 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0° C and 75g of dimethyl N-cyanoiminodithiocarbonate (0.514 moles) is added keeping the inside temperature at 5° C or less. After the end of addition, the mixture is allowed to react at 0 to 5° C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20° C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36percent w/w), then further heated to 40° C and stirred for 2 hours. After stirring, the reaction mixture is cooled to 0° C and the crystals are suction filtered and the slurry thus obtained is washed with 225ml of chilled water to obtain 66g of 2-cyanoimino-l, 3-thiazolidine. The wet crystals are dried in vacuo at 80° C under reduced pressure for 5 hours to obtain 58g of 2-cyanoimino-l, 3-thiazolidine (yield 85.8percent) with 99.9percent HPLC purity.
81.6%
Stage #1: With sodium hydroxide In water Stage #2: for 2 h; Stage #3: With hydrogenchloride In water at 20 - 40℃; for 2 h;
Example 1 A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 11.2 g of 99percent by weight sodium hydroxide (0.28 mole, 1.12 moles based upon 1 mole of 2-aminoethane thiol hydrochloride) was added while cooling and agitating to be dissolved in the water, then 28.8 g of 99.5percent by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein, then the reaction mixture was cooled to 0°C. To this reaction mixture, 36.9 g of 99.5percent by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was added so that the temperature inside the system became 5°C or less.. After the end of addition, the mixture was allowed to react at 0 to 5°C for 2 hours. Thereafter, the reaction mixture was heated to 20°C, adjusted in PH to 4.0 with 36percent by weight aqueous hydrochloric acid solution, then further heated to 40°C and allowed to age for 2 hours. After aging, the reaction mixture was cooled to 20°C, then the crystals were suction filtered and washed with 100 g of water (5.6 moles) to obtain 36.6 g of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 84°C under 6.7 x 10-4 MPa for 5 hours to obtain 28.6 g of 99.7percent purity 2-cyanoimino-1,3-thiazolidine (yield 89.8percent = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester). Note that the purity was analyzed by means of high pressure liquid chromatography (HPLC). Example 2; A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 12.3 g of 99percent by weight sodium hydroxide (0.31 mole, 1.24 moles based upon 1 mole of 2-aminoethane thiol hydrochloride) was added, while cooling and agitating to be dissolved in the water, then 28.8 g of 99.5percent by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein. Thereafter, the reaction mixture was cooled to 0°C., then 36.9 g of 99.5percent by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added so that the temperature inside the system became 5°C or less. After the end of addition, the mixture was allowed to react for further 2 hours. Next, the reaction mixture was heated to 20°C, adjusted in pH to 3.9 with 4.56 g (0.045 mole) of 36percent by weight aqueous hydrochloric acid solution, then further heated to 40°C and allowed to age for 2 hours. After aging, the reaction mixture was cooled to 20°C, then suction filtered and washed with 200 g of water (11.1 moles) to obtain 34.7 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals obtained above, were dried in vacuo at 80°C under 6.7 x 10-4 MPa for 5 hours to obtain 27.9 g of 100percent purity 2-cyanoimino-1,3-thiazolidine (yield 87.9percent = value converted to purity, based on charged dimethyl N-cyanoiminodithiocarbonate ester). Further, the total weight of the filtrate combined with the washings was 371.5 g. The filtrate included 0.98percent of 2-cyanoiminothiazolidine (value converted to yield: 11.5percent). Example 3; A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 10.6 g of 99percent by weight sodium hydroxide (0.26 mole, 1.04 moles based upon 1 mole of 2-aminoethane thiol hydrochloride) was added, while cooling and agitating to be dissolved in the water, then 28.8 g of 99.5percent by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein. Thereafter, the reaction mixture was cooled to 0°C, then 36.9 g of 99.5percent by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added so that the temperature inside the system became 5°C or less, then was allowed to react for 2 hours. Next, the reaction mixture was heated to 20°C, adjusted in pH to 9.2 with 0.25 g of 36percent by weight aqueous hydrochloric acid solution (0.0025 mole), then further heated to 40°C and allowed to age for 2 hours. After aging, the reaction mixture was cooled to 20°C, then suction filtered and washed with 200 g of water (11.1 moles) to obtain 36.33 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 80°C under 6.7 x 10-4 MPa for 5 hours to obtain 27.2 g of 95.2percent purity 2-cyanoimino-1,3-thiazolidine (yield 81.6percent = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester). Further, the total weight of the filtrate combined with the washings was 361.5 g. The filtrate included 0.95percent of 2-cyanoiminothiazolidine (value converted to yield: 10.8percent).
59.4%
Stage #1: With sodium hydroxide In water Stage #2: for 2 h; Stage #3: With hydrogenchloride In water
Comparative Example 2 A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 114 g of water (6.3 moles), then 20.9 g of 99percent by weight sodium hydroxide (0.50 mole) was added, while cooling and agitating, to be dissolved therein, then 28.8 g of 99.5percent by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein.. Then, the reaction mixture was cooled to 0°C, then 36.9 g of 99.5percent by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added, while holding the temperature to 5°C or less, then the mixture was allowed to react for 2 hours. Next, 30.9 g of 36percent by weight aqueous hydrochloric acid solution (0.29 mole) was added to try to adjust the PH, but the mixture violently started bubbling at around PH 9.0 and finally the PH became 9.5.. Next, the reaction mixture was suction filtered and washed with 200 g of water (11.1 moles) to obtain 28.6 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 80°C under 6.7 x 10-4 MPa for 5 hours to obtain 18.9 g of 100percent purity 2-cyanoimino-1,3-thiazolidine (yield 59.4percent = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester). Comparative Example 3; A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 20.9 g of 99percent by weight sodium hydroxide (0.50 mole) was added, while cooling and agitating, to be dissolved, then 28.8 g of 99.5percent by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein. Thereafter, the reaction mixture was cooled to 0°C, then 36.9 g of 99.5percent by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added, while holding the temperature to 5°C or less, the mixture was then allowed to react for 2 hours. Next, 31.7 g of 36percent by weight aqueous hydrochloric acid solution (0.31 mole) was added to try to adjust the pH, but the mixture violently started bubbling at around pH 9.0 and finally the pH became 1.7. Next, the reaction mixture was suction filtered and washed with 200 g of water (11.1 moles) to obtain 34.8 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 80°C under 6.7 x 10-4 MPa for 5 hours to obtain 20.7 g of 100percent purity 2-cyanoimino-1,3-thiazolidine (yield 65.2percent = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester).
47.7%
Stage #1: With sodium hydroxide In water Stage #2: for 3 h; Heating / reflux
Comparative Example 1 A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 100 g of water (5.6 moles), then 10.1 g of 99percent by weight sodium hydroxide (0.25 mole) was added, while cooling and agitating to dissolve it.. Next, 28.8 g of 99.5percent by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein, then 36.9 g of dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was added and the mixture was heated and refluxed under agitation for 3 hours.. After the end of the reaction, the reaction mixture was cooled to room temperature, then the crystals were suction filtered and washed with methanol and dried in vacuo at 80°C under 6.7 x 10-4MPa for 5 hours to obtain 15.2 g of 99.7percent purity 2-cyanoimino-1,3-thiazolidine (yield 47.7percent = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester).
Reference Example 1 To 500 ml of ethanol 146.24 g of dimethyl N-cyanoiminodithiocarbonate ester (1 mole) and 77.15 g of 2-aminoethane thiol (1 mole) were added.. The mixture was heated and refluxed under agitation for 3 hours.. After the end of the reaction, the mixture was cooled to room temperature, then the precipitated crystals were filtered.. The crystals thus obtained were washed with ethanol, then dried to obtain 85.25 g of the above compound. (If making the purity of the above product 100percent, the yield of the N-cyanoiminothiazolidine becomes 67.1percent.)
Reference：
[1] Patent: WO2018/157800, 2018, A1, . Location in patent: Paragraph 0997-0999
[2] Patent: EP1460068, 2004, A1, . Location in patent: Page 5
[3] Archiv der Pharmazie, 1972, vol. 305, # 10, p. 731 - 737
13
[ 623-51-8 ]
[ 10191-60-3 ]
[ 39736-29-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With diisopropylamine In N,N-dimethyl-formamide at 100℃; for 5 h;
The synthesis of ethyl 4-amino-2-(methylthio)thiazole-5-carboxylate Ethyl 2-mercaptoacetate (50 g, 0.416 mol) was dissolved in 500 ml of dimethylformamide and added with dimethyl N-thienodithioimino carbonate (67 g, 0.416 mol) and diisopropylamine (112 ml, 0.624 mol). After heating at 100° C. for 5 hours, the mixture was extracted with 500 ml of saturated ammonium chloride and 500 ml of ethylacetate, dried with sodium sulfate, filtered and concentrated under vacuum. After washing the solid with n-hexane, the title compound (90 g, 99percent) was obtained. 1H-NMR (400 MHz, CDCl3); δ 5.84 (brs, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LC-MS 219 (MH+)
89%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃;
Ethyl 2-mercaptoacetate (5 g, 42 mmol, 1.0 eq) was dissolved in DMF (50 mL) and added with N-thienodi-thioimino carbonate (6.1 g, 42 mmol, 1.0 eq) and DIPEA (16.3 g, 126 mmol, 3.0 eq). After heating at 100 °C for 5 h, the mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (100 mLx2). The combined organic layer was washed with brine, dried, concentrated. The solid was washed with n-hexane and dried under vacuum to give the title compound (8 g, yield: 89percent) as a yellow solid. ESI-MS (M+H)+: 219.0.
Reference：
[1] Advanced Synthesis and Catalysis, 1997, vol. 339, # 8, p. 750 - 753
15
[ 109-01-3 ]
[ 10191-60-3 ]
[ 89292-91-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: at 70℃; for 2 h; Stage #2: With hydrazine hydrate In acetonitrile at 70℃; for 5 h;
General procedure: A solution of N-cyanocarbonimidodithioic acid dimethyl ester (17.4mmol), acetonitrile (10mL), and appropriate amine (17.4mmol) was refluxed for 2h. After cooling to room temperature, hydrazine monohydrate (25.6mmol) was added and the reaction mixture was further refluxed for additional 5h. The solvent was evaporated under reduced pressure and the resulting product recrystallized from ethyl acetate. Following general procedure B, compound 11k was isolated as a pale yellow solid. Yield 80percent, mp=103–104°C. 1H NMR (200MHz, DMSO-d6) δ: 10.95 (br s, 1H); 5.72 (br s, 2H); 3.16–3.11 (m, 4H); 2.34–2.29 (m, 4H); 2.17 (s, 3H)
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 11 - 27
16
[ 10191-60-3 ]
[ 765-30-0 ]
[ 109-77-3 ]
[ 112636-83-6 ]
Yield
Reaction Conditions
Operation in experiment
80 g
Stage #1: With sodium methylate In methanol at 0 - 5℃; for 0.5 h; Stage #2: at 0 - 5℃; for 12 h;
In the first step, the condensation reaction was carried out. Into a 2L four-necked flask was added 270 g of 500 g of anhydrous methanol and sodium methoxide in methanol. Cool the ice water bath, cool to 0-5°C, add 72.8g malononitrile, stir for 30 minutes, keep the temperature at 0-5°C,In batchwise addition of 146.5 g of N-cyanoimino-S,S-dithiocarbonate dimethyl carbonate, the reaction was stirred at 0-5° C. for 12 h, and the reaction was completed and filtered. The filter cake was washed with 100 mL of cold anhydrous methanol and pumped dry. After being used directly for the next reaction without drying;In the second step, the cyclization reaction, the above wet product was dissolved in 860 g of water and added to a four-necked bottle.After stirring and dissolving, the ice water bath is cooled to 0-5°C, and 1200g of industrial hydrochloric acid is added dropwise. It takes about 4-5 hours to complete the addition.Stir at 0-5 ° C overnight, after the reaction is complete, filter, filter cake washed, washed twice with 10percent sodium carbonate, dried, dried in an oven to obtain dried product 157g; In the third step, the cyclopropylation reaction was carried out. In the 2L four-necked bottle, 3157 g of the product in the second step, 1000 g of ethanol and 66.7 g of cyclopropylamine were added, stirred, and the mixture was heated to reflux. The reaction was completed overnight and the reaction was cooled to 0-5. °C, filtration, filter cake washed, drained, dried in an oven to obtain dry product 147g;The fourth step, the oxidation reaction, in the 5L four-necked flask is added to the product of the fourth step 4147g, acetic acid 810g, sodium tungstate 5.5g, heated to 50 ~ 55 °C, while stirring with hydrogen peroxide 230g, plus complete in 50-55 °C reaction 4h, the reaction is complete, recovery of acetic acid under reduced pressure, the residue was added water 800g, cooled to below 10 °C, filtered, the filter cake was washed with water to pH 5-6, drained and used directly in the next reaction without drying;The fifth step, the ammoniation reaction, in the 5L four-necked flask, the fourth step product, ethanol 610g and ammonia water 1450g, 20-25 ° C under stirring for 5h, the reaction is complete, cooled to 5-10 ° C, filtration, filter cake washed, Dry in an oven to obtain 88g of dry product. Dissolve 88g of dry product in 560mL of NN-dimethylamide.Heated to 90 ° C, dissolved, added powdered activated carbon 5g, stirred for 10 minutes, filtered, cooled and placed in the refrigerator overnight, the next day, filtered, filter cake washed with deionized water, drained, dried in an oven, white Powder is 80g.
Reference：
[1] Patent: CN107698519, 2018, A, . Location in patent: Paragraph 0008
With diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 5h;
The synthesis of ethyl 4-amino-2-(methylthio)thiazole-5-carboxylate Ethyl 2-mercaptoacetate (50 g, 0.416 mol) was dissolved in 500 ml of dimethylformamide and added with dimethyl N-thienodithioimino carbonate (67 g, 0.416 mol) and diisopropylamine (112 ml, 0.624 mol). After heating at 100 C. for 5 hours, the mixture was extracted with 500 ml of saturated ammonium chloride and 500 ml of ethylacetate, dried with sodium sulfate, filtered and concentrated under vacuum. After washing the solid with n-hexane, the title compound (90 g, 99%) was obtained. 1H-NMR (400 MHz, CDCl3); delta 5.84 (brs, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LC-MS 219 (MH+)
89%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃;
Ethyl 2-mercaptoacetate (5 g, 42 mmol, 1.0 eq) was dissolved in DMF (50 mL) and added with N-thienodi-thioimino carbonate (6.1 g, 42 mmol, 1.0 eq) and DIPEA (16.3 g, 126 mmol, 3.0 eq). After heating at 100 C for 5 h, the mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (100 mLx2). The combined organic layer was washed with brine, dried, concentrated. The solid was washed with n-hexane and dried under vacuum to give the title compound (8 g, yield: 89%) as a yellow solid. ESI-MS (M+H)+: 219.0.
With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;
General p Oroced "ure for the sy onthesi -s of Ul To a stirred solution of ethyl 2-mercaptoacetate (0.82 g, 6.80 mol)in N,N- dimethylformamide(8.5 mL)were added triethylamine (1.5 mL, 10.0 mmol) and dimethyl cyanocarbonimidodithioate (1.0 g, 6.80 mol)and the mixture was stirred at 100 Cfor 2 h. The reaction mixture was cooled to room temperature, diluted with EtO Ac (30 mL) and washed with water (30 mL). The organic layer was dried over MgS04 and concentrated invacuomd the resulting crude residue was purified by flash column chromatography (n- hexane:EtOAc = 20: 1) to give U1.1H NMR (400MHz, acetone-^) delta 6.56 (brs, 2H), 4.19 (q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 1.27 (t, J= 7.2 Hz, 3H).
General Synthetic Route for Methyl N-Substituted-N′-Cyanocarbamimidothioate Compounds
General procedure: Arylamines or alkylamines (4.78 mmol) in ethanol (8 mL) was dropwise added to a stirred solution of dimethyl N-cyanodithioiminocarbonate (0.438 g, 3.00 mmol) in ethanol (15 mL). Then the mixture was heated at 40-45 °C for 4-5 h and then cooled to 0 °C. The precipitate was isolated by suction filtration and washed by cool ethanol and diethyl ether sequentially to give the corresponding products. White solid, yield: 0.501 g (87.3%), 1H NMR (400 MHz, DMSOd6): δ (ppm) 7.38-7.17 (m, 5H, Ph), 2.64 (s, 3H, SCH3),1.88(s, 1H, NH). IR (KBr disc, cm-1): 3223, 2183, 2160, 1519.
78%
In ethanol for 3h; Heating;
4; 12 Synthesis of methyl N-cyano-N'-phenylimidothiocarbamate (Used as Intermediate)
Aniline (0.093 mol) was added to a solution of dimethylcyanodithioimidocarbonate (0.146 mol) dissolved in 250 mL of ethanol (99.9%). The suspension was heated for 3 hours. The reaction was allowed to reach room temperature and the resulting precipitate was removed by filtration. The solid was washed with cooled ethanol and dried under vacuum to afford the product. Yield: 78% 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.46-7.24 (m, 5H), 2.47 (s, 3H) MS m/z 192.05 (M+H)
78%
In ethanol for 3h; Heating;
4
Example 4: Synthesis of methyl N-cyano-iV'-phenylimidothiocarbamate (used as intermediate) Aniline (0.093 mol) was added to a solution of dimethylcyanodithioirnidocarbonate (0.146 mol) dissolved in 250 mL of ethanol (99.9%). The suspension was heated for 3 hours. The reaction was allowed to reach room temperature and the resulting precipitate was removed by filtration. The solid was washed with cooled ethanol and dried under vacuum to afford20 the product. Yield: 78%1H NMR (400 MHz, CDQ) δ 7.91 (s, IH), 7.46-7.24 (m, 5H), 2.47 (s, 3H) MS m/z 192.05 (M+H)
64%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 5℃; for 6h;
46%
In isopropanol Reflux;
In ethanol
In ethanol Heating;
In lithium hydroxide monohydrate; propan-2-one at 20℃;
In methanol for 3h; Reflux;
In isopropanol Reflux;
Synthesis of 3-(N-arylamino)-5-amino-1H-1,2,4-triazoles 1b-1e (general procedure).
General procedure: Appropriateaniline (0.1 mol) was added to 0.1 mol of S,S-dimethylcyanodithioimidocarbamate. The mixture was refl uxedfor 3-4 h in isopropyl alcohol. After the amine conversionwas complete, 0.2 mol of hydrazine hydrate was added,and the mixture was refl uxed for 1 h. The precipitatewas fi ltered off and washed with hot isopropanol.
Reference Example 1 To 500 ml of ethanol 146.24 g of dimethyl N-cyanoiminodithiocarbonate ester (1 mole) and 77.15 g of 2-aminoethane thiol (1 mole) were added.. The mixture was heated and refluxed under agitation for 3 hours.. After the end of the reaction, the mixture was cooled to room temperature, then the precipitated crystals were filtered.. The crystals thus obtained were washed with ethanol, then dried to obtain 85.25 g of the above compound. (If making the purity of the above product 100%, the yield of the N-cyanoiminothiazolidine becomes 67.1%.)
III 3-Amino-1-methyl-5-methylthio-1H-1,2,4-triazole
EXAMPLE III 3-Amino-1-methyl-5-methylthio-1H-1,2,4-triazole At 0°, 6.5 grams of methyl hydrazine was added dropwise to a stirred suspension of 20.0 grams (0.137 mole) dimethyl cyanodithioimidocarbonate in 35 ml of acetonitrile. A yellow solution immediately formed after the addition followed by precipitation of a white solid. The ice bath was removed, and upon warming to room temperature a yellow solution formed which was stirred at room temperature overnight. After stirring overnight, a solid precipitated which was filtered, washed with cold acetonitrile, followed by 1-chlorobutane, yield 8.5 grams, m.p. 104°-109°.
340 g
In ethanol at 5 - 24℃; for 23h; Inert atmosphere;
3
After the reactor was purged with nitrogen, 1000 ml of ethanol and 378 g of Dimethyl N-cyanodithioiminocarbonate were added, stirred and stirr ed, and then allowed to warm to room temperature. After stirring at 5 ° C, 310 g (40%) of methylhydrazine The reaction was allowed to cool at 24 ° C for 23 hours. The reaction was cooled to 9 ° C. The filter was washed with water and dried to give an off-white solid 340 g, and the liquid content was 99.0%.
With sodium carbonate; In water; at 10 - 20℃; for 2h;Product distribution / selectivity;
Example 1Into a solution of 26.5 g of sodium carbonate in 150 ml of water are metered, at room temperature, 28.8 g of cysteamine hydrochloride. The reaction mixture is cooled to 100C and 37.1 g of dimethyl N-cyanocarbonimidodithiocarbonate are metered in. After the end of the metered addition, the mixture is stirred at 1O0C for a further 2 hours and then heated to 200C. At 200C, 37 g of 20% hydrochloric acid are added dropwise. The mixture is then filtered and the solids are washed with 100 ml of water. After drying under reduced pressure, 30.3 g of cyanimino-l,3-thiazolidine are obtained (corresponds to a yield of 94.7%).Example 2Into a solution of 26.5 g of sodium carbonate in 150 ml of water are metered, at room temperature, 28.8 g of cysteamine hydrochloride. The reaction mixture is cooled to 100C and 37.1 g of dimethyl N-cyanocarbonimidodithiocarbonate are metered in. After the end of the metered addition, the mixture is stirred at 1O0C for a further 2 hours and then heated to 200C. The mixture is subsequently filtered and the solids are washed with 2 x 100 ml of water. After drying under reduced pressure, 29.8 g of cyanimino-l,3-thiazolidine are obtained (corresponds to a yield of 93 %).
92%
With sodium hydrogencarbonate; In water; at 10 - 20℃; for 3h;Product distribution / selectivity;
Example 3Into a solution of 23.8 g of sodium hydrogencarbonate in 200 ml of water are metered, at room temperature, 28.8 g of cysteamine hydrochloride. The reaction mixture is cooled to 100C and 37.1 g of dimethyl N-cyanocarbonimidodithiocarbonate are metered in. After the end of the metered addition, the mixture is stirred at 100C for a further 3 hours and then heated to 200C. The mixture is then filtered and the solids are washed with 100 ml of water. After drying under reduced pressure, 29.4 g of cyanimino-l,3-thiazolidine are obtained (corresponds to a yield of 92%).
87.5%
With sodium hydroxide; In water; at 0 - 10℃; for 0.666667h;
Add 300 ml of water to the three-necked bottle, then add 16.4 g of sodium hydroxide, stir and dissolve,Cool down to below 10 C,Rapid addition of cysteamine hydrochloride 56g (0.50 mol),After stirring and dissolving,The temperature was lowered to 0 to 5 C, and then a compound HRB-1365-0 (cyanimide dimethyl ester molecular formula: C4H6N2S2) 61 g (0.41 mol) was added, and after stirring for 40 minutes, the reaction was completed and filtered.The filter cake was washed with 200 ml of water, the filter cake was white solid, and the wet product was 57 g.Drying under reduced pressure at 60-65 C gave a white crystalline solid 46 g.That is, the compound HRB-1365-2 (2-cyanoimido-1,3-thiazolidine molecular formula: C4H5N3S),The yield was 87.5%, and the HPLC (High Performance Liquid Chromatograph) content was ?99%.
85.8%
EXAMPLE 3; A 1 litre four-necked flask provided with a thermometer and stirrer is charged with 9Og of methanol (2.815 moles) and 36g of sodium methoxide (0.667 moles, 1.3 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in <n="16"/>methanol, then 63.5g of 2-aminoethane thiol hydrochloride (0.564 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0 C and 75g of dimethyl N-cyanoiminodithiocarbonate (0.514 moles) is added keeping the inside temperature at 5 C or less. After the end of addition, the mixture is allowed to react at 0 to 5 C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20 C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36% w/w), then further heated to 40 C and stirred for 2 hours. After stirring, the reaction mixture is cooled to 0 C and the crystals are suction filtered and the slurry thus obtained is washed with 225ml of chilled water to obtain 66g of 2-cyanoimino-l, 3-thiazolidine. The wet crystals are dried in vacuo at 80 C under reduced pressure for 5 hours to obtain 58g of 2-cyanoimino-l, 3-thiazolidine (yield 85.8%) with 99.9% HPLC purity.
81.6 - 89.8%
Example 1 A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 11.2 g of 99% by weight sodium hydroxide (0.28 mole, 1.12 moles based upon 1 mole of 2-aminoethane thiol hydrochloride) was added while cooling and agitating to be dissolved in the water, then 28.8 g of 99.5% by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein, then the reaction mixture was cooled to 0C. To this reaction mixture, 36.9 g of 99.5% by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was added so that the temperature inside the system became 5C or less.. After the end of addition, the mixture was allowed to react at 0 to 5C for 2 hours. Thereafter, the reaction mixture was heated to 20C, adjusted in PH to 4.0 with 36% by weight aqueous hydrochloric acid solution, then further heated to 40C and allowed to age for 2 hours. After aging, the reaction mixture was cooled to 20C, then the crystals were suction filtered and washed with 100 g of water (5.6 moles) to obtain 36.6 g of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 84C under 6.7 x 10-4 MPa for 5 hours to obtain 28.6 g of 99.7% purity 2-cyanoimino-1,3-thiazolidine (yield 89.8% = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester). Note that the purity was analyzed by means of high pressure liquid chromatography (HPLC). Example 2; A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 12.3 g of 99% by weight sodium hydroxide (0.31 mole, 1.24 moles based upon 1 mole of 2-aminoethane thiol hydrochloride) was added, while cooling and agitating to be dissolved in the water, then 28.8 g of 99.5% by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein. Thereafter, the reaction mixture was cooled to 0C., then 36.9 g of 99.5% by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added so that the temperature inside the system became 5C or less. After the end of addition, the mixture was allowed to react for further 2 hours. Next, the reaction mixture was heated to 20C, adjusted in pH to 3.9 with 4.56 g (0.045 mole) of 36% by weight aqueous hydrochloric acid solution, then further heated to 40C and allowed to age for 2 hours. After aging, the reaction mixture was cooled to 20C, then suction filtered and washed with 200 g of water (11.1 moles) to obtain 34.7 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals obtained above, were dried in vacuo at 80C under 6.7 x 10-4 MPa for 5 hours to obtain 27.9 g of 100% purity 2-cyanoimino-1,3-thiazolidine (yield 87.9% = value converted to purity, based on charged dimethyl N-cyanoiminodithiocarbonate ester). Further, the total weight of the filtrate combined with the washings was 371.5 g. The filtrate included 0.98% of 2-cyanoiminothiazolidine (value converted to yield: 11.5%). Example 3; A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 10.6 g of 99% by weight sodium hydroxide (0.26 mole, 1.04 moles based upon 1 mole of 2-aminoethane thiol hydrochloride) was added, while cooling and agitating to be dissolved in the water, then 28.8 g of 99.5% by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein. Thereafter, the reaction mixture was cooled to 0C, then 36.9 g of 99.5% by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added so that the temperature inside the system became 5C or less, then was allowed to react for 2 hours. Next, the reaction mixture was heated to 20C, adjusted in pH to 9.2 with 0.25 g of 36% by weight aqueous hydrochloric acid solution (0.0025 mole), then further heated to 40C and allowed to age for 2 hours. After aging, the reaction mixture was cooled to 20C, then suction filtered and washed with 200 g of water (11.1 moles) to obtain 36.33 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 80C under 6.7 x 10-4 MPa for 5 hours to obtain 27.2 g of 95.2% purity 2-cyanoimino-1,3-thiazolidine (yield 81.6% = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester). Further, the total weight of the filtrate combined with the washings was 361.5 g. The filtrate included 0.95% of 2-cyanoiminothiazolidine (value converted to yield: 10.8%).
59.4 - 65.2%
Comparative Example 2 A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 114 g of water (6.3 moles), then 20.9 g of 99% by weight sodium hydroxide (0.50 mole) was added, while cooling and agitating, to be dissolved therein, then 28.8 g of 99.5% by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein.. Then, the reaction mixture was cooled to 0C, then 36.9 g of 99.5% by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added, while holding the temperature to 5C or less, then the mixture was allowed to react for 2 hours. Next, 30.9 g of 36% by weight aqueous hydrochloric acid solution (0.29 mole) was added to try to adjust the PH, but the mixture violently started bubbling at around PH 9.0 and finally the PH became 9.5.. Next, the reaction mixture was suction filtered and washed with 200 g of water (11.1 moles) to obtain 28.6 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 80C under 6.7 x 10-4 MPa for 5 hours to obtain 18.9 g of 100% purity 2-cyanoimino-1,3-thiazolidine (yield 59.4% = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester). Comparative Example 3; A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 150 g of water (8.3 moles), then 20.9 g of 99% by weight sodium hydroxide (0.50 mole) was added, while cooling and agitating, to be dissolved, then 28.8 g of 99.5% by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein. Thereafter, the reaction mixture was cooled to 0C, then 36.9 g of 99.5% by weight dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was gradually added, while holding the temperature to 5C or less, the mixture was then allowed to react for 2 hours. Next, 31.7 g of 36% by weight aqueous hydrochloric acid solution (0.31 mole) was added to try to adjust the pH, but the mixture violently started bubbling at around pH 9.0 and finally the pH became 1.7. Next, the reaction mixture was suction filtered and washed with 200 g of water (11.1 moles) to obtain 34.8 g of wet crystals of 2-cyanoimino-1,3-thiazolidine. The wet crystals were dried in vacuo at 80C under 6.7 x 10-4 MPa for 5 hours to obtain 20.7 g of 100% purity 2-cyanoimino-1,3-thiazolidine (yield 65.2% = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester).
47.7%
Comparative Example 1 A 300 ml four-necked flask provided with a thermometer and an agitator was charged with 100 g of water (5.6 moles), then 10.1 g of 99% by weight sodium hydroxide (0.25 mole) was added, while cooling and agitating to dissolve it.. Next, 28.8 g of 99.5% by weight 2-aminoethane thiol hydrochloride (0.25 mole) was added thereto and dissolved therein, then 36.9 g of dimethyl N-cyanoiminodithiocarbonate ester (0.25 mole) was added and the mixture was heated and refluxed under agitation for 3 hours.. After the end of the reaction, the reaction mixture was cooled to room temperature, then the crystals were suction filtered and washed with methanol and dried in vacuo at 80C under 6.7 x 10-4MPa for 5 hours to obtain 15.2 g of 99.7% purity 2-cyanoimino-1,3-thiazolidine (yield 47.7% = value converted to purity, based on the charged dimethyl N-cyanoiminodithiocarbonate ester).
Stage #1: 2-naphthalenesulphonamide; dimethyl N-cyanodithioiminocarbonate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h;
Stage #2: With hydrogenchloride In N,N-dimethyl-formamide at 20℃; for 8h;
methyl 2-([(cyanoimino)(methylsulfanyl)methyl]amino}sulfonyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: methyl 2-(aminosulfonyl)benzoate; dimethyl N-cyanodithioiminocarbonate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h;
Stage #2: With hydrogenchloride In N,N-dimethyl-formamide at 20℃; for 8h;
Stage #1: 2-chlorobenzenesulfonamide; dimethyl N-cyanodithioiminocarbonate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h;
Stage #2: With hydrogenchloride In N,N-dimethyl-formamide at 20℃; for 8h;
In N,N-dimethyl-formamide at 150℃; for 0.166667h; Microwave irradiation;
Method A
General procedure: A solution of compounds 1a-e (10 mmol) and dimethyl Ncyanodithioiminocarbonate8 (10 mmol) in DMF (20 mL) was heated at150°C under microwave 600 W for 10 min. The reaction mixture was monitoredby TLC (petroleum ether 60-80 - EtOAc 3:1) until the reactantsdisappeared. The solvent was then evaporated and the resulting residue wastriturated with MeOH to afford compounds 9a-e, which were recrystallizedfrom the appropriate solvent.
With sodium hydroxide In water at 0 - 5℃; for 0.666667h;
step one:Under ice-cooling, the compound HRB-1365-0, compound HRB-1365-1, and water, under basic conditionsThe reaction was stirred and filtered to give a white solid,The compound HRB-1365-2; the preparation of the compound HRB-1365-2:Add 300 ml of water to the three-necked flask and add 16.4 g of sodium hydroxide. After stirring, the mixture was cooled to below 10 ° C and 56 g (0.50 mol) of cysteamine hydrochloride was rapidly added. After stirring, the temperature dropped to 0- 5 ° C,The compound HRB-1365-0 was then added 61 g (0.41 mol),After the reaction was complete for 40 minutes, the reaction was filtered and the filter cake was washed with 200 ml of water. The filter cake was white solid, and the wet product was 57g and dried at 60-65 ° C to obtain 46 g of white crystalline solid, which was compound HRB-1365- 2,The yield was 87.5% and the HPLC content was more than 99%.
139.1
(Step 1) Dimethyl cyanodithioiminocarbonate (3.00 g, 20.5 mmol) was dissolved in THF (15 mL) and a solution of N-(3-hydroxypropyl)ethylenediamine (2.55 g, 20.5 mmol) in THF (15 mL) was added thereto dropwise under ice-cooling. After stirring under ice-cooling for 1 hour and at room temperature for 21 hours, the mixture was added with diisopropylether and the supernatant was removed to obtain an oily substance. The obtained oily substance was dissolved in acetone and the solution was added with diisopropylether. Then, the supernatant was removed in a similar manner. The obtained oily substance was concentrated under reduced pressure to obtain 1-(3-hydroxypropyl)imidazolidin-2-ylidenecyanoamide (2.83 g, 82.1 %) as a brown oily substance. 1H NMR (CDCl3, δppm): 1.67-1.77 (m, 2H), 3.36-3.45 (m, 2H), 3.57-3.68 (m, 6H).
(2Z)-2-aza-3-[(5-chloro(2-thienyl))sulfonyl]amino}-3-[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]amino}prop-2-enenitrile[ No CAS ]
[ 353245-75-7 ]
Yield
Reaction Conditions
Operation in experiment
24%
With dmap; 1,8-diazabicyclo[5.4.0]undec-7-ene; In pyridine;
EXAMPLE 1 Preparation of 5-chloro-2-{4-[([(5-chloro(2-thienyl)) sulfonyl]amino}(cyanoimino)methyl)amino]-2-methylphenyl}benzo[c]azolidine-1,3-dione A solution of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (0.14 g, 0.5 mmol) and dimethyl N-cyanodithioiminocarbonate (0.13 g, 1 mmol) in pyridine (1.3 mL) was stirred at 115 C. for 8 hr. The reaction mixture was then cooled and concentrated in vacuo. To a solution of this crude intermediate (56 mg, 0.11 mol) in pyridine (0.7 mL) was added DBU (33 μL, 0.22 mmol) and <strong>[53595-66-7]5-chlorothiophene-2-sulfonamide</strong> (44 mg, 0.22 mmol). The reaction mixture was heated at 115 C. for 23 hr with addition of DMAP (10 mg) after 2 hr. Acidification and HPLC purification yielded (2Z)-2-aza-3-[(5-chloro(2-thienyl))sulfonyl]amino}-3-[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]amino}prop-2-enenitrile (14 mg, 24%). ES-MS (M+H)+=534, 536 (Cl). 1H-NMR (DMSO-d6): δ2.03 (s, 3H), 7.06-7.07 (d, 1H), 7.18-7.20 (d, 1H), 7.30-7.31 (d, 1H), 7.37 (s, 2H), 7.93-7.94 (2H), 8.03 (d, 1H), 8.84 (s, 1H).
24%
With dmap; 1,8-diazabicyclo[5.4.0]undec-7-ene; In pyridine;
EXAMPLE 1 Preparation of 5-chloro-2-{4-[([(5-chloro(2-thienyl)) sulfonyl]amino}(cyanoimino)methyl)amino]-2-methylphenyl}benzo[c]azolidine-1,3-dione A solution of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (0.14 g, 0.5 mmol) and dimethyl N-cyanodithioiminocarbonate (0.13 g, 1 mmol) in pyridine (1.3 mL) was stirred at 115 C. for 8 hr. The reaction mixture was then cooled and concentrated in vacuo. To a solution of this crude intermediate (56 mg, 0.11 mol) in pyridine (0.7 mL) was added DBU (33 μL, 0.22 mmol) and <strong>[53595-66-7]5-chlorothiophene-2-sulfonamide</strong> (44 mg, 0.22 mmol). The reaction mixture was heated at 115 C. for 23 hr with addition of DMAP (10 mg) after 2 hr. Acidification and HPLC purification yielded (2Z)-2-aza-3-[(5-chloro(2-thienyl))sulfonyl]amino}-3-[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]amino}prop-2-enenitrile (14 mg, 24%). ES-MS (M+H)+=534, 536 (Cl). 1H-NMR (DMSO-d6): δ 2.03 (s, 3H), 7.06-7.07 (d, 1H), 7.18-7.20 (d, 1H), 7.30-7.31 (d, 1H), 7.37 (s, 2H), 7.93-7.94 (2H), 8.03 (d, 1H), 8.84 (s, 1H).
N-cyano-N'-(2,2,2-trifluoroethyl)-S-methylisothiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In ethanol;
(a) N-Cyano-N'-(2,2,2-trifluoroethyl)-S-methylisothiourea A mixture of 8.0 g (0.055 moles) of dimethyl N-cyanodithioiminocarbonate, of 8.1 g (0.060 moles) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> and of 6.0 g (0.059 moles) of triethylamine in 75 ml of ethanol is heated to 40 C. for 7 hours. A release of methyl mercaptan is produced. 3.7 g (0.027 moles) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong> and 2.7 g (0.027 moles) of triethylamine are then added to the reaction mixture and heating to 40 C. is continued for 4 hours. The same quantities of reactants are added again and heating to 40 C. is continued for 3 more hours. After cooling, a very slight precipitate is removed by filtration. The filtrate is concentrated to dryness under reduced pressure. The residue is washed with water and recrystallized from ethanol. Yld: 4.9 g (45%), mp=151-153 C. Percentage analysis: C5 H6 F3 N3 S (FW=197.18)
With citric acid In methanol; ethanol; acetonitrile
52 N"-Cyano-N',N'-bis[2-(dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(phenylsulfonyl)ethyl]guanidine citrate
EXAMPLE 52 N"-Cyano-N',N'-bis[2-(dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(phenylsulfonyl)ethyl]guanidine citrate The title compound is prepared utilizing the procedure of Method F. N'-[2-(dimethylamino)ethyl]-N,N-dimethyl-1,2-ethanediamine is reacted with dimethyl-N-cyanodithioiminocarbonate in absolute ethanol solvent. After stirring at room temperature for 16-20 hours and refluxing for 4-8 hours, solvent is removed in vacuo to give an oil residue. This residue is then partitioned between water and methylene chloride, the methylene chloride layer is then stripped to dryness over magnesium sulfate and solvent removed in vacuo to give an oil which is then reacted with N-[2-(phenylsulfonyl)ethyl]-2-propanamine in acetonitrile solvent, and refluxed for 2-10 days. The solvent is removed in vacuo and the residue partitioned between methylene chloride and water. The methylene chloride solution is dried over magnesium sulfate and the solvent removed in vacuo to give an oil. The oil is then subjected to flash chromatography and the desired fraction collected. Dissolving the oil in methanol and treating it with citric acid followed by recrystallization gives the title compound.
A. N-{2-[(4-{2-Chlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethyl}-N'-cyano-S-methyl-isothiourea STR23 2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.3 g) and dimethyl N-cyanoimidodithiocarbonate (2 g) in isopropanol (15 ml) were allowed to stand at room temperature for 4 hours. Ether (30 ml) was then added and the mixture was stood at room temperature overnight. The crystalline precipitate was filtered, washed with ether and dried, yield of the title compound 5.0 g, m.p. 177-179. Analysis %: Found: C, 54.35; H, 5.4; N, 11.2. Calculated for C23 H27 ClN4 O5 S: C, 54.5; H, 5.4; N, 11.05.
N'-cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10.7 g (76 %)
With sodium hydroxide In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol
4 N'-Cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea
EXAMPLE 4 N'-Cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea A solution of 10.6 g (43.2 mmol) of 2,5-dichloro-benzenesulfonamide, 7.15 g (44.0 mmol) of 90 percent dimethyl N-cyanodithioiminocarbonate and 1.8 g (44 mmol) of NaOH in 60 ml of ethanol and 10 ml of H2 O was heated at reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into 600 ml of ice water. The resulting solution was acidified with 6N HCl to separate 2.2 g of the desired product as a white solid. Concentration of the filtrate gave an additional 8.5 g of the desired product. The total yield of material was 10.7 g (76 percent) of white solid, mp 145° C. IR and 1 H NMR spectra were consistent with the assigned structure. Analysis: Calculated for C9 H7 Cl2 N3 O2 S2: C, 33.34; H, 2.18; N, 12.96. Found: C, 33.50; H, 2.39; N, 12.82.
10.7 g (76 %)
With sodium hydroxide In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol
6 N'-Cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea
EXAMPLE 6 N'-Cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea A solution of 10.6 g (43.2 mmol) of 2,5-dichlorobenzenesulfonamide, 7.15 g (44.0 mmol) of 90 percent dimethyl N-cyanodithioiminocarbonate and 1.8 g (44 mmol) of NaOH in 60 ml of ethanol and 10 ml of H2 O was heated at reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into 600 ml of ice water. The resulting solution was acidified with 6N HCl to separate 2.2 g of the desired product as a white solid. Concentration of the filtrate gave an additional 8.5 g of the desired product. The total yield of material was 10.7 g (76 percent) of white solid, mp 145° C. IR and 1 H NMR spectra were consistent with the assigned structure. Analysis: Calculated for C9 H7 Cl2 N3 O2 S2: C, 33.34; H, 2.18; N, 12.96. Found: C, 33.50; H, 2.39; N, 12.82.
7.b EXAMPLE 7
(b) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (23.4 g.) in ethanol was added slowly to a solution of dimethyl-N-cyanoimidodithiocarbonate (20.0 g.) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea, m.p. 148°-150°. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water and the solid obtained, filtered off and recrystallized twice from isopropyl alcohol/ether to yield further product, m.p. 148°-150°.
In ethanol
7.b EXAMPLE 7
b. A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (23.4 g) in ethanol was added slowly to a solution of dimethyl-N-cyanoimidodithiocarbonate (20.0 g) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea, m.p. 148°-150°. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water and the solid obtained, filtered off and recrystallized twice from isopropyl alcohol/ether to yield further product, m.p. 148°-150°.
In ethanol
13.b EXAMPLE 13
(b) A solution of 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole (23.4 g.) in ethanol was added slowly to a solution of dimethyl-N-cyanoimidodithiocarbonate (20.0 g.) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-S-methylisothiourea, m.p. 148°-150° C. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water and the solid obtained, filtered off and recrystallized twice from isopropyl alcohol/ether to yield further product, m.p. 148°-150° C.
EXAMPLE 4 Preparation of N-2-propynyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine A solution was prepared from 3.07 g. of dimethyl cyanodithioimidocarbonate and 35 ml. of ethanol. A second solution containing 4.62 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine in 50 ml. of ethanol was added in dropwise fashion with stirring to the first solution over a period of about 1.5 hours. The resulting reaction mixture was stirred for an additional 20 hours after which time the volatile constituents were removed in a rotary evaporator. Chromatography of the residue over silica by gradient elution using ethyl acetate containing increasing quantities of methanol as the eluant yielded fractions containing methyl N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate, formed in the above reaction. These fractions were combined and the solvent removed from the combined fractions in a rotary evaporator. The residue weighed 4.8 g. and, after recrystallization from carbon tetrachloride, melted at about 75°-77° C. Analysis Calculated: C, 43.74; H, 5.81; N, 21.25; S, 29.19 Found: C, 43.46; H, 5.71; N, 20.98 S, 29.15 1.32 Grams of the above thioester and 1.98 g of redistilled propargylamine dissolved in 6 ml. of anhydrous methanol, and the solution stirred at reflux temperature under a positive nitrogen pressure for 5 hours, an additional gram of propargylamine was added and the reaction mixture refluxed for an additional 6 hours. The solvent and excess amine were then removed by evaporation on a rotary evaporator. The residue was purified by gradient elution high pressure liquid chromatography (silica-ethyl acetate-methanol). Fractions containing N-2-propynyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine formed in the above reaction as shown by TLC were combined to yield 0.96 g. of a glassy residue upon evaporation of the solvent. Rf =0.33 (silica, 5:95 NH4 OH; ethanol). Mass spectrum; m/e 337. The nmr spectrum in CDCl3 (TMS internal standard) shows the following signals (delta): 2.33 (singlet, 6H); 2.28 (multiplet, 1H); 2.73 (triplet, 2H); 3.43 (doublet of triplets, 2H); 3.72 (singlet, 2H); 3.80 (singlet, 2H); 4.0 (multiplet, 2H); 6.36 (multiplet, 1H); 6.63 (multiplet, 1H); 7.01 (singlet, 1H).
11.b EXAMPLE 11
(b) A solution of 23.4 g of 4-(2-aminoethyl)thiomethyl-5-methylimidazole in ethanol was added slowly to a solution of 20.0 g of dimethyl-N-cyanoimidodithiocarbonate in ethanol, with stirring at ambient temperature. Filtration afforded N-cyano-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-S-methylisothiourea, m.p. 148°-150°. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water to give a solid material which was collected by filtration and recrystallized twice from isopropanolether, m.p. 148°-150°.
In ethanol
17.b EXAMPLE 17
(b) A solution of 23.4 g. of 4-(2-aminoethyl)-thiomethyl-5-methylimidazole in ethanol was added slowly to a solution of 20.0 g. of dimethyl-N-cyanoimidodithiocarbonate in ethanol, with stirring at ambient temperature. Filtration afforded N-cyano-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-S-methylisothiourea, m.p. 148°-150°. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water to give a solid material which was collected by filtration and recrystallized twice from isopropanol-ether, m.p. 148°-150°.
R.56 Methyl N-cyano-4-morpholinecarbimidothioate
Reference Example 56 Methyl N-cyano-4-morpholinecarbimidothioate Dimethylcyanodithioiminocarbonate (50 g) was dissolved in ethanol (500 mL), and morpholine (45 mL) was added thereto at room temperature, and stirred for 2 hours. The precipitated crystals were collected and washed with ethanol. The obtained crystals were dried to obtain the desired compound (51 g). 1H-NMR(300MHz, CDCl3) δ ppm: 2.80(s, 3H), 3.70-3.75(m, 4H), 3.83-3.88(m, 4H)
N-cyano-N'-{2-[(4-methylthiazol-2-yl)methylthio]ethyl}-S-methylisothiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride;
EXAMPLE 16 When 2-chloromethyl-4-methylthiazole [prepared from 2-hydroxymethyl-4-methylthiazole and thionyl chloride] is reacted with cysteamine hydrochloride and about two equivalents of a strong base such as sodium methoxide and the resultant amine treated with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{2-[(4-methylthiazol-2-yl)methylthio]ethyl}-S-methylisothiourea.
1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-(4-pyridylmethyl)-piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrazine hydrate; In ethanol;
A 17.7 g (0.1 mole) amount of <strong>[62089-74-1]1-(4-pyridylmethyl)piperazine</strong> (prepared as described above) was dissolved in 25 ml of ethanol and then added dropwise over 30 minutes to a stirred solution of 14.6 g (0.1 mole) of dimethyl cyanodithioiminocarbonate in 125 ml of ethanol. The mixture was refluxed for 20 hours, the evolved gas being led into a sodium hypochlorite trap, for the first 3 hours. Then 6.0 ml (0.12 mole) of hydrazine hydrate was added into the refluxing reaction mixture through the condenser and the mixture was refluxed for 6 hours longer. The mixture was evaporated to a solid residue which was recrystallized with ether and gave 25.8 g of the product of the Example as pale yellow crystals, mp 191-193 C.
Example 1 Preparation of N-[4-(pyridin-4-yloxy)phenyl]-4H-1,2,4-triazole-3,5-diamine ("1") 4-(Pyridin-4-yloxy)phenylamine (9.80 g, 52.6 mmol) is dissolved in ethanol (250 ml), dimethyl N-cyanodithioiminocarbonate (7.75 g, 52.6 mmol) is added, and the mixture is stirred under reflux for 2 days. The volatile constituents are completely removed under reduced pressure, the residue is again taken up in ethanol (250 ml), hydrazine hydrate (50 ml) is added, and the mixture is heated under reflux for 2 h. The product precipitated after cooling is filtered off, washed with diethyl ether and dried, giving 10.6 g (3.95 mmol, 75%) of "1", [M+H]+ 269, Rf 0.573 min.
PREPARATION 7; Preparation of TV-(I -benzylimidazolidin-2-ylidene)cyanamide; To a solution of /V-benzylethane- l ,2-diamine (3.00 g, 19.96 mmol) in anhydrous dioxane ( 15 mL) was added dimethyl cyanocarbonimidodithioate (3.50 g, 23.96 mmol). The mixture was refluxed for 16 hours, then diluted with dichloromethane (200 mL), washed with water (200 mL) and brine ( 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane ( 1 /4) to afford the title compound as a colorless solid in 95% yield (3.88 g): mp 120- 122 0C (ethyl acetate/hexanes); 1 H NMR (300 MHz, CDCl3) delta 7.36-7.22 (m, 5H), 6.86 (br s, I H), 4.38 <n="98"/>(s, 2H), 3.58-3.52 (m, 2H), 3.44-3.88 (m, 2H); 13C NMR (75 MHz, CDCI3) delta 164.0, 135.5, 128.8, 128.1 , 127.9, 1 19.4, 48.3, 46.1, 40.2; MS (ES+) m-z 201.2 (M + 1 ).
Compound 15: 1-(4-amin -6-(methylthio)-1 ,3,5-triazin-2-yl)ethanol; Under a nitrogen atmosphere <strong>[89799-34-8]2-hydroxypropanimidamide hydrochloride</strong> (4.97 g) was suspended in dry N,N-dimethylformamide (25 mL) and sodium hydride (1.66 g, 60 wt% in mineral oil) was added in one portion. When gas evolution ceased the white suspension was heated to 65C. After 1 h dimethyl cyanocarbonimidodithioate (6.24 g) was added and the mixture was stirred at 65 C for 18 hours. The reaction mixture was concentrated and triturated with water (200 mL). The resulting precipitate was filtered off, washed with water and the aqueous layer was extracted with 5% methanol indichloromethane (3 x 100 mL). The combined organic extracts were dried (sodium sulfate) and concentrated before being purified by flash chromatography eluting with 10% methanol in dichloromethane to give the title compound (300 mg) as a yellow oil that solidified on standing.
Stage #1: dimethyl N-cyanodithioiminocarbonate; imidazo[1,2-a]pyridin-7-amine With dmap In N,N-dimethyl-formamide
Stage #2: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 4h;
2.A
EXAMPLE 2 2-cvano-l-(imidazo[l,2-alpyridin-7-yl)-3-(4-(phenylsulfonyl)benzyl)guanidineA: methyl N'-cvano-N-(imidazo[l,2-alpyridin-7-yl)carbamimidothioate:In a lOOmL round-bottomed flask was added imidazo[l,2-a]pyridin-7-amine (lg, 7.51mmol), dimethyl cyanocarbonimidodithioate (1.318g, 9.01mmol), and DMAP (0.092g, 0.751mmol) in DMF (Volume: lOmL) to give a yellow solution. The reaction was cooled to 0 °C and sodium hydride (0.323 g, 12.77 mmol) was added portionwise. The reaction was stirred at 0 °C for 4 hours and then allowed to warm to room temperature overnight. The reaction was then concentrated under reduced pressure and then diluted with methylene chloride and washed with sat. aq. NH4C1. A large amount of solid was formed in separatory funnel, so filtered entire mixture. Isolated 2.25g of a yellow powder which showed product by NMR along with an impurity. Purfied solid on Biotage to give the title compound.1H NMR (300 MHz, DMSO-d6): δ 11.25 (br. s, 1H), 8.49 (d, 1H), 7.93 (s, 1H), 7.52 (d, 1H), 7.64 (s, 1H), 7.03 (dd, 1H), 2.82 (s, 3H);LC-MS (ESI): 232.09 (M+l).
The flask was charged with 60 mL of absolute ethanol, 6.0 g (19.3 mmol) of 1 (desloratadine) and 2.9 g (20 mmol) of dimethyl cyanocarbonimidodithioate. The resulting solution was stirred at rt for over 2 h. Then the white suspension was filtered under suction and the solid was washed with a small amount of cold ethanol to give the white product 4 (6.4 g). Yield: 81.2% of a white solid; mp: 162-164 C. ESI-MS: 409.0 [M+H]+. IR (cm-1): 3080, 2929, 2894, 2852, 2180, 1548, 1540, 1456, 1434, 991, 834. 1H NMR (CDCl3) delta: 2.36-2.44 (m, 2H, =C(CH2)2); 2.47-2.72 (m, 2H, =C(CH2)2); 2.76 (s, 3H, SCH3); 2.78-2.90 (m, 2H, N(CH2)2); 3.28-3.39 (m, 2H, N(CH2)2); 3.50-3.60 (m, 2H, PhCH2); 4.03-4.15 (m, 2H, CH2); 7.09-7.18 (m, 3H, Ar-H); 7.26 (m, 1H, pyridine-H); 7.47 (dd, 1H, J = 7.3 Hz, pyridine-H); 8.40 (dd, 1H, J = 4.7 Hz, pyridine-H).
General procedure: A solution of N-cyanocarbonimidodithioic acid dimethyl ester (17.4mmol), acetonitrile (10mL), and appropriate amine (17.4mmol) was refluxed for 2h. After cooling to room temperature, hydrazine monohydrate (25.6mmol) was added and the reaction mixture was further refluxed for additional 5h. The solvent was evaporated under reduced pressure and the resulting product recrystallized from ethyl acetate. Following general procedure B, compound 11k was isolated as a pale yellow solid. Yield 80%, mp=103-104C. 1H NMR (200MHz, DMSO-d6) delta: 10.95 (br s, 1H); 5.72 (br s, 2H); 3.16-3.11 (m, 4H); 2.34-2.29 (m, 4H); 2.17 (s, 3H)
(Z)-methyl N'-cyano-N-(3,4-dimethoxybenzyl)carbamimidothioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In isopropyl alcohol at 20℃; for 24h;
4.1.2. General Procedure A for the Synthesis of Compounds 10a-o
General procedure: To a solution of dimethyl cyanodithioimidocarbonate 9 (292 mg, 2 mmol) in isopropanol (10 mL)was added the appropriate amine (2 mmol, 1 equiv.), and the mixture was stirred for 24 h atroom temperature. After this time, the suspension was filtered, and the solid residue was washedwith ethyl ether to furnish the final compound 10a-o that was used for the next reaction withoutfurther purification.
(Z)-N'-cyano-N-(1-(thiophen-3-yl)propan-2-yl)aminothiocarbimide methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.9%
In ethanol for 6h; Reflux;
7 (Z)-N'-cyano-N-(1-(thiophen-3-yl)propan-2-yl)aminothiocarbimide methyl ester (III-7)
In a 100mL three-necked flask, add XII-1 (3.2g, 22.7mmol), 30mL of absolute ethanol and cyanocarbonimide disulfate (4.91g, 34.1mmol), stir at room temperature for 10 minutes to dissolve the solid, and heat under reflux for 6h , TLC (dichloromethane: methanol = 15:1) monitoring the completion of the raw material reaction. The reaction system was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a dark yellow oil. Add 20 mL of diethyl ether and 1 mL of dichloromethane and stir at room temperature for 12 h, a large amount of pale yellow solid was formed, suction filtered, the filter cake was washed with a small amount of diethyl ether, and dried under infrared light to obtain 2.06 g of pale yellow solid, yield 37.9%,
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