Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 2114-02-5 | MDL No. : | MFCD00014472 |
Formula : | C2H6N4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OKGXJRGLYVRVNE-UHFFFAOYSA-N |
M.W : | 118.16 | Pubchem ID : | 2724563 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 31.33 |
TPSA : | 120.01 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.82 cm/s |
Log Po/w (iLOGP) : | -0.09 |
Log Po/w (XLOGP3) : | -1.13 |
Log Po/w (WLOGP) : | -1.29 |
Log Po/w (MLOGP) : | -1.51 |
Log Po/w (SILICOS-IT) : | -0.36 |
Consensus Log Po/w : | -0.88 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.27 |
Solubility : | 221.0 mg/ml ; 1.87 mol/l |
Class : | Highly soluble |
Log S (Ali) : | -0.9 |
Solubility : | 14.9 mg/ml ; 0.126 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.59 |
Solubility : | 462.0 mg/ml ; 3.91 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.25 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1-methyl-pyrrolidin-2-one; hydrogen sulfide at 70 - 80℃; | |
50.5% | With ammonium sulfide; sulfuric acid In water at 60 - 65℃; for 17h; | |
With hydrogen sulfide; water at 60 - 70℃; |
With hydrogen sulfide; water | ||
With hydrogenchloride; monophenylthiourea | ||
With tri-n-propylamine; hydrogen sulfide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In acetone for 4h; Heating / reflux; | 5 EXAMPLE 5; Synthesis of 1-(4-methyl-1,3-thiazol-2-yl)-4-phenyl-1H-2-imidazolamine (Compound 5) A mixture of amidinothiourea (2.0 g, 16.9 mmol), chloroacetone (1.56 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with dry acetone, and dried to give N-(4-methyl-1,3-thiazol-2-yl)guanidine (2.19 g, 83%). |
Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In 1,4-dioxane for 7h; Reflux; | |
87% | In acetone for 4h; Heating / reflux; | 6 EXAMPLE 6; Synthesis of 1-(4-phenyl-1,3-thiazol-2-yl)-4-(2-thienyl)-1H-2-imidazolamine (Compound 6) A mixture of amidinothiourea (2.0 g, 16.9 mmol), 2-bromoacetophenone (3.4 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with acetone, and dried to give N-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 87%). A mixture of amidinothiourea (2.0 g, 16.9 mmol), 2-bromoacetophenone (3.4 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with acetone, and dried to give N-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 87%) |
87% | In ethanol at 80℃; for 4h; |
In methanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium acetate In ethanol for 0.5h; Heating; | |
75% | With pyridine In ethanol at 100℃; | |
75% | With pyridine In ethanol at 100℃; |
60% | In 1,4-dioxane for 7h; Reflux; | |
In ethanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: amidinothiocarbamide; di-<i>tert</i>-butyl dicarbonate In N,N-dimethyl-formamide for 1h; Stage #2: With dmap at 35℃; for 20h; | 19 tert-Butyl [(aminocarbonothioyl)amino] (imino)methyl)carbamate (B) : A solution of di-tert-butyl dicarbonate (1.7 g, 7.8 mmol) in DMF - (10 ml) was added dropwise over 1 h to amixture of compound A (1 g, 7.8 mmol) and 4-dimethylaminopyridine (85 mg, 0.7 mmol) in DMF (10 ml ). After complete addition the mixture was stirred for 20 h at 35 °C. The mixture was concentrated in vacuo and the residue was manually shaken with water (10 ml) .The precipitate starts coming within 1 mm and manual shaking was continued for another 6 mm, and the mixture was kept at 4 °C for 1 h. The precipitate was collected by filtration, washed with cold water (15 ml) and driedin vacuoto afford compound B as white solid(1 .36 g, 80% yield). 1H NMR (DMSO-d6): 7.96 (brs,1H, NH), 7.31 (brs, 1H, NH), 1.42 (s, 9H, CH3). |
80% | With dmap In N,N-dimethyl-formamide at 35℃; for 21h; | 1 Example 1 fert-Butyl ( [(aminocarbonothiovDamino] (iminoimethyll carbamate; A solution of di-tert-butyl dicarbonate (100 g, 458 mmol) in N,iV-dimethylformamide (50 niL) was added dropwise over 1 h to a mixture of l-[amino(imino)methyl]thiourea (50 g, 424 mmol) and 4-dimethylaminopyridine (0.450 g, 3.68 mmol) in iζN-dimethylformamide (100 mL). After complete addition the mixture was stirred for 20 h at 35 0C. The mixture was concentrated in vacuo and the residue was manually shaken with water (70 mL).Within 1 min the residue solidified. Shaking was continued for 6 min, and the mixture was kept at 4 °C for 1 h. The precipitate was collected by filtration, washed with cold water (30 mL) and dried in vacuo to afford 73.39 g (80% yield) of the title compound: 13C NMR (125.7 MHz, DMSO-J5): δ 162.98, 157.70, 156.36, 79.93, 28.50; MS (ESI) m/z 219.2 [M+l]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: acetylacetone With sodium hydroxide; bromine; sodium bromide In water at 0℃; for 0.666667h; Stage #2: amidinothiocarbamide In ethanol for 1h; Heating / reflux; Stage #3: With ammonia In methanol; dichloromethane | 11 Example 11N-("5-Acetyl-4-methyl-1.3-thiazol-2-vDguanidine; Bromine (4.87 mL, 95 mmol) was added to a solution of sodium bromide (39.96 g, 388 mmol) in water (150 mL). This mixture was thoroughly mixed and added dropwise over 40 min to a cooled (0 °C) suspension of 2,4-pentanedione (10.26 mL, 100 mmol) in aqueous sodium hydroxide (0.25 M, 500 mL). Once the addition was complete, aqueous hydrogen bromide (1 M, 35 mL) was added. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in ethanol (20 mL) and added to a refluxing solution of l-[amino(imino)methyl]thiourea (8.85 g, 75 mmol) in ethanol (200 mL). The reaction mixture was refluxed for 1 h, cooled and filtered to afford 5.20 g of the title compound as the hydrobromide. The filtrate was evaporated and the crude product was purified by column chromatography, using a gradient of 3-7% methanol in dichloromethane containing 1% ammonia, to afford 0.371 g of the title compound: MS (ESI) m/z 199 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | In methanol at 50℃; for 16h; | 37 Example 37 l-r5-("2-NitrophenylVl,3-thiazol-2-vnguanidine; l-[Amino(imino)methyl]thiourea (0.726 g, 6.15 mmol) was added in one portion to a stirred solution of bromo(2-nitrophenyl)acetaldehyde (1.427, 6.15 mmol) in methanol (70 mL) and the mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated to 5 mL. Diethyl ether was added and the mixture was concentrated in vacuo, 7 M ammonia in methanol was added and the solution was stirred for 15 min. The solution was concentrated and purified by column chromatography, using 0-10% 7 M ammonia in methanol and dichloromethane as the eluent, to give 0.43 g (27% yield) of the title compound: MS (ESI) m/z 264 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol for 2h; Heating / reflux; | 1 Synthesis of Compound KHG23168; [2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2-fIuoro-5- nitrophenyl)acetamide hydrochloride] [n=0, (R, R'; containing benzyl group, identical thereafter) = C6H3(2-F, 5-NO2)]; The compound was synthesized by conducting the reaction of following Reaction Formula 1 :[Reaction Formula 1](III); 0.549 g of Compound I [4-chloro-N-(2-fluoro-5-nitrophenyl)-3- oxobutyramide, 0.002 mol] was dissolved in 5 mL of ethanol. Then, 0.236 g of Compound II (guanylthiourea, 0.002 mol) was added hereto, and heated to reflux for 2 hours. The obtained reaction mixture was cooled to room temperature, and then the suitable amount of ethylether was added to crystallize, generating precipitation within 12 hours. The precipitation was filtrated to obtain white crystalline solid III (0.648 g). yield: 86 %, melting point: 248.4-250.1 °C1H NMR (300 MHz, DMSOd6) δ 3.88 (s, 2H, 4-CH2), 7.16 (s, IH, vinyl-H), 7.58 (app. t, IH, J= 9.5 Hz, ArH), 8.05 (ddd, IH, J= 9.1 Hz, ArH), 8.28 (br. s, 3H, NH), 8.95 (dd, IH, J= 6.7, 2.9 Hz, ArH), 10.45 (s, IH, amide NH), 12.23 (br. s, IH, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | In ethanol at 10℃; for 24h; Heating / reflux; | 22.1 2-guanyl-4-methylthiazole hydrochloride After refluxing a solution of 2-aminothiourea(11.08 g, 93.77 mmol) in ethanol(85 ml), chloroacetone(8.2 ml, 103.15 mmol) was added dropwise to the solution. The reaction mixture was stirred for 4 hours, and then stand for 1 day, while maintaining the temperature under 10° C. The resulting solid was filtered, washed with ethyl ether, and then dried under a reduced pressure to give 11.7 g of the titled compound. (Yield: 64.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide In acetone at 10 - 15℃; for 5 - 6h; | II.a EXAMPLE-II a) Preparation of 2-guanidino-4-thiozole methyl chloride hydrochloride In a 2KL GLR, àCETONE (7501TS) WAS charged and cooled to 10°-15° C. 1,3 DICHLOROACETONE (150kg) and potassium iodide (6.75kg) was charged into the reactor. To this reaction mixture under stirring, 141 kg of gunadinothiourea was charged maintaining the temperature at 10°-12° C. The addition took about 4-5hours. After the addition, the reaction mixture was stirred at 10°-12° C for one hour and the precipitated cake was centrifuged. The cake was washed with cold acetone (2 x 50ITS), spin dried, and dried at 75°-80° C to yield 250 kg of the title product with the melting point of 185-190°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-chloro-3-phthalimido-propionaldehyde; amidinothiocarbamide In butan-1-ol at 110℃; for 1.25h; Stage #2: With ammonia In dichloromethane; water | I.I.A.a 31 g (130 mmol) of 2-chloro-3-(1,3-dioxo-1,3-dihydro-2H-iso-indol-2-yl)propanal (preparation described in THL 39 (1998), 8085-8088) and 15.4 g of amidinothiourea were heated in 200 ml of n-butanol at 110° C. for 75', and then the mixture was evaporated and the residue was mixed with CH2Cl2 and concentrated NH3. Evaporation of the organic phase, purification of the residue by chromatography on silica gel ((CH2Cl2/CH3OH 0 to 5%) and crystallization from acetone afforded 12.3 g of N-{5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazol-2-yl}guanidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol | 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide N-Amidinothiourea (0.663 g, 5.62 mM) was added to a solution of 3(trifluoromethyl)phenacylbromide (1.5 g, 5.62 mM) in EtOH (10 mL) and the reaction mixture was heated at reflux for 3 hours (h). The mixture was concentrated in vacuo to one half volume and the resulting solid precipitate was isolated. This solid was washed with EtOH and dried in vacuo to give the title compound as a solid: melting point (mp) 219°-221° C.; 1 H NMR (DMSO d6): δ 8.28 (m, 5H), 8.07 (s, 1H), 7.71 (m, 2H); MS: 287 (MH+). | |
In ethanol | 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide 2-Amidino-4-(3-trifluoromethylphenyl)thiazole Hydrobromide N-Amidinothiourea (0.663 g, 5.62 mM) was added to a solution of 3-(trifluoromethyl)phenacylbromide (1.5 g, 5.62 mM) in EtOH (10 mL) and the reaction mixture was heated at reflux for 3 hours (h). The mixture was concentrated in vacuo to one half volume and the resulting solid precipitate was isolated. This solid was washed with EtOH and dried in vacuo to give the title compound as a solid: melting point (mp) 219°-221° C.; 1 H NMR (DMSO d6): δ 8.28 (m, 5H), 8.07 (s, 1H), 7.71 (m, 2H); MS: 287 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 19 2-Guanidino-4-methyl-5-(2-pyridyl)thiazole (0.16 g) was obtained according to substantially the same manner as that of Example 17 from 1-(2-pyridyl)acetone (2.8 g) and N-amidinothiourea (1.18 g). mp 166-168 C. IR (Nujol): 3440, 3400, 3270, 3080, 1630, 1600, 1580, 1540, 1520, 1420, 1320, 1240 cm-1 NMP (DMSO-d6, delta): 2.42 (3H, s), 6.8-7.1 (1H, m), 7.36 (1H, d, J=7 Hz), 7.5-7.8 (1H, m), 8.33 (1H, d d., J=2 Hz, 7 Hz) Mass. 233 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; acetone; | (A) Ethyl 2-Guanidino-5-thiazolecarboxylate Hydrochloride A solution of amidinothiourea (117 g; 0.99 mole) and ethyl chloro-alpha-formylacetate (150 g; 1.0 mole) in 3.5 liters of absolute ethanol was stirred at ambient temperature for 18 hours and then heated at reflux temperature for 1 hour. At this time additional ethyl chloro-alpha-formylacetate (20.0 g; 0.13 mole) was added and 1 hour later another 20.0 g of ethyl chloro-alpha-formylacetate was added. After 2 hours of additional heating at reflux temperature, the reaction mixture was evaporated under reduced pressure and the residue triturated with 1.5 liters of acetone and filtered to give 103 g of product. Recrystallization from 2-propanol yielded the title compound, mp 204-206. Anal. Calcd for C7 H11 ClN4 O2 S: C, 33.53; H, 4.43; N, 22.35; Cl, 14.14; S, 12.79. Found: C, 33.38; H, 4.40; N, 22.54; Cl, 13.97; S, 12.92. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; bromine; In ethanol; chloroform; acetic acid; acetonitrile; | The 2-guanidino-4-(2-amino-5-methylphenyl)thiazole used as starting material may be prepared as follows: To a solution of 2-methyl-5-nitroacetophenone (2.5 g.) in chloroform (50 ml.) was added 2 drops of 45% w/v hydrogen bromide in acetic acid. Bromine (0.75 ml.) was then added dropwise. After the addition the mixture was stirred until the colour of bromine disappeared. The clear solution was then evaporated and the residue dissolved in acetonitrile (25 ml.) and added to a solution of amidinothiourea (1.7 g.) in hot ethanol (50 ml.). The mixture was then heated under reflux for 15 minutes, cooled and the precipitate was filtered off and air-dried to give 3.25 g. of 2-guanidino-4-(2-methyl-5-nitrophenyl)thiazole hydrobromide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; bromine; In ethanol; chloroform; acetic acid; | The 2-guanidino-4-(3-aminophenyl)-5-methylthiazole dihydrochloride used as starting material may be prepared as follows: To a stirred mixture of <strong>[17408-16-1]m-nitropropiophenone</strong> (3.6 g.) in chloroform (50 ml.) was added 3 drops of a solution of hydrogen bromide in acetic acid (45% w/v). Bromine (3.2 g.) in chloroform (10 ml.) was then added dropwise. After addition the mixture was stirred until colourless, evaporated to dryness, the residue dissolved in ethanol (50 ml.) and this solution added to amidinothiourea (2.4 g.) in ethanol (150 ml.) at reflux. The mixture was heated under reflux for 30 minutes and then evaporated to approximately 50 ml. On standing overnight at room temperature a crystalline solid was produced. This was filtered off, washed with ethanol and air-dried to give 6.05 g. of 2-guanidino-4-(3-nitrophenyl)-5-methylthiazole hydrobromide, m.p. 217-222 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; bromine; In ethanol; chloroform; acetic acid; | The 2-guanidino-4-(3-amino-4-fluorophenyl)thiazole used as starting material may be prepared as follows: To a solution of <strong>[72802-25-6]3-fluoro-4-nitroacetophenone</strong> (6 g.) in chloroform (40 ml.) was added 2 drops of hydrogen bromide in acetic acid (45% w/v) followed by bromine (1.75 ml.) added dropwise. After the bromine colour had disappeared the clear yellow solution was evaporated to dryness and the residue, dissolved in hot ethanol (40 ml.), was added to amidinothiourea (4.0 g.) in ethanol (100 ml.) under reflux. The mixture was heated under reflux for 15 minutes and then cooled to room temperature. The crystalline solid was filtered off to give 8.8 g. of 2-guanidino4-(3-fluoro-4-nitrophenyl)thiazole hydrobromide, m.p. 248-252 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydrogencarbonate In ethanol; water | 2.1 Preparation of 2-guanidino-4-hydroxymethylthiazole: (1) A suspension of guanylthiourea (2.36 g) and ethyl 3-bromopyruvate (4.8 g) in dry ethanol (50 ml) is refluxed under stirring for 2.5 hours. The reaction mixture is concentrated in vacuum to dryness, and the residue is dissolved in water (about 100 ml). The aqueous solution is washed with ethyl acetate and made alkaline with 5% sodium hydrogencarbonate solution. The precipitated crystals are filtered, washed with water and dried to give 2-guanidino-4-ethoxycarbonylthiazole (3.6 g) as crystals. The yield is 84%. NMR (d6 -DMSO), δ1.28 (t, 3H, J=7 Hz), 4.23 (q, 2H, J=7 Hz), 6.93 (br. s, 4H), 7.55 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | In methanol;Heating / reflux; | Method 61,1-Dibromopinacolone, 10 mmol (2.58 g) and 2-Imino-4-thiobiuret, 10 mmol (1.18 g) were mixed with 20 ml methanol and refluxed overnight. The white precipitate formed was filtered off; and the filtrate was concentrated to give 0.773 g (39%) of 3 as a cream colored solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: amidinothiocarbamide; 1,3-Dichloroacetone With potassium iodide In acetone at 10 - 30℃; for 5 - 6h; Stage #2: With acetic acid In acetone at 25 - 40℃; for 0.5h; Stage #3: thiourea In acetone at 40℃; for 4 - 5h; Heating / reflux; | I EXAMPLE-I One pot preparation of N- [4-(AMINO IMINOETHYL) THIO] METHYL]-2-THIOZOLYL]- guanidine dihydrochloride 150kg of 1,3 DICHLOROACETONE and 6.75 kg potassium iodide was charged in 2KL GLR containing 7501TS of acetone (2-propanone). The mixture was cooled under stirring to a temperature of 10-15°C. To this reaction mixture guanidino thiourea (141 kg) was charged in instalments maintaining the reaction temperature at 10-12°C. The duration of the addition was 4-5hours. After the addition, the reaction mixture was stirred at 10-12° C for another hour. The reaction mass was allowed to warm to about 25°-30° C and ethanoic acid (144KG) was charged into the reactor in about 30min. Then the reaction mass was warmed to 40° C under stirring and thiourea (90KG) was charged. After charging thiourea, the reaction mass was heated to reflux temperature and maintained for 4-5hours. Then the reaction mass was cooled to 10° C and the precipitated product was centrifuged. The cake was washed with isopropyl alcohol (2 x 901TS). The product was dried at 75°-80° C to yield 330 kg of the dihydrochloride with melting point of 205-210°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol at 100℃; for 0.25h; Sealed tube; Microwave irradiation; | 5 Typical Reaction Conditions for Synthesis of Compounds 3.; A lO milliliter (mL) microwave reaction tube is charged with the benzyl halide (1 0 milhmole, mmol) and thiourea (76 mg, 1 0 mmol) in ethanol (1 5 mL) The tube is capped and irradiated in the microwave reactor (single-mode CEM Discover system, CEM,Matthews, NC) at 100 0C for 15 minutes The solid is filtered and solid washed with cold ethanol The solid product is dϖed under high vacuum to give the productThe following compounds were prepared by the foregoing methodsExample 5. (2-Chloro-4-fluorophenyl)methyl Amidinoisothiourea Hydrochloride (10a).; White solid, 75%; m.p. 154-156 0C; 1H NMR (400 MHz, DMSO-^) δ 4.28 (s, 2H), 7.20 (td, J= 8.5, 2.6 Hz, IH), 7.48 (dd, J= 8.8, 2.6 Hz, IH), 7.57 (dd, J =8.7, 6.24 Hz, IH), 8.00 (bs, 4H), 8.10(s, 2H); HRMS calcd. for C9HnClFN4S (M-Cl)+ 261.03715, found 261.03737. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In N,N-dimethyl-formamide at 20℃; for 6h; | Synthesis of (E)-1-(4,5-dicyanothiazol-2(3H)-ylidene)guanidine (3) To a magnetically stirred solution of tetracyanoethylene (2) (128 mg, 1 mmol) in DMF (5 mL), a solution of 1 (118 mg, 1 mmol) in DMF (5 mL) was added. The color of the solution changed to red, then to reddish brown. The reaction mixture was stirred at room temperature for 6 h. After completion of the reaction (followed by TLC), the formed precipitate was collected by filtration, washed and recrystallized by using a mixture of DMF-EtOH to afford the thiazole derivative 3. Reddish-brown crystals (yield: 69%), m. p. 300 °C (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In N,N-dimethyl-formamide at 20℃; for 2h; | Synthesis of (E)-1-(4,9-dioxonaphtho[2,3-d]thiazol-2(3H,4H,9H)-ylidene)guanidine (5) To a solution of 2,3-dicyano-1,4-napthoquinone (DCNQ,4) (208 mg, 1 mmol) dissolved in DMF (5 mL), a N-amidinothiourea (1) (118 mg, 1 mmol) dissolved in DMF (5 mL) was added slowly. The initially orange solution turned to brown, then to yellowish green. The solution was stirred for 2 h at room temperature. After completion of the reaction, the formed yellow precipitate was collected and recrystallized from DMF-EtOH to form the thiazole derivative 5. Yellowish-green crystals (yield: 65%), m. p. >300 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In N,N-dimethyl-formamide at 20℃; for 2h; | Synthesis of (E)-1-(5,6-dibromo-4,7-dioxobenzo[d]thiazol-2(3H,4H,7H)-ylidene)guanidine (7) To a well-stirred solution of 2,3,5,6-tetrabromo-1,4-benzoquinone (6) (227 mg, 1 mmol) in DMF (5 mL), a solution of 1 (118 mg, 1 mmol) in DMF (5 mL) was added slowly. The yellow color of the reaction mixture gradually turned to red. A grey precipitate started to be formed. The reaction mixture was stirred for 2 h at room temperature, the precipitate was collected and crystallized by using a mixture of DMF-EtOH. Grey powder (yield: 60%), m. p. 240 - 242 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In N,N-dimethyl-formamide at 20℃; for 2h; | Synthesis of (E)-1-(4-chloro-5-oxonaphtho[1,2-d]thiazol-2(5H)-ylidene)guanidine (9) To a round-bottom flask containing a solution of 2,3-dichloro-1,4-naphthoquinone (DCHNQ, 8) (227 mg,1 mmol) in DMF (5 mL), a solution of 1 (118 mg, 1 mmol) in DMF (5 mL) was added slowly with stirring; the yellow solution turned to red, then to brown. A brown precipitate started to be formed. The reaction mixture was stirred for 2 hat room temperature, the precipitate was collected and crystallized from acetonitrile. Brown crystals (yield: 60%), m. p. 284 - 286 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In N,N-dimethyl-formamide at 20℃; for 3h; | Synthesis of (E)-1-(5,6-dichloro-4,7-dioxobenzo[d]thiazol-2(3H,4H,7H)-ylidene)guanidine (14) To a magnetically stirred solution of 2,3,5,6-tetrachloro-1,4-benzoquinone (13) (245 mg, 1 mmol) in DMF (5 mL), a solution of 1 (118 mg, 1 mmol) in DMF (5 mL) was added; the yellow color of the solution changed to red, then to reddish brown. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (TLC analysis), the formed precipitate was collected by filtration, washed and recrystallized from DMF to afford the product 14. Reddish brown crystals (yield: 68%), m. p. 360 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In N,N-dimethyl-formamide at 20℃; for 3h; | Synthesis of (E)-1-(7-chloro-4,5-dicyano-6-oxobenzo[d]thiazol-2(6H)-ylidene)guanidine (16) To a solution of 2,3-dicyano-5,6-dichloro-1,4-benzoquinone (DDQ, 15) (227 mg, 1 mmol) in 10 mL of DMF, a solution of 1 (118 mg, 1 mmol) in 10 mL of DMF was added slowly; the initially yellow solution turned to dark blue and then to reddish brown. The solution was stirred for 3 h at room temperature. A brown precipitate was formed, which after completion of the reaction (TLC control) was collected and recrystallized from 1,4-dioxane. Brown crystal (yield: 60%), m. p. 172 - 174 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In N,N-dimethyl-formamide at 20℃; for 5h; | Synthesis of (E)-1-(5'-cyano-1,3-dioxo-1,3-dihydrospiro-[indene-2,4'-thiazolidin]-2'-ylidene)guanidine (18) To a well-stirred solution of 2-dicyanomethyleneindan-1,3-dione (CNIND, 17) (208 mg, 1 mmol) dissolved in DMF (10 mL), a solution of 1 (118 mg, 1 mmol) dissolved in DMF (10 mL) was added dropwise with constant stirring. of the reaction mixture changed from yellow to reddish brown. The reaction mixture was stirred at room temperature for 5 h. The formed precipitate was collected by filtration and recrystallized from DMF-EtOH. Brown crystals (yield:63%), m. p. 320 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In ethanol for 2h; Reflux; | Synthesis of methyl 2-((diaminomethylene)amino)-4-oxo-4H-1,3-thiazine-6-carboxylate (22) A mixture of equimolar amounts of N-amidinothiourea (1) (118 mg, 1 mmol) and dimethyl acetylenedicarboxylate (21) (142 mg, 1 mmol) in the presence of a catalytic amount of p-TSA was refluxed in absolute ethanol (20 mL) for 2 h. The resulting precipitate obtained after cooling was filtered off, dried, and recrystallized from ethanol. Yellow powder yield: 85%), m. p. 250 - 252 °C (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With toluene-4-sulfonic acid In ethanol for 2h; Reflux; | Synthesis of (E)-N-((4-formylbenzylidene)carbamothioyl)-guanidine (28) Equimolar quantities of terephthalaldehyde (27) (134 mg,1 mmol) and 1 (118 mg, 1 mmol) in the presence of a catalytic amount of p-TSA in absolute ethanol (20 mL) were heated under reflux. A yellow precipitate commenced to be formed after 30 min. The reaction was continued under reflux conditions for 2 h. After completion of the reaction(monitoring by TLC), the precipitate was filtered off and recrystallized from DMF-EtOH. Yellow powder (yield: 81%), m. p. > 360°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With toluene-4-sulfonic acid In ethanol for 2h; Reflux; | Synthesis of (E,Z)-N,N'-(1,4-phenylenebis-(methanylylidene))carbamothioyldiguanidine (29) Compound 1 (236 mg, 2 mmol) and terephthalaldehyde (27) (134 mg, 1 mmol) in the presence of a catalytic amountof p-TSA were heated in absolute ethanol (20 mL) under reflux. A yellow precipitate was formed after 30 min. The reaction was continued for 2 h. After completion of the reaction (TLC analysis), the precipitate was filtered off, washed, dried and recrystallized from DMF-EtOH. Yellow powder (yield: 79%), m. p. 276 - 278 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: amidinothiocarbamide; (4aR,5S,6S,6aR,9S,11aS,11bS,14R)-2-bromo-5,6,14-trihydroxy-4,4-dimethyl-8-methylenedecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-1,7(8H)-dione In ethanol for 3h; Reflux; Stage #2: With hydrogenchloride In ethanol; water | 12 EXAMPLE 121 -((5 aR ,6S,7S,7aR , lOS, 1 2a5, 1 2bR, 1 5R)-6,7, 15 -trihydroxy-5 ,5 -dimethyl-9-methylene-8-oxo-5 ,5a,6,7,8,9, 10,11,12,1 2a-decahydro-4H-7, 1 2b-(epoxymethano)-7a, 10- methanocyclohepta[7,8]naphtho [1 ,2-d]thiazol-2-yl)guanidine (CYD-6-29) [0102] To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added amidinothiourea (19 mg, 0.16 mmol) at room temperature. The reaction mixture was heated under reflux for 3 h. After cooling, the mixture was acidified with 5% HC1 aqueous solution, and concentrated in vacuo to give an oily residue. The residue was purified by silica gel column; elution with 5% MeOH in CH2C12 afforded the desired product CYD-6-29 (28 mg, 50%) as a colorless solid; [CL]D25+108 (c 0.1, CHC13/CH3OH = 4:1); HPLC purity 95.1% (tp. =5.7 mm); 1H NMR (600 MHz,CD3OD + CDC13): ö 6.19 (s, 1H), 5.62 (s, 1H), 5.06 (s, 1H),4.44 (d, 1H, J 9.6 Hz), 4.00 (d, 1H, J 9.0 Hz), 3.85 (d, 1H, J 8.4 Hz), 3.05 (d, 1H, J=9.0 Hz), 2.66 (d, 1H, J= 16.2 Hz), 2.55 (m, 2H), 2.24 (m, 1H), 2.09 (dd, 1H, J= 4.8 Hz, 13.2 Hz), 1.81 (d, 1H, J = 8.4 Hz), 1.72 (m, 1H), 1.62 (m, 1H), 1.30 (s, 3H), 1.01 (s, 3H). 13C NMR (150 MHz, CDC13): ö 206.7, 156.5, 154.4, 151.1, 142.9, 126.6, 120.9, 97.5, 72.5, 64.8, 61.7, 58.8, 52.5, 43.1, 40.2, 38.0, 34.7, 30.0, 29.7, 29.3, 20.1, 19.6. MS (+ESI-LR): mlz =461.1 [M+H] HRMS calc. for C22H28N4055: [M+H] 461.1853; found 461.1856. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water Heating; | Preparation of 1-(diaminomethylene)thiouron-1-ium 4-hydroxybenzenesulfonate and its deuterated D8 analogue General procedure: Commercially available 2-imino-4-thiobiuret (Aldrich, CAS No.2114-02-05), which is in fact the tautomeric form 1-(diaminomethylene)thiourea and the 4-hydroxybenzenesulfonic acid were added to hot water in a molar proportion of 1:1. When the solution became homogeneous it was cooled slowly and kept at roomtemperature. After several days, transparent colourless crystals of C6H4(OH)SO3C2H7N4S were formed. Analysis: calculated for C8H12N4S2O4: C, 32.86; N, 19.17; O, 21.89; S, 21.94 and H, 4.14%. Found: C, 32.66; N, 19.10; O, 22.04; S, 22.09 and H, 4.09%. Deuterated d8 analogue of 1-(diaminomethylene)thiouron-1-ium4-hydroxybenzenesulfonate was prepared by the usual reactionwith heavy water. The crystals of 1-(diaminomethylene)thiouron-1-ium 4-hydroxybenzenesulfonate were dissolved in heavywater, and left in the atmosphere saturated with heavy water for one weak, in order to avoid the contamination of the crystals. The procedure was repeated twice. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water-d2 | Preparation of 1-(diaminomethylene)thiouron-1-ium 4-hydroxybenzenesulfonate and its deuterated D8 analogue General procedure: Commercially available 2-imino-4-thiobiuret (Aldrich, CAS No.2114-02-05), which is in fact the tautomeric form 1-(diaminomethylene)thiourea and the 4-hydroxybenzenesulfonic acid were added to hot water in a molar proportion of 1:1. When the solution became homogeneous it was cooled slowly and kept at roomtemperature. After several days, transparent colourless crystals of C6H4(OH)SO3C2H7N4S were formed. Analysis: calculated for C8H12N4S2O4: C, 32.86; N, 19.17; O, 21.89; S, 21.94 and H, 4.14%. Found: C, 32.66; N, 19.10; O, 22.04; S, 22.09 and H, 4.09%. Deuterated d8 analogue of 1-(diaminomethylene)thiouron-1-ium4-hydroxybenzenesulfonate was prepared by the usual reactionwith heavy water. The crystals of 1-(diaminomethylene)thiouron-1-ium 4-hydroxybenzenesulfonate were dissolved in heavywater, and left in the atmosphere saturated with heavy water for one weak, in order to avoid the contamination of the crystals. The procedure was repeated twice. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In acetone at 75℃; | 1.1.b Synthesis of 2-[4-(4-chlorobutyl)thiazole-2-yl] guanidine (Compound 3)[1] Liquid mixture prepared by mixing 1,6-dichlorohexane-2-one (4.7g, 28mmol) and guanylthiourea (3.3g, 28mmol) in 80ml of aceton as a solvent was stirred and refluxed at 75°C overnight. Disappearance of starting material was confirmed by thin layer chromatography (TLC), the solvent was removed under reduced pressure, and the residue was refined by chromatography (dichloromethane/methanol, 50/1) to obtain 2-[4-(4-chlorobutyl)thiazole-2-yl]guanidine (3.77g, 58%) (Compound 3). 1H-NMR (d6-DMSO, 300MHz):δ1.71(br, 2H);1.92(br, 2H);2.53(br, 2H);3.34(br, 2H, NH);3.66(br, 2H);6.35(S, 1H) ; 6.94 (br, 2H, NH). M.W.:232, ESI-MS: 233(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In acetone at 20℃; for 12h; | 15.a 2- (5- (Chloromethyl) thiazol-2-yl) guanidine (2) [1] A suspension of amidinothiourea 1 (118g, 1mol) in acetone (600ml) was treated with 1,3-dichloroacetone (126g, 1mol). After stirring overnight at room temperature, the solid was filtered off and washed with acetone. Crystallization from ethanol gave the compound 2 (122g, 54%). 1H-NMR (d6-DMSO, 200MHz): δ 3.44 (br, 4H, NH) ; 4.76(s, 2H) ; 7.43 (s, 1H) ; 8.41(br, 1H, N3+H). M.W.: 226(hydrochloride); ESI-MS: 191 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In acetone at 20℃; for 12h; | 20.a 2-(5-(Chloromethyl)thiazol-2-yl)guanidine (2) [1]: A suspension of amidinothiourea 1 (118g, 1mol) in acetone (600ml) was treated with 1,3-dichloroacetone (126g, 1mol). After stirring overnight at room temperature, the solid was filtered off and washed with acetone, Crystallization from ethanol gave the compound 2 (122g, 54%, Rf=0.4, DCM/Methanol, 5/1). 1H-NMR (d6-DMSO, 300MHz): δ 3.44 (b, 4H) ; 4.76 (s, 2H); 7.43 (s, 1H); 8.41 (b, 1H). M.W.: 226 (hydrochloride); ESI-MS: 191 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.6% | In acetone at 50℃; for 12h; Inert atmosphere; | 26.e SR 3131 [3] : A mixture of compound 5 (1.07g, 5mmol) and amidinothiourea (0.59g, 5mmol) in acetone (50ml)) was stirred at 50°C under nitrogen atmosphere for 12h. When TLC showed no starting material remained, the solvent was removed under reduced pressure and the residue was purified by chromatography (DCM/Methanol, 60/1) to give compound SR 3131 (690mg, 49. 6%). 1H-NMR (CD3OD, 300MHz): δ 2.01(m, 2H); 2.66(m, 4H); 4.93(br, 4H, NH); 6.78(s, 1H); 7.01(m, 2H); 7.20(m, 2H). M.W.: 278, ESI-MS: 279(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: cyanocarboxamidine With hydrogenchloride In water at 20℃; Stage #2: With ammonium hydroxide; Sodium thiosulfate pentahydrate In water at 0℃; for 1h; | 19 1-[Amino(imino)methyl]thiourea (Guanyithiourea) (A): To a solution ofdicyandiamide (1 g, 1.9 mmol) in water (250 ml) conc. HC1 (2.38 ml) was added dropwise over aperiod of 10 minutes by maintaining the reaction temperature below 20 °C. With continued stirring, a solution of sodium thiosulfate pentahydrate (2.98 g, 1.9 mmol) in water (125 ml ) was added dropwise over 30 minutes, by then the nearly insoluble gutimine hydrogen sulfate was precipitated out. After that pH of the mixture was adjusted to 8-10 by addition of ammonium hydroxide (2.86 ml,25%) at 0 °C. The obtained precipitate was collected, washed with cold water and dried to obtain2.25 g (80%) of compound A as colorless crystals. 1H NMR (DMSO-d6): 3 7.15 (brs, 3H, NH), 6.99 (brs, 3H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide In water at 50℃; for 8h; | 2.1. Synthesis and growth General procedure: White amidinothiourea (2-imino-4-thiobiuret aminoiminoethylthiourea guanylthiourea, 98%) powder was purchased from Aladdin.Yellow bismuth(III) oxide (AR) powder, hydrochloric acid(AR, 36%-38% wt), hydrobromic acid (AR, 40% wt), and hydroiodicacid (AR, 45% wt) were purchased from Sinophrm ChemicalReagent Co., Ltd. All chemical reagents were used without purification.Three title compounds were synthesized as shown inScheme 1. The mole ratios of bismuth oxide and amidinothioureaof HATU-BCH, HATU-BB, and OHATU-BI are 1:3, 1:2, and 1:2,respectively. For HATU-BCH and HATU-BB, amidinothiourea andbismuth oxide were dissolved in hydrochloric acid aqueous solutionand hydrobromic acid aqueous solutions, respectively. ForOHATU-BI, amidinothiourea was dissolved in hydrogen peroxideaqueous solution (3%) [33] and bismuth oxide was dissolved inhydroiodic acid aqueous solution. The mixed solutions were stirredunder 50 C for 8 h. The single crystals of the title compounds wereobtained by slow evaporation of the reaction mixtures in about 2or 3 weeks. The as-grown crystals with colorless, yellow, and redcolor, respectively, are shown in Fig. 1. All the crystals are stablein air for several months. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With hydrogen bromide; In water; at 100℃; | To the solution of guanylthiourea (500mg, 4.23mmol) in 48% aq HBr (2mL) was added the 3-iodobenzyl alcohol (894mg, 3.82mmol) and resultant mixture was heated under reflux (oil bath temp 100C) for 12h. The reaction was cooled to 0C and treated with 6M aq NaOH (5mL). The solid that precipitated was filtered and recrystallized in ethanol to get the final product in 90% (1.15g) yield as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With hydrogen bromide In water at 100℃; | 4.2.1 Alkylation with corresponding benzylic alcohols. (3-Iodo)benzyl amidinoisothiourea (1) To the solution of guanylthiourea (500mg, 4.23mmol) in 48% aq HBr (2mL) was added the 3-iodobenzyl alcohol (894mg, 3.82mmol) and resultant mixture was heated under reflux (oil bath temp 100°C) for 12h. The reaction was cooled to 0°C and treated with 6M aq NaOH (5mL). The solid that precipitated was filtered and recrystallized in ethanol to get the final product in 90% (1.15g) yield as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogen bromide In water at 100℃; | 4.2.1 Alkylation with corresponding benzylic alcohols. (3-Iodo)benzyl amidinoisothiourea (1) To the solution of guanylthiourea (500mg, 4.23mmol) in 48% aq HBr (2mL) was added the 3-iodobenzyl alcohol (894mg, 3.82mmol) and resultant mixture was heated under reflux (oil bath temp 100°C) for 12h. The reaction was cooled to 0°C and treated with 6M aq NaOH (5mL). The solid that precipitated was filtered and recrystallized in ethanol to get the final product in 90% (1.15g) yield as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydrogen bromide In water at 100℃; | 4.2.1 Alkylation with corresponding benzylic alcohols. (3-Iodo)benzyl amidinoisothiourea (1) To the solution of guanylthiourea (500mg, 4.23mmol) in 48% aq HBr (2mL) was added the 3-iodobenzyl alcohol (894mg, 3.82mmol) and resultant mixture was heated under reflux (oil bath temp 100°C) for 12h. The reaction was cooled to 0°C and treated with 6M aq NaOH (5mL). The solid that precipitated was filtered and recrystallized in ethanol to get the final product in 90% (1.15g) yield as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With hydrogen bromide In water at 100℃; | 4.2.1 Alkylation with corresponding benzylic alcohols. (3-Iodo)benzyl amidinoisothiourea (1) To the solution of guanylthiourea (500mg, 4.23mmol) in 48% aq HBr (2mL) was added the 3-iodobenzyl alcohol (894mg, 3.82mmol) and resultant mixture was heated under reflux (oil bath temp 100°C) for 12h. The reaction was cooled to 0°C and treated with 6M aq NaOH (5mL). The solid that precipitated was filtered and recrystallized in ethanol to get the final product in 90% (1.15g) yield as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In acetonitrile Reflux; | General procedure: 2-(benzthiazol-2-yloxy)ethyl bromide (550mg, 2.13mmol) was then added to guanylthiourea (665mg, 1.92mmol) in acetonitrile and refluxed for 36h to obtain white precipitates. On complete consumption of guanylthiourea, the reaction mixture was cooled to room temperature and concentrated under vacuum. The semi-solid mass was washed with diethyl ether (2×5mL) and n-hexane and recrystallized from ethanol (3mL) to obtain white solid compound 11 in 72% yield (453mg). The remaining alkylated GTU derivatives were prepared following this typical procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen bromide In water at 100℃; | 4.2.1 Alkylation with corresponding benzylic alcohols. (3-Iodo)benzyl amidinoisothiourea (1) To the solution of guanylthiourea (500mg, 4.23mmol) in 48% aq HBr (2mL) was added the 3-iodobenzyl alcohol (894mg, 3.82mmol) and resultant mixture was heated under reflux (oil bath temp 100°C) for 12h. The reaction was cooled to 0°C and treated with 6M aq NaOH (5mL). The solid that precipitated was filtered and recrystallized in ethanol to get the final product in 90% (1.15g) yield as white solid; mp>200°C; 1H NMR (400MHz, DMSO-d6): δ 7.70 (s, 1H), 7.59 (d, 1H, J=7.76Hz), 7.56 (s, 2H), 7.35 (d, 1H, J=7.60Hz), 7.11 (t, 1H, J=7.72Hz), 4.02 (s, 2H); 13C NMR (100MHz, DMSO-d6): δ 160.11, 151.43, 137.62, 136.06, 131.02, 128.64, 124.23, 110.17, 31.16; MS (MALDI) m/z calculated for C9H11IN4S [M]+ 334.19; found [M+2] 336.62. The remaining benzylated GTU derivatives using benzylic alcohol were prepared following this typical procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | In acetonitrile at 100℃; for 0.25h; Microwave irradiation; Sealed tube; | 4.2.7 Alkylation with corresponding benzylic bromides. (3-Trifluoromethyl)benzyl amidinoisothiourea (7) The mixture of (3-trifluoromethyl)benzyl bromide (250mg, 2.12mmol) and guanylthiourea (460mg, 1.92mmol) in acetonitrile (1mL) was placed in a 5mL capacity sealed microwave vessel and subjected to microwave irradiation at 100°C for 15min. The mixture was cooled to 50°C, the precipitated hydrobromide salt of the (3-trifluoromethyl)benzyl amidinoisothiourea was collected by filtration and washed with acetonitrile (2mL) to obtain the final product in 45% yield (240mg). White solid; mp>200°C; IR (neat) νmax=2959, 2917, 2857, 1961, 1914, 1696, 1592, 1484, 1253, 1231, 1146, 1016; 1H NMR (400MHz, DMSO-d6): 1H NMR (DMSO-d6, 400MHz): δ 8.08 (s, 2H), 8.03 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=7.76Hz, 1H), 7.58 (t, J=7.64Hz, 1H), 4.32 (s, 2H); 13C NMR (100MHz, DMSO-d6): δ 163.77, 162.43, 139.57, 133.64, 129.76, 125.95, 124.47, 123.24, 65.39, 34.25; MS (LCMS) m/z calculated for C10H12F3N4S+ [M]+ 277.28; found [M]+ 277.11. The remaining benzylated GTU derivatives using benzylic alcohol were prepared following this typical procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In acetonitrile at 100℃; for 0.25h; Microwave irradiation; Sealed tube; | 4.2.7 Alkylation with corresponding benzylic bromides. (3-Trifluoromethyl)benzyl amidinoisothiourea (7) The mixture of (3-trifluoromethyl)benzyl bromide (250mg, 2.12mmol) and guanylthiourea (460mg, 1.92mmol) in acetonitrile (1mL) was placed in a 5mL capacity sealed microwave vessel and subjected to microwave irradiation at 100°C for 15min. The mixture was cooled to 50°C, the precipitated hydrobromide salt of the (3-trifluoromethyl)benzyl amidinoisothiourea was collected by filtration and washed with acetonitrile (2mL) to obtain the final product in 45% yield (240mg). White solid; mp>200°C; IR (neat) νmax=2959, 2917, 2857, 1961, 1914, 1696, 1592, 1484, 1253, 1231, 1146, 1016; 1H NMR (400MHz, DMSO-d6): 1H NMR (DMSO-d6, 400MHz): δ 8.08 (s, 2H), 8.03 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=7.76Hz, 1H), 7.58 (t, J=7.64Hz, 1H), 4.32 (s, 2H); 13C NMR (100MHz, DMSO-d6): δ 163.77, 162.43, 139.57, 133.64, 129.76, 125.95, 124.47, 123.24, 65.39, 34.25; MS (LCMS) m/z calculated for C10H12F3N4S+ [M]+ 277.28; found [M]+ 277.11. The remaining benzylated GTU derivatives using benzylic alcohol were prepared following this typical procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In acetonitrile at 100℃; for 0.25h; Microwave irradiation; Sealed tube; | 4.2.7 Alkylation with corresponding benzylic bromides. (3-Trifluoromethyl)benzyl amidinoisothiourea (7) The mixture of (3-trifluoromethyl)benzyl bromide (250mg, 2.12mmol) and guanylthiourea (460mg, 1.92mmol) in acetonitrile (1mL) was placed in a 5mL capacity sealed microwave vessel and subjected to microwave irradiation at 100°C for 15min. The mixture was cooled to 50°C, the precipitated hydrobromide salt of the (3-trifluoromethyl)benzyl amidinoisothiourea was collected by filtration and washed with acetonitrile (2mL) to obtain the final product in 45% yield (240mg). White solid; mp>200°C; IR (neat) νmax=2959, 2917, 2857, 1961, 1914, 1696, 1592, 1484, 1253, 1231, 1146, 1016; 1H NMR (400MHz, DMSO-d6): 1H NMR (DMSO-d6, 400MHz): δ 8.08 (s, 2H), 8.03 (s, 1H), 7.71 (m, 2H), 7.64 (d, J=7.76Hz, 1H), 7.58 (t, J=7.64Hz, 1H), 4.32 (s, 2H); 13C NMR (100MHz, DMSO-d6): δ 163.77, 162.43, 139.57, 133.64, 129.76, 125.95, 124.47, 123.24, 65.39, 34.25; MS (LCMS) m/z calculated for C10H12F3N4S+ [M]+ 277.28; found [M]+ 277.11. The remaining benzylated GTU derivatives using benzylic alcohol were prepared following this typical procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In ethanol Reflux; | 4.1.3. Preparation of compounds 4a-i General procedure: General procedure. To a solution of bromoacetyl 3 (0.56 mmol)in absolute ethanol (5 mL), proper thiourea or thioamide(1.25-2.5 mmol) and anhydrous potassium carbonate (0.2 g,1.4 mmol) were added. The reaction mixture was heated at reflux for 4-8 h. After consuming all starting materials, as monitored by TLC, the reaction was quenched with cold water (50 mL). The formed flocculated solid was filtered, washed with water and purified by crystallization from absolute ethanol or via acid-base extraction using HCl (1 M, 50 mL). Upon neutralization with sodium carbonate to pH 7-8, the desired products were precipitated. Physical properties and spectral analysis of isolated products are listed below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In ethanol Reflux; | 4.1.3. Preparation of compounds 4a-i General procedure: General procedure. To a solution of bromoacetyl 3 (0.56 mmol)in absolute ethanol (5 mL), proper thiourea or thioamide(1.25-2.5 mmol) and anhydrous potassium carbonate (0.2 g,1.4 mmol) were added. The reaction mixture was heated at reflux for 4-8 h. After consuming all starting materials, as monitored by TLC, the reaction was quenched with cold water (50 mL). The formed flocculated solid was filtered, washed with water and purified by crystallization from absolute ethanol or via acid-base extraction using HCl (1 M, 50 mL). Upon neutralization with sodium carbonate to pH 7-8, the desired products were precipitated. Physical properties and spectral analysis of isolated products are listed below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In ethanol Reflux; | 4.1.3. Preparation of compounds 4a-i General procedure: General procedure. To a solution of bromoacetyl 3 (0.56 mmol)in absolute ethanol (5 mL), proper thiourea or thioamide(1.25-2.5 mmol) and anhydrous potassium carbonate (0.2 g,1.4 mmol) were added. The reaction mixture was heated at reflux for 4-8 h. After consuming all starting materials, as monitored by TLC, the reaction was quenched with cold water (50 mL). The formed flocculated solid was filtered, washed with water and purified by crystallization from absolute ethanol or via acid-base extraction using HCl (1 M, 50 mL). Upon neutralization with sodium carbonate to pH 7-8, the desired products were precipitated. Physical properties and spectral analysis of isolated products are listed below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In methanol for 3h; Reflux; | 2-Diaminomethyleneamino-4-(5-bromo-1-methoxyindol-3-yl)thiazole (47) from 43a Guanylthiourea (38.4 mg, 2 eq.) was added to a solution of 43a (49.0 mg, 0.16 mmol) in MeOH 2.0 mL)and refluxed with stirring for 3 h. Water and 8% aq. NaOH were added and the whole was extracted withCH2Cl2-MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated underreduced pressure to leave an oil, which was column chromatographed on SiO2 with CHCl3-MeOH-28%NH3 (50:5:0.5, v/v) to give 47 (53.2 mg, 90%). 47: mp 145.5-146.5 oC (pale brown prisms, recrystallizedfrom MeOH). IR (KBr): 3410, 3109, 1639, 1610, 1539, 1450, 1438, 1248 cm-1. 1H-NMR (CDCl3) : 4.13(3H, s), 6.83 (1H, s), 7.35 (1H, dd, J = 8.6, 1.6 Hz), 7.39 (1H, dd, J = 8.6, 0.4 Hz), 7.87 (1H, s), 8.11 (1H,dd, J = 1.6, 0.4 Hz). Anal. Calcd for C13H12BrN5OS: C, 42.63; H, 3.30; N, 19.12. Found: C, 42.75; H,3.26; N, 18.92 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In acetone at 20℃; for 21h; Reflux; | 2 Building guanidine-substituted thiazole To a stirred solution of 12.4g of intermediate 7 in 1120 ml of Acetone, 52.3 grams of 2-Imino-4-thiobiuret were added. The solution was refluxed for 5 hours and left to cool down at room temperature and stirred for additional 16 hours. The suspension was filtered the solid discarded and the acetone removed under reduced pressure. The solid residue was taken-up with 500ml of dichloromethane and 500ml of water. The aqueous phase was extracted twice with 250ml of dichloromethane and the pooled organic phases were dried over MgSO4, filtered and the solvent removed under vacuum giving 15.3g of intermediate 8 as yellowish solid, that was purified by flash-chromatography (SiO2) (from cyclohexane/ethyl acetate 1/1 + 1% of TEA - ethyl acetate 99% + 1% of TEA as eluent) to give 8.95 grams of pure product 8 (73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In acetone at 20℃; for 21h; Reflux; | 4 Building guanidine-substituted imidazole ring To a stirred solution of 0.64g of intermediate H in 52ml of Acetone, 2.39 grams of 2-Imino-4-thiobiuret (Amidinothiourea, commercial) were added. The solution was refluxed for 5 hours, cooled down at room temperature and stirred for additional 16 hours. The suspension was filtered, the solid discarded and the acetone removed under reduced pressure. The solid residue was dissolved with 20 ml of dichloromethane and washed with water. The organic phase was dried over MgSO4, filtered and the solvent removed under vacuum giving 0.59 grams of crude product as yellow solid, that was purified by flash-chromatography (Si02) (from ethyl acetate/cyclohexane 8/2 + 1% of TEA - ethyl acetate 99% + 1% of TEA as eluent) obtaining 0.40 grams of pure product I (62%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Oxone; lithium chloride In methanol at 60℃; for 1h; | 21 Example 21: Synthesis of 2-guanidino-4-chloromethylthiazole (Formula 28) Add acetone (0.23 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (4.18 g, 8.8mmol) sequentiallyAnd LiCl (0.38 g, 8.8 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is complete after refluxing for 1h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained is recrystallized with methyl tert-butyl ether,The product 2-guanidino-4-chloromethylthiazole (0.74 g) with the following structure was obtained,The yield was 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 25 Example 25: Synthesis of 2-guanidino-4-bromomethylthiazole (Formula 32) Add acetone (0.23 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (4.18 g, 8.8mmol) sequentiallyAnd NaBr (0.70 g, 8.8 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained is recrystallized with methyl tert-butyl ether,The product 2-guanidino-4-bromomethylthiazole (0.91 g) with the following structure was obtained,The yield was 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With Oxone; sodium bromide In methanol at 60℃; for 3h; | 1 Example 1: Synthesis of 2-guanidino-4-methylthiazole (Formula 8 Add acetone (0.23 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture slowly warm up to 60°C,The reaction is complete after refluxing for 3h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation, suction filtration,Take the filter cake and dry it. At last,The crude product obtained was recrystallized with MeOH,Get the following structure product2-guanidino-4-methylthiazole (0.56 g),The yield is 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Oxone; potassium bromide In ethanol at 80℃; for 2h; | 2 Example 2: Synthesis of 2-guanidino-4-methylthiazole-5-carboxylic acid ethyl ester (Formula 9) Ethyl acetoacetate (0.52 g, 4.0 mmol)Dissolved in EtOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd KBr (0.52g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture, slowly warm up to 80°C,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with EtOH,The product with the following structure, 2-guanidino-4-methylthiazole-5-carboxylic acid ethyl ester (0.85 g),The yield was 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Oxone; sodium chloride In ethanol at 80℃; for 1h; | 3 Example 3: Synthesis of 2-guanidino-4-methylthiazole-5-carboxylic acid methyl ester (Formula 10) Methyl acetoacetate (0.46 g, 4.0 mmol)Dissolved in EtOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaCl (0.25 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 80,It should be completed after 1h reflux,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with EtOH,The product 2-guanidino-4-methylthiazole-5-carboxylic acid methyl ester (0.81 g) with the following structure was obtained,The yield was 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 5 Example 5: Synthesis of N-(4-(4-fluorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 12) Combine 4-fluoroacetophenone (0.56 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation, suction filtration,Take the filter cake and dry it. At last,The crude product obtained was recrystallized with MeOH,Get the following structure productN-(4-(4-fluorophenyl)-1,3-thiazol-2-yl)guanidine (0.86 g),The yield was 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 6 Example 6: Synthesis of N-(4-(4-chlorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 13) Add 4-chloroacetophenone (0.62 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take filter cake, dryFinally, the crude product obtained is recrystallized with MeOH,The product N-(4-(4-chlorophenyl)-1,3-thiazol-2-yl)guanidine (0.88 g) was obtained with the following structure,The yield was 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 7 Example 7: Synthesis of N-(4-(4-bromophenyl)-1,3-thiazol-2-yl)guanidine (Formula 14) Add 4-bromoacetophenone (0.80 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Amidinothiourea (0.47 g, 4.0 mmol) was addedInto the mixture slowly warm up to 60°C,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with MeOH,The product N-(4-(4-bromophenyl)-1,3-thiazol-2-yl)guanidine (1.10 g) was obtained with the following structure,The yield was 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With Oxone; sodium bromide In methanol at 60℃; for 3h; | 8 Example 8: Synthesis of N-(4-(4-iodophenyl)-1,3-thiazol-2-yl)guanidine (Formula 15) Add 4-iodoacetophenone (0.98 g, 0.4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is complete after refluxing for 3h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with MeOH,N-(4-(4-iodophenyl)-1,3-thiazol-2-yl)guanidine (1.14 g) was obtained as the product with the following structure,The yield was 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 9 Example 9: Synthesis of N-(4-(4-methoxyphenyl)-1,3-thiazol-2-yl)guanidine (Formula 16) Combine 4-methoxyacetophenone (0.61 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with MeOH,The product N-(4-(4-methoxyphenyl)-1,3-thiazol-2-yl)guanidine (0.86g) was obtained with the following structure,The yield was 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With Oxone; sodium bromide In methanol at 60℃; for 4h; | 10 Example 10: Synthesis of N-(4-(4-nitrophenyl)-1,3-thiazol-2-yl)guanidine (Formula 17) Combine 4-nitroacetophenone (0.66 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is complete after refluxing for 4h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with MeOH,The product N-(4-(4-nitrophenyl)-1,3-thiazol-2-yl)guanidine (0.83g) with the following structure was obtained,The yield was 79%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With Oxone; sodium bromide In methanol at 60℃; for 1h; | 11 Example 11: Synthesis of N-(4-(3-fluorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 18) Add 3-fluoroacetophenone (0.56 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Slowly increase to 60,After refluxing for 1h,Add amidinothiourea (0.47g, 4.0 mmol)Into the mixture.After 5h, the reaction is complete,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with MeOH,N-(4-(3-fluorophenyl)-1,3-thiazol-2-yl)guanidine (0.83g) was obtained as the product with the following structure,The yield was 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 12 Example 12: Synthesis of N-(4-(3-chlorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 19) Add 3-chloroacetophenone (0.62 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry.Finally, the crude product obtained is recrystallized with MeOH,The product N-(4-(3-chlorophenyl)-1,3-thiazol-2-yl)guanidine (0.93 g) was obtained with the following structure,The yield was 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 13 Example 13: Synthesis of N-(4-(3-bromophenyl)-1,3-thiazol-2-yl)guanidine (Formula 20) Add 3-bromoacetophenone (0.80 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70 g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(3-bromophenyl)-1,3-thiazol-2-yl)guanidine (1.06 g) was obtained with the following structure,The yield is 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 14 Example 14: Synthesis of N-(4-(3-methylphenyl)-1,3-thiazol-2-yl)guanidine (Formula 21) Combine 3-methylacetophenone (0.54 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,N-(4-(3-methylphenyl)-1,3-thiazol-2-yl)guanidine (0.86g) was obtained as the product with the following structure,The yield was 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 15 Example 15: Synthesis of N-(4-(3-methoxyphenyl)-1,3-thiazol-2-yl)guanidine (Formula 22) Combine 3-methoxyacetophenone (0.61 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(3-methoxyphenyl)-1,3-thiazol-2-yl)guanidine (0.84g) was obtained with the following structure,The yield was 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With Oxone; sodium bromide In methanol at 60℃; for 3h; | 16 Example 16: Synthesis of N-(4-(3-nitrophenyl)-1,3-thiazol-2-yl)guanidine (Formula 23) Combine 3-nitroacetophenone (0.66 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.70g, 4.4 mmol) sequentiallyAnd NaBr (0.45 g, 4.4 mmol),Add amidinothiourea (0.47 g, 4.0 mmol) toInto the mixture,Slowly increase to 60,The reaction is complete after refluxing for 3h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(3-nitrophenyl)-1,3-thiazol-2-yl)guanidine (0.79g) was obtained with the following structure,The yield is 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 17 Example 17: Synthesis of N-(4-(2-chlorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 24) Combine 2-chloroacetophenone (0.62 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.09g, 4.4 mmol) sequentiallyAnd NaBr (0.35g, 4.4 mmol),Add amidinothiourea (0.37g, 4.0 mmol)Into the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(2-chlorophenyl)-1,3-thiazol-2-yl)guanidine (0.78 g) was obtained with the following structure,The yield was 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 18 Example 18: Synthesis of N-(4-(2,6-dichloro-3-fluorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 25) 2,6-Dichloro-3-fluoroacetophenone (0.77 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.09g, 4.4 mmol) sequentiallyAnd NaBr (0.35g, 4.4 mmol),Add amidinothiourea (0.37g, 4.0 mmol)Into the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(2,6-dichloro-3-fluorophenyl)-1,3-thiazol-2-yl)guanidine (0.82 g) was obtained with the following structure,The yield was 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 19 Example 19: Synthesis of N-(4-(3,4-Dichloro-3-fluorophenyl)-1,3-thiazol-2-yl)guanidine (Formula 26) 3,4-Dichloroacetophenone (0.76 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.09g, 4.4 mmol) sequentiallyAnd NaBr (0.35g, 4.4 mmol),Add amidinothiourea (0.37g, 4.0 mmol)Into the mixture,Slowly heat up to 60,The reaction is complete after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Then adjust the pH to 8-9 with ammonia,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(3,4-dichloro-3-fluorophenyl)-1,3-thiazol-2-yl)guanidine (0.99 g) was obtained with the following structure,The yield was 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Oxone; sodium bromide In methanol at 60℃; for 2h; | 20 Example 20: Synthesis of N-(4-(2-naphthyl)-1,3-thiazol-2-yl)guanidine (Formula 27) The 2-naphthyl-ethanone (0.68 g, 4.0 mmol)Dissolved in MeOH (40 mL),Add Oxone (2.09g, 4.4 mmol) sequentiallyAnd NaBr (0.35g, 4.4 mmol),Add amidinothiourea (0.37g, 4.0 mmol)Into the mixture,Slowly increase to 60,The reaction is completed after refluxing for 2h,The reaction mixture is filtered,The filtrate was taken and concentrated in vacuo.Dissolve the crude product in water,Adjust the pH to 8-9 with ammonia water,There is solid precipitation,Suction filtration, take the filter cake, and dry. At last,The crude product obtained was recrystallized with MeOH,The product N-(4-(2-naphthyl)-1,3-thiazol-2-yl)guanidine (0.98 g) was obtained with the following structure,The yield was 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; hydrogen sulfide In water at 80℃; for 80h; | 1; 4 (Synthesis of guanylthiourea and dithiobiuret) In a 200 mL four-necked flask, 1 g of dicyandiamide, Charged with 0.56 g of 25% ammonia water and 100 ml of water, The reaction was carried out at 80 ° C. for 80 hours under a hydrogen sulfide stream by hydrogen sulfide gas bubbling. As a result of analyzing the reaction mixture by HPLC, the molar ratio of guanylthiourea to dicyandiamide was 80%. 8% of dithiobiuret was produced. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In ethanol for 2h; Reflux; | Methyl (2Z)-[2[(diaminomethylene)amino]-4-oxothiazol-5(4H)-ylidene]acetate (9). A mixture of equimolaramounts of N-amidinothiourea (118 mg, 1.00 mmol) and dimethyl acetylenedicarboxylate (142 mg, 1.00mmol) in the presence of a catalytic amount of p-TsOH (8.6 mg, 5 mol %) was refluxed in absolute ethanol (20mL) for 2 h.30 The resulting precipitate obtained after cooling was filtered off, dried, and recrystallized fromethanol to give (2Z)-[2[(diaminomethylene)amino]-4-oxothiazol-5(4H)-ylidene)acetate 9 as a yellow powder(193 mg, 0.85 mmol, 85%); mp 260-262 °C (EtOH) (lit. mp. 250-252 °C34); IR (cm-1): 3481, 3294, 3084 (NH),1689 (C=O, ester), 1656 (C=O, oxothiazol), 1641 (C=), 1244, 1170 (C-O, ester); 1H NMR (500 MHz, (CD3)2SO):δH 3.37 (3H, s, CH3), 6.60 (1H, s, CH), 7.6 (2H, s, NH2), 8.39 (s, 2H, 2NH); 13C NMR (125 MHz, (CD3)2SO): δC 52.6,113.8, 149.3, 160.9, 166.8, 179.1, 181.1; Found, m/z: 229.0403 [M+]+. C7H8N4O3S. Calculated, m/z: 229.0390. |
[ 21770-81-0 ]
1-Methylguanidine hydrochloride
Similarity: 0.50
[ 21770-81-0 ]
1-Methylguanidine hydrochloride
Similarity: 0.50
[ 21770-81-0 ]
1-Methylguanidine hydrochloride
Similarity: 0.50