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CAS No. : | 18202-73-8 | MDL No. : | MFCD00051988 |
Formula : | C5H13ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ARDGQYVTLGUJII-UHFFFAOYSA-N |
M.W : | 136.62 | Pubchem ID : | 2781880 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 39.15 |
TPSA : | 49.87 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.12 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.43 |
Log Po/w (WLOGP) : | 1.77 |
Log Po/w (MLOGP) : | 1.27 |
Log Po/w (SILICOS-IT) : | 0.09 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.52 |
Solubility : | 4.11 mg/ml ; 0.0301 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.08 |
Solubility : | 1.13 mg/ml ; 0.00827 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.75 |
Solubility : | 24.5 mg/ml ; 0.179 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
46% | With ammonia In methanol; ethanol | Step (1) Preparation of t-Butyl Amidine Hydrochloride To a cooled (0° C.), magnetically stirred solution of 2,2-dimethyl-1-propanenitrile (25.0 g, 0.30 mol), dry methanol (26.8 mL, 0.79 mol), and ether (30 mL) was added acetyl chloride (25.7 mL, 0.36 mol) dropwise. After the addition, cooling was continued for 15 minutes. The mixture was stirred at room temperature for 3 days. The resulting white crystals were filtered, washed with ether, and dried in vacuo. After drying, the crystals were combined with 10percent NH3 /ethanol (150 mL, 0.90 mol), and stirred at room temperature for 3 days. The solution was filtered, and the filtrate was concentrated to give a white solid. Recrystallization from ethanol yielded white crystals (18.9 g, 46percent), m.p. 188°-190° C. NMR (DMSO-d6): δ1.22 (s, 9H), 8.63 (br d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium hydroxide; In water; | To t-butyl amidine hydrochloride salt (1.38 g, 10.1 mmol) in 5% NaOH / H2O (w/v) (17 mL) was added compound 3.1 (2.76 g, 20.0 mmol, 2eq.). The reaction mixture was stirred overnight and then acidified to pH=5 with cone. HCl. The solution was extracted with chloroform (3X); the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel column chromatography eluting with hexanes and ethyl acetate to provide compound 3.2 (0.82 g, 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium acetate; In N,N-dimethyl-formamide; at 20 - 80℃; for 24h; | 3 Synthesis of 2-(t-butyl)-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: 100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide was dissolved in 5 ml of DMF. 54.5 mg (0.399 mmol) of t-butyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate were added at room temperature and stirred at 80 C. for one day. After DMF was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound. Yield: 62.2 mg (0.136 mmol) (51%) MS (ESI, m/z) 456 (M+H)+ 454 (M-H)- 1H-NMR (CDCl3): 1.42 (9H, s), 1.76 (2H, quint), 2.50 (2H, t), 2.58 (3H, s), 3.35 (2H, q), 5.50 (1H, br s), 7.08 (21H, d), 7.15-7.21 (1H, m), 7.24-7.29 (2H, m) 7.40-7.41 (1H, m), 7.73 (2H, d). |
With sodium acetate; In N,N-dimethyl-formamide; | 3) Synthesis of 2-(t-butyl)-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: 100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide was dissolved in 5 ml of DMF. 54.5 mg (0.399 mmol) of t-butyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate were added at room temperature and stirred at 80ØC for one day. After DMF was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane / ethyl acetate = 10/1 to 1/1) to obtain the title compound. Yield: 62.2 mg (0.136 mmol) (51%) MS (ESI, m/z) 456 (M+H)+ 454 (M-H)- 1H-NMR (CDCl3): 1.42 (9H, s), 1.76 (2H, quint), 2.50 (2H, t), 2.58 (3H, s), 3.35 (2H, q), 5.50 (1H, br s), 7.08 (2H, d), 7.15-7.21 (1H, m), 7.24-7.29 (2H, m), 7.40-7.41 (1H, m), 7.73 (2H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10A 7-Benzyl-2-Tert-Butyl4-Chloro-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine A mixture of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (4.36 g, 14.6 mmol), t-butylcarbamidine hydrochloride (2.00 g, 14.6 mmol) and sodium ethoxide (2.7 M in ethanol, 12.5 mL, 33.8 mmol) in ethanol (38 mL) was heated to 60 C. and stirred overnight. The mixture was cooled to about 25 C., concentrated, diluted with water and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and concentrated. The concentrate was heated in phosphorus oxychloride (Aldrich, 50 mL) at 90 C. for 3 hr. The mixture was cooled to 25 C., concentrated, diluted with saturated, aqueous NaHCO3, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, concentrated, and filtered through SiO2 with 25% diethyl ether in hexanes to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With sodium methylate; In methanol; at 10 - 20℃; | a.1.2: 2-terf-Butvl-4-hvdroxv-6-cvclobutvl-pvrimidine; 9.2 g of tert-butyl amidinium chloride (67.3 mmol, Maybridge) and 12.6 g of methyl-2-cyclobutanoyl acetate (80.7 mmol) were dissolved/suspended in 100 ml of methanol. 14.5 g of sodium methanolate (268.4 mmol) were added in portions to the solution at 10C. The suspension was then stirred at room temperature overnight. The reaction mixture was concentrated to roughly half the volume and filtered. The filtrate was extracted with water and dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and then concentrated to dryness. The residue was stirred with acetone and the precipitate was collected by filtration. Yield: 11.9 g (85.7 %).MS (ESI) m/z: 207.2 [M+H]+ |
85.7% | With sodium methylate; In methanol; at 10 - 20℃; | a.1.2: 2-terf-Butyl-4-hydroxy-6-cyclobutyl-pyrimidine; 9.2 g of te/t-butyl amidinium chloride (67.3 mmol, Maybridge) and 12.6 g of methyl-2- cyclobutanoyl acetate (80.7 mmol) were dissolved/suspended in 100 ml of methanol. 14.5 g of sodium methanolate (268.4 mmol) were added in portions to the solution at 1O0C. The suspension was then stirred at room temperature overnight. The reaction mixture was concentrated to roughly half the volume and filtered. The filtrate was ex- traded with water and dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and then concentrated to dryness. The residue was stirred with acetone and the precipitate was collected by filtration. Yield: 1 1.9 g (85.7 %). EPO <DP n="20"/>MS (ESI) m/z: 207.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | a 2-(1,1-Dimethylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-one Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong>. Yield: 90%. White solid, m/z 267(M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | a 2-(1,1-Dimethylethyl)-10-fluoro-5,7-dihydro-6H-pyrimido[5.4-d][1]benzazepin-6-one Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong>. Yield: 54%. White solid, m/z (ISP) 286 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | a 10-Chloro-2-(1,1-dimethylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong>. Yield: 88%. Off-white solid, m/z (ISP) 302 (MH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 7A 2,2-Dimethylpropaneimidamide Hydrochloride In analogy to the procedure for Example 3A, 8,31 g (100 mmol) pivalonitrile and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification. Yield: 6 g crude product | ||
In ethanol; | EXAMPLE 1 The Example illustrates the preparation of 2,2-dimethylpropionamidine hydrochloride. Dry hydrogen chloride gas (ca 59 g) was passed through a solution of 2-cyano-2-methylpropane (86 g) in ethanol (60 cm3) at 0 C. The solution was kept for 60 hours at the ambient temperature (ca. 20 C.), then diluted with diethyl ether (1000 cm3) and the precipitated 1-ethoxy-1-imino-2,2-dimethylpropane hydrochloride collected by filtration, washed on the filter with diethyl ether and dried. This precipitate was then slurried with ethanol (150 cm3) and aqueous ammonia passed into the mixture at the ambient temperature until the solid was completely dissolved. The mixture was kept at the ambient temperature for 40 hours, diluted with diethyl ether (500 cm3) and the solid precipitate collected by filtration and dried to yield 2,2dimethylpropionamidine hydrochloride (25.75 g), melting point 192-194 C. A second crop (50.29 g) was obtained by evaporation of the filtrate. Infra red (paraffin mull): 3300, 3100, 1680, 1520 1230, 995, 980 cm-1 | |
With ammonia; In ethanol; | EXAMPLE 1 This Example illustrates the preparation of pivalamidine hydrochloride. A stirred mixture of trimethylacetonitrile (43 g; 0.51M) and dry ethanol (24 g, 0.51M) was cooled using an ice/salt bath whilst dry hydrogen chloride gas was passed into the mixture over a period of 90 minutes, until a total of 21 gms has been taken up. The mixture was then kept for 2 days at the ambient temperature after which it was diluted with dry diethyl ether (500 cm3) to precipitate ethyl trimethyl acetimidate hydrochloride which was collected be filtration (34.5 g). To this was added portionwise a solution of dry ammonia gas (6 g) in dry ethanol (50 cm3) with vigorous stirring. The solid gradually dissolved during the course of the addition and the resultant solution was kept at the ambient temperature for 20 hours after which the solvent was removed by evaporation under reduced pressure and the residual solid washed with diethyl ether to yield pivalamidine hydrochloride (23 g). |
With hydrogenchloride; In ethanol; | EXAMPLE 1 This Example illustrates the preparation of 2,2-dimethylpropionamidine hydrochloride. Dry hydrogen chloride gas (ca. 59 g) was passed through a solution of 2-cyano-2-methylpropane (86 g) in ethanol (60 cm3) at 0 C. The solution was kept for 60 hours at the ambient temperature (ca. 20 C.), diluted with diethyl ether (1000 cm3) and the precipitated 1-ethoxy-1-imino-2,2-dimethylpropane hydrochloride collected by filtration, washed on the filter with diethyl ether and dried. This was then slurried with ethanol (150 cm3) and gaseous ammonia passed into the mixture at the ambient temperature until the solid was completely dissolved. The mixture was kept at this ambient temperature for 40 hours, diluted with diethyl ether (500 cm3) and the solid precipitate collected by filtration and dried to yield 2,2-dimethylpropionamidine hydrochloride (25.75 g), melting point 192-194 C. A second crop (50.29 g) was obtained by evaporation of the filtrate. Infra red (liquid paraffin): 3300, 3100, 1680, 1520 1230, 995, 980 cm-1. | |
In ethanol; | EXAMPLE 1 The Example illustrates the preparation of 2,2-dimethylpropionamidine hydrochloride. Dry hydrogen chloride gas (ca 59 g) was passed through a solution of 2-cyano-2-methylpropane (86 g) in ethanol (60 cm3) at 0C. The solution was kept for 60 hours at the ambient temperature (ca. 20C), then diluted with diethyl ether (1000 cm3) and the precipitated 1-ethoxy-1-imino-2,2-dimethylpropane hydrochloride collected by filtration, washed on the filter with diethyl ether and dried. This precipitate was then slurried with ethanol (150 cm3) and gaseous ammonia passed into the mixture at the ambient temperature until the solid was completely dissolved. The mixture was kept at the ambient temperature for 40 hours, diluted with diethyl ether (500 cm3) and the solid precipitate collected by filtration and dried to yield 2,2-dimethylpropionamidine hydrochloride (25.75 g), melting point 192-194C. A second crop (50.29 g) was obtained by evaporation of the filtrate. Infra red (paraffin mull): 3300, 3100, 1680, 1520 1230, 995, 980 cmmin1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-methoxy-ethanol; | EXAMPLE 62 Preparation of 3-[3-(4-Hydroxy-5-oxo-2-phenyl-2-imidazolin-4-yl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil A mixture of 5-[3-,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-glyoxylate (0.620 g, 1.50 mmol), phenyl amidine hydrochloride (0.258 g, 1.65 mmol) and 2-methoxyethanol is stirred 40 minutes at reflux, cooled to room temperature and poured into water. The resultant yellow precipitate is filtered and saved. The filtrate is extracted four times with methylene chloride; the combined organic layers are concentrated in vacuo and the residue is triturated with ether to afford a yellow solid. The yellow solids are combined and chromatographed on silica gel with methylene chloride-methanol to afford the title compound as a solid (0.110 g, 14.6%, mp 139-141 C.) which is identified by NMR spectral analysis. Using essentially the same procedure and employing tert-butyl amidine hydrochloride, the following product is obtained (mp 192 C.): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With sodium methylate; In methanol; at 10 - 20℃; | a.2.2: 2-terf-Butvl-4-hvdroxv-6-cyclopropvl-pyrimidine; 16.3 g tert-butyl amidinium chloride (119.6 mmol, Maybridge) were dissolved/suspended in 350 ml of methanol at room temperature. 30.4 g of sodium methanolate (562.8 mmol) were added in portions to the solution at 10C,. After stirring for 30 minutes, a solution of 20 g of methyl-2-cyclopropanoyl acetate (140.7 mmol) in 150 ml of methanol was added over 2 h. The suspension was then stirred at room temperature overnight, concentrated to roughly half the volume, and filtered. 200 ml of dichloromethane were added to the filtrate and theorganic layer was washed 3 times with water. The aqueous phases were combined. The aqueous phase was adjusted to pH 3 with aq. HCI, whereby a white precipitate was formed. The precipitate was collected by filtration, redissolved in dichloromethane, dried over magnesium sulfate and filtered. The solvent was concentrated to dryness to yield 14.8 g (67.2 %) of the title compound.MS (ESI) m/z: 193.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; sodium; In ethanol; water; | EXAMPLE 9 This Example illustrates the preparation of ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate. A solution of sodium ethoxide in ethanol was prepared by the addition of sodium (0.276 g) to ethanol (20 cm3) under a nitrogen atmosphere. The solution was cooled to the ambient temperature (ca 20 C.) and <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong> (1.64 g) was added. A solution of a 1:1 mixture of ethyl (RS)-4-dimethylamino-3-formyl-2-(1,1-dimethylethyl)-3-butenoate and ethyl (RS)-4-ethoxy-3-formyl-2-(1,1-dimethylethyl)-3-butenoate (2.6 g prepared according to the method of Example 6) in ethanol (25 cm3) was added to the reaction mixture which was then heated at the reflux temperature for 3.5 hours. The mixture was cooled to the ambient temperature and the solvent evaporated under reduced pressure. Water (200 cm3) was added to the residue and the products extracted into diethyl acetate (2*150 cm3). The combined organic layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to leave a brown oil. The crude product was purified by column chromatography on a silica gel support, eluding with dichloromethane containing 2% by volume ethyl acetate to give the title compound (1.5 g) as a pale yellow oil. 1 H NMR (CDCl3): 1.0 (9H,s); 1.25 (3H,t); 1.42 (9H,s); 3.35 (1H,s); 4.15 (2H,m); 8.75 (2H,s). | |
With sodium ethanolate; sodium; In ethanol; water; | EXAMPLE 9 This Example illustrates the preparation of ethyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate. A solution of sodium ethoxide in ethanol was prepared by the addition of sodium (0.276 g) to ethanol (20 cm3) under a nitrogen atmosphere. The solution was cooled to the ambient temperature (ca 20C) and <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong> (1.64 g) was added. A solution of a 1:1 mixture of ethyl (RS)-4-dimethylamino-3-formyl-2-(1,1-dimethylethyl)-3-butenoate and ethyl (RS)-4-ethoxy-3-formyl-2-(1,1-dimethylethyl)-3-butenoate (2.6 g prepared according to the method of Example 6) in ethanol (25 cm3) was added to the reaction mixture which was then heated at the reflux temperature for 3.5 hours. The mixture was cooled to the ambient temperature and the solvent evaporated under reduced pressure. Water (200 cm3) was added to the residue and the products extracted into diethyl acetate (2 x 150 cm3). The combined organic layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to leave a brown oil. The crude product was purified by column chromatography on a silica gel support, eluding with dichloromethane containing 2% by volume ethyl acetate to give the title compound (1.5 g) as a pale yellow oil. 1H NMR (CDCl3):1.0 (9H,s); 1.25 (3H,t); 1.42 (9H,s); 3.35 (1H,s); 4.15 (2H,m); 8.75 (2H,s). Infra Red (liquid film) 2962, 2872, 1732, 1586, 1539, 1482, 1433, 1369, 1333, 1200, 1149, 1036, 939, 854, 821 cmmin1 GLC Retention Time: 4.87 minutes Molecular ion: 278 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; ethanol; | STR52 13.6 g (0.1 mol) of <strong>[18202-73-8]pivalamidine hydrochloride</strong> are added in portions to a solution of 9 g (0.1 mol) of 1,3-diamino-propan-2-ol in 30 ml of ethanol. The mixture is boiled under reflux for 90 minutes and cooled to room temperature, and 70 ml of diethyl ether are added. The precipitated product is filtered off with suction. 19 g (99% of theory) of 2-tert-butyl-5-hydroxy-3,4,5,6-tetrahydropyrimidine hydrochloride are thus obtained in the form of colorless, strongly hygroscopic crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In ethanol; | (ii) ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]acetate. A solution of sodium ethoxide obtained by dissolving sodium (6.9 g) in ethanol (120 cm3) was added portionwise to a stirred suspension of <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong> (41.0 g) in ethanol (150 cm3). The precipitated sodium chloride was removed by filtration. Diethyl (RS)-formylsuccinate (60 g) was added dropwise to the stirred filtrate at the ambient temperature. After keeping the mixture for 16 hours it was heated to the reflux temperature for 1 hour, after which the solvent was removed by evaporation under reduced pressure to give a solid residue which was washed with petroleum ether (boiling range 60-80 C.) to yield ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]acetate (40 g), melting point 98-102 C. A further quantity (15 g) was recovered from the petroleum ether washings by evaporation of the solvent and column chromatographic purification of the residue using a silica column and eluding with a mixture (1:1 by volume) of ethyl acetate and petroleum ether (boiling range 60-80 C.). | |
With sodium; In ethanol; | (ii) ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]acetate. A solution of sodium ethoxide obtained by dissolving sodium (6.9 g) in ethanol (120 cm3) was added portionwise to a stirred suspension of <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong> (41.0 g) in ethanol (150 cm3). The precipitated sodium chloride was removed by filtration. Diethyl (RS)-formylsuccinate (60 g) was added dropwise to the stirred filtrate at the ambient temperature. After keeping the mixture for 16 hours it was heated to the reflux temperature for 1 hour, after which the solvent was removed by evaporation under reduced pressure to give a solid residue which was washed with petroleum ether (boiling range 60-80C) to yield ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]acetate (40 g), melting point 98-102C. A further quantity (15 g) was recovered from the petroleum ether washings by evaporation of the solvent and column chromatographic purification of the residue using a silica column and eluding with a mixture (1:1 by volume) of ethyl acetate and petroleum ether (boiling range 60-80C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With ammonia; In methanol; ethanol; | Step (1) Preparation of t-Butyl Amidine Hydrochloride To a cooled (0 C.), magnetically stirred solution of 2,2-dimethyl-1-propanenitrile (25.0 g, 0.30 mol), dry methanol (26.8 mL, 0.79 mol), and ether (30 mL) was added acetyl chloride (25.7 mL, 0.36 mol) dropwise. After the addition, cooling was continued for 15 minutes. The mixture was stirred at room temperature for 3 days. The resulting white crystals were filtered, washed with ether, and dried in vacuo. After drying, the crystals were combined with 10% NH3 /ethanol (150 mL, 0.90 mol), and stirred at room temperature for 3 days. The solution was filtered, and the filtrate was concentrated to give a white solid. Recrystallization from ethanol yielded white crystals (18.9 g, 46%), m.p. 188-190 C. NMR (DMSO-d6): delta1.22 (s, 9H), 8.63 (br d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; sodium; In ethanol; | EXAMPLE 2 This Example illustrates the preparation of 5-bromo-2-(2-methylprop-2-yl)pyrimidine-4-carboxylic acid. A solution of sodium ethoxide in ethanol (14.5 cm3 of the solution obtained by dissolving sodium (1.38 g) in dry ethanol (24 cm3)) was added carefully to a stirred mixture of <strong>[18202-73-8]pivalamidine hydrochloride</strong> (5.18 g) and dry ethanol (5 cm3) at 40 C. After stirring the mixture for a further 10 minutes a solution of mucobromic acid (5.4 cm3 of the solution obtained be dissolving mucobromic acid (5.16 g) in dry ethanol (8.0 cm3) was added to the mixture resulting in an exothermic react on during which the temperature rose to 65 C. After a perid the temperature had reduced to 50 C. and the remainder of the sodium ethoxide solution and the remainder of mucobromic acid solution were added. The reaction temperature was maintained at 50 C. for 1 hour by external heating, after which the insoluble portion was removed by filtration at that temperature, washed with ethanol and the washings and filtrate combined. After removing the solvent by evaporation under reduced pressure the residual solid was washed with dilute hydrochloric acid (2M, 10 cm3), with water and dried to yield 5-bromo-2(2-methylpro-2-yl)pyrimidine-4-carboxylic acid (3.8 g), melting point 142-144 C. (with decomposition) N.m.r and infrared spectra were consistent with this identification. 1 H NMR (CDCl3) delta: 1.45 (s,9H); 9.05 (s,1H); 9.44 (broad s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In ethanol; dichloromethane; | EXAMPLE 11 This Example illustrates the preparation of ethyl (RS)-2-[2-(2-methylprop-2-yl)pyrimidin-5-yl]-3-methylbutyrate. <strong>[18202-73-8]2,2-dimethylpropionamidine hydrochloride</strong> (0.14 g), prepared according to Example 1, was added to a solution of a 4:3 mixture of ethyl (RS)-4-dimethylamino-3-formyl-2-(1-methylethyl)-3-butenoate and ethyl (RS)-4-ethoxy-3-formyl- 2-(1-methylethyl)-3-butenoate (0.2 g), prepared according to the method of Example 10, in ethanol (2 cm3). A solution of sodium methoxide (0.06 g) in ethanol (1 cm3) was added to the stirred mixture, which was then heated at the reflux temperature for 2 hours. After cooling, the ethanol was evaporated under reduced pressure. The residual oil was purified by column chromatography on a silica gel support (Merck 7729), using dichloromethane, followed by dichloromethane containing 2% by volume ethyl acetate, as eluent, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)pyrimidin-5-yl]-3-methylbutyrate (0.068 g) as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In tert-butyl alcohol; for 48h;Heating / reflux; | 2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride. To a tert-BuOH (17 mL) solution of 4-oxo-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (2.18 g, 8.05 mmol), and 2,2-dimethyl-propionamidine hydrochloride (1.0 g, 7.3 mmol) was added Et3N (3.0 mL, 22.0 mmol). The reaction solution was heated at reflux for 48 h, cooled to rt, and concentrated. The resulting solid was dissolved in CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried and concentrated to give a yellow solid that was triturated with Et2O to give 1.74 g (70%) of the title compound as a white solid. MS (ESI): exact mass calcd. for C16H25N3O3, 307.19; m/z found, 308.4 [M+H]+. 1H NMR (CDCl3): 4.35 (s, 2H), 3.68-3.67 (m, 2H), 2.74-2.65 (m, 2H), 1.49 (s, 9H), 1.37 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h; | A solution of 2,4'-dibromoacetophenone (4.17 g, 15.0 mmol) in N, N- dimethylformamide (60.0 tnL) was treated with f-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 {4.15 g, 30.0 mmol) and heated to 50 0C for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography ( 10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81 %). 1H NMR (400 MHz, CHLOROFORM-*/) 5 ppm 7.58 (d, 7=8.1 Hz, 2 H) 7.46 (d, 7=8.6 Hz, 2 H) 7.18 (s, 1 H) 1.42 (s, 9 H). MS (ES+) m/e 279/281 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; In acetonitrile; for 1h;Reflux; | EXAMPLE 45 3-(2-tert-Butyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazol-4-yl)benzonitrile (Compound 45) Step 1; A mixture of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol), tert-butylcarbamidine hydrochloride (610 mg, 4.46 mmol), potassium carbonate (770 mg, 5.58 mmol), and acetonitrile (10 mL) was refluxed for 1 hour. After the reaction was completed, the mixture was left to cool to room temperature. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give 3-(2-tert-butyl-1H-imidazol-4-yl)benzonitrile (500 mg, 2.22 mmol, yield: 99%). 1H-NMR (dppm, CDCl3) : 8.95 (brs, 1H), 8.08 (s, 1H), 8.00-7.98 (m, 1H), 7.52-7.38 (m, 2H), 7.24 (s, 1H), 1.43 (s, 9H). Mass (m/e) : 226 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In acetonitrile; at 90℃; for 3h; | EXAMPLE 26 2-tert-Butyl-4-(2-chlorophenyl)-1-cyclohexylmethyl-1H-imidazole (Compound 26); Step 1 A mixture of 2-chlorophenacyl bromide (310 mg, 1.33 mmol), tert-butylcarbamidine hydrochloride (210 mg, 1.53 mmol), potassium carbonate (0.420 mg, 3.04 mmol), and acetonitrile (6 mL) was refluxed at 90C for 3 hours. After the mixture was left to cool to room temperature, an aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give 2-tert-butyl-4-(2-chlorophenyl)-1H-imidazole (132 mg, 0.56 mmol, yield: 42%). 1H-NMR (dppm, CDCl3): 9.14 (brs, 1H), 8.17 (brs, 1H), 7.64-7.38 (m, 2H), 7.32-7.26 (m, 1H), 7.24-7.09 (m, 1H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 130℃; for 0.416667h;Microwave irradiation; Sealed tube; | Step D: 2-7grt-butyl-7-(2-chlorophenyl')-6-(4-chlorophenyl)pyrido[2,3-tf1pyrimidin-4-amine. An 80 mL CEM corporation Discover microwave tube was charged with the product of Step C (3.1 g, 8.62 mmol), <strong>[18202-73-8]2,2-dimethylpropanimidamide hydrochloride</strong> (1.766 g, 12.93 mmol), DMF (15 mL) and DBU (2.21 mL, 14.7 mmol). The tube was sealed and heated (with air cooling) to 130 C for 25 min. The reaction was cooled and diluted with EtOAc (250 mL) and MeOH (8 mL). The solution was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-15% EtOAc in CH2Cl2 affording the product. HPLC/MS: 423.1 (M+l), 425.1 (M+3); R1 = 3.06 min. | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 130℃; for 0.416667h;Sealed microwave tube; | Step D: 2-rert-butyl-7-(2-chlorophenyl)-6-(4-chlorophenyl)pyridor2,3-<^lpyrimidin-4-amine. An 80 mL CEM corporation Discover microwave tube was charged with the product of Step C (3.1 g, 8.62 mmol), <strong>[18202-73-8]2,2-dimethylpropanimidamide hydrochloride</strong> (1.766 g, 12.93 mmol), DMF (15 mL) and DBU (2.21 mL, 14.7 mmol). The tube was sealed and heated (with air cooling) to 130 C for 25 min. The reaction was cooled and diluted with EtOAc (250 mL) and MeOH (8 mL). The solution was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel by gradient elution with 0-15% EtOAc in CH2Cl2 to afford the title compound. HPLC/MS: 423.1 (M+l), 425.1 (M+3); R, = 3.06 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 24h;Sealed tube; | General procedure: A 5 mL reaction tube was charged with Phen-MCM-41-CuBr (36 mg, 0.025 mmol), amidine 4 (0.75 mmol), nitrile 2 (0.5 mmol), Cs2CO3 (489 mg, 1.5 mmol), and DMSO (1.5 mL) under an air atmosphere. The reaction tube was sealed and placed in an oil bath at r.t. The reaction mixture was stirred at 120 C for 24 h. After cooling to r.t., the reaction mixture was diluted with EtOAc (10 mL) and filtered. The supported copper catalyst was washed with water (2 5 mL) and acetone (2 5 mL), and reused in the next run. The filtrate was washed with 5% aqueous NaHCO3 and brine. The organic layer was dried over Mg-SO4 and concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 3:2) to provide the desired product 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 24h;Sealed tube; | General procedure: A 5 mL reaction tube was charged with Phen-MCM-41-CuBr (36 mg, 0.025 mmol), amidine 4 (0.75 mmol), nitrile 2 (0.5 mmol), Cs2CO3 (489 mg, 1.5 mmol), and DMSO (1.5 mL) under an air atmosphere. The reaction tube was sealed and placed in an oil bath at r.t. The reaction mixture was stirred at 120 C for 24 h. After cooling to r.t., the reaction mixture was diluted with EtOAc (10 mL) and filtered. The supported copper catalyst was washed with water (2 5 mL) and acetone (2 5 mL), and reused in the next run. The filtrate was washed with 5% aqueous NaHCO3 and brine. The organic layer was dried over Mg-SO4 and concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 3:2) to provide the desired product 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3 g of tert-butyl amidinium chloride (Maybridge) (31.7 mmol) were dissolved in 50 ml of ethanol. 12.7 ml of sodium methanolate (30 % in methanol) were added at room temperature. After 15 min., 4,82 g of methyl 4,4-difluoro-3-oxo butanoate (31.7 mmol) were added and the mixture was stirred at 78 C for 4 h and 14 h at room temperature. The solvent was evaporated. 150 ml of water were added, and the pH adjusted to 6-7 by addition of 2N HCl. The precipitate was filtered, washed with water and dried in an oven under vacuum. Yield: 2.3 g MS (ESI) m/z: 203.1 [M+H]+ | ||
b.1 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-methyl-pyrimidine ; 2-tert-butyl-4-hydroxy-6-difluoromethyl-pyrimidine; 3 g of tert-butyl amidinium chloride (Maybridge) (31.7 mmol) were dissolved in 50 ml of ethanol. 12.7 ml of sodium methanolate (30% in methanol) were added at room temperature. After 15 min., 4.82 g of methyl 4,4-difluoro-3-oxo butanoate (31.7 mmol) were added and the mixture was stirred at 78 C. for 4 h and 14 h at room temperature. The solvent was evaporated. 150 ml of water were added, and the pH adjusted to 6-7 by addition of 2N HCl. The precipitate was filtered, washed with water and dried in an oven under vacuum. Yield: 2.3 g; MS (ESI) m/z: 203.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation C1: Synthesis of 2-tert-butylpyrimidine-4-carboxylic Acid Preparation C1, Step 1: A 22% solution of sodium ethoxide in ethanol (53 mL, 165 mmol) was added dropwise to a magnetically stirred suspension of tert-butylcarbamidine hydrochloride (20.0 g, 146 mmol) in ethanol (100 mL). When the addition was complete, the yellow suspension was warmed to 50 C., the heating mantle was removed, and a solution of mucobromic acid (15.7 g, 61 mmol) in ethanol (50 mL) was added dropwise at a rate which did not allow the temperature to exceed 55 C. When this addition was complete, a 22% solution of sodium ethoxide in ethanol (32 mL, 98 mmol) was added dropwise, then the mixture was allowed to cool to room temperature. The suspension was filtered, the solids were rinsed with ethanol (2*20 mL), and the combined filtrates were concentrated in-vacuo. The residue thus obtained was stirred in 2 N aqueous HCl (30 mL). The resulting solids were collected by filtration, rinsed with ice-cold water (2*20 mL), and air dried to yield 12.1 g of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid as a beige powder. MS (ES+)=259, 261 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydroxide; In dichloromethane; water; at -15 - 20℃; for 3h; | To a stirred solution of the HCI salt of 2,2-dimethylpropanamidine (1.6 g, 1 1.8 mmol) in dichloromethane (30 ml) at -15 C was added trichloromethyl thiohypochlorite (2.0 g, 10.8 mmol) and aqueous sodium hydroxide solution (2.36 g, 59 mmol; dissolved in 12 ml water) slowly. After addition, the temperature of the reaction mixture was slowly raised to room temperature and stirring was continued for 3 h. The reaction mixture was diluted with dichloromethane and washed with water (50 ml x 3). The combined organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give 3-tert-butyl-5-chloro-1,2,4-thiadiazole (1.7 g, 9.6 mmol, 89 % yield). |
With sodium hydroxide; In dichloromethane; water; at -15 - 20℃; | 3-(tert-Butyl)-5-chloro-1,2,4-thiadiazole 6.83 g (50.00 mmol) of tert-butylcarbamidine hydrochloride are dissolved in 60 ml of dichloromethane and treated with 8.37 g (45.00 mmol) of trichloromethanesulphenyl chloride, before the reaction mixture is cooled to -15 C. A solution of 10.00 g (250 mmol) of sodium hydroxide in 20 ml of water is added dropwise and the mixture obtained is stirred at AT for 3 h. After adding 50 ml of dichloromethane, extracting three times with water and drying the combined organic phases over MgSO4, the solvent is evaporated under vacuum. (5.81 g, 90% purity, 60% yield, log P (pH 2.3)=3.44). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol; sodium ethanolate; at 80℃;Cooling with ice; | Reference Example 1 ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate [Show Image] To a solution of diethyl <strong>[18202-73-8]2,2-dimethylpropanimidamide hydrochloride</strong> (1.36 g) and (ethoxymethylene)malonate (2.16 g) in ethanol (100 ml) was added 20% sodium ethoxide-ethanol solution (6.8 g) under ice-cooling, and the mixture was stirred at 80C for 5 hr. The reaction mixture was concentrated under reduced pressure, 1 M hydrochloric acid (10 ml) was added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, hexane was added to the residue, and the precipitate was collected by filtration to give the object compound (1.65 g) as a powder. MS (ESI+, m/e) 225 (M+1) 1H-NMR (CDCl3) delta 1.33-1.41 (3H, m), 1.43 (9H, s), 4.32-4.41 (2H, m), 8.72 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 14 Synthesis of 2-tert-butyl-5-methyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 80 ml of ethanol is cooled down to 0 C. by an ice bath, 4 g (55.6 mmoles) of sodium ethylate and 3.8 g (27.8 mmoles) of tert-butylcarbamidine hydrochloride are added. The reaction mixture is left to return to ambient temperature, then 5 ml (27.8 mmoles) of diethyl ester methylmalonate is added dropwise. Stirring is maintained at ambient temperature overnight. The ethanol is then condensed under reduced pressure (2 kPa). The crude product obtained is solubilized in a minimum amount of water (approximately 40 ml), then acidified at 0 C. with pure acetic acid until a pH comprised between 4 and 5 is achieved. The white precipitate formed is filtered, rinsed successively with water, ethyl ether and with pentane. Then the white powder obtained is dried over P2O5 under reduced pressure (0.2 kPa). 2.4 g of expected product is obtained. TLC: Rf=0.56 (silica gel, eluent: dichloromethane-methanol 90-10). MS: (MH+)=183, (MH-)=181 1H-NMR (DMSOd6): delta 1.25 (s, 9H, tert-butyl); 1.72 (s, 3H, N=C-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 12.58 g of sodium methoxide (28% methanol solution), 2.97 g of 2, 2-dimethylpropionamidine hydrochloride and 4 g of 4, 4 , 4-trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 80C for 10 hours and then heated under reflux for 6 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added, followed by extraction three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 2.4 g of 2- (1, 1-dimethylethyl) -6-trifluoromethylpyrimidin-4- ol.2- (1, 1-dimethylethyl) -6-trifluoromethylpyrimidin-4-ol 1 H-NMR ( DMSO-d6 ) : 1 . 30 ( s , 9H ) , 6 . 72 ( s , lH ) , 12 . 70 (bs , lH ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 160℃; for 6.5h;Sealed vessel; | Stage A.3: N-(8-tert-butyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamidePyridine (13 mL) was added to N-(6-formyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage A.4, 3.05 g, 12.8 mmol) and tert.butylamidine hydrochloride (1.788 g, 12.8 mmol) and the mixture was heated in a sealed vessel at 160 C. for 6.5 h. After cooling the reaction mixture was filtered to give a solid. The filtration mother liquor was evaporated to give further solid material. The combined solids were triturated repeatedly with hot CH3CN and the CH3CN mother liquors evaporated to give a solid which was shown to be predominantly the title product. The crude product was dissolved in ca. 10 ml of a 10% DMSO in MeOH to give a slightly hazy orange solution which was filtered and added dropwise to water (100 ml) at it with stirring. The precipitate solid was collected by filtration to give the title compound as an orange solid. LCMS: tR 1.37 min and M+H=303.0 (method A3). 1H-NMR in DMSO-d6, 400 MHz: 12.40 (s, 1H); 8.44 (s, 1H); 2.88-3.00 (m, 4H); 2.17 (s, 3H); 1.32 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 2-methoxy-ethanol; at 125℃; for 3h; | Stage A.1: 8-tert-Butyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-ylamineIntermediate A.1 was obtained by two different routes. Both routes start from 2-amino-5,6-dihydro-4H-benzothiazol-7-one and described below:Route 1:To a mixture of N'-{6-[1-dimethylamino-meth-(E)-ylidene]-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl}-N,N-dimethyl-formamidine (Stage A.2, 2.2 g, 7.90 mmol) in 2-methoxyethanol (20 mL) was added at rt sodium hydroxide (1.185 g, 29.6 mmol) and 2,2-dimethyl-propionamidine hydrochloride (1.620 g, 11.85 mmol). The RM was stirred at 125 C. for 3 h. After cooling to rt, the RM was diluted with MeOH, adsorbed onto silica gel and purified by flash chromatography (CombiFlash Companion system, with RediSep silica gel column, eluent: DCM/MeOH/Ammonia 95:5:0.5). LC: tR 3.64 min (method D). MS: M+H=261. 1H-NMR in DMSO-d6: 8.24 (s, 1H); 7.70 (s, 2H); 2.89-2.84 (m, 2H); 2.76-2.71 (m, 2H); 1.28 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; TPGS-450-M; caesium carbonate; In water; at 20℃; for 12h;Inert atmosphere; Green chemistry; | General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt % TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | To a solution of dimethyl 2-(benzyloxy)malonate (7.0 g, 29 mmol) in MeOH (27 ml_) at O 0C was added NaOMe (5.5 g, 0.10 mol) portion wise over approximately 10 min. Te/t-butylcarbamidine hydrochloride (4.23 g, 31 mmol) was then added portion wise over approximately 15 min and the resulting mixture was stirred for 30 min at 0 0C. The mixture was affixed with a reflux condenser, heated to 85 0C, and was stirred for 3.5 h. The mixture was cooled to 0 0C, treated with cone. HCI (-10 ml_), and stirred for 15 min. The resultant yellow solid was filtered off thru a medium glass - sintered funnel and was washed with cold water (3 x 15 ml_). The solid was dried in a vacuum oven at 35 0C for 12h to afford 5.8 g (73% yield) of an off-white solid which was used without further purification. LC-MS: M+H = 275.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In N-formyldiethylamine; at 20℃; for 168h; | Example 1 Synthesis of 2,5-di-tertbutylimidazole 5.44g (0.04 moles) of 2,2-dimethylpropanimideamide hydrochloride were mixed with 7.2 g (0.04 moles) of 1-bromopinacolone and 11.2g of triethylamine in 16.0g of diethylformamide (DEF) and stirred at room temperature for 7 days. The reaction mixture was then poured into water and extracted three times with 50 ml units of hexane. The hexane fractions were combined and washed three times with 50 ml aliquots of water. The hexane layer was then stirred with 5g of anhydrous magnesium sulfate over night. The hexane was then removed by vacuum down to a volume of 5 ml to yield a fine suspension. This was filtered and the resulting solid washed with fresh hexane to yield 4.22g (59% theoretical) of colorless fine crystalline product, 99% pure by Gas Chromatography Mass Spectrometry gave a parent ion at 180 amu. Structure confirmed by X-ray crystallography (see Figure 1) GCMS. 1H NMR : (500 MHz, D8 THF): delta = 1.23 (s, 9H), delta = 1.3 (s, 9H), delta = 6.48 (s,1H), 5=10 (bs, 1H). 1H NMR : (500 MHz, D8 THF): delta = 30.3 (s, 3C), delta = 30.8 (s, 3C), delta = 32.1 (s, 1C), delta = 33.6 (s, 1 C), delta = 111 (bs, 1 C), delta = 148 (bs, 1 C), delta = 155 (s, 1 C). X-ray |
59% | With triethylamine; In N-formyldiethylamine; at 20℃; for 168h; | Example 1Synthesis of 2,5-di-tert-butylimidazole[001238] 5.44g (0.04 moles) of 2,2-dimethylpropanimideamide hydrochloride were mixed with 7.2 g (0.04 moles) of 1-bromopinacolone and 1 1.2g of triethylamine in 16.0g of diethylformamide (DEF) and stirred at room temperature for 7 days. The reaction mixture was then poured into water and extracted three times with 50 ml units of hexane. The hexane fractions were combined and washed three times with 50 ml aliquots of water. The hexane layer was then stirred with 5g of anhydrous magnesium sulfate over night. The hexane was then removed by vacuum down to a volume of 5 ml to yield a fine suspension. This was filtered and the resulting solid washed with fresh hexane to yield 4.22g ( 59% theoretical) of colorless fine crystalline product, 99% pure by GasChromatography Mass Spectrometry gave a parent ion at 180 amu. Structure confirmed by X-ray crystallography (see Figure 1 )H NMR : (500 MHz, D8 THF): delta = 1.23 (s, 9H), delta = 1.3 (s, 9H), delta = 6.48 (s,1 H), delta = 10 (bs, 1 H).H NMR : (500 MHz, D8 THF): delta = 30.3 (s, 3C), delta = 30.8 (s, 3C), delta = 32.1 (s, 1 C), delta = 33.6 (s, 1 C), delta = 11 1 (bs, 1 C), delta = 148 (bs, 1 C), delta = 155 (s, 1 C). |
59% | With triethylamine; In N-formyldiethylamine; at 20℃; for 7h; | Example 1; Synthesis of 2,5-di-tertbutylimidazole; 5.44 g (0.04 moles) of 2,2-dimethylpropanimideamide hydrochloride were mixed with 7.2 g (0.04 moles) of 1-bromopinacolone and 11.2 g of triethylamine in 16.0 g of diethylformamide (DEF) and stirred at room temperature for 7 days. The reaction mixture was then poured into water and extracted three times with 50 ml units of hexane. The hexane fractions were combined and washed three times with 50 ml aliquots of water. The hexane layer was then stirred with 5 g of anhydrous magnesium sulfate over night. The hexane was then removed by vacuum down to a volume of 5 ml to yield a fine suspension. This was filtered and the resulting solid washed with fresh hexane to yield 4.22 g (59% theoretical) of colorless fine crystalline product, 99% pure by Gas Chromatography Mass Spectrometry gave a parent ion at 180 amu. Structure confirmed by X-ray crystallography (see FIG. 1)GCMS.1H NMR: (500 MHz, D8THF): delta=1.23 (s, 9H), delta=1.3 (s, 9H), beta=6.48 (s, 1H), beta=10 (bs, 1H).1H NMR: (500 MHz, D8THF): delta=30.3 (s, 3C), beta=30.8 (s, 3C), beta=32.1 (s, 1C), beta=33.6 (s, 1C), beta=111 (bs, 1C), beta=148 (bs, 1C), beta=155 (s, 1C).X-ray |
Tags: 18202-73-8 synthesis path| 18202-73-8 SDS| 18202-73-8 COA| 18202-73-8 purity| 18202-73-8 application| 18202-73-8 NMR| 18202-73-8 COA| 18202-73-8 structure
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P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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