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Structure of 593-85-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: To a suspension of guanidine carbonate (1.5-5 eq) in ethanol (2 mL/mmol) was added γ-aryl-β-ketoester (1.43-26.6 mmol), and the reaction mixture heated at 80 °C for 15-64 h. Followingreaction completion by TLC, the mixture was cooled to ambient temperature, filtered and thesolid triturated with water (5-20 mL) and acetone (5-20 mL) to give the title compound.
Reference：
[1] Tetrahedron, 2015, vol. 71, # 39, p. 7339 - 7343
[2] Journal of the American Chemical Society, 1998, vol. 120, # 27, p. 6761 - 6769
[3] Justus Liebigs Annalen der Chemie, 1891, vol. 262, p. 365
[4] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 47, p. 203
2
[ 36437-19-1 ]
[ 593-85-1 ]
[ 5428-89-7 ]
Reference：
[1] Yakugaku Zasshi, 1951, vol. 71, p. 39
[2] Journal of the American Chemical Society, 1942, vol. 64, p. 567,569,570
3
[ 41850-84-4 ]
[ 593-85-1 ]
[ 1193-74-4 ]
Reference：
[1] Yakugaku Zasshi, 1951, vol. 71, p. 1345,1347[2] Chem.Abstr., 1952, p. 8034
4
[ 22428-91-7 ]
[ 593-85-1 ]
[ 1193-74-4 ]
Reference：
[1] Chemische Berichte, 1930, vol. 63, p. 2601,2607
5
[ 64-17-5 ]
[ 50421-80-2 ]
[ 593-85-1 ]
[ 1193-74-4 ]
Reference：
[1] Chemische Berichte, 1950, vol. 63, p. 2604
6
[ 593-85-1 ]
[ 4949-44-4 ]
[ 5734-66-7 ]
Reference：
[1] Journal of the American Chemical Society, 1936, vol. 58, p. 287
[2] Journal of the Chemical Society, 1936, p. 157
7
[ 609-32-5 ]
[ 593-85-1 ]
[ 3073-77-6 ]
Reference：
[1] Kagaku Kenkyusho Hokoku, 1951, vol. 27, p. 401; vgl. E I 24 231[2] Chem.Abstr., 1953, p. 2181
8
[ 593-85-1 ]
[ 118-92-3 ]
[ 20198-19-0 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 1212[2] Chemische Berichte, 1910, vol. 43, p. 1021
Reference：
[1] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 3, p. 343 - 348
12
[ 7520-69-6 ]
[ 124-41-4 ]
[ 593-85-1 ]
[ 738-70-5 ]
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 13, p. 3531 - 3535
13
[ 593-85-1 ]
[ 55314-16-4 ]
[ 66521-66-2 ]
Yield
Reaction Conditions
Operation in experiment
66%
With sodium hydroxide In butan-1-ol at 120℃; for 2 h;
NaOH (0.78 g, 19.5 mmol) was added to a mixture of 3-(dimethylamino)-l-(pyridin-3- yl)prop-2-en-l-one (3.52 g, 20.0 mmol) and guanidine carbonate (1.80 g) in n-butanol (20 mL). The mixture was heated at 1200C for 2 h. After cooling, the precipitates formed was collected by filtration and dried under vacuum to afford the desired product (2.3g, 66percent). LCMS: (M+H)+= 173.2.
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 4, p. 398 - 406[2] Khimiya Geterotsiklicheskikh Soedinenii, 1991, # 4, p. 502 - 511
15
[ 593-85-1 ]
[ 50-01-1 ]
Reference：
[1] Zeitschrift fur Anorganische und Allgemeine Chemie, 2018, vol. 644, # 5, p. 280 - 287
16
[ 593-85-1 ]
[ 105942-08-3 ]
[ 137553-43-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364
17
[ 593-85-1 ]
[ 93777-26-5 ]
[ 190273-89-3 ]
Yield
Reaction Conditions
Operation in experiment
68%
at 140℃;
Step 1 : 5-Bromo-2-fluorobenzaldehyde (4.0 g, 19.7 mmol, 1.0 equiv) and guanidine carbonate (2.68 g, 29.7 mmol, 1.51 equiv) were dissolved in DMA (20 mL) and heated to 140°C & stirred for overnight. After completion of starting material, reaction mixture was poured onto ice cold water. The solid was filtered, washed with diethyl ether and dried to get 6-bromoquinazolin-2- amine (3.0 g, 68percent) as off white solid. LCMS (ES) m/z = 234.0, 236.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 2H), 7.34 (d, J = 8.8 Hz, 1 H), 7.74 - 7.77 (m, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 9.07 (s, 1 H).
60%
at 140℃; for 5 h;
2-Fluoro-5-bromobenzaldehyde (10 g, 49.2 mmol) and bisguanidinium carbonate (13.3 g, 74 mmol) were dissolved in N,N-dimethylacetamide (50 mL). The resulting mixture was heated to reflux and stirred for 5 h. After cooling to room temperature, 120 mL water was added and the reaction mixture was allowed to stir for another 2 h at room temperature. The product was collected by filtration and dried under vacuum to afford 6-bromo-2-quinazolinamine (2) (5.0 g, 60percent).
4 g
at 160℃; for 0.5 h;
To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). The mixture was stirred at 160°C for 0.5 h, cooled to rt and concentrated. The residue was diluted with H20 (300 mL) and extracted with ethyl acetate (200 mL χ 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to get compound 1A-2 (4.0 g).
Reference：
[1] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 49
[2] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 506 - 518
[3] Journal of Organic Chemistry, 2006, vol. 71, # 10, p. 3959 - 3962
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 19, p. 5671 - 5686
[5] Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3065 - 3068
[6] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 2, p. 385 - 387
[7] Patent: WO2008/20203, 2008, A1, . Location in patent: Page/Page column 72
[8] Patent: WO2018/102751, 2018, A1, . Location in patent: Paragraph 00208
18
[ 593-85-1 ]
[ 93777-26-5 ]
[ 190273-89-3 ]
Yield
Reaction Conditions
Operation in experiment
73%
at 150℃; for 5 h;
Guanidine carbonate (2) (4.47 g, 36.9 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (1) (5.00 g, 24.6 mmol) in dimethylacetamide (50 ml). The reaction mixture was heated at 150°C for 5 h. The progress of the reaction was monitored by TLC using AcOEt–hexane, 1:1, as eluent. The reaction mixture was cooled and quenched with ice water, and stirred for 30 min. Then the obtained solid was filtered off, and water was removed by azeotropic distillation with PhMe to get 4.00 g (73percent) of compound 3. Mp 270–272°C. 1H NMR spectrum (300 MHz), δ, ppm (J, Hz): 7.04 (2H, s,NH2); 7.37 (1H, d, J = 9.0, H Ar); 7.78 (1H, dd, J = 9.0,J = 2.4, H Ar); 8.05 (1H, d, J = 2.4, H Ar); 9.09 (1H, s,H Ar). Mass spectrum, m/z: 225 [M+H]+.
Reference：
[1] Chemistry of Heterocyclic Compounds, 2015, vol. 51, # 1, p. 60 - 66[2] Khim. Geterotsikl. Soedin., 2015, vol. 51, # 1, p. 60 - 66,7
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 5, p. 1996 - 2015
Preparation 12 6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine A solution of 1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidine carbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate (32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17 hours and the solvent was removed in vacuo. The residue was diluted with water and the mixture was swirled for a few minutes. The undissolved white solid was collected and washed with water, followed by a small amount of cold ethyl acetate to give the title compound (4.10 g, 55percent).
General procedure: To a suspension of guanidine carbonate (1.5-5 eq) in ethanol (2 mL/mmol) was added gamma-aryl-beta-ketoester (1.43-26.6 mmol), and the reaction mixture heated at 80 C for 15-64 h. Followingreaction completion by TLC, the mixture was cooled to ambient temperature, filtered and thesolid triturated with water (5-20 mL) and acetone (5-20 mL) to give the title compound.
2-Amino-6-(diethoxymethyl)pyrimidin-4(3H)-one (Scheme 1, B). To a stirring solution of <strong>[10495-09-7]ethyl 4,4-diethoxy-3-oxobutanoate</strong> (Scheme 1, A) (approximately 25 g, 114 mmol) in ethanol (600 mL) was added guanidine carbonate (10.42 g, 57.8 mmol), washing in with additional ethanol (200 mL) before the reaction was heated under reflux for 18 h. Upon cooling the resultant white crystals were collected by filtration, washing with cold ethanol. Subsequent concentrations of the filtrate to reduced volumes by rotary evaporation and cooling afforded additional crops of white crystals, which were collected by filtration and washed with cold ethanol. The crops were dried under high vacuum at ambient temperature over night to afford the title compound as a white solid (15.5 g, 64%). 1H NMR (300 MHz, DMSO-J6) delta 1.13 (t, J= 7.1 Hz, 6H), 3.45 - 3.58 (m, 4H), 4.90 (s, IH), 5.62 (s, IH), 6.57 (br s, 2H), 10.73 (br s, IH); m/z (ES+) M+l = 214.1; HPLC /R = 0.70 min.
With sodium ethanolate; In ethanol; at 80℃; for 16h;Inert atmosphere;
To a suspension of guanidine carbonate (199 mg, 2.21 mmol) in ethanol (22 mL) were addedethyl 2-methyl-3-oxo-3-phenylpropanoate 15 (380 mg, 1.84 mmol) and sodium ethoxide solution(25%; 1.00 mL, 3.69 mmol). The reaction mixture was heated at 80 C for 16 h, cooled toambient temperature and concentrated under reduced pressure to approximately 5 mL. Water (20mL) was added and the resulting precipitate collected by filtration and triturated with water (5ml) and methanol (5 mL) to give the title compound as a colourless solid (94 mg, 25%); mp 256-257 C (lit.,7 mp 271-273 C); (Found: M+H+, 202.0985. C11H12N3+ requires 202.0975); numax(CHCl3)/cm-1 3693, 3607, 2919, 1717, 1638, 1601, 1514, 1348, 1242, 1061, 988; deltaH (400 MHz;DMSO-d6) 7.50-7.47 (5 H, m, ArH), 6.92 (2 H, br s, NH2), 1.81 (3 H, s, Me); deltaC (100 MHz;DMSO-d6) 163.2 (C), 155.2 (C), 152.7 (C), 136.2 (C), 129.1 (CH), 128.5 (CH), 128.2 (CH),108.1 (C), 11.7 (Me); m/z (ESI) 202 (M+H+, 100%).Spectroscopic data in agreement with those previously reported.7
Step 1 : 5-Bromo-2-fluorobenzaldehyde (4.0 g, 19.7 mmol, 1.0 equiv) and guanidine carbonate (2.68 g, 29.7 mmol, 1.51 equiv) were dissolved in DMA (20 mL) and heated to 140C & stirred for overnight. After completion of starting material, reaction mixture was poured onto ice cold water. The solid was filtered, washed with diethyl ether and dried to get 6-bromoquinazolin-2- amine (3.0 g, 68%) as off white solid. LCMS (ES) m/z = 234.0, 236.0 [M+H]+. H NMR (400 MHz, DMSO-d6) delta 6.96 (s, 2H), 7.34 (d, J = 8.8 Hz, 1 H), 7.74 - 7.77 (m, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 9.07 (s, 1 H).
60%
In N,N-dimethyl acetamide; at 140℃; for 5h;
2-Fluoro-5-bromobenzaldehyde (10 g, 49.2 mmol) and bisguanidinium carbonate (13.3 g, 74 mmol) were dissolved in N,N-dimethylacetamide (50 mL). The resulting mixture was heated to reflux and stirred for 5 h. After cooling to room temperature, 120 mL water was added and the reaction mixture was allowed to stir for another 2 h at room temperature. The product was collected by filtration and dried under vacuum to afford 6-bromo-2-quinazolinamine (2) (5.0 g, 60%).
In N,N-dimethyl acetamide; at 140℃; for 5h;
2-Fluoro-5-bromo benzaldehyde (1.0 g, 4.9 mmol) and guanidine carbonate (1.3 g, 7.4 mmol, 1.5 equiv) were dissolved in DMA and heated to 140 0C for 5 h. The reaction was treated with H2O and the resulting precipitate was collected by vacuum filtration; m/z 225.
4 g
In N,N-dimethyl acetamide; at 160℃; for 0.5h;
To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). The mixture was stirred at 160C for 0.5 h, cooled to rt and concentrated. The residue was diluted with H20 (300 mL) and extracted with ethyl acetate (200 mL chi 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to get compound 1A-2 (4.0 g).
Example 30; 5-p-Tolylethynylquinazoline-2,4-diamine; [00121] Step 1; 2-Fluoro-6-iodobenzonitrile (700 mg; 2.83 mmol) is dissolved in dimethylacetamide (5 mL) with guanidine carbonate (766 mg; 4.25 mmol). The vessel is purged with N2, sealed, and heated to 165 C for 5 hours. After cooling to room temperature, the reaction mixture is placed in the freezer overnight. The precipitate which has formed is removed by filtration and purified by recrystallization from 50% EtOH/water. The resulting solids are filtered and dried at room temperature to yield 158 mg of 5-iodoquinazoline-2,4-diamine.
EXAMPLE 5; This example illustrates an exemplary process for preparing imiquimod by reaction of compound II with 2 molar equivalents of guanidine carbonate in DMSO at 140-150 C.A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (6.0 g, 0.0232 mol), guanidine carbonate (8.4 g, 0.0466 mol, 2.0 molar equiv.) and DMSO (50 ml) was heated under stirring at 140-150 C. for 1 hour. A sample was withdrawal and injected to an HPLC system. According to the HPLC chromatogram the product contained 5.76% of imiquimod, 93.58% of the compound III and 0.66% of the compound II in the reaction mixture. Stirring was continued at 140-150 C. for Her 9 hours, after which time a sample was withdrawn and injected to an HPLC system. According to the HPLC chromatogram the product contained 99.4% of imiquimod and 0.6% of compound III. Then, the reaction mixture was cooled to ambient temperature and a precipitate was collected by filtration, washed with water (3×40 ml) and methanol (35 ml) and dried at 80 C. under reduced pressure overnight to yield 4.5 g of crude Imiquimod in 81.2% yield, having a purity of 99.85% (by HPLC).The crude imiquimod (4.5 g) was dissolved in DMSO (80 ml) at 140 C. The hot solution was filtered off and the filtrate was kept at 20 C. overnight. A precipitate was collected by filtration, washed with water (3×20 ml) and methanol (3×10 ml) and dried at 80 C. under reduced pressure overnight to obtain 4.0 g of pure imiquimod in 87.8% yield, overall yield: 71.3%; having a purity of 99.93% (by HPLC).
EXAMPLE 4; This example illustrates an exemplary process for preparing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-guanidine (III).; A mixture of <strong>[99010-64-7]4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline</strong> (II) (9.0 g, 0.0346 mol), guanidine carbonate (15.6 g, 0.0866 mol, 2.5 molar equiv.) and DMSO (50 ml) was heated under stirring at 130-135+C for 5.5 hours. Then, the reaction mixture was cooled to 60 C. and water (90 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 2 hours and a precipitate was collected by filtration, washed with water (3×40 ml) and methanol (35 ml) and dried at 80 C. under reduced pressure overnight to yield 7.1 g of crude compound III, having a purity of 93.5% (by HPLC). The crude compound III was purified via its hydrochloride salt to yield 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-guanidine (III), having a purity of 99.7% by HPLC); mp 226-228 C.NMR 13C (DMSO-d6). delta=19.27 2CH3, 28.36 [CH(CH3)2], 53.41 (CH2), 115.25, 120.27, 122.60, 126.65, 126.94, 132.16, 133.06, and 143.11 (Carom.), 143.52 (N-CHN), 155.19 [NC(NH-)C], and 159.12 [H2N-C(NH)NH-]. ESI MS (m/z): 283.3 [MH+].
With sodium hydroxide; In butan-1-ol; at 120℃; for 2h;
NaOH (0.78 g, 19.5 mmol) was added to a mixture of 3-(dimethylamino)-l-(pyridin-3- yl)prop-2-en-l-one (3.52 g, 20.0 mmol) and guanidine carbonate (1.80 g) in n-butanol (20 mL). The mixture was heated at 1200C for 2 h. After cooling, the precipitates formed was collected by filtration and dried under vacuum to afford the desired product (2.3g, 66percent). LCMS: (M+H)+= 173.2.
In iso-butanol; for 24h;Heating / reflux;
4-Pyridin-3 - yl-pyrimidin-2- ylamine (7)[0042] A mixture of 3-acetylpyridine (20.72 g, 171.0 mmol) and N, N-dimethylformamide dimethyl acetal (60 mL, 450 mmol) is heated at 110 0C. After reaction overnight, the reaction mixture is cooled to room temperature and concentrated. Ethyl ether (20 mL) and hexanes (60 <n="17"/>P A T E N TGNF Docket No.: P1286PC10mL) are added to the residue. The resulting solid is collected by filtration, washed with hexanes, and dried to afford 3-dimethylamino-l-pyridin-3-yl-propenone which is used for next reaction without further purification. A mixture of 3-dimethylamino-l-pyridin-3-yl-propenone (17.6 g, 100 mmol) and guanidine carbonate (10.8 g, 60.0 mmol) in 2-butanol (100 mL) is heated at reflux. After 24 hours, the reaction mixture is cooled to room temperature and concentrated. The residue is triturated in water (50 mL). The solid is collected by filtration, washed with water and dried to afford the desired product 4-pyridin-3-yl-pyrimidin-2-ylamine as a white solid. C29H31N7O Exact MS: 172.07. Found MS m/z 173.1 (M+l). 1H NMR (DMSO-J6): delta 9.23 (s, IH), 8.69 (m, IH), 8.37 (m, 2H), 7.54 (d, IH), 7.20 (d, IH), 6.80 (s, 2H).
Preparation of I where R1 and R2 are Hydrogen, R3 is 1-methylindol-3-yl, and R4 and R5 are Hydrogen 3-Acetyl-1-methylindole (0.870 g) was dissolved in 3 ml of absolute ethanol. Tert-butoxybis(dimethylamino)methane (Bredereck's reagent) (0.960 g) in 3 ml of ethanol was added to this solution at reflux temperature. The solution was refluxed for 2 days and the solvent was removed at room temperature under vacuum. The residue was triturated with a 7:3 mixture of hexane/ethyl acetate to give a solid (0.094 g). The solid was mixed with guanidine carbonate (0.037 g) and the mixture was heated to 120C for 14 hours. The reaction mixture was dissolved in hot absolute ethyl alcohol, filtered, and recrystallized to give a white, crystalline solid of 2-amino-4-(1-methylindol-3-yl)-pyrimidine (0.039 g). Treatment of the crystalline solid with hydrochloric acid-ethyl alcohol and recrystallization of the salt from ethanol gave 2-amino-4-(1-methylindol-3-yl)-pyrimidine hydrochloride (0.0098 g), m.p. 274-276C.
Procedure for preparation of Intermediate B-1.A-1 B-1To a stirred suspension of NaH (45.30 g, 1.13 mol) in anhydrous THF (1 .2 L) was added ethyl formate (114.42 g, 1 .54 mol). The suspension was cooled in an ice bath, and then compound A-1 (200 g, 1 .03 mol) in anhydrous THF (300 ml_) was added dropwise via an addition funnel. The white mixture was stirred at 0C to room temperature for 5 hours. During this time, the reaction was exothermic and turned yellow. In a separate flask, guanidine carbonate [593-85-1 ] (111 .31 g, 0.618 mol) was treated with a sodium ethoxide solution, freshly prepared by the careful addition of Na (28.41 g, 1 .24 mol) to anhydrous ethanol (750 mL) at room temperature. The off-white slurry obtained after stirring for 1 hour, was then added to the yellow solution prepared above. The resulting pale yellow reaction mixture was heated to reflux for 15 hours. The solvent was removed, and then the crude residue was dissolved in water (1 .5 L). The mixture was adjusted to pH=5 with acetic acid. The solid was collected, washed extensively with water and ethanol to give intermediate B-1 (160 g).1H NMR (400 MHz, DMSO-d6) delta ppm 4.90 (s, 2 H), 6.33 (br. s., 2 H), 7.25 (s, 1 H), 7.29 - 7.42 (m, 5 H), 1 1 .21 (br. s., 1 H)
Guanidine carbonate (2) (4.47 g, 36.9 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (1) (5.00 g, 24.6 mmol) in dimethylacetamide (50 ml). The reaction mixture was heated at 150C for 5 h. The progress of the reaction was monitored by TLC using AcOEt-hexane, 1:1, as eluent. The reaction mixture was cooled and quenched with ice water, and stirred for 30 min. Then the obtained solid was filtered off, and water was removed by azeotropic distillation with PhMe to get 4.00 g (73%) of compound 3. Mp 270-272C. 1H NMR spectrum (300 MHz), delta, ppm (J, Hz): 7.04 (2H, s,NH2); 7.37 (1H, d, J = 9.0, H Ar); 7.78 (1H, dd, J = 9.0,J = 2.4, H Ar); 8.05 (1H, d, J = 2.4, H Ar); 9.09 (1H, s,H Ar). Mass spectrum, m/z: 225 [M+H]+.
48%
With caesium carbonate; diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150 - 160℃; for 3h;
Barium carbonate (281 g, 1.56 mol),A mixed solution of DIEA (540 mL, 3.12 mol) and NMP (1 L) was heated to 150-160 C under stirring.A solution of 5-bromo-2-fluorobenzaldehyde (250 g, 1.20 mol) in NMP (100 ml) was slowly added dropwise.After 3 hours of reaction, the temperature was lowered to 100 C.Add ice (2kg) and water (4L),A yellow-brown solid precipitated and stirring was continued for 30 minutes.Filter under reduced pressure,Wash with water (1L) and ethanol (1L),The resulting filter cake was transferred to a 5 L flask.Add ethanol (2L) and stir for 2 hours.Then filtered, followed by ethanol (0.5 L),Wash with toluene/ethanol (1:1, 0.5 L) and toluene (0.5 L).Compound 3 was obtained as a pale yellow solid (168 g, 48%).
Preparation 12 6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine A solution of 1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidine carbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate (32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17 hours and the solvent was removed in vacuo. The residue was diluted with water and the mixture was swirled for a few minutes. The undissolved white solid was collected and washed with water, followed by a small amount of cold ethyl acetate to give the title compound (4.10 g, 55%).
A mixture of compound 12c (1.0 g, 4.26 mmol) and guanidine carbonate (1.04 g, 8.52 mmol) in DMA (25 mL) was stirred at 135 C for 3hrs. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (50 mL×2) and brine (50 mL), dried over anhydrous Na 2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol/ammonium water 400:10:1, v/v) to give the title compound 12d (340 mg, 42% yield) as a brown solid.
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.6%
N-tert-butoxycarbonyl-4-piperidone (58, 5.8 g, 31.4 mmol) wasdissolved in N,N-dimethylformamide dimethyl acetal (45.0 mL),and the solution was heated under reflux for 1.5 h and concentrated.The residue was triturated with hexane, filtered, andwashed with hexane to give 59 as a yellow powder (5.1 g, 63.8%):mp 135e136 C; To a solution of 59 (5.0 g, 20.8 mmol) in EtOH(200.0 mL) were added guanidine carbonate (15.0 g, 84.0 mmol)and sodium acetate (13.7 g, 167.0 mmol), and the solution washeated under reflux for 48 h. The reaction mixturewas filtered, andthe insoluble material was extracted with CHCl3 and washed withwater. The organic layer was dried over anhydrous MgSO4 andevaporated. The resultant solid was triturated with 2-propanol,filtered, and washed with 2-propanol and Et2O to give a colorlesspowder. It was dissolved in TFA (50.0 mL) at 0 C, and the solutionwas stirred at room temperature for 1 h and concentrated. Theresidue was dissolved in 2-propanol and treated with concentrated HCl (4.0 mL). The precipitated solidwas filtered andwashed with 2-propanol and Et2O to give 60a (4.2 g, 81.6%) as a colorless powder: Mp 258e260 C; Compound 57g was obtained from 60a in thesame way as 57f.
In N,N-dimethyl acetamide; at 140℃; for 4h;Inert atmosphere;
0.500 g of <strong>[64113-84-4]2-fluoro-5-methylbenzonitrile</strong> 41 (3.70 mmol) and 1.00 g (5.60 mmol) of guanidine carbonate were dissolved in 5 ml of abs. N,N-dimethylacetamide and heated to 140 C for 4 h under argon. After cooling a white solid precipitated. The mixture was stored for 18 h in the refrigerator and the product was separated by filtration. After recrystallization from water 350 mg (54 %) of 20 were obtained as colorless crystals. Mp.: 255 C (lit.255.5-256.6 C [14]). 1H-NMR(250 MHz, DMSO-d6): / ppm = 7.76 (s, 1H, Ar-H),7.37-7.26 (dd,J =8.5 Hz,J =1.8 Hz, 1H, Ar-H),7.14 (br, 2H, NH2),(d,J =8.5 Hz, 1H, Ar-H),5.84 (s, 2H, NH2),2.32 (s, 3H, CH3). 13C-NMR(75.4 MHz, DMSO-d6): / ppm = 162.0, 160.2, 150.6, 133.9, 128.6, 124.1, 122.6, 110.0,20.7. IR: nu = 3426 (s), 3344 (w), 3066 (s), 2796 (w), 2681 (w), 1923 (w), 1734 (w), 1672 (s), 1626 (s), 1576 (s), 1516 (s), 1474 (m), 1455 (m), 1427 (s), 1399 (s), 1329 (m), 1289 (m), 1220 (w), 1172 (m), 1139 (w), 1092 (s), 1038 (m), 1002 (m), 962 (w), 922 (m), 874 (m), 857 (m), 824 (s),797 (m), 720 (m), 684 (m), 654 (m), 590 (m), 570 (s). Anal. calcd.for C9H10N4(174.20): C 62.05; N 5.79; 32.16; found: C 61.77; N 5.89; 32.40.
General procedure: To a suspension of guanidine carbonate (1.5-5 eq) in ethanol (2 mL/mmol) was added gamma-aryl-beta-ketoester (1.43-26.6 mmol), and the reaction mixture heated at 80 C for 15-64 h. Followingreaction completion by TLC, the mixture was cooled to ambient temperature, filtered and thesolid triturated with water (5-20 mL) and acetone (5-20 mL) to give the title compound.
With piperazine immobilized inside the mesochannels of magnetic MCM-41 as an organic base (a-Fe2O3-MCM-41-piperazine); In neat (no solvent); at 80℃; for 1h;Green chemistry;
General procedure: A mixture of benzaldehyde derivatives (1 mmol), acetophenone or 4-methylacetophenone(1 mmol), and benzamidine hydrochloride (1 mmol) or guanidiniumcarbonate (0.75 mmol) along with the catalyst (0.05 g) was thoroughly ground and then transferred into a reaction vessel where this mixture was stirred at 80 C for appropriate times. The reactions were monitored by thin-layer chromatography[TLC; ethyl acetate (EtOAc):petroleum ether, 1:4]. After completion of the reaction,the mixture was allowed to cool to room temperature, then chloroform (3 mL) wasadded and the mixture was stirred for an extra 30 min. After collecting the magneticcatalyst with an external magnet, the solvent was removed in vacuo and theprecipitates were recrystallized from ethanol to furnish the desired trisubstitutedpyrimidine derivatives.
4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile[ No CAS ]
[ 593-85-1 ]
1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-yl)-1H-pyrrole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14.9%
<strong>[7126-39-8]1H-pyrrole-3-carbaldehyde</strong> (58 mg, 0.61 mmol) and 4,6-difluoro-2,3-dihydro-3-methylbenzofuran- 7-carbonitrile (97.6 mg, 0.5 mmol) were dissolved in DMF (1 ml) and cooled in ice-water bath. NaH (40 mg) was slowly added. The reaction was stirred for 1 hour then directly purified through RPLC (5 to 54 percent CH3CN in water with 0.1 percent formic acid). The fractions of the mixture of the desired product and its isomer were concentrated by rotary evaporation to a white solid. The mixture was re-dissolved in NMP (1 ml) and added with guanidine carbonate (80 mg), K2CO3 (140 mg), and water (0.2 ml). The resulting mixture was heated in microwave at 130 oC for 40 minutes. It was then purified through RPLC (50 g, 5 - 20 percent CH3CN in water with 0.1 percent formic acid). The collected fractions were lyophilized to afford the product as a white solid (23mg, 14.9 percent).1H NMR (DMSO, 300 MHz): delta = 9.79 (s, 1 H), 8.21 (s, 1 H), 8.09-8.07 (t, J = 1.65 Hz, 1 H), 7.36-7.35 ( t, J = 2.22 Hz, 1 H), 6.69-6.68 (m, 3 H), 6.22 (br, 2 H), 4.93-4.87 (t, J = 8.97 Hz, 1 H), 4.42-4.37 (q, J = 5.07, 8.91 Hz, 1 H), 4.00-3.91 (m, 1 H), 0.80-0.78 (d, J = 6.72 Hz, 3 H); LCMS: C16H15N5O2 [M + H]+ = 310.
<strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong> (100 mg, 64 mmol), phenol (120 mg, 1.2 mmol) and potassium carbonate (87 mg, 64 mmol) were irradiated in the microwave in NMP (3 mL) at 120C for 10 minutes at which point LCMS indicated that the reaction was complete. Guanidine carbonate (231 mg, 1.91 mmol) was added and the reaction irradiated in the microwave at 150C for 15 minutes. The mixture was cooled and purified directly by reversed phase HPLC (15 to 95% ACN in DI water containing 0.1% TFA: 15 minute gradient). The pure fractions were pooled and concentrated to afford the product as an off white solid.135 mg, 61% yield, 2 steps.1H-NMR (300 MHz, DMSO d6) delta 12.68 (s, 1H), 8.93 (s, 1H), 8.40 (bs, 2H), 7.54-7.43 (m, 6H), 7.37-7.28 (m, 2H), 7.15 (d, 2H, J=7.2 Hz), 6.42 (s, 1H), 6.01 (s, 1H). LC/MS [M+H]+ 345.4.
benzyl 2-amino-4-hydroxy-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tert-butyl alcohol; at 80℃; for 24h;Inert atmosphere;
General procedure: Acetamidine hydrochloride (16.94 g, 179 mmol) was added to a solution of 1-benzyl 3- ethyl 4-oxopyrrolidine-l,3-dicarboxylate (CAS 51814-19-8) (29 g, 100 mmol) and triethylamine (25 mL, 179 mmol) in tert-BuOH (250 mL). The mixture was heated at 80 C for 24 hours under nitrogen. The mixture was concentrated in vacuo and partitioned between water and EtOAc. THF was added and the mixture filtered to give benzyl 4- hyckoxy-2-memyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (11.18 g). The organic phase from the filtrate was passed through a pad of silica, eluting with EtOAc, and the resulting solution concentrated in vacuo. The residue was suspended in ether and THF (4:1, 200 mL) and filtered to afford the title compound. 1H NMR (400 MHz, DMSO-i): delta ppm 2.32 (s, 3H), 4.33 - 4.54 (m, 4H), 5.14 (s, 2H), 7.29 - 7.45 (m, 5H), 12.57 (br s, 1H). MS ES+ 286
To a solution of compound 12-2 (1.2 g, 5.8 mmol) in DMA (10.0 mL) was added carbonic acid-guanidine (1.5 g, 8.7 mmol). The mixture was stirred at 160C for 0.5 h, cooled to rt, diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated. The residue was washed with dichloromethane (50 mL chi 3) to give a product compound 12-3 (120 mg).
With sodium acetate; In ethanol; at 80.0℃; for 5.0h;
To a stirred solution of Intermediate 43A (12.00 g, 87.00 mmol) in EtOH (25 mL) was added guanidine carbonate (31.30 g, 174.00 mmol) and sodium acetate (21.37 g, 261.00 mmol) and the reaction was stirred at 80 oC for 5 h. The reaction mixture was cooled to ambient temperature, concentrated to dryness and diluted with n-hexane (200 mL). The solid precipitate was filtered, washed with EtOH (30 mL) and dried under vacuum to obtain Intermediate 43B (9.50 g, 82.00%).1H NMR (400 MHz, DMSO-d6) G ppm 2.38 (s, 3 H), 7.62 (s, 2 H), 8.53 (s, 1 H). LCMS (Method-L): retention time 0.54 min, [M+H] 135.1.
In N,N-dimethyl acetamide; at 130℃; for 3h;Sealed tube;
In a sealed tube, a mixture of 2- fluoro-6-(trifluoromethyl)benzonitrile (4.5 g, 23.8 mmol) and guanidine carbonate (8.57 g, 47.6 mmol) in DMA (54 ml_) was stirred at 130 C for 3h. The reaction mixture was cooled to rt, diluted with EtOH and the solvent was removed under reduced pressure. The residue was mixed with cold water and the solid was isolated by filtration to give the title compound as a tan solid (5.2 g), and was used in the next step without further purification.
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