* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 19, p. 7841 - 7844
2
[ 124-42-5 ]
[ 70-11-1 ]
[ 13739-48-5 ]
Yield
Reaction Conditions
Operation in experiment
21%
With potassium carbonate In acetonitrile at 99.84℃; for 0.666667 h; Microwave irradiation; Sealed tube; Autoclave
General procedure: By following the general procedure at 373 K and by maintainingthat temperature for 40 min in the reaction with 2-bromo-1-phenylethanone [(1a); 200 mg, 1.01 mmol], 1H-imidazole (3a)(yield 16 mg, 20percent) was obtained as a white solid (m.p. 436–438 K). Recrystallization of this compound from methanol afforded colourless crystals suitable for X-ray diffractionanalysis. 1H NMR (400 MHz, CDCl3): 2.37 (s, 3H), 7.18 (s,1H), 7.20 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.66 (d, J =7.3 Hz, 2H), 8.76 (br s, 1H, NH). 13C{1H} NMR (100 MHz,CDCl3): 13.8 (CH3), 115.0 (CH), 124.6 (CH), 126.7 (CH),128.7 (CH), 132.7 (C), 137.7 (C), 145.2 (C). HRMS (ESI+):calculated for C10H11N2+ 159.0922 [M+H]+; found 159.0921.
Reference：
[1] Yakugaku Zasshi, 1954, vol. 74, p. 756[2] Chemical and Pharmaceutical Bulletin, 1964, vol. 12, p. 393[3] Chem.Abstr., 1955, p. 11663
8
[ 124-42-5 ]
[ 594-42-3 ]
[ 21734-85-0 ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydroxide In water at -5 - 20℃;
Preparation of 2-(3-Methyl[1,2,4]thiadiazol-5-yl)octanedioic Acid 8-Hydroxyamide 1-Phenylamide (Compound 67022.6, which is Also Referred to as Compound 2021032 Below) The overall reaction scheme is as follows: Preparation of 5-Chloro-3-methyl-1,2,4-thiadiazole (2009380) To a stirred mixture of acetamidine hydrochloride (38.1 g, 0.40 mol) and trichloromethanesulfenyl chloride (75 g, 0.40 mol) at +-5° C. was added dropwise over 2.5 h a solution of NaOH (75.7 g, 0.40 mol) in water (126 mL). The resultant reaction mixture was then stirred at 0° C. for 30 min before being allowed to warm to room temperature. The mixture was subsequently filtered, the layers were separated, and the aqueous phase was extracted with dichloromethane (3*150 mL). The combined organic fractions were washed with brine (2*150 mL), dried (MgSO4), and the solvent was removed under reduced pressure to afford 5-chloro-3-methyl-1,2,4-thiadiazole (2009380) (43 g, 83percent) as a dark oil.
41.8%
With sodium hydroxide In dichloromethane; water at -5℃; for 0.5 h;
To a mixture of perchloromethyl mercaptan (Gl) (60 g, 323 mmol) and acetamidine hydrochloride (30.6 g, 323 mmol) in dichloromethane(200 mL) was added dropwise a solution of NaOH (64.8 g in water (200 mL) at -5 0C. The resulting mixture was stirred at -5 0C for 30 min and then allowed to warm to room temperature. The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with water (50 mL x 2) and brine (100 mL), dried over Na2SO^ and the solvent was removed. The residue was distilled under reduced pressure to give 5-chloro-3-methyl-l,2,4- thiadiazole (G2) (bp 700C /0.85 Mpa, 18 g, 41.8percent). 1H-NMR (300 MHz, CDCl3) δ 2.59 (s, 3H).
Reference：
[1] Chemische Berichte, 1957, vol. 90, p. 182,186
11
[ 124-42-5 ]
[ 333-20-0 ]
[ 17467-35-5 ]
Reference：
[1] Gazzetta Chimica Italiana, 1977, vol. 107, p. 1 - 5
[2] Bioorganic and medicinal chemistry, 2001, vol. 9, # 12, p. 3231 - 3241
12
[ 124-42-5 ]
[ 17467-35-5 ]
Reference：
[1] Chemische Berichte, 1954, vol. 87, p. 68,74[2] Chemische Berichte, 1956, vol. 89, p. 1534,1540
13
[ 124-42-5 ]
[ 70807-22-6 ]
[ 461-98-3 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 3, p. 427 - 431
14
[ 100368-38-5 ]
[ 124-42-5 ]
[ 73-70-1 ]
Reference：
[1] Yakugaku Zasshi, 1958, vol. 78, p. 637,642[2] Chemical and Pharmaceutical Bulletin, 1966, vol. 14, p. 238[3] Chem.Abstr., 1958, p. 18411
15
[ 6967-82-4 ]
[ 124-42-5 ]
[ 18731-19-6 ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(l) iodide; TPGS-450-M; caesium carbonate In water at 20℃; for 12 h; 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 percent 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.
Reference：
[1] Green Chemistry, 2009, vol. 11, # 11, p. 1881 - 1888
17
[ 87-56-9 ]
[ 124-42-5 ]
[ 74840-47-4 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1949, vol. 14, p. 223,228
18
[ 766-38-1 ]
[ 124-42-5 ]
[ 100707-39-9 ]
Yield
Reaction Conditions
Operation in experiment
42%
Stage #1: With sodium ethanolate In ethanol at 50℃; Stage #2: With sodium ethanolate In ethanol
Step 42a: 5-Bromo-2-methylpyrimidine (Compound 0601-120)Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared sodium ethoxide in ethanol solution (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixture was warmed to 50 °C, then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide in ethanol solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M x 2.4 mL). The brown precipitate was filtered and washed with cold water, then freeze-dried to give 5-bromo-2- methylpyrimidine-4-carboxylic acid (350 mg, 42percent) as a brown solid. LCMS: 218 [M+l]+, 1H NMR (400 MHz, DMSO-d6): δ 2.62 (s, 3H), 9.03 (s, 1H).
42%
at 50℃;
Step 42a: 5-Bromo-2-methylpyrimidine (Compound 0601-120)[0365]Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared sodium ethoxide in ethanol solution (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixture was warmed to 50° C., then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide in ethanol solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M×2.4 mL). The brown precipitate was filtered and washed with cold water, then freeze-dried to give 5-bromo-2-methylpyrimidine-4-carboxylic acid (350 mg, 42percent) as a brown solid. LCMS: 218 [M+1]+, 1H NMR (400 MHz, DMSO-d6): δ2.62 (s, 3H), 9.03 (s, 1H).
42%
With sodium ethanolate In ethanol at 50℃;
Sodium (356mg, 15.5mmol) was added to the carefully ethanol (5.9mL), and in ethanolSodium ethoxide solution was prepared. Sodium ethoxide in freshly prepared ethanol solution of the above (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91g, 9.69mmol). The mixture was allowed to warm up to 50 , and then the heating bath was removed, Mukoburomu acid (1g, 3.87mmol) a solution in ethanol, was dropped so that a constant temperature is maintained, then further, ethanol solution (2mL) sodium ethoxide was dropped of. After cooling, the mixture was filtered, and the residue was evaporated, stirred vigorously with hydrochloric acid (2Mx2.4mL). The brown precipitate was filtered, washed with cold water, and then to obtain a freeze-dried to give 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (350mg, 42percent) as a brown solid.
Reference：
[1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 176
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0364; 0365
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0319
19
[ 90994-06-2 ]
[ 124-42-5 ]
[ 100707-39-9 ]
Yield
Reaction Conditions
Operation in experiment
25.2%
With sodium ethanolate In ethanol at 20 - 50℃; for 17 h;
To a solution of the commercially available ethanimidamide ii, ashydrochloride, (6.0 g, 63.83 mmol) in anhydrous EtOH (20 mL) was added sodium ethoxide (20 mL of a 2i percent solution in ethanol) and the reactionmixture was stirred at 50 00 and the commercially available (2E)-2,3-dibromo-4-oxobut-2-enoic acid i 2 (6.82 g, 26.74 mmol) in EtOH (i 0 mL) was added into the mixture. After stirring at 50 00 for i hour, a further portion of sodiumethoxide (i 0 mL of a 2i percent solution in ethanol) was added and the mixture was stirred at r.t. for i6 h. The reaction mixture was filtrated and the filtratereduced in vacuo. The residue was then treated with 2 M aqueoushydrochloric acid (30 mL) and stirred vigorously for 30 mm. The resulting solid was filtrated, washed with water and air dried to give KR-i 3 (i .46 g, 25.2percent) as a pale yellow solid. ESI-MS (M+i): 2i7 calc. for C6H5BrN2O2:2i6.0.
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1949, vol. 14, p. 223,228
21
[ 68965-62-8 ]
[ 124-42-5 ]
[ 19178-21-3 ]
Yield
Reaction Conditions
Operation in experiment
71%
With copper; sodium t-butanolate In N,N-dimethyl-formamide at 100℃; for 0.5 h; Microwave irradiation
General procedure: A 10 mL microwave reaction tube was charged with the appropriate β-bromo α,β-unsaturated carboxylic acid 1 (0.5mmol) and amidine hydrochloride 2 (1 mmol), together withCu powder (0.05 mmol), t-BuONa (2 mmol), and DMF (3mL). The mixture was heated to 100 °C for 30 min by microwave irradiation (CEM Discover Microwave System) at 100 W initial power. The mixture was then cooled to r.t.and filtered through a short column of silica gel (CHCl3–MeOH) to remove inorganic salts. Evaporation of the solvent gave a crude mixture that was purified by TLC [silica gel 60 GF254 (Merck), CHCl3–MeOH].
With copper(l) iodide; TPGS-450-M; caesium carbonate In water at 20℃; for 12 h; 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 percent 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.
Stage #1: at 0℃; for 0.333333 h; Stage #2: at 0℃; for 0.5 h; Stage #3: With triethylamine In ethanol for 2 h; Reflux
(0294) To a solution of sodium (2.90 g, 126 mmol) in ethanol (150 mL) was added acetoamidine hydrochloride (11.9 g, 126 mmol) at 0° C. The mixture was stirred at 0° C. for 20 minutes, diethyl (ethoxymethylene)malonate (28.6 g, 132 mmol) was added dropwise thereto, the mixture was stirred at 0° C. for 30 minutes, and triethylamine (20 mL, 145 mmol) was added thereto. The mixture was heated under reflux for 2 hours, the reaction mixture was concentrated, water (400 mL) was added thereto, citric acid was added to adjust pH to 4 to 5, and the mixture was extracted with dichloromethane (200 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtrated, and concentrated. To the resulting concentrated residue was added tert-butyl methyl ether (200 mL), and the precipitate was collected on a filter to give the title compound (14.0 g, 61percent) (0295) 1H-NMR (400 MHz, CDCl3) δ: 1.40 (3H, t, J=7.2 Hz), 2.61 (3H, s), 4.39 (2H, q, J=7.2 Hz), 8.73 (1H, s).
27%
With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate
EXAMPLE 30 Ethyl 2-methyl-pyrimidin-6(1H)-one-5-carboxylate STR55 Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane). The title compound also was prepared by the route described in Example 102.
27%
With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate
Example 30 Ethyl 2-methyl-pyrimidin-6(1H)-one-5-carboxylate STR57 Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane). The title compound also was prepared by the route described in Example 102.
27%
With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate
Example 30 Ethyl 2-methyl-pyrimidin-6(1H)-one-5-carboxylate STR52 Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane). The title compound also was prepared by the route described in Example 102.
27%
With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate
Example 30 Ethyl 2-Methyl-pyrimidin-6(1H)-one-5-carboxylate STR50 Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane). The title compound also was prepared by the route described in Example 102.
27%
With sodium ethanolate In ethanol for 5 h; Heating / reflux
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 ML of a 21percent solution, 0.20 mole) for 5 minutes.. diethyl ethoxymethylenemalonate (31.5 ML, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours.. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 ML).. The solution was filtered, washing the solid cake with dichloromethane.. The filtrate was concentrated at reduced pressure.. The residue was dissolved in dichloromethane (150 ML) and 2.0N HCl (30 ML).. The PH of the aqueous layer was 1.. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.. The residue was dissolved in hot dichloromethane (50 ML).. ethyl acetate was added (50 ML).. The product precipitated.. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 ML).. The resulting crystals were filtered, then washed with ethyl acetate (20 ML) followed by hexanes (50 ML) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf=0.27 (silica gel, 10percent isopropanol in dichloromethane).. The title compound also was prepared by the route described in Example 102.
Reference：
[1] Patent: US2016/122319, 2016, A1, . Location in patent: Paragraph 0293-0295
[2] Patent: US6008351, 1999, A,
[3] Patent: US6011158, 2000, A,
[4] Patent: US5656645, 1997, A,
[5] Patent: US5658930, 1997, A,
[6] Patent: US6342504, 2002, B1, . Location in patent: Page column 58
[7] Journal of Organic Chemistry, 1946, vol. 11, p. 741,749
[8] Journal of the Chemical Society, 1937, p. 367[9] Journal of the Chemical Society, 1938, p. 28
30
[ 124-42-5 ]
[ 5571-03-9 ]
Reference：
[1] Synthesis, 2002, # 6, p. 720 - 722
31
[ 124-42-5 ]
[ 5571-03-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 37, p. 5081 - 5085
32
[ 124-42-5 ]
[ 105-53-3 ]
[ 1194-22-5 ]
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3559 - 3561
[2] Tetrahedron Letters, 2009, vol. 50, # 41, p. 5729 - 5732
33
[ 24771-25-3 ]
[ 124-42-5 ]
[ 1668-54-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium hydroxide In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate
EXAMPLE 2 Acetamidine hydrochloride (9.5 g) was added to a predissolved solution of methanol (50 mL) and KOH pellets (6.8 g) at 10° C. It was then dropped into a solution of 11.4 g of dimethyl N-cyanoimidocarbonate and 40 mL of methanol at 10° C. After the addition, the reaction mixture was stirred at 25° C. for 2 hours onto 40 mL of ice water. The solid crystals were collected by filtering and washing with water and methanol. After drying at 70° C. overnight, 11.8 g (84percent yield) of 2-methyl-4-amino-6-methoxy-1,3,5-triazine was obtained.
With sodium ethanolate In ethanol for 20 h; Reflux
2,6-dimethylpyrimidin-4-ol. Ethyl 3-oxobutanoate (10.0 g, 77 mmol) and acetimidamide hydrochloride (7.23 g, 77 mmol) were added to the solution of sodium ethanolate (10.5 g, 154 mmol) in ethanol (200 mL). And the mixture was refluxed for 20 hours. Water (10 mL) was added to the mixture. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane /methanol = 15: 1) to give 2,6-dimethylpyrimidin-4-ol as a yellow solid (3.43 g, 36percent). LRMS (M + H+) m/z: calcd 124.06; found 124.
29%
With potassium carbonate In water at 20℃; for 0.25 h; Microwave irradiation
General procedure: The corresponding amidine hydrochloride (2.54 mmol) and powdered K2CO3 (5.76 mmol) were dissolved in water (5.0 mL) in a 20-mL vessel. The β-keto ester (2.31 mmol) was added and the resulting mixture was irradiated for 5–15 min (see Table 2). Upon the end of the reaction (TLC, hexanes/EtOAc, 5:1), the mixture was diluted with sat. aq NH4Cl (5.0 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (anhyd Na2SO4) and filtered. The filtrate was rotary evaporated and the obtained crude product was purified by column chromatography [silica gel, hexane/EtOAc mixtures or recrystallized (EtOH)].
Reference：
[1] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 6, p. 1745 - 1750
[2] Org.Synth.Coll.Vol., 1932, vol. I, p. 5;deutsche Ausgabe,S.5
45
[ 1000-84-6 ]
[ 124-42-5 ]
Reference：
[1] Chemische Berichte, 1917, vol. 50, p. 234
46
[ 60-29-7 ]
[ 1000-84-6 ]
[ 124-42-5 ]
Reference：
[1] Chemische Berichte, 1917, vol. 50, p. 234
47
[ 64-17-5 ]
[ 1000-84-6 ]
[ 124-42-5 ]
Reference：
[1] Chemische Berichte, 1917, vol. 50, p. 234
48
[ 64-17-5 ]
[ 2208-07-3 ]
[ 7664-41-7 ]
[ 124-42-5 ]
Reference：
[1] Die Imidoaether und ihre Derivate <Berlin 1892> S.107,
49
[ 60-35-5 ]
[ 7647-01-0 ]
[ 625-77-4 ]
[ 124-42-5 ]
[ 64-19-7 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1857, vol. 103, p. 325
[2] Recueil des Travaux Chimiques des Pays-Bas, 1883, vol. 2, p. 339
50
[ 124-42-5 ]
[ 39254-63-2 ]
Reference：
[1] Chemistry - A European Journal, 2007, vol. 13, # 12, p. 3414 - 3423
51
[ 124-42-5 ]
[ 3490-92-4 ]
[ 15908-63-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 959 - 968
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 4, p. 814 - 823
52
[ 17823-58-4 ]
[ 124-42-5 ]
[ 15908-63-1 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 7, p. 754 - 759
53
[ 124-42-5 ]
[ 90905-33-2 ]
Yield
Reaction Conditions
Operation in experiment
10 g
With sodium In ethanol for 5 h; Reflux
To 500 mL of EtOH was added sodium (12 g, 0.50 mol) in portions at room temperature and the resulting mixture was stirred until the sodium was dissolved completely. To a suspension of the previously prepared salt (60 g, 0.17 mol) and acetamidine hydrochloride (17.4 g, 0.19 mol) in EtOH (2.5 L) was added the above solution at room temperature and the resulting mixture was heated to reflux for 5 h. After filtration, the solvent was removed under reduced pressure to give the remains, which was suspended in H2O (200 mL) and extracted with DCM (3 mL×100). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc=5:1 to 2:1) to afford 2-methyl-pyrimidine-5-carbaldehyde (10 g, yield: 50percent). 1H NMR (CDCl3 400 MHz): δ10.10 (s, 1H), 9.07 (s, 2H), 2.84 (s, 3H)
Reference：
[1] Angewandte Chemie - International Edition, 2004, vol. 43, # 16, p. 2099 - 2103
[2] Patent: US2014/107340, 2014, A1, . Location in patent: Paragraph 0120
54
[ 124-42-5 ]
[ 79-08-3 ]
[ 68-12-2 ]
[ 90905-33-2 ]
Reference：
[1] Journal of medicinal chemistry, 2004, vol. 47, # 20, p. 4829 - 4837
55
[ 2009-81-6 ]
[ 124-42-5 ]
[ 90905-33-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1281 - 1285
56
[ 124-42-5 ]
[ 4949-44-4 ]
[ 52421-75-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 12, p. 4533 - 4538
Stage #1: With sodium methylate In methanol at 20℃; Stage #2: With hydrogenchloride In water
Part A: 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine. A solution of 200 ml. of 25percent wt sodium methoxide in methanol (0.84 mol) was diluted with an additional 200 ml. of methanol. Acetamidine-HCI (40 g , 0.42 mol) was added to the sodium methoxide solution (white precipitate formed), followed by addition of dimethyl fluoromalonate (70 g, 0.46 mol). The contents were stirred at room temperature overnight, then concentrated in vacuo to dryness. The resulting residue was redissolved in hot water (300 ml_). After cooling the aqueous solution to room temperature, concentrated HCI was added slowly until crystal formation (fine white prisms) took place at about pH 5. Concentrated HCI was added dropwise until pH 3, and then the contents were filtered. The isolated crystals were rinsed with 1 M HCI and dried under vacuum to provide 5-fluoro-4,6-dihydroxy-2-methylpyrimidine (65.5 g, >100percent). LCMS: (M+H)+: 145.
65.5 g
at 20℃; Inert atmosphere
Part A: 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine A solution of 200 ml. of 25percent wt sodium methoxide in methanol (0.84 mol) was diluted with an additional 200 ml. of methanol. Acetamidine-HCI (40 g , 0.42 mol) was added to the sodium methoxide solution (white precipitate formed), followed by addition of dimethyl fluoromalonate (70 g, 0.46 mol). The contents were stirred at room temperature overnight, then concentrated in vacuo to dryness. The resulting residue was redissolved in hot water (300 ml_). After cooling the aqueous solution to room temperature, concentrated HCI was added slowly until crystal formation (fine white prisms) took place at about pH 5. Concentrated HCI was added dropwise until pH 3, and then the contents were filtered. The isolated crystals were rinsed with 1 M HCI and dried under vacuum to provide 5-fluoro-4,6-dihydroxy-2-methylpyrimidine (65.5 g, >100percent). LCMS: (M+H)+: 145.
Stage #1: at 20℃; for 3 h; Heating / reflux Stage #2: at 20℃; for 1 h;
Part A: A mixture of sodium metal (1.55 g, 67.4 mmol) and EtOH (15.0 mL, 257 mmol) was stirred at RT until nearly all sodium had reacted. Diethyl fluoromalonate (3.54 mL, 22.4 mmol) was added followed by acetamidine hydrochloride (2.14 g, 22.7 mmol). The reaction mixture was heated at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The residue was diluted with water (ca. 50 mL) and acidified (pH=2) with 6M aqueous HCl, and the mixture was stirred at RT for 1 h as a precipitate formed. The solids were collected by suction filtration and washed with water. Excess solvent was removed in vacuo to give 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.08 g, 64percent) as a light gray solid. LCMS (m/z): 145 (M+H)+
With sodium methylate In methanol at 25℃; for 20 h; Inert atmosphere
General procedure: To a solution of sodium methoxide (25 wt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 °C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 °C for 20 h. The mixture was cooled to 0 °C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 °C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; LC/MS:m/z 242.06 (M + H)+, 0.598 min (method 12). 1H-NMR (500 MHz, CDCl3) δ12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H),3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H).
77%
With sodium ethanolate In ethanol for 16 h; Heating / reflux
Example 51Preparation of Compounds 211, 215, 216, 225, 226 and 231Compounds 211, 215, 216, 225, 226 and 231 were prepared using the method set forth below. <n="193"/>Step A - Synthesis of7-benzyl-2-methyl-5,6, 7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-oneTo a solution of l-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (5.0 g, 16.8 mmol) in 80 mL ethanol was added acetamidine hydrochloride (2.4 g, 25.2 mmol) followed by sodium ethoxide (21percent in ethanol, 10.6 mL, 33.6 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 16 hours. The reaction was then cooled to room temperature, diluted with dichloromethane, and the organic phase was washed with water and brine, dried and concentrated in vacuo, the resulting residue was purified using flash column chromatography (5percent methanol in dichloromethane) to provide 7-benzyl-2- methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one in 77percent yield.
95%
With sodium ethanolate In ethanol; water; acetic acid
Step A: 7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one A solution of sodium ethoxide in ethanol was prepared by addition of sodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all dissolved, ethyl 1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (21 g, 70.5 mmol) was added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, and concentrated. The residue was dissolved in a minimum amount of water and the pH was adjusted to about 7 with glacial acetic acid. The resulting yellow precipitate was filtered, washed with water (3*), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95percent) of the title compound of Example 86, Step A as a yellow solid. 1H NMR (CDCl3, 250 MHz) δ7.35-7.25 (c, 5H), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH+).
Preparation of 2-(3-Methyl[1,2,4]thiadiazol-5-yl)octanedioic Acid 8-Hydroxyamide 1-Phenylamide (Compound 67022.6, which is Also Referred to as Compound 2021032 Below) The overall reaction scheme is as follows: Preparation of 5-Chloro-3-methyl-1,2,4-thiadiazole (2009380) To a stirred mixture of acetamidine hydrochloride (38.1 g, 0.40 mol) and trichloromethanesulfenyl chloride (75 g, 0.40 mol) at +-5 C. was added dropwise over 2.5 h a solution of NaOH (75.7 g, 0.40 mol) in water (126 mL). The resultant reaction mixture was then stirred at 0 C. for 30 min before being allowed to warm to room temperature. The mixture was subsequently filtered, the layers were separated, and the aqueous phase was extracted with dichloromethane (3*150 mL). The combined organic fractions were washed with brine (2*150 mL), dried (MgSO4), and the solvent was removed under reduced pressure to afford 5-chloro-3-methyl-1,2,4-thiadiazole (2009380) (43 g, 83%) as a dark oil.
41.8%
With sodium hydroxide; In dichloromethane; water; at -5℃; for 0.5h;
To a mixture of perchloromethyl mercaptan (Gl) (60 g, 323 mmol) and acetamidine hydrochloride (30.6 g, 323 mmol) in dichloromethane(200 mL) was added dropwise a solution of NaOH (64.8 g in water (200 mL) at -5 0C. The resulting mixture was stirred at -5 0C for 30 min and then allowed to warm to room temperature. The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with water (50 mL x 2) and brine (100 mL), dried over Na2SO^ and the solvent was removed. The residue was distilled under reduced pressure to give 5-chloro-3-methyl-l,2,4- thiadiazole (G2) (bp 700C /0.85 Mpa, 18 g, 41.8%). 1H-NMR (300 MHz, CDCl3) delta 2.59 (s, 3H).
With sodium hydroxide; In dichloromethane; water; at -5℃; for 0.5h;
Dry chlorine gas was bubbled into the stirring CS2 (Cl ) (1000 mL, added about 1.0 g of iodine) at 5 0C for 48 hours. The excess CS2 (Cl) was evaporated off and the residue was distilled fractionally to give trichloromethyl hypochlorothioite (C2) (bp 144-145 C/latm, 300 g, 10%). 13C-NMR (300 MHz, CDC13) delta 96.69 (1 C).|00149| To a suspension of trichloromethyl hypochlorothioite (C2) (60 g, 323 mmol) and acetamidine hydrochloride (30.6 g, 323 mmol) in dichloromethane(200 mL) was added dropwise a solution of NaOH (64.8 g in water (200 mL) at -5 "C- The resulting mixture was stirred at -5 0C for 30 min and then allowed to warm to room temperature. The organic layer <n="46"/>was separated and the aqueous phase was extracted with dichloromethane (30 mL chi 3). The combined organic layers were washed with water (50 mL x 2) and brine (100 mL), dried over Na2SO4 and the solvent was removed. The residue was distilled under reduced pressure to give 5-chIoro-3 -methyl- 1 ,2,4-thiadiazole (C3) (bp 70 C /0.85 Mpa, 18 g.). IH-NMR (300 MHz, CDC13) delta 2.59 (s, 3 H).
A solution of sodium ethoxide (1.15g, 50mmol), and acetamidine hydrochloride (4.7g, 50mmol) in ethanol solution (60mL) was stirred at room temperature for 1h. After this, the reaction mixture was filtered out affording filtrate. Then 2-(ethoxymethylene)malononitrile (6.1g, 50mmol) was added to the filtrate, and the mixture was stirred at room temperature for 3h. After this, the reaction mixture was filtered and washed with 10mL ethanol and dried to give the desired compound 4-amino-2-methylpyrimidine-5-carbonitrile 1a, which was used directly for the next step. Under the same condition, the intermediate compounds 1b and 1c were also prepared.
2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane bistetrafluoroborate[ No CAS ]
[ 90905-33-2 ]
Yield
Reaction Conditions
Operation in experiment
10 g
With sodium; In ethanol; for 5h;Reflux;
To 500 mL of EtOH was added sodium (12 g, 0.50 mol) in portions at room temperature and the resulting mixture was stirred until the sodium was dissolved completely. To a suspension of the previously prepared salt (60 g, 0.17 mol) and acetamidine hydrochloride (17.4 g, 0.19 mol) in EtOH (2.5 L) was added the above solution at room temperature and the resulting mixture was heated to reflux for 5 h. After filtration, the solvent was removed under reduced pressure to give the remains, which was suspended in H2O (200 mL) and extracted with DCM (3 mL×100). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc=5:1 to 2:1) to afford 2-methyl-pyrimidine-5-carbaldehyde (10 g, yield: 50percent). 1H NMR (CDCl3 400 MHz): delta10.10 (s, 1H), 9.07 (s, 2H), 2.84 (s, 3H)
With potassium carbonate; In ethanol; for 2.5h;Heating / reflux;
(B-60) To a solution of 3-ethoxyacrylic acid ethyl ester (12.95g, 89.82mmol) and acetoamidine hydrochloride(25.44g, 269.1mmol) in ethanol(130ml), was added potassium carbonate (37.23g, 269.4mmol) and the mixture was refluxed for 2.5 hours.. After filtrating, the solvent was evaporated under reduced pressure and the precipitated crystals were washed with chloroform and dried under reduced pressure to give crude 2-methyl-3H-pyrimidine-4-one.
To a solution of Na (1. 39 g) in EtOH (42 mL) were added diethyl methylmalonate (5.00 g) and acetamidine hydrochloride (2.71 g). The mixture was stirred at reflux for 2.5 h and cooled to ambient temperature. The precipitate was collected by filtration, washed with EtOH, and dried at 80C under reduced pressure to give a white solid. To a solution of the above solid in H2O (30 mL) was added conc. HCI (2.5 mL) and the mixture was stirred at 4C for 1 h. The precipitate was collected by filtration, washed with H2O (twice), EtOH (twice), and Et2O (twice), and dried at 80C under reduced pressure to give the title compound (3.02 g). HNMR (300 MHz, DMSO-d6, 8) : 1.69 (s, 3H), 2.19 (s, 3H), 11.42-11. 66 (m, 2H); ESI MS m/z 139 (M--1, 100%).
Synthesis of 2,5-dimethyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled down to 0 C. using an ice bath, 9.72 g of sodium methylate (i.e. a solution concentration c=3 mol.l-1) is added to the reaction mixture then 5 g (53 mmoles) of acetamidine hydrochloride is added at 0 C. and in small quantities. Stirring is maintained at ambient temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added dropwise. Stirring is maintained for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The crude product obtained is taken up with a minimum quantity of water, cooled down to 0 C. then acidified with pure acetic acid to a pH between 4 and 5. The white precipitate formed is filtered, rinsed with water, ethyl ether and pentane. Then the white product is dried over P2O5 under reduced pressure (0.2 kPa). 3.3 g of expected product is obtained. TLC: Rf=0.2 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2). 1H-NMR (DMSO d6): delta 1.68 (s, 3H, OH-CH=C-); 2.18 (s, 3H, N=C-).
Example 7A; 7 -Benzyl4 -Chloro-2 -Methyl-5,6,7,8 -Tetrahydropyrido[3,4-d]Pyrimidine ; A mixture of <strong>[52763-21-0]ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride</strong> (0.512 g, 1.72 mmol), acetamidine hydrochloride (Aldrich, 0.166 g, 1.75 mmol) and sodium ethoxide (2.7 M in ethanol, 1.5 mL, 4.0 mmol) in ethanol (4.5 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 5 hr. The mixture was cooled to about 25 C., concentrated, diluted with saturated, aqueous NaHCO3, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound.
With sodium methylate; In methanol; diethyl ether; water; acetic acid;
a) A solution of 10 g of <strong>[150726-89-9]dimethyl-(o-methoxyphenoxy)malonate</strong> (Example 1 b) in 80 ml dry methanol was cooled to 0 C. 6.71 g of sodium methylate was added portionenwise. To the suspension was added 2.84 g of acetamidine hydrochloride and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with another portion of 100 ml of diethyl ether and dissolved in 50 ml of water. The pH was adjusted to 4 by adding 25 ml of glacial acetic acid. The white precipitate that formed was filtered off, washed with water and dried to yield 5.17 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a tautomer) as a white powder.
With sodium methylate; In methanol; diethyl ether; water; acetic acid;
a) A solution of 10 g of <strong>[150726-89-9]dimethyl-(o-methoxyphenoxy)malonate</strong> in 80 ml dry methanol was cooled to 0 C. 6.71 g of sodium methylate was added portionwise. To the suspension was added 2.84 g of acetamidine hydrochloride and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with another portion of 100 ml of diethyl ether and dissolved in 50 ml of water. The pH was adjusted to 4 by adding 25 ml of glacial acetic acid. The white precipitate that formed was filtered off, washed with water and dried to yield 5.17 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a tautomer) as a white powder.
With sodium methylate; In methanol; at 25℃; for 20h;Inert atmosphere;
General procedure: To a solution of sodium methoxide (25 wt-% in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 C for 20 h. The mixture was cooled to 0 C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 %) as an off-white solid; LC/MS:m/z 242.06 (M + H)+, 0.598 min (method 12). 1H-NMR (500 MHz, CDCl3) delta12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H),3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H).
77%
With sodium ethanolate; In ethanol; for 16h;Heating / reflux;Product distribution / selectivity;
Example 51Preparation of Compounds 211, 215, 216, 225, 226 and 231Compounds 211, 215, 216, 225, 226 and 231 were prepared using the method set forth below. <n="193"/>Step A - Synthesis of7-benzyl-2-methyl-5,6, 7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-oneTo a solution of l-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (5.0 g, 16.8 mmol) in 80 mL ethanol was added acetamidine hydrochloride (2.4 g, 25.2 mmol) followed by sodium ethoxide (21% in ethanol, 10.6 mL, 33.6 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 16 hours. The reaction was then cooled to room temperature, diluted with dichloromethane, and the organic phase was washed with water and brine, dried and concentrated in vacuo, the resulting residue was purified using flash column chromatography (5% methanol in dichloromethane) to provide 7-benzyl-2- methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one in 77% yield.
17.1 g (95%)
With sodium ethanolate; In ethanol; water; acetic acid;
Step A: 7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one A solution of sodium ethoxide in ethanol was prepared by addition of sodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all dissolved, ethyl 1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (21 g, 70.5 mmol) was added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, and concentrated. The residue was dissolved in a minimum amount of water and the pH was adjusted to about 7 with glacial acetic acid. The resulting yellow precipitate was filtered, washed with water (3*), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95%) of the title compound of Example 86, Step A as a yellow solid. 1H NMR (CDCl3, 250 MHz) delta7.35-7.25 (c, 5H), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH+).
Example 2Preparation of Compound 6To a solution of compound IA (4.00 g, 13.4 mmol) in ethanol (10 mL) was added a suspension of acetamidine hydrochloride (1.43 g, 15.1 mmol) in ethanol (5 mL), followed by a freshly made solution of NaOEt (0.93 g of sodium in 10 mL of ethanol). The reaction was allowed to stir at 1000C for about 15 hours, then cooled to room temperature and concentrated in vacuo to provide a crude residue which was dissolved in water. The aqueous solution was adjusted to pH 11 using IN HCl and a solid precipitated out of solution. The solution was then filtered to provide a crude residue which was then reacted with benzyhydryl bromide using the method described in Example 1 , Step C to provide compound 6.
Part A The preparation of 5,6,7,8-tetrahydro-2-methyl-4-quinazolone To 50 mL of absolute ethanol under a nitrogen atmosphere was added 5.65 g of sodium metal. After all the sodium had reacted, 20.15 g of 2-carboethoxycyclohexanone was added followed by 14.50 g of acetamidine hydrochloride. The reaction was refluxed gently overnight. The reaction was cooled to room temperature and all solvents were removed by evaporation. The pH of the residue was adjusted to 6 with dilute hydrochloric acid and refluxed briefly and allowed to cool. The resulting solid was collected. Successive crops of solid were collected by concentration of the mother liquors (13.1 g, 65%): 1 H NMR (DMSO-d6, 300 MHz) delta 12.18 (s, 1H), 2.22 (m, 2H), 2.15 (m, 2H), 2.10 (s, 3H), 1.65 (m, 4H).
With sodium ethanolate; In ethanol; for 6h;Heating / reflux; Argon atmosphere;
745mg, 5.17mmol) was dissolved in ethanol (15ml). Acetamidine hydrochloride (489mg, 5.17mmol) and sodium ethoxide in ethanol (0.41ml, 5.17mmol) were added and the mixture heated under argon at reflux for 6 hours and then overnight. The solvent was evaporated and the residue was treated with water (50ml) and extracted with diethyl EPO <DP n="34"/>ether (4 x 30ml). The diethyl ether layers were combined, dried over magnesium sulphate, filtered and evaporated. The crude product was purified using silica gel chromatography, eluting with a mixture of ethyl acetate and pentane (20-50percent) to afford the product (D33); MS (ES+) m/e 167 [M+H]+.
With potassium hydroxide; In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
EXAMPLE 2 Acetamidine hydrochloride (9.5 g) was added to a predissolved solution of methanol (50 mL) and KOH pellets (6.8 g) at 10° C. It was then dropped into a solution of 11.4 g of dimethyl N-cyanoimidocarbonate and 40 mL of methanol at 10° C. After the addition, the reaction mixture was stirred at 25° C. for 2 hours onto 40 mL of ice water. The solid crystals were collected by filtering and washing with water and methanol. After drying at 70° C. overnight, 11.8 g (84percent yield) of 2-methyl-4-amino-6-methoxy-1,3,5-triazine was obtained.
As shown in Scheme 1, to a 250 mL round-bottomflask, trifluoroacetoacetate (0.05 mol), acetamidine hydrochloride (0.05 mol), sodium methoxide (0.075 mol),and ethanol (100 mL) were added and refluxed for 10 h. After that, the mixture was acidified with 1 mol/L HCl to pH 7. The crude products were extracted using ethylacetate to produce intermediate 1. Then, intermediate 1(0.05 mol), POCl3(0.1 mol), and CH3CN(120 mL) wereadded to a 250 mL round-bottom flask to react for 0.5 hat a reflux temperature, and then, diisopropylethylamine(0.06 mol) was added dropwise. After continuously refluxingfor 8 h, excess POCl3and CH3CNwere distilled, andthen, ice water mixture (60 mL) was added. Finally, themixture was alkalify with 5 mol/L to pH 9 and extractedusing CH2Cl2to give intermediate 2 (Xie et al. 2013).2-Methyl-6-(trifluoromethyl)pyrimidin-4-ol (1) White crystals;yield 85.7%; m.p. 140-142 C; 1H NMR (DMSO-d6,500 MHz, ppm) delta: 13.03 (s, 1H, pyrimidine-OH), 6.68 (s,1H, pyrimidine-H), 2.36 (s, 3H); 13C NMR (DMSO-d6,125 MHz, ppm) delta: 162.78, 162.16, 152.03 (q, J = 35.5 Hz),122.33, 120.15, 111.12, 21.74.
With sodium methylate; In ethanol; water;
(1) To a suspension of ethyl trifluoroacetoacetate (18.4g, 0.1mol) and acetamidine hydrochloride (9.5g, 0.1mol) in ethanol (100ml) was dropwise added 28% sodium methylate (19.3g, 0.1mol) under cooling with ice. The resulting mixture was stirred at room temperature for 1 hour, and further refluxed for 12 hours. After cooling, the reaction mixture was evaporated, water (150ml) was added to the residue, then the mixture was neutralized with concentrated hydrochloric acid. The crystal separated was collected by filtration, washed with water, and dried to give 4-hydroxy-2-methyl-6-trifluoromethylpyrimidine (9.8g). m.p.:141-143 ØC 1H-NMR(CDCl3) delta 2.57(3H, s), 6.72(1H, s), 13.4(1H, br s). 1H-NMR(DMSO-d6) delta 2.36(3H, s), 6.67(1H, s). 19F-NMR(DMSO-d6) delta -72.13.
To 12.6 g of sodium methoxide (28% methanol solution), 3.1 g of acetoamidine hydrochloride and 3 g of 4,4,4- trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 800C for 20 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-methyl-6-trifluoromethylpyrimidin-4-ol . 2-methyl-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6): 2.35(s,3H), 6.68(s,lH), 13.02(bs,lH)
With potassium tert-butylate; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide;
a) 6-(3,4,5-trifluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine. To a solution of acetamidine hydrochloride (1.41 g, 14.9 mmol.) In DMF (10 mL) was added a solution of potassium tert-butoxide (12 mL, 1.0 M in THF) at 0 C. After stirred for 10 minutes, a solution of methyl {2-(3,4,5-trifluorophenyl)methylene}-3-oxobutanoate (2.10 g, 10.0 mmol) in DMF (10 mL) was added and the mixture was stirred for 2 hours while warmed up to room temperature. p-Toluenesulfonic acid monohydrate (4.50 g, 23.6 mmol) was added to the solution and the reaction mixture was heated at 110-120 C. for 2 hours. The mixture was cooled to room temperature and poured into ice (100 g) and aqueous NaOH solution (3 N, 200 mL), and extracted with ether (3*100 mL). The organic layers were combined, dried (K2CO3) and evaporated. The residue was purified by flash chromatography over silica gel (eluent: 10-15% MeOH in methylene chloride) to afford the product in 47% yield (1.4 g) as an oil.
Part A: A mixture of sodium metal (1.55 g, 67.4 mmol) and EtOH (15.0 mL, 257 mmol) was stirred at RT until nearly all sodium had reacted. Diethyl fluoromalonate (3.54 mL, 22.4 mmol) was added followed by acetamidine hydrochloride (2.14 g, 22.7 mmol). The reaction mixture was heated at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The residue was diluted with water (ca. 50 mL) and acidified (pH=2) with 6M aqueous HCl, and the mixture was stirred at RT for 1 h as a precipitate formed. The solids were collected by suction filtration and washed with water. Excess solvent was removed in vacuo to give 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.08 g, 64%) as a light gray solid. LCMS (m/z): 145 (M+H)+
With sodium methylate; In methanol; at 40℃; for 2.0h;Heating / reflux;
I. Preparation of pyrimidinyl-4-yl methylamine compounds; 1.1 Preparation of (2-methyl-pyrimidin-4-yl)-methylamine; 1.1.1 4-Dimethoxymethyl-2-methyl-pyrimidine; Acetamidine hydrochloride (3 mol) and 4-dimethylamino-1 ,1-dimethoxy-but-3-en-2-one (2 mol) were mixed in methanol (500 ml) and the reaction mixture was warmed to 400C. A solution of sodium methoxide in methanol (558 g, 30%) was added quickly and a brown suspension was formed. The reaction mixture was heated under reflux for 2 h, cooled to room temperature overnight followed by evaporation of methanol under reduced pressure. The resulting residue was taken up in dichloromethane (500 ml) and washed several times with water (100 ml_). The solvent was removed to give 307 g of black oil. The distillation of this oil gave a colourless liquid of boiling point 55-58C (0.5 mbar).
With potassium carbonate; In methanol; water; at 70℃; for 1.5h;Inert atmosphere;
tert-butyl 4-hydroxy-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate K2CO3 (535 mg, 3.87 mmol) and acetamidine hydrochloride (185 mg, 1.93 mmol) were added to a suspension of ethyl N-BOC-3-oxopiperidine-4-carboxylate (525 mg, 1.93 mmol) in MeOH (3 mL) and H2O (1 mL) in a 40 mL vial. The reaction was heated in an aluminum block at 70° C. for 90 minutes. LCMS analysis indicated complete consumption of the starting material. The reaction mixture was then acidified to pH 3 and extracted with DCM (3*). The combined organic extracts were dried over MgSO4, filtered and concentrated to obtain tert-butyl 4-hydroxy-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate as a yellow oil.
77%
With potassium carbonate; In methanol; water; at 60℃; for 15h;
Step B - Synthesis of Intermediate Compound 1 CA mixture of compound IB (4.0 g, 14.7 mmol) and K2CO3 (2.96 g, 21.4 mmol) was diluted with a solution of acetamidine hydrochloride (1.67 g, 17.7 mmol) in water (32 mL) and methanol (8 mL). The resulting reaction was allowed to stir for about 15 hours at 60 0C, then cooled to room temperature. The reaction mixture was neutralized using IN HCl and the organic phase was extracted with CH2Cl2 (20 mL). The organic extract was dried over Na2SO4 and concentrated in vacuo to provide a crude product which solidified upon trituration hexanes to provide compound 1C as a pale yellow solid (3.0 g, 77percent).
Acetamidine hydrochloride (413 mg, 4.4 mmol) was added to a solution of sodium ethoxide (594 mg, 2.0 equiv.) in ethanol (8 mL). After stirring for half an hour at room temperature, the resultant sodium chloride was removed by filtration. The filtrate was added to ethyl 2-cyano- 4,4-diethoxybutanoate (1.0 g, 4.4 mmol) and the mixture was refluxed for 5 hours. Most of the solvent was removed and the remaining slurry was <n="73"/>dissolved in ice water, and extracted with ethyl acetate. The extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (100percent methanol). The desired product was obtained as a red solid (421 mg, 40percent). MS: (M + H)/z = 242.
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 percent 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.
Part A: 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine. A solution of 200 ml. of 25% wt sodium methoxide in methanol (0.84 mol) was diluted with an additional 200 ml. of methanol. Acetamidine-HCI (40 g , 0.42 mol) was added to the sodium methoxide solution (white precipitate formed), followed by addition of <strong>[344-14-9]dimethyl fluoromalonate</strong> (70 g, 0.46 mol). The contents were stirred at room temperature overnight, then concentrated in vacuo to dryness. The resulting residue was redissolved in hot water (300 ml_). After cooling the aqueous solution to room temperature, concentrated HCI was added slowly until crystal formation (fine white prisms) took place at about pH 5. Concentrated HCI was added dropwise until pH 3, and then the contents were filtered. The isolated crystals were rinsed with 1 M HCI and dried under vacuum to provide 5-fluoro-4,6-dihydroxy-2-methylpyrimidine (65.5 g, >100%). LCMS: (M+H)+: 145.
65.5 g
With methanol; sodium methylate; at 20℃;Inert atmosphere;
Part A: 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine A solution of 200 ml. of 25% wt sodium methoxide in methanol (0.84 mol) was diluted with an additional 200 ml. of methanol. Acetamidine-HCI (40 g , 0.42 mol) was added to the sodium methoxide solution (white precipitate formed), followed by addition of <strong>[344-14-9]dimethyl fluoromalonate</strong> (70 g, 0.46 mol). The contents were stirred at room temperature overnight, then concentrated in vacuo to dryness. The resulting residue was redissolved in hot water (300 ml_). After cooling the aqueous solution to room temperature, concentrated HCI was added slowly until crystal formation (fine white prisms) took place at about pH 5. Concentrated HCI was added dropwise until pH 3, and then the contents were filtered. The isolated crystals were rinsed with 1 M HCI and dried under vacuum to provide 5-fluoro-4,6-dihydroxy-2-methylpyrimidine (65.5 g, >100%). LCMS: (M+H)+: 145.
2-Methyl-4-hydroxypyrrolo[2,3-d]pyrimidine (3).; Acetamidine hydrochloride (2, 0.05 mol, 4.7 g) was added to the 0.1 M sodium ethoxide solution (75 ml) and kept stirring under room temperature for 0.5 h. After removing the formed sodium chloride by filtration, the filtrate was added the ethyl alpha-cyano-gamma,gamma-diethoxybutyrate (1, 0.05 mol, 11.5 g) and the solution was heated under reflux for 5 h. After the removal of most solvent under vacuum, acetic acid was added to adjust the pH to 7.0 and 10.8 g precipitation as white powder. Ethanol (110 ml) with concentrated sulfuric acid (2 ml) was added to the collected powder and was refluxed for 2 h. By the end of the reaction an equal volume of water was added and kept at 4° C. overnight. The pyrrolopyrimidine 3 precipitated as white powder (2.1 g) was used for next step without further purification.
To 10 ml of methanol, 12.5 g of sodium methoxide (28% methanol solution) , 5 g of acetoamidine hydrochloride and 2.5 g of 3-OXO-3- (2-pyridyl) propanoic acid ethyl ester were added. This mixture was heated under reflux for 20 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added. A precipitated crystal was collected by filtration and then washed with water and hexane to obtain 1.7 g of 2- methyl-6- (2-pyridyl) pyrimidin-4-ol . 2-methyl-6- (2-pyridyl ) pyrimidin-4-ol 1H-NMR (DMSO-d6): 2.39(s,3H), 7.06(s,lH), 7.48-7.50 (m, IH) , 7.93-7.98 (m, IH) , 8.26(d,lH), 8.68-8.70 (m, IH) , 12.57(bs,lH)
2-methyl-4(3H)-oxo-7H-pyrrolo<2,3-d>pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium ethanolate; In ethanol; for 3h;Reflux;
The synthesis of target compound 3 (Scheme 1C), started with the synthesis of a reported method for compound i.?3 2-Bromo-i,i-diethoxyethane (compound 10) was reacted with ethyl2-cyanoacetate to obtain compound 1 lwhich was cyclized to compound 12 using acetamidine hydrochloride under basic conditions. Chlorination of compound 12 using POC13 provided compound 13 in 80% yield. Displacement of the chloride of compound 13 with 4-methoxy-N- methyl aniline (compound 14) and catalytic amounts of HC1 in isopropanol, provided compound1. Methylation of compound 1 with Mel under basic conditions afforded compound 3 in 85% yield. The synthesis of target compound 5 (Scheme 1C), involved N-formylation of 4-methoxy- 2-methylanline (compound 15) to afford compound 16 in 70% yield. LAH reduction of compound 16 provided substituted aniline compound 17. Displacement of the chloride of compound 13 with anilines (compounds 15 and 17) and catalytic amounts of HC1 in isopropanol provided compounds 4 and 5 (75% and 70% respectively).
With sodium hydroxide; In dichloromethane; water; at -10 - 0℃;Inert atmosphere;
To a suspension of acetamidine hydrochloride (7 g, 0.07 mol) in dichloromethane (75 mL) was added perchloromethyl mercaptan (12 g, 0.063 mol) at room temperature under an argon atmosphere. After cooling to -10 C a solution of sodium hydroxide (14 g, 0.348 mol) in water (22.5 mL) was added slowly. The reaction mixture was stirred at 0 C for 12 hours. Water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was purified by short-path vacuum distillation (75 C, 30 mbar) to give the title compound as a colorless liquid. 1H NMR (CDCls, 300 MHz): (ppm) = 2.64 (s, 3H).
With acetic anhydride; In 1,4-dioxane; for 14h;Reflux;
Example 2; 4- Amino-5-cyano-2-methylpyrimidine (I, R = methyl); To a solution of sodium 2,2-dicyanoethenolate (2.0 g, 16.9 mmol, prepared according to Example 1) in 1,4-dioxane (8 mL) was added acetamidine hydrochloride (1.98 g, 20.3 mmol) and acetic anhydride (1.91 mL). The reaction mixture was heated under reflux for 14 hours. Afterwards the solvent was completely evaporated and the resulting solid was taken up in hot water (80 C). The suspension was cooled to room temperature under stirring, then filtered and washed with water. Drying of the residue under reduced pressure at 60 C gave 4-amino-5- cyano-2-methylpyrimidine as a white powder.
Example 3; 4-Amino-5-cyano-2-methylpyrimidine (I, R = methyl); Reagent 1 :To a solution of sodium 2,2-dicyanoethenolate (7.6 g, 70 mmol, prepared according to Example 1) in dichloromethane (45.6 mL) was added acetyl chloride (5.3 g, 70 mmol) within 30 min. After complete addition the mixture was heated under reflux (about 43 C) for 1.5 h, then cooled to about 0 C and afterwards stirred for additional 1.5 h. The mixture was used as reagent 1.Reagent 2:Acetamidine hydrochloride (18.42 g, 0.19 mol) was dissolved in ethanol (37.5 mL). Sodium methoxide (10.94 g, 0.2 mol) was added within 5 min and the reaction mixture was stirred for about 30 min. The resulting white suspension was filtered and the filter cake washed with ethanol. The filtrate comprising the acetamidine was used as reagent 2.Within 45 min Reagent 2 was added dropwise to Reagent 1 at 0 C and stirred for additional 2.5 h. The resulting orange suspension (104 g) was concentrated by evaporating the solvent under reduced pressure (50 C/65 kPa (650 mbar)) to about ½ volume (28.8 g). Water (35 mL) was added to the residue to obtain an orange suspension which was filtrated with a P3 frit. The filter cake was washed four times with water (10, 20, 25, and 30 mL, wherein the first 10 mL where prior used to wash the vessel). Finally the filter cake was dried at 1.7 kPa (17 mbar) and 45 C to obtain a yellow solid.Yield: 3.65 g (42.2%, based on sodium 2,2-dicyanoethenolate)
Step 42a: 5-Bromo-2-methylpyrimidine (Compound 0601-120)Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared sodium ethoxide in ethanol solution (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixture was warmed to 50 C, then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide in ethanol solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M x 2.4 mL). The brown precipitate was filtered and washed with cold water, then freeze-dried to give 5-bromo-2- methylpyrimidine-4-carboxylic acid (350 mg, 42%) as a brown solid. LCMS: 218 [M+l]+, 1H NMR (400 MHz, DMSO-d6): delta 2.62 (s, 3H), 9.03 (s, 1H).
42%
With ethanol; sodium; at 50℃;
Step 42a: 5-Bromo-2-methylpyrimidine (Compound 0601-120)[0365]Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared sodium ethoxide in ethanol solution (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixture was warmed to 50 C., then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide in ethanol solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M×2.4 mL). The brown precipitate was filtered and washed with cold water, then freeze-dried to give 5-bromo-2-methylpyrimidine-4-carboxylic acid (350 mg, 42%) as a brown solid. LCMS: 218 [M+1]+, 1H NMR (400 MHz, DMSO-d6): delta2.62 (s, 3H), 9.03 (s, 1H).
42%
With sodium ethanolate; In ethanol; at 50℃;
Sodium (356mg, 15.5mmol) was added to the carefully ethanol (5.9mL), and in ethanolSodium ethoxide solution was prepared. Sodium ethoxide in freshly prepared ethanol solution of the above (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91g, 9.69mmol). The mixture was allowed to warm up to 50 , and then the heating bath was removed, Mukoburomu acid (1g, 3.87mmol) a solution in ethanol, was dropped so that a constant temperature is maintained, then further, ethanol solution (2mL) sodium ethoxide was dropped of. After cooling, the mixture was filtered, and the residue was evaporated, stirred vigorously with hydrochloric acid (2Mx2.4mL). The brown precipitate was filtered, washed with cold water, and then to obtain a freeze-dried to give 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (350mg, 42%) as a brown solid.
(a) 2,5-Dimethylpyrimidine-4,6-diol[00433] A solution of CH3ONa (5.02 g, 93 mmol) in CH3OH (31 mL) was cooled to 0 C. Acetamidine hydrochloride (3.21 g, 34 mmol) was added slowly. The reaction mixture was stirred at 0 C for 30 min. Then dimethyl 2-methylmalonate (4.5 g, 31 mmol) was added. The mixture was stirred at 75 C for 4 h, during which time a precipitate formed. The solid was filtered and dissolved in water and HC1 (cone.) was added until pH 1-2. The white precipitate was filtered, and dried in vacuum to give 2,5-dimethylpyrimidine-4,6-diol as a white solid (3.41 g). MS (ESI): m/z 141 [M+H]+.
With sodium ethanolate; In ethanol; for 20h;Reflux;
2,6-dimethylpyrimidin-4-ol. Ethyl 3-oxobutanoate (10.0 g, 77 mmol) and acetimidamide hydrochloride (7.23 g, 77 mmol) were added to the solution of sodium ethanolate (10.5 g, 154 mmol) in ethanol (200 mL). And the mixture was refluxed for 20 hours. Water (10 mL) was added to the mixture. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane /methanol = 15: 1) to give 2,6-dimethylpyrimidin-4-ol as a yellow solid (3.43 g, 36%). LRMS (M + H+) m/z: calcd 124.06; found 124.
29%
With potassium carbonate; In water; at 20℃; for 0.25h;Microwave irradiation;
General procedure: The corresponding amidine hydrochloride (2.54 mmol) and powdered K2CO3 (5.76 mmol) were dissolved in water (5.0 mL) in a 20-mL vessel. The beta-keto ester (2.31 mmol) was added and the resulting mixture was irradiated for 5-15 min (see Table 2). Upon the end of the reaction (TLC, hexanes/EtOAc, 5:1), the mixture was diluted with sat. aq NH4Cl (5.0 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (anhyd Na2SO4) and filtered. The filtrate was rotary evaporated and the obtained crude product was purified by column chromatography [silica gel, hexane/EtOAc mixtures or recrystallized (EtOH)].
Example 326Synthesis of (1R,2S)-2-[(2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (326)(1) 2,6-dimethylpyrimidin-4-ol (326-1)Sodium (3.6 g) was added by portions to ethanol (92 ml) over 2 hours, while the solution was stirred at room temperature. Thereafter, ethyl acetoacetate (10 ml) and acetamidine hydrochloride (7.42 g) were added to the reaction solution, and the obtained mixture was stirred at 70 C. for 16 hours. Thereafter, the reaction mixture was stirred at 100 C. for 9 hours, and the temperature of the reaction solution was returned to room temperature. Concentrated hydrochloric acid was added to the reaction solution, so that the pH value was adjusted to around 5. The obtained mixture was concentrated under reduced pressure, so as to obtain a crude title compound (25.6 g).1H-NMR (400 MHz, CDCl3) delta (ppm): 2.30 (s, 31-1), 2.46 (s, 3H), 6.17 (s, 1H)
With sodium methylate; In methanol; at 0℃; for 0.333333h;Product distribution / selectivity;
Sodium methoxide solution (26.5 g, 0.49 mol) in methanol (400 mL) was cooled down to 0C. After acetamidine hydrochloride (46.3 g, 0.49 mol) was added in portions, the mixture was stirred at 0C for 20mins and then filtrated. The filtrate was poured into the above oily product and stirred at 25C for 12 hours. The produced mixture was filtrated, washed with methanol (3x20 mL) and dried under vacuum (50C, 2 hours, -O.lMPa) to obtain 51.8 g white solid with 65% yield (based on cyanoacetamide) and 99% purity (GC).1H-NMR (DMSO, 400MHz): 8.59 (s, 1H), 1.78 (br s, 2H), 2.37 (s, 1H), 13C-NMR (DMSO, 400MHz): 170.5, 162.8, 151.5, 116.1, 87.1.m/z (GC-MS), 134 (M+), 94, 66
With sodium methylate; In methanol; at 0℃; for 0.333333h;
Sodium methoxide solution (25.4 g, 0.47 mol) in methanol (400 mL) was cooled down to 0C. After acetamidine hydrochloride (44.4g, 0.47mol) was added in portions, the mixture was stirred at 0"C for 20mins and then filtrated. The filtrate was poured into the above oily product and stirred at 25 C for 12 hours. The produced mixture was filtrated, washed with methanol (3x20mL) and dried under vacuum (50C, 2 hours, -O.lMPa) to obtain 50.2 g white solid with 63% yield (based on cyanoacetamide) and 98% purity (GC).1H-NMR and MS are identical with Example 1.
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.
General procedure: A 25 mL Schlenk tube wascharged with a magnetic stirrer and DMSO (2.0 mL). Substituted(2-bromophenyl)methylamine (1) (0.5 mmol), amidine hydrochloride (2) (1.0 mmol),CuBr (0.1 mmol, 14.2 mg), and K2CO3 (1.5 mmol, 207 mg) were added to the tube.The mixture was stirred at 80-120 oC under nitrogen atmosphere for 24 h, and thenunder air for 0.5 h. The resulting mixture was cooled to room temperature and filtered,and the solid was washed with ethyl acetate for two times (3 × 3 mL). The combinedfiltrate was concentrated by the rotary evaporator, and the residue was purified bycolumn chromatography on silica gel using petroleum ether/ ethyl acetate as eluent togive the desired target product.
With caesium carbonate; copper(I) bromide; In dimethyl sulfoxide; at 120℃; for 3h;
A solution of <strong>[42872-74-2]3-bromo-4-methylbenzonitrile</strong> (1 g), acetamidine hydrochloride (714 mg), cesium carbonate (5 g) and copper (I) bromide (36 mg) in dry dimethyl sulfoxide (25 mL) was stirred at 120 C. for 3 h. The mixture was chilled, diluted with EtOAc (200 mL) and washed with water. The organic layer was dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (SiO2, 150 g, DCM/MeOH) to yield the desired product (36% yield). LC-MS (Method 1): m/z [M+H]+=252.1 (MW calc.=252.11); Rt=3.5 min.
36%
With caesium carbonate; copper(I) bromide; In dimethyl sulfoxide; at 120℃; for 3h;
Intermediate 28a) A solution of <strong>[42872-74-2]3-bromo-4-methylbenzonitrile</strong> (1 g), acetamidine hydrochloride (714 mg), cesium carbonate (5 g) and copper (I) bromide (36 mg) in dry dimethyl sulfoxide (25 mL) was stirred at 120 C for 3 h. The mixture was chilled, diluted with EtOAc (200 mL) and washed with water. The organic layer was dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si02, 150 g, DCM/ MeOH) to yield the desired product (36% yield). LC-MS (Method 1): m/z [M+H]+ = 252.1 (MW calc. = 252.11 ); R, = 3.5 min.
With sodium ethanolate; In ethanol; at 20 - 50℃; for 17.0h;
To a solution of the commercially available ethanimidamide ii, ashydrochloride, (6.0 g, 63.83 mmol) in anhydrous EtOH (20 mL) was added sodium ethoxide (20 mL of a 2i % solution in ethanol) and the reactionmixture was stirred at 50 00 and the commercially available (2E)-2,3-dibromo-4-oxobut-2-enoic acid i 2 (6.82 g, 26.74 mmol) in EtOH (i 0 mL) was added into the mixture. After stirring at 50 00 for i hour, a further portion of sodiumethoxide (i 0 mL of a 2i % solution in ethanol) was added and the mixture was stirred at r.t. for i6 h. The reaction mixture was filtrated and the filtratereduced in vacuo. The residue was then treated with 2 M aqueoushydrochloric acid (30 mL) and stirred vigorously for 30 mm. The resulting solid was filtrated, washed with water and air dried to give KR-i 3 (i .46 g, 25.2%) as a pale yellow solid. ESI-MS (M+i): 2i7 calc. for C6H5BrN2O2:2i6.0.
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.
2-methyl-6-(trifluoromethyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
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.
6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium acetate; In 2-methoxy-ethanol; at 120℃; for 6h;
The compound <strong>[58483-95-7]5-amino-2-chloropyridine-4-carboxylic acid</strong> (1000 g, 5.8 mol) was dissolved in 5000 ml of ethylene glycol monomethyl ether and acetamidine hydrochloride (2193 g, 23.2 mol) Sodium (2360 g, 17.4 mol). The reaction was heated to 120 ° C for 6 hours. After the reaction was complete, the reaction was cooled to room temperature, poured into 4000 ml of water and extracted twice with ethyl acetate. The organic phase was combined, dried and concentrated to afford the crude product which was filtered to give 6-chloro- Pyridine [3,4-d] pyrimidin-4 (3 H) -one (976 g, 5.01 mol)
To a 50 ml three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser were added 10 g of t-butanol,1.13 g (12 mmol) of acetamidine hydrochloride, 0.66 g (0.1 mol) of malononitrile and 1.2 g (12 mmol) of 30% aqueous formaldehyde were added, and the mixture was reacted at 65-70 C for 4 hours.Cooled to 20 ~ 25 C, 1.4 g of 70wt% t-butylperoxy peroxide was added and the reaction was carried out at 30-35 C for 1 hour. Samples were taken and detected by external standard method. The product 2-methyl-4-amino-5-cyanopyrimidine The yield was 92.6% and the HPLC purity was 99.6%.
benzyl 4-hydroxy-2-methyl-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;
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
tert-butyl 4-hydroxy-2-methyl-5H,6H, 7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tert-butyl alcohol;Reflux;
A mixture of 1-tert-butyl 3-ethyl 4-oxopyrrolidine-l,3-dicarboxylate (CAS 146256-98-6) (20 g, 78 mmol), acetamidine hydrochloride (7.35 g, 78 mmol), and triethylamine (28.2 mL, 202 mmol) in tert-butanol (100 mL) was heated under reflux overnight. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was dried (phase separator) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with 0-15 percent MeOH in EtOAc to afford the title compound. H NMR (400 MHz, DMSO- 6): delta ppm 1.42 - 1.47 (m, 9H), 2.31 (s, 3H), 4.25 - 4.39 (m, 4H), 12.52 (br s, 1H). MS ES+ 252
With potassium carbonate; In acetonitrile; at 99.84℃; for 0.666667h;Microwave irradiation; Sealed tube; Autoclave;
General procedure: By following the general procedure at 373 K and by maintainingthat temperature for 40 min in the reaction with 2-bromo-1-phenylethanone [(1a); 200 mg, 1.01 mmol], 1H-imidazole (3a)(yield 16 mg, 20%) was obtained as a white solid (m.p. 436-438 K). Recrystallization of this compound from methanol afforded colourless crystals suitable for X-ray diffractionanalysis. 1H NMR (400 MHz, CDCl3): 2.37 (s, 3H), 7.18 (s,1H), 7.20 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.66 (d, J =7.3 Hz, 2H), 8.76 (br s, 1H, NH). 13C{1H} NMR (100 MHz,CDCl3): 13.8 (CH3), 115.0 (CH), 124.6 (CH), 126.7 (CH),128.7 (CH), 132.7 (C), 137.7 (C), 145.2 (C). HRMS (ESI+):calculated for C10H11N2+ 159.0922 [M+H]+; found 159.0921.
6-methylimidazo[4,5-e][1,3]diazepine-4,8(1H,5H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In ethanol; at 10 - 120℃;
Dimethyl 1H-imidazole-4,5-dicarboxylate (3.68 g, 20 mmol, 1 eq) was added with about 50 ml of ethanol and acetamidine hydrochloride (1 to 6 eq). The mixture was stirred at 10 to 120 C. for 2 to 24 hours, and precipitate was observed. After filtration, the filter cake was washed with 100 ml of water and dried at 50 C. in an oven to obtain 3 g of product (6-methylimidazo[4,5-e][1,3]diazepine-4,8(1H,5H)-dione), with a yield of 84%. 1HNMR (DMSO, 500 MHz): delta 8.961 (1H,s), delta 8.585 (1H,s), delta 7.625 (1H,s), delta 2.119 (2H,s)
6-(dimethoxymethyl)-2-methylpyrimidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In water; at 20.0℃;
To a solution of <strong>[60705-25-1]methyl 4,4-dimethoxy-3-oxobutanoate</strong> (300 mg, 1.7 mmol) and acetamidine hydrochloride (320 mg, 3.4 mmol) in water (10 mL) was added K2CO3(940 mg, 6.8 mmol). The reaction was stirred at room temperature overnight. The mixture was quenched with AcOH to pH acid and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over Na2S04, filtered and evaporated. The residue was purified by silica gel column chromatography(dichloromethane/methanol = 50/1) to give the desired product (110 mg, 35%) as a white solid.
(2S,4aR,6R,7R,8S,8aR)-7-acetoxy-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid[ No CAS ]
[ 124-42-5 ]
[ 21938-47-6 ]
(2S,4aR,6S,7R,8R,8aR)-6-(1-(2,3-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26.3%
A mixture of (4aR,6R,7R,8R,8aR)-7- hydroxy-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (55 mg, 0.115 mmol), acetimidamide hydrochloride, HCl (37.7 mg, 0.288 mmol), HATU (59.1 mg, 0.156 mmol), and N,N-diisopropylethylamine (0.121 mL, 0.691 mmol) in DMF (1 mL) was stirred at rt for 4 h. Then, (2,3-dichlorophenyl)hydrazine, HCl (49.2 mg, 0.230 mmol) was added, followed by acetic acid (0.132 mL, 2.304 mmol). The mixture was heated at 80 oC for 8 h. Upon cooling to rt, the mixture was diluted with ethyl acetate (60 mL), washed with saturated NaHCO3 solution (20 mL), water (2 x 20 mL), and brine (20 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was subjected to flash chromatography (24 g silica gel, solid loading, 0-5% methanol/dichloromethane) to afford (4aR,6S,7R,8R,8aR)-6-(1-(2,3-dichlorophenyl)-3- methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)hexahydropyrano[3,2-d][1,3]dioxin-7-ol (20 mg, 0.030 mmol, 26.3 % yield) as a beige solid. MS (ESI) m/z: 658.9 [M+H]+.
[4-cyano-3-(trifluoromethyl)phenyl]carbamodithioic acid acetamidine complex[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30 g
With triethylamine; In acetone; at 20 - 30℃;
4-amino-2-(trifluromethyl benzonitrile (20 g) was charged to acetone (40 ml) at 25-30C. The reaction mixture was stirred well at 30C. Acetamidine Hydrochloride (31 g) and Triethylamine (32.64 g) was added to the mixture. The mixture was cooled to 20C and carbon disulfide (43 g) was charged drop wise till half an hour. The mass was stirred for 8- 9 hours. The precipitate obtained was filtered and washed with acetone and suck dried.[4-cyano-3-(trifluoromethyl)phenyl]carbamodithioic acid, acetamidine complex (30 gm) was isolated.
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