* 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.
With sodium acetate In water at 72 - 80℃; for 1 h;
To a suspended solution of 6-aminouracil (32, 6.35 g, 50.0 mmol) and sodium acetate (4.10 g, 50.0 mmol) in H20 (50 mL) at a temperature of 72 °C was added a solution of chloroacetaldehyde (50percent in water, 11.8 g, 75.2 mmol) drop-wise. The reaction mixture was heated to 80 °C and stirring was continued for 60 mm. After cooling the reaction mixture to room temperature, the resulting solid was collected by filtration, washed with water and acetone, and dried under vacuum to afford 33 as a light-brown solid (6.46 g, 86percent). ‘H-NMR (400 MHz, DMSO-d6) ö 11.45 (s, 1H), 11.10 (s, 1H), 10.48 (s, 1H), 6.64-6.51 (m, 1H), 6.22 (t, J = 2.5 Hz, 1H); MS (m/z) [M+Hj 152.06.
33%
With sodium acetate In water for 3 h; Heating / reflux
A solution of commercially available 6-amino-1 H-pyrimidine-2,4-dione (25 g, 0.2 mol) and NaOAc (20 g, 0.24 mol) in 1.25 L of distilled water was treated with chloroacetaldehyde (25 ml_, 50percent w/w in water). After 3 h at reflux, the reaction mixture was filtered while still warm, to remove the brown solid. The yellow mother liquor was cooled to RT then acidified to pH ~ 4 by addition of 2.5 M HCI. The desired product (9.722 g, 33percent) was isolated by filtration and finally dried in the oven. 1H NMR (cfe-DMSO) δ 11.46 (1 H, br s), 11.11 (1 H, br s), 10.49 (1 H, br s), 6.57 (1 H, dd, J = 2.0, 3.6 Hz), 6.22 (1 H, dd, J = 2.0, 3.2 Hz).
Reference：
[1] Liebigs Annalen der Chemie, 1984, vol. 1984, # 2, p. 273 - 282
3
[ 271-70-5 ]
[ 39929-79-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5247 - 5250
[2] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
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[ 3680-71-5 ]
[ 39929-79-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5247 - 5250
[2] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
5
[ 107-20-0 ]
[ 873-83-6 ]
[ 39929-79-8 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
6
[ 39929-79-8 ]
[ 90213-67-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
7
[ 39929-79-8 ]
[ 90213-67-5 ]
Reference：
[1] Patent: WO2018/137036, 2018, A1,
8
[ 39929-79-8 ]
[ 90213-66-4 ]
Yield
Reaction Conditions
Operation in experiment
52%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 70 - 106℃; for 18.5 h;
Example 15; Preparation of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine:; A reactor was equipped with 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol(10.0g, 66.2 mmol) and toluene (30 ml) with stirring. Phosphorusoxychloride (18.5 ml, 198.5 mmol) was added and the reactor was warmed to 7O0C. Diisopropylethylamine (23.0 m, 132.3 mmol) was added over 2.5 h to control the exotherm. After completion of the base addition, the reactor was heated to 1060C and stirred at temperature for 16 h. The mixture was cooled to 250C and added slowly to a flask containing water (230 ml) and ethyl acetate (120ml) at room temperature, then stirred overnight at room temperature. After filtration through Celite, the layers were separated the aqueous layer was extracted with ethyl acetate (3 x 75ml). The organic layers were combined and washed with brine (100ml). Darco KBB (1.24 g) was added to the organics, then filtered through Celite and dried over sodium sulfate (10.0 g). The solution was concentrated in vacuo to obtain the title compound (52percent yield).
43%
With N,N-diethylaniline; trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 120℃; for 0.5 h; Microwave irradiation
Step 2: Synthesis of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine To a 20 mL vial were added 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (2.5 g, 16.6 mmol), POCl3 (10 mL, 107 mmol) and N,N-dimethylaniline (1 mL, 7.9 mmol). The resulting mixture was heated at 120° C. for 30 min in microwave oven. The reaction mixture was cooled to room temperature, and poured into ice, and neutralized by the addition of concentrated ammonium hydroxide to pH 5-7. The resulting solid was filtered, and washed with water to give the title compound as brown solid (1.323 g, 43percent yield). MS(ESI, M+1) m/z 188.2.
28%
at 180℃; for 4 h;
A suspension of 7H-Pyrrolo[2,3-d]pyrimidine-2,4-diol (2.25 g, 0.015 mol) in phenylphosphinic dichloride (PhPOCl2) (15 mL) was heated at 180° C. for 4 h. The resulting dark syrup was poured slowly to ice water, the black precipitates were filtered off, and the filtrate was extracted with ether. The ether layers were combined, washed sequentially with sat. NaHCO3, brine, dried over Na2SO4 and concentrated to give 2,4-Dichloro-7H-Pyrrolo[2,3-d]pyrimidine (0.8 g, 28percent yield).
28%
at 165 - 180℃; for 6 h;
A suspension of 7H-pyrrolo [2,3-d]pyrimidine-2,4-diol (2.25 g, 0.015 mol) in PhPOCl2 was heated at 165 0C for 3 h and 180 °C for additonal 3 h, the resulting dark syrup was poured slowly to ice water, the black precipitates were filtered off, and the filtrate was extracted with ether. Ether layers were combined, washed with Sat NaHCO3, brine, dried over Na2SO4 and concentrated to give 2, 4-dichloro-7H-pyrrolo[2,3-
28%
at 165℃; for 2 h;
Step 3 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidineA solution of 7H-Pyrrolo[2,3-d]pyrimidine-2,4-diol (1.28 g; 8.5 mmol) in phenylphosphonic dichloride (7 ml) was heated at 165 0C for 2 h. The hot reaction mixture was then poured slowly onto ice water (150 ml) and extracted with ethyl acetate (2 x 100 ml). The organic extract was washed with water (100 ml) followed by sat. sodium chloride (aq) solution (100 ml). The organic phase was dried over Na2SO4 then filtered and filtrate solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (2Og) eluting with 75percent ethyl acetate in hexane to afford the desired product as a yellow solid, (0.45 g; 28percent). LC/MS: RT = 1.98 min; m/z = 188 [M+H]+. Total run time 3.75 mins
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[2] Patent: WO2007/12953, 2007, A2, . Location in patent: Page/Page column 24
[3] Patent: US2010/3250, 2010, A1, . Location in patent: Page/Page column 20
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3169 - 3182
[5] Patent: US2009/54425, 2009, A1, . Location in patent: Page/Page column 21
[6] Patent: WO2009/131687, 2009, A2, . Location in patent: Page/Page column 131
[7] Patent: WO2007/104944, 2007, A1, . Location in patent: Page/Page column 38
[8] Journal of Medicinal Chemistry, 1988, vol. 31, # 8, p. 1501 - 1506
[9] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 584 - 589
[10] Patent: WO2016/130920, 2016, A2, . Location in patent: Page/Page column 114; 115
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Yield
Reaction Conditions
Operation in experiment
48%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 70 - 108℃; for 16.5 h; Inert atmosphere
To a suspension of 33 (5.75 g, 38.0 mmol) in toluene (30 mL) under argon, was added POd3 (10.6 mL, 114 mmol). To the mixture DIPEA (13.3 mL, 76.1 mmol) was added drop-wise over a period of 2.5 h at 70 °C, and then the temperature was increased to 108 °C and stirring continued for 14 h. The reaction mixture was cooled to room temperature and then poured into a mixture of 150 mL ethyl acetate and 200 mL ice cold water, and then filtered through a pad of Celite. The aqueous layer was extracted with ethyl acetate (3 x 200 mL) and the combined organic layers were washed with brine and concentrated to give the 34 (3.42 g, 48percent) as a light- brown solid. ‘H-NMR (400 MHz, DMSO-d6) ö 12.79 (s, 1H), 7.94 — 7.24 (m, 1H), 6.66 (ddd, J= 5.3, 3.5, 1.7 Hz, 1H); MS (m/z): [Mdi 188.03.
Reference：
[1] Tetrahedron, 2014, vol. 70, # 33, p. 4947 - 4956
[2] Patent: WO2018/137036, 2018, A1, . Location in patent: Paragraph 00234; 00235
[3] Journal of the American Chemical Society, 1984, vol. 106, # 21, p. 6379 - 6382
Step 1: Synthesis of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol To a suspended solution of 6-aminouracil (12.7 g, 100 mmol) and sodium acetate (8.2 g, 100 mmol) in H2O (100 mL) at a temperature of 70-75 C., was added a solution of <strong>[107-20-0]chloroacetaldehyde</strong> (50% in water, 23.6 g, 150 mmol). The resulting reaction mixture was stirred at 80 C. for 20 min, and then cooled to room temperature. The separated solid was collected by filtration, washed with water and acetone, and dried in vacuum to give the title compound as brown solid (14.74 g, 98% yield). MS(ESI, M-1) m/z 150.2.
98%
With sodium acetate; In water; at 70 - 80℃; for 0.333333h;
To a suspended solution of 6-aminouracil (12.7 g, 100 mmol) and sodium acetate (8.2 g, 100 mmol) in H20 (100 mL) at a temperature of 70-75 C was added a solution of <strong>[107-20-0]chloroacetaldehyde</strong> (50% in water, 23.6 g, 150 mmol). The resulting reaction mixture was stirred at 80 C for 20 mm and then cooled to room temperature. The resulting solid was collected by filtration, washed with water and acetone, and dried in vacuo to give the title compound as a light-brown solid (14.74 g, 98% yield). ?HNMR(DMSO-d6, 400 MHz) 11.38 (br, 1H), 11.10 (br, 1H), 10.46 (s, 1H), 6.53 (s, 1H), 6.18 (s, 1H), MS m/z 152.43 [M+1].
91.6%
With sodium acetate; In water; at 70 - 90℃; for 3.5h;Autoclave; Large scale;
Compound 1 (21 kg, 165 mol) was added to a 500 L autoclave, anhydrous sodium acetate (14.91 kg, 181.8 mol) and water (100 L) were added and the temperature was raised to 70-75 C.Chloroacetaldehyde (49 kg, 40% aqueous solution, 249.7 mol) was added dropwise. Drop finished, heated to 90 C reaction for 3.5 hours,Cooled to room temperature, the reaction solution by centrifugation centrifuge, washing,Dried to give 22.8 kg of a brown powder as Compound 2 in a yield of 91.6%
81%
With sodium acetate; In water; for 4h;Heating / reflux;
Example 1; 1-(4-(4-(4-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone and N4-(1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine; To a suspension of 6-aminouracil (15 g, 0.118 mol) in H2O (600 mL) was added sodium acetate (NaOAc) (15 g, 0.183 mol) and chloroethanal (ClCH2CHO) (50% in H2O, 30 mL). The mixture was heated at reflux for 4 h and then cooled to room temperature. The resulting dark brown precipitates were collected by filtration to afford crude 7H-Pyrrolo[2,3-d]pyrimidine-2,4-diol (14.4 g, 81% yield).
Urea (30 g) was added to a solution of sodium ethoxide prepared from sodium (22 g), and absolute ethanol (300 mL) previously cooled to 5-10 °C. The mixture was stirred for 5 min and was treated with ethyl 2-cyano-4, 4-diethoxybutanoate (110 g). The resulting mixture was allowed to warm with stirring. The sodium salt dissolved with the evolution of heat, and the temperature of the mixture was maintained at 80 °C overnight. The reaction mixture was cooled and poured into 300 mL of water, and the solution was concentrated in vacuo. Next, the residue was acidified with concentrated HCl to produce a white precipitate, which was collected by filtration, washed with water and dried on a funnel to provide compound 17a (66.8 g, yield: 92.1percent).1H-NMR (400MHz, DMSO-d6): delta11.44 (1H, s), 11.09 (1H, s), 10.47 (1H, s), 6.56 (1H, t, J= 2.4 Hz), 6.22 (1H, t, J= 2.4 Hz). ESI-MS calculated for (C6H5N3O2) [M+H]+, 152.0, found 152.1.
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