* 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.
Stage #1: With sodium ethanolate In ethanol at 20℃; for 3.5 h; Reflux Stage #2: With hydrogenchloride In water at 10℃;
b. To a freshly prepared solution of sodium ethoxide [ethanol (250 mL) and sodium metal (9.02 g, 392.55 mmol)] was added ethyl 2-cyano-4,4-diethoxybutanoate (82) (45 g, 196.27 mmol) and thiourea (14.94 g, 196.27 mmol) in ethanol (200 mL). The reaction mixture was heated with stirring at reflux for 3.5 h. The reaction mixture was allowed to cool to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and concentrated in vacuum to remove ethanol. The residue obtained was dissolved in water (100 mL) and neutralized to pH 7 using dilute aqueous hydrochloric acid (3N) by maintaining the temperature below 10 °C. The solid obtained was collected by filtration to afford on drying in vacuum 6-amino-5-(2,2-diethoxyethyl)-2- mercaptopyrimidin-4-ol (83) (30.6 g, 60.19percent) as a pale yellow solid. 1HNMR (300 MHz, DMSO) δ 11.75 (s, IH, D2O exchangeable), 11.44 (s, IH, D2O exchangeable), 6.07 (s, 2H, D2O exchangeable), 4.50 (t, J= 5.6, IH), 3.59 (dq, J= 7.0, 9.5, 2H), 3.40 (dq, J= 7.0, 9.6, 2H), 2.44 (d, J = 5.6, 2H), 1.07 (t, J= 7.0, 6H); IR (KBr): 3226, 2973, 2909, 1624, 1569, 1474, 1376, 1287, 1213, 1114, 1049, 993, 892, 822, 789 and 763 cm"1; MS (ES+1) 260.1 (M+l), 282.1 (M+23), (ES ): 258.3 (M -1); HPLC [(Column: Zorbax SBC3, 3.0 x 150 mm, 5 μm, with a ZGC SBC3, 2.1 x 12.5 mm guard cartridge. Mobile phase: 0.1 M Ammonium Acetate /Acetonitrile) Rt= 11.408 min (99.64percent]); Analysis: Calculated for C10Hi7N3O3S: C, 46.45; H, 6.72; N, 16.06; Found: C, 46.31; H, 6.60; N, 16.20.
36%
Stage #1: With sodium In ethanol at 85℃; for 18 h; Stage #2: With ammonium chloride In water at 20℃; for 18 h;
To ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in small portions. The solution was stirred until complete dissolution of the sodium metal. 2-Cyano-4,4- diethoxy-butyric acid ethyl ester (J. Chem. Soc, I960, 131-138) (9.292 g, 40.5 mmol) was then added as a solution in ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4 mmol). The solution was heated at 85 °C for 18 hours, and then cooled to room temperature. The solution was concentrated, and saturated aqueous ammonium chloride solution (150 ml) was added. The mixture was stirred EPO <DP n="125"/>at room temperature for 18 hours, after which time the solid was collected by filtration, and washed with water (20 ml) to yield the product (3.376 g, 36percent).
36%
Stage #1: at 85℃; for 18 h; Stage #2: With ammonium chloride In water at 20℃; for 18 h;
PREPARATION 2; 4-Chloro-7H-pyrrolor2,3-
36%
Stage #1: With sodium In ethanol at 85℃; for 18 h; Stage #2: With ammonium chloride In water at 20℃; for 18 h;
To ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in small portions. The solution was stirred until complete dissolution of the sodium metal. 2-Cyano-4,4- diethoxy-butyric acid ethyl ester (J. Chem. Soc, 1960, 131-138) (9.292 g, 40.5 mmol) was then added as a solution in ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4 mmol). The solution was heated at 85 0C for 18 hours, and then cooled to room temperature. The solution was concentrated, and saturated aqueous ammonium chloride solution (150 ml) was added. The mixture was stirred at room temperature for 18 hours, after which time the solid was collected by filtration, and washed with water (20 ml) to yield the product (3.376 g, 36percent).
36%
Stage #1: at 85℃; for 18 h; Stage #2: With ammonium chloride In water at 20℃; for 18 h;
EXAMPLE 12 1-(7/-/-Pyrrolor2,3-cf1pyrimidin-4-yl)-piperidin-4-ylamine12A. 6-Amino-5-(2,2-diethoxy-ethyl)-2-mercapto-pyrimidin-4-olTo ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in small portions. The solution was stirred until complete dissolution of the sodium metal. 2-Cyano-4,4-diethoxy-butyric acid ethyl ester {J. Chem. Soc, 1960, 131-138) (9.292 g, 40.5 mmol) was then added as a solution in ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4 mmol). The solution was heated at 85 0C for 18 hours, and then cooled to room temperature. The solution was concentrated, and saturated aqueous ammonium chloride solution (150 ml) was added. The mixture was stirred at room temperature for 18 hours, after which time the solid was collected by filtration, and washed with water (20 ml) to yield the product (3.376 g, 36percent).
36%
Stage #1: at 85℃; for 18 h; Stage #2: With ammonium chloride In water at 20℃; for 18 h;
EXAMPLE 18; C-f1-(7H-Pyrrolof2,3-o1Pyrimidin-4-yl)-piperidin-4-yl|-methylamine; 18A. 6-Amino-5-(2,2-diethoxy-ethyl)-2-mercapto-pyrimidin-4-olTo ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in small portions. The solution was stirred until complete dissolution of the sodium metal. 2-Cyano-4,4-diethoxy-butyric acid ethyl ester (J. Chem. Soc, 1960, 131-138) (9.292 g, 40.5 mmol) was then added as a solution in ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4 mmol). The solution was heated at 85 0C for 18 hours, and then cooled to room temperature. The solution was concentrated, and saturated aqueous ammonium chloride solution (150 ml) was added. The mixture was stirred at room temperature for 18 hours, after which time the solid was collected by filtration, and washed with water (20 ml) to yield the product (3.376 g, 36percent).
Reference：
[1] Patent: WO2010/14930, 2010, A2, . Location in patent: Page/Page column 60
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6770 - 6789
[3] Patent: WO2006/46023, 2006, A1, . Location in patent: Page/Page column 122-123
[4] Patent: WO2008/75109, 2008, A1, . Location in patent: Page/Page column 112
[5] Patent: WO2006/46024, 2006, A1, . Location in patent: Page/Page column 117
[6] Patent: WO2007/125321, 2007, A2, . Location in patent: Page/Page column 116
[7] Patent: WO2007/125315, 2007, A2, . Location in patent: Page/Page column 121
[8] European Journal of Organic Chemistry, 1998, # 5, p. 827 - 835
[9] Patent: US2010/160356, 2010, A1, . Location in patent: Page/Page column 33
8
[ 52133-67-2 ]
[ 57564-94-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6770 - 6789
9
[ 105-56-6 ]
[ 2032-35-1 ]
[ 52133-67-2 ]
Yield
Reaction Conditions
Operation in experiment
78%
at 145℃; for 4 h;
Method AI: Ethyl 2-cyano-4,4-diethoxybutanoate (xlii-a):_ 2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq.) was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq.), K2CO3 (2.8 g, 20 mmol, 1.0 eq.) and NaI (200 mg, 1.3 mmol, 0.06 eq.), as described in J. Chem. Soc., 1960, 131-138. The reaction mixture was refluxed for 4 h at 145° C. After cooling, the reaction mixture was purified by chromatography on silica gel (eluted with petroleum ether/ethyl acetate (80:1→40:1→40:1) to give 3.57 g of xlii-a as a colorless oil (78percent). 1H NMR (400 MHz, CDCl3): δ 4.70 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.78-3.64 (m, 3H), 3.62-3.45 (m, 2H), 2.35-2.14 (m, 2H), 1.34 (q, J=7.2 Hz, 3H), 1.25-1.16 (m, 6H).
78%
at 145℃; for 4 h;
As described in J. Chem. Soc., 1960, 131-138,2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq)Was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq), K 2 CO 3 (2.8 g, 20 mmol, 1.0 eq) and NaI (200 mg, 1.3 mmol, 0.06 eq) .The reaction mixture was refluxed at 145 ° C. for 4 hours.After cooling, the reaction mixture was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (80: 1 → 40: 1 → 10: 1)) to give 3.57 g of xlii-a as a colorless oil I got it (78percent).
74%
at 145℃; for 4.5 h; Inert atmosphere
To a dry 3-necked round bottomed flask fitted with a condenser was added 11.3 g (81.5 mmol) of oven dried K2CO3 and 0.82 g (5.5 mmol) of NaI. The solids were placed under high vacuum for an hour to ensure dryness. The flask was refilled with argon and 44.0 mL (0.413 mol) of ethyl cyanoacetate was added followed by 13.0 mL (83.8 mmol) of bromoacetal. The yellow mixture was heated to 145°C for 4.5 hours and was then cooled to room temperature. The mixture was dissolved in 100 mL of water and 100 mL of diethyl ether. The organic layer was separated and the aqueous layer was extracted with an additional 100 mL of ether. The organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography (9:1 Hex/EtOAc) to give 14.2 g (62.0 mmol, 74percent yield) of a light yellow oil. (Rf: 0.53; 1:1 Hex/EtOAc). 1H-NMR (CDCl3, 600 MHz): σ 1.18 - 1.22 (m, 6H), 1.31 (t, 3H, J = 7.2 Hz), 2.16 - 2.21 (m, 1H), 2.24 - 2.29 (m, 1H), 3.49 - 3.55 (m, 2H), 3.64 - 3.71 (m, 3H), 4.24 (q, 2H, J = 7.2 Hz), 4.68 (t, 1H, J = 5.4 Hz). 13C-NMR (CDCl3, 150 Mz): σ 14.1, 15.3, 33.7, 62.8, 62.9, 100.1, 116.5, 166.0. HRMS (FAB): expected for C11H20NO4 (M+H)+:230.13868. Found: 230.13861. IR(neat): vmax 2989, 1774 cm-1.
70%
With sodium methylate In N,N-dimethyl-formamide at 90℃; for 4 h;
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 80percent 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 85percent yield. The synthesis of target compound 5 (Scheme 1C), involved N-formylation of 4-methoxy- 2-methylanline (compound 15) to afford compound 16 in 70percent 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 (75percent and 70percent respectively).
63%
Reflux
Example A1; Preparation of 4-chloro-5-iodopyrrolo[2,3-d]pyrimidine in Accordance with the Following Reaction Scheme; (a) 130 ml (860 mmol) of bromoacetaldehyde diethyl acetal are refluxed for 10 h with ethyl cyanoacetate (430 ml, 4.04 mol), sodium iodide (8.1 g; 54.04 mmol) and potassium carbonate (115.9 g; 839 mmol). After cooling to room temperature (RT), the batch is stirred with 800 ml of water, the aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated. Chromatography gives 124.99 g (63percent) of a colourless liquid ethyl 2-cyano-4,4-diethoxybutyrate.
60%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; benzene at -10 - 20℃; for 1 h; Stage #2: at 100℃; for 2 h;
To a suspension of NaH (60percent dispersion in mineral oil, 1.62 g, 40.5 mmol) in DMF (35 mL) and benzene (12 mL) was added ethyl cyanoacetate (4.7 mL, 44.2 mmol) dropwise at -10 0C. After stirring for 1 hour at room temperature, 2-bromo-1 ,1-diethoxyethane (5.6 mL, 0.82 equiv.) was added and the reaction mixture was heated at 100 0C for 2 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was condensed, and water was added. The mixture was extracted with ether. The extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (20percent EtOAc/hexanes). The desired product was obtained as colorless oil (5 g, 60percent). MS: (M + Na)/z = 252.
60%
Stage #1: With sodium ethanolate; sodium iodide In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 90℃; for 4 h;
Take a 500 mL two-necked flask and ethyl cyanoacetate (50 g, 0.44 mol) in anhydrous DMF(N, N-dimethylformamide) (300 mL) was added sodium ethoxide (36 g, 0.528 mol, 1.2 eq.) And sodium iodide (catalytic amount) at room temperature Stirring for 30min,2-Bromo-1,1-diethoxyethane was added(66.5 mL, 0.44 mol, 1 equiv)The temperature was raised to 90 ° C and stirred for 4 h. Cooled to room temperature, evaporated under reduced pressure to remove most of the DMF, add EA (ethyl acetate), stirring 10min, filter, take the filtrate to add saturation Salt water extraction. The organic phase was collected, dried, dried and dried (PE: EA = 12: 1, i.e., the volume ratio of petroleum ether: ethyl acetate was12) was obtained as a pale yellow oily product (61.3 g) in 60percent yield.
57%
at 140 - 150℃;
2-Cyano-4,4-diethoxy-butyric acid ethyl ester (4).; Bromoacetaldehyde diethylacetal (3, 541 g, 2.75 mol) was added to a suspension of powdered potassium carbonate (379.6 g, 2.75 mol, 1.0 equiv) and sodium iodide (33 g, 0.22 mol, 0.08 equiv) in ethyl cyanoacetate(2, 1.55 Kg, 13.75 mol, 5.0 equiv). Upon addition of the aldehyde to the reaction mixture, the resulting solution turned yellow. The reaction mixture was slowly heated to 140-150° C. collecting the volatile material in a Dean Stark trap. This material was discarded. Fairly vigorous gas evolution was observed to begin at 140° C. The reaction was monitored by G.C. and was observed to be near completion at 90 minutes. Heating was continued for an additional 45 minutes when gas evolution was observed to have ceased. The reaction mixture was then cooled to room temperature and partitioned between 4 L water and 2 L methyl tent-butyl ether (MTBE). The layers were separated and the aqueous layer was extracted with an additional 2 L of MTBE. The aqueous layer was checked for product by G.C. then discarded. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by fractional distillation (91-105° C. (at) 0.53-0.65 mm/Hg) to afford 2-cyano-4,4-diethoxy-butyric acid ethyl ester (4, 359.4 g, 630.5 g theoretical, 57percent) as a oil. For 4: 1H NMR (DMSO-d6, 300 MHz) δ ppm 4.60 (t, 1H, J=5.6 Hz), 4.15 (m, 3H), 3.59 (m, 2H), 3.45 (m,1H), 2.11 (t, 2H, J=6.2 Hz), 1.22 (t, 3H, J=6.9 Hz), 1.10 (dt, 6H, J=7.1, 6.9 Hz).
51%
for 24 h; Reflux
Preparation of intermediate compound (87) a. A mixture of ethyl cyanoacetate 81 (227.97 g, 2015.52 mmol), bromo acetaldehyde diethyl ether (80) (80 g, 405.94 mmol), potassium carbonate (55.99 g, 405.13 mmol) and sodium iodide (4 g, 26.67 mmol) was refluxed for 20 h (CO2 evolution was observed during the reaction). The reaction mixture was stirred at reflux for additional 4 h after the evolution of CO2 has ceased. The reaction was cooled to room temperature, diluted with water (400 mL) and diethyl ether (400 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (250 mL). The ether layers were combined washed with water (2 x 100 mL), brine (200 mL), dried, filtered and concentrated in vacuum. The product obtained was distilled under vacuum to furnish ethyl-2- cyano-4, 4-diethoxybutanoate (82) (47.5 g, 51.0 percent) as a colorless oil; B.P: 103 °C/1 mm Hg. 1HNMR (300 MHz, DMSO) δ 4.61 (t, J= 5.7, IH), 4.24 - 4.08 (m, 3H), 3.67 - 3.54 (m, 2H), 3.53 - 3.40 (m, 2H), 2.12 (t, J= 6.0, 2H), 1.23 (t, J= 7.1, 3H), 1.11 (td, J= 4.9, 7.0, 6H); IR (neat): 3482, 2980, 2901, 2361, 2252, 1749, 1446, 1374, 1262, 1218, 1128, 1062 and 857 cm"1; MS (ES"): 263.6 (M + 35); Analysis: CaIc for CnHi9NO4.0.25 H2O: C, 56.51; H, 8.40; N, 5.99; Found: C, 56.71; H, 8.16; N, 5.96.
29.2%
for 12 h; Reflux
Step 5: Preparation of ethyl 2-cyano-4,4-diethoxybutanoate A mixture of ethyl 2-cyanoacetate (1000 g, 8.84 mol), 2-bromo-1,1-diethoxyethane (400 g, 2.03 mol), KI (33.4 g, 0.201 mol) and K2CO3 (280 g, 2.03 mol) was heated to reflux for 12 hrs. The reaction mixture was diluted with CH2Cl2 (1000 mL) and the resulting precipitate was filtered off and the filtrate was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue distilled to give the title compound (136 g, 29.2percent yield) as a light yellow oil that was used as is in the next step.
Reference：
[1] Patent: US2015/307477, 2015, A1, . Location in patent: Paragraph 1563
[2] Patent: JP6121658, 2017, B2, . Location in patent: Paragraph 1270; 1271
[3] Archiv der Pharmazie, 2018, vol. 351, # 8,
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 4064 - 4067
[5] Organic Letters, 2017, vol. 19, # 9, p. 2214 - 2217
[6] Patent: WO2016/22890, 2016, A1, . Location in patent: Page/Page column 50
[7] Russian Journal of Bioorganic Chemistry, 1995, vol. 21, # 11, p. 756 - 761[8] Bioorganicheskaya Khimiya, 1995, vol. 21, # 11, p. 874 - 880
[9] Patent: US2010/160356, 2010, A1, . Location in patent: Page/Page column 33
[10] Patent: WO2009/9740, 2009, A1, . Location in patent: Page/Page column 71
[11] Patent: CN107033206, 2017, A, . Location in patent: Paragraph 0091; 0093; 0094; 0095
[12] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 100
[13] Patent: WO2010/14930, 2010, A2, . Location in patent: Page/Page column 59-60
[14] Patent: US2013/79324, 2013, A1, . Location in patent: Paragraph 0835; 0836
[15] Journal of the Chemical Society, 1960, p. 131 - 138
[16] European Journal of Organic Chemistry, 1998, # 5, p. 827 - 835
[17] European Journal of Medicinal Chemistry, 2008, vol. 43, # 6, p. 1248 - 1260
[18] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 8116 - 8128
[19] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6770 - 6789
10
[ 105-56-6 ]
[ 2032-35-1 ]
[ 52133-67-2 ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium carbonate In dimethyl sulfoxide at 70 - 80℃; for 15 h;
General procedure: Halo acetal 2a or 2b, 0.25 mol, was added with stirring to a mixture of 0.25 mol of the corresponding CH acid and 28 g (0.2 mol) of calcined potassium carbonate in 100 mL of DMSO. The mixture was stirred for 15 h at 70– 80°C (in the reactions with 2a), or at 100–120°C (2b), cooled, and treated with water and diethyl ether (2 100 mL). The combined extracts were dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure.
Reference：
[1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1390 - 1393[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1390 - 1393,4
11
[ 64-17-5 ]
[ 1187-46-8 ]
[ 109-92-2 ]
[ 52133-67-2 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 2, p. 675 - 678
12
[ 105-56-6 ]
[ 621-62-5 ]
[ 52133-67-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 6, p. 1523 - 1531
13
[ 52133-67-2 ]
[ 123148-78-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 4064 - 4067
[2] Patent: CN107033206, 2017, A,
14
[ 52133-67-2 ]
[ 84955-31-7 ]
Reference：
[1] Russian Journal of Bioorganic Chemistry, 1995, vol. 21, # 11, p. 756 - 761[2] Bioorganicheskaya Khimiya, 1995, vol. 21, # 11, p. 874 - 880
15
[ 52133-67-2 ]
[ 90213-67-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
16
[ 52133-67-2 ]
[ 90213-66-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 205 - 212
[2] Patent: WO2007/104944, 2007, A1,
With potassium carbonate; sodium iodide; at 145℃; for 4h;
Method AI: Ethyl 2-cyano-4,4-diethoxybutanoate (xlii-a):_ 2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq.) was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq.), K2CO3 (2.8 g, 20 mmol, 1.0 eq.) and NaI (200 mg, 1.3 mmol, 0.06 eq.), as described in J. Chem. Soc., 1960, 131-138. The reaction mixture was refluxed for 4 h at 145 C. After cooling, the reaction mixture was purified by chromatography on silica gel (eluted with petroleum ether/ethyl acetate (80:1?40:1?40:1) to give 3.57 g of xlii-a as a colorless oil (78%). 1H NMR (400 MHz, CDCl3): delta 4.70 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.78-3.64 (m, 3H), 3.62-3.45 (m, 2H), 2.35-2.14 (m, 2H), 1.34 (q, J=7.2 Hz, 3H), 1.25-1.16 (m, 6H).
78%
With potassium carbonate; sodium iodide; at 145℃; for 4h;
As described in J. Chem. Soc., 1960, 131-138,2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq)Was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq), K 2 CO 3 (2.8 g, 20 mmol, 1.0 eq) and NaI (200 mg, 1.3 mmol, 0.06 eq) .The reaction mixture was refluxed at 145 C. for 4 hours.After cooling, the reaction mixture was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate (80: 1 ? 40: 1 ? 10: 1)) to give 3.57 g of xlii-a as a colorless oil I got it (78%).
74%
With potassium carbonate; sodium iodide; at 145℃; for 4.5h;Inert atmosphere;
To a dry 3-necked round bottomed flask fitted with a condenser was added 11.3 g (81.5 mmol) of oven dried K2CO3 and 0.82 g (5.5 mmol) of NaI. The solids were placed under high vacuum for an hour to ensure dryness. The flask was refilled with argon and 44.0 mL (0.413 mol) of ethyl cyanoacetate was added followed by 13.0 mL (83.8 mmol) of bromoacetal. The yellow mixture was heated to 145C for 4.5 hours and was then cooled to room temperature. The mixture was dissolved in 100 mL of water and 100 mL of diethyl ether. The organic layer was separated and the aqueous layer was extracted with an additional 100 mL of ether. The organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography (9:1 Hex/EtOAc) to give 14.2 g (62.0 mmol, 74% yield) of a light yellow oil. (Rf: 0.53; 1:1 Hex/EtOAc). 1H-NMR (CDCl3, 600 MHz): ? 1.18 - 1.22 (m, 6H), 1.31 (t, 3H, J = 7.2 Hz), 2.16 - 2.21 (m, 1H), 2.24 - 2.29 (m, 1H), 3.49 - 3.55 (m, 2H), 3.64 - 3.71 (m, 3H), 4.24 (q, 2H, J = 7.2 Hz), 4.68 (t, 1H, J = 5.4 Hz). 13C-NMR (CDCl3, 150 Mz): ? 14.1, 15.3, 33.7, 62.8, 62.9, 100.1, 116.5, 166.0. HRMS (FAB): expected for C11H20NO4 (M+H)+: 230.13868. Found: 230.13861. IR(neat): vmax 2989, 1774 cm-1.
70%
With sodium methylate; In N,N-dimethyl-formamide; at 90℃; for 4h;
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).
70%
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃;
The 113 g (1mol)Ethyl cyanoacetate and 98.5 g (0.5 mol)Bromo acetal is dissolved in 450 g of DMF,Add 138 grams (1 mol) of potassium carbonate,Warm up to about 150 degrees, after the reaction is over,Cool to about 20 degrees and add 450 grams of water.Extracted twice with 500 g of chloroform,Wash once with saturated brine and dry.Vacuum distillation,78.1 g of ethyl 2-cyano-4,4-diethanolbutanoate were obtained in a yield of 70%.
63%
With potassium carbonate; sodium iodide;Reflux;
Example A1; Preparation of 4-chloro-5-iodopyrrolo[2,3-d]pyrimidine in Accordance with the Following Reaction Scheme; (a) 130 ml (860 mmol) of bromoacetaldehyde diethyl acetal are refluxed for 10 h with ethyl cyanoacetate (430 ml, 4.04 mol), sodium iodide (8.1 g; 54.04 mmol) and potassium carbonate (115.9 g; 839 mmol). After cooling to room temperature (RT), the batch is stirred with 800 ml of water, the aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated. Chromatography gives 124.99 g (63%) of a colourless liquid ethyl 2-cyano-4,4-diethoxybutyrate.
60%
To a suspension of NaH (60% dispersion in mineral oil, 1.62 g, 40.5 mmol) in DMF (35 mL) and benzene (12 mL) was added ethyl cyanoacetate (4.7 mL, 44.2 mmol) dropwise at -10 0C. After stirring for 1 hour at room temperature, 2-bromo-1 ,1-diethoxyethane (5.6 mL, 0.82 equiv.) was added and the reaction mixture was heated at 100 0C for 2 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was condensed, and water was added. The mixture was extracted with ether. The extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (20% EtOAc/hexanes). The desired product was obtained as colorless oil (5 g, 60%). MS: (M + Na)/z = 252.
60%
Take a 500 mL two-necked flask and ethyl cyanoacetate (50 g, 0.44 mol) in anhydrous DMF(N, N-dimethylformamide) (300 mL) was added sodium ethoxide (36 g, 0.528 mol, 1.2 eq.) And sodium iodide (catalytic amount) at room temperature Stirring for 30min,2-Bromo-1,1-diethoxyethane was added(66.5 mL, 0.44 mol, 1 equiv)The temperature was raised to 90 C and stirred for 4 h. Cooled to room temperature, evaporated under reduced pressure to remove most of the DMF, add EA (ethyl acetate), stirring 10min, filter, take the filtrate to add saturation Salt water extraction. The organic phase was collected, dried, dried and dried (PE: EA = 12: 1, i.e., the volume ratio of petroleum ether: ethyl acetate was12) was obtained as a pale yellow oily product (61.3 g) in 60% yield.
57%
With potassium carbonate; sodium iodide; at 140 - 150℃;
2-Cyano-4,4-diethoxy-butyric acid ethyl ester (4).; Bromoacetaldehyde diethylacetal (3, 541 g, 2.75 mol) was added to a suspension of powdered potassium carbonate (379.6 g, 2.75 mol, 1.0 equiv) and sodium iodide (33 g, 0.22 mol, 0.08 equiv) in ethyl cyanoacetate(2, 1.55 Kg, 13.75 mol, 5.0 equiv). Upon addition of the aldehyde to the reaction mixture, the resulting solution turned yellow. The reaction mixture was slowly heated to 140-150 C. collecting the volatile material in a Dean Stark trap. This material was discarded. Fairly vigorous gas evolution was observed to begin at 140 C. The reaction was monitored by G.C. and was observed to be near completion at 90 minutes. Heating was continued for an additional 45 minutes when gas evolution was observed to have ceased. The reaction mixture was then cooled to room temperature and partitioned between 4 L water and 2 L methyl tent-butyl ether (MTBE). The layers were separated and the aqueous layer was extracted with an additional 2 L of MTBE. The aqueous layer was checked for product by G.C. then discarded. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by fractional distillation (91-105 C. (at) 0.53-0.65 mm/Hg) to afford 2-cyano-4,4-diethoxy-butyric acid ethyl ester (4, 359.4 g, 630.5 g theoretical, 57%) as a oil. For 4: 1H NMR (DMSO-d6, 300 MHz) delta ppm 4.60 (t, 1H, J=5.6 Hz), 4.15 (m, 3H), 3.59 (m, 2H), 3.45 (m,1H), 2.11 (t, 2H, J=6.2 Hz), 1.22 (t, 3H, J=6.9 Hz), 1.10 (dt, 6H, J=7.1, 6.9 Hz).
51.0%
With potassium carbonate; sodium iodide; for 24h;Reflux;
Preparation of intermediate compound (87) a. A mixture of ethyl cyanoacetate 81 (227.97 g, 2015.52 mmol), bromo acetaldehyde diethyl ether (80) (80 g, 405.94 mmol), potassium carbonate (55.99 g, 405.13 mmol) and sodium iodide (4 g, 26.67 mmol) was refluxed for 20 h (CO2 evolution was observed during the reaction). The reaction mixture was stirred at reflux for additional 4 h after the evolution of CO2 has ceased. The reaction was cooled to room temperature, diluted with water (400 mL) and diethyl ether (400 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (250 mL). The ether layers were combined washed with water (2 x 100 mL), brine (200 mL), dried, filtered and concentrated in vacuum. The product obtained was distilled under vacuum to furnish ethyl-2- cyano-4, 4-diethoxybutanoate (82) (47.5 g, 51.0 %) as a colorless oil; B.P: 103 C/1 mm Hg. 1HNMR (300 MHz, DMSO) delta 4.61 (t, J= 5.7, IH), 4.24 - 4.08 (m, 3H), 3.67 - 3.54 (m, 2H), 3.53 - 3.40 (m, 2H), 2.12 (t, J= 6.0, 2H), 1.23 (t, J= 7.1, 3H), 1.11 (td, J= 4.9, 7.0, 6H); IR (neat): 3482, 2980, 2901, 2361, 2252, 1749, 1446, 1374, 1262, 1218, 1128, 1062 and 857 cm"1; MS (ES"): 263.6 (M + 35); Analysis: CaIc for CnHi9NO4.0.25 H2O: C, 56.51; H, 8.40; N, 5.99; Found: C, 56.71; H, 8.16; N, 5.96.
29.2%
With potassium carbonate; potassium iodide; for 12h;Reflux;
Step 5: Preparation of ethyl 2-cyano-4,4-diethoxybutanoate A mixture of ethyl 2-cyanoacetate (1000 g, 8.84 mol), 2-bromo-1,1-diethoxyethane (400 g, 2.03 mol), KI (33.4 g, 0.201 mol) and K2CO3 (280 g, 2.03 mol) was heated to reflux for 12 hrs. The reaction mixture was diluted with CH2Cl2 (1000 mL) and the resulting precipitate was filtered off and the filtrate was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue distilled to give the title compound (136 g, 29.2% yield) as a light yellow oil that was used as is in the next step.
Stepi 6-Amino-5-(2,2-diethoxyethyl)-pyrimidine-2,4-diolTo a solution of urea (5.24 g; 87.2 mmol) in anhydrous ethanol (200 ml), under a nitrogen atmosphere, was added 2-cyano-4,4-diethoxy butyric acid ethyl ester [prepared as detailed in Davoll. J. J. Chem. Soc, 1960, pp131-138] (20 g; 87.2 mmol) followed by sodium ethoxide (11.88 g; 172.6 mmol). The reaction mixture was heated at reflux overnight. The reaction was allowed to cool to ambient temperature and then water (500 ml) and acetic acid (5 ml) were added. The solution was cooled to approximately 5 0C and a pale brown solid formed which was collected by filtration (8.4 g; 40percent). LC/MS: RT = 1.37 min; m/z = 198 [M -EtOH]+. Total run time 3.75 mins <n="39"/>1H NMR (dbeta DMSO): delta 1.07 (t, 3H); 2.40 (d, 2H); 3.39 (m, 2H); 3.60 (m, 2H); 4.45 (t, 1H); 10.08 (s, 1H); 10.8 (br s, 1 H).
With sodium ethanolate; sodium; In ethanol; ethyl acetate;
EXAMPLE 2 SYNTHESIS OF 4-CHLORO-5,7-DIHYDRO-PYRROLO[2,3-D]PYRMIDIN-6-ONE To a solution of 45.2 mmol of sodium ethoxide (made in situ from sodium and absolute ethanol) in 40 mL of absolute ethanol was added formamidine hydrochloride (1.74 g, 21.5 mmol) and <strong>[52133-67-2]2-cyano-4,4-diethoxy-butyric acid ethyl ester</strong> (2.47 g, 11 mmol, literature reference: Davoll, J., J. Chem. Soc. 131-138 (1960)). The mixture was refluxed for 6 hours, cooled to room temperature and filtered. The solid was washed with hot acetonitrile. The filtrate was neutralized with acetic acid to pH 6.5 and then evaporated to half of the volume. Ethyl acetate (50 mL) was added to the resultant filtrate. The precipitate was filtered, washed with EtOAc to give 1.6 g (66percent) of 6-amino-5-(2,2-diethoxy-ethyl)-3H-pyrimidin-4-one as a white solid which was used without further purification. 1H NMR (300 MHz, DMSO-d6)delta 11.46 (s, br, 1H, NH), 7.68 (s, 1H), 6.07 (s, br, 2H, NH2), 4.54 (t, J=6.0 Hz, 1H, CH(OCH2CH3)2), 3.53-5.62 (m, 2H, CH(OCH2CH3)2), 3.31-3.49 (m, 2H, CH(OCH2CH3)2), 2.50 (m, 2H, CH2), and 1.05 (t, J=6.93 Hz, 6H, CH(OCH2CH3)2).
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 sodium ethanolate; In ethanol; at 140℃; for 0.5h;Microwave irradiation;
Compound 44 (2.5 g, 10.7 mmol) and <strong>[52133-67-2]2-cyano-4,4-diethoxy-butyric acid ethyl ester</strong> (3.2 g, 13.0 mol) were suspended in 15 mL of sodium ethoxide solution (2.8 g of sodium dissolved in 60 mL of ethanol), and the reaction mixture irradiated with microwave at 140 0C for 30 min. TLC (DCM: MeOH = 10:1) showed the starting material was reacted completely. The reaction mixture was cooled and evaporated under reduced pressure to get the residue, which was dissolved in a mixture of water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the title compound (4.0 g, 90percent) as a white solid.
A solution of 17 in 50percent TFA/DCM (10 mL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound (4.6 g, 99percent), which was used in the next step without purification.; To a microwave reaction tube was charged with 18 (2.3 g, 5.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (2.3 g, 10.0 mmol) and NaOMe (25percent by wt in MeOH; 12 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated 10percent NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.6 g, 96percent). The material was used in the next step without purification.
Example 54 Preparation of 2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolor2,3- (ilpyrimidin-4-ol (25)25[0231] To a microwave reaction tube was charged with 24 (2.3 g, 5.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (2.3 g, 10.0 mmol) and NaOMe (25percent by wt in MeOH; 12 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated 10percent NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.6 g, 96percent). The material was used in the next step without purification.
To a microwave reaction tube was charged with 37 (1.1 g, 5.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (1.7 g, 7.4 mmol) and NaOMe (25percent by wt in MeOH; 10 mL). The reaction tube was sealed and the solution irradiated with microwave at 150 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated NH4OH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a grey solid (1.5 g, 94percent). The material was used in the next step without purification.[0234] 1H NMR (500 MHz, DMSO-J6) delta 2.25 (s, 3H), 5.07 (s, 2H), 6.29 (dd, J = 3.0, 2.2 Hz, IH), 6.75 (t, J = 2.7 Hz, IH), 6.76 (d, J = 0.7 Hz, IH), 7.09-7.15 (m, 3H), 7.60 (d, J = 8.5 Hz, 2H), 8.71 (s, IH), 10.28 (br s, IH), 11.36 (s, IH) MS (ES+): m/z 321 (M+H)+
A solution of 55 in 50% TFA/DCM (10 niL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound, which was used in the next step without purification.57 2-(4-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-rf]pyrimidin-4-ol (57)[0292] To a microwave reaction tube was charged with 56 (10.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (2.3 g, 10.0 mmol) and NaOMe (25% by wt in MeOH; 15 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated 10% NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid. The material was used in the next step without purification.
A solution of 4 (2.0 g, 4.5 mmol) in 50percent TFA/DCM (10 niL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound (quant, yield), which was used in the next step without purification. MS (ES+): m/z 249 (M+H)+; To a microwave reaction tube was charged with 5 (1.6 g, 4.5 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (0.15 g, 7.4 mmol) and NaOMe (25percent by wt in MeOH; 10 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the peta adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the peta adjusted to 9 with concentrated NH4OH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (0.8 g, 52percent). The material was used in the next step without purification. MS (ES+): m/z 340 (M+H)+
52%
A solution of 32 (2.0 g, 4.5 mmol) in 50percent TFA/DCM (10 mL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound (quant, yield), which was used in the next step without purification.[0264] MS (ES+): m/z 249 (M+H)+; Example 69 Preparation of 2-r4-(2-Pyrrolidin-l-yl-ethoxy)-phenylaminol-7H-pyrrolor2,3- (ilpyrimidin-4-ol (34)34 [0265] To a microwave reaction tube was charged with 33 (1.6 g, 4.5 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (1.7 g, 7.4 mmol) and NaOMe (25percent by wt in MeOH; 10 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated NH4OH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (0.8 g, 52percent). The material was used in the next step without purification.[0266] MS (ES+): m/z 340 (M+H)+
With sodium methylate; In methanol; at 150℃; for 0.5h;Microwave irradiation;
To a microwave reaction tube was charged with 53 (1.1 g, 5.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (1.7 g, 7.4 mmol) and NaOMe (25% by wt in MeOH; 10 mL). The reaction tube was sealed and the solution irradiated with microwave at 150 0C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the peta adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the peta adjusted to 9 with concentrated NH4OH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a grey solid (1.5 g, 94%). The material was used in the next step without purification. [0362] H NMR (500 MHz, DMSO-J6) delta 2.25 (s, 3H), 5.07 (s, 2H), 6.29 (dd, J = 3.0, 2.2 Hz, IH), 6.75 (t, J = 2.7 Hz, IH), 6.76 (d, J = 0.7 Hz, IH), 7.09-7.15 (m, 3H), 7.60 (d, J = 8.5 Hz, 2H), 8.71 (s, IH), 10.28 (br s, IH), 11.36 (s, IH)[0363] MS (ES+): m/z 321 (M+H)+
3-(tetrahydro-2-pyranyloxy)propyl chloride[ No CAS ]
[ 341028-44-2 ]
Yield
Reaction Conditions
Operation in experiment
85.4%
The compound (1) (30.0 g, 0.313 mol) was added to a suspension of sodium hydride (3.77 g, 0.617 mol) in dimethylformamide (100 ml) under nitrogen atmosphere below 20° C., and the mixture was stirred at room temperature for 30 min. To the resulting mixture was added 2-(3-chloropropyl)tetrahydro-2H-pyran (25.7 g, 0.144 mol) at the same temperature, then the mixture was stirred in an oil bath at 60° C. for 16 h. The reaction mixture is evaporated under reduced pressure to remove dimethylformamide, to the residue was added water and the mixture was extracted with toluene. After the toluene layer was washed with water, dried over magnesium sulfate, and evaporated to remove toluene, the excess of 2-(3-chloropropyl)tetrahydro-2H-pyran was distilled and removed in an oil bath at 150° C. under reduced pressure to give the compound (2) (41.5 g, 85.4percent). [00174] 1H NMR (CDCl3); 1.18 (3H, t, J=6.9 Hz), 1.21 (3H, t, J=6.9 Hz), 1.33 (3H, t, J=7.2 Hz), 1.52-2.04 (12H, m), 2.40 (1H, m), 3.39-3.86 (7H, m), 4.24 (2H, m), 4.57 (1H, m), 4.77 (1H, m).
3,4-Dihydroxybenzamidine hydrochloride as obtained above (61.7 g) was dissolved in absolute ethanol (2000 ml.) and a part of the ethanol (1400 ml.) was subsequently distilled off again. More absolute ethanol (1400 mL) was added to this receiving solution, together with DBU (1 13 mL), <strong>[52133-67-2]2-cyano-4,4-diethoxy-butyric acid ethyl ester</strong> (148.0 g) and triethyl amine (96 mL). The resulting mixture was heated until reflux and further refluxed for 57 hrs. Most of the solvent (1700 mL) was then distilled off while the remainder was allowed to cool to 50 0C. An aqueous solution of hydrochloric acid (2.3 M, 930 mL) was added slowly, then the reaction mixture was allowed to cool to ambient temperature and stirring was continued for 25 hrs. The resulting precipitate was filtered off, washed with water (3 x 150 mL) and dried in vacuo at 40 0C to yield 31.5 g 4-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)- benzene-1 ,2-diol.
3-Dihydroxybenzamidine hydrochloride as obtained above (89.2 g) was dissolved in absolute ethanol (3080 mL) and a part of the ethanol (2200 mL) was subsequently distilled off again. More absolute ethanol (2200 mL) was added to this receiving solution, together with DBU (175 g), <strong>[52133-67-2]2-cyano-4,4-diethoxy-butyric acid ethyl ester</strong> (237.0 g) and triethyl amine (1 1 1 g). The resulting mixture was heated until reflux and further refluxed for 22 hrs. Most of the solvent (2950 mL) was then distilled off while the remainder was allowed to cool to 50 0C. An aqueous solution of hydrochloric acid (2.3 M, 1360 mL) was added slowly, the reaction mixture was allowed to cool to ambient temperature and stirring was continued for 1 hr. The resulting precipitate was filtered off, washed with water (3 x 100 mL) and dried in vacuo at 40 0C for 2 days to yield 82.8 g 2-(3-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol.
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.
7H-Pyrrolo[2,3-d]pyrimidin-4-ol (7).; Formamidine acetate (5, 1.04 Kg,10 mol, 1.25 equiv) was added to 7.52 L of (21percent wt) sodium ethoxide (EtONa) in ethanol (EtOH, 62.5 equiv) and the resulting solution was stirred for 60 minutes. <strong>[52133-67-2]2-cyano-4,4-diethoxy-butyric acid ethyl ester</strong> (4, 1.8 Kg, 8.0 mol) was then added and the resulting reaction mixture was refluxed for seven hours. The stirring was turned off after the solution was cooled and the solids were allowed to settle. The supernatant ethanol solution was removed, leaving the solids in the bottom of the reaction flask. The ethanol was evaporated and the residue was added back to the solids remaining in the reaction flask with water and ice at a ratio of 600 mL/mol. A solution of 6 N aqueous HCl was added to the resulting solution at a ratio of 500 mL/mol at 15° C. The resulting solution was then heated at 45° C. for 45 minutes. The solution was again cooled to 15° C. and the pH was adjusted to 8.0 with the addition of aqueous ammonium hydroxide. The precipitated solids were collected by filtration, washed with water (2.x.225 mL/mol) and pulled dry. The solids were further washed with 1:1 ethyl acetate/heptane (500 mL/mol), then heptane (2.x.250 mL/mol) and dried in vacuum to afford 7H-pyrrolo[2,3-d]pyrimidin-4-ol (7, 738.6g, 1081 g theoretical, 68.3percent) as yellow to brown to yellow crystalline material. For 7: 1H NMR (DMSO-d6, 300 MHz) delta ppm 11.88 (bs, 1H), 11.80 (bs, 1H), 7.81 (s,1H), 7.02 (dd,1H, J=3.2, 2.3 Hz), 6.42 (dd, 1H, J=3.5, 2.3 Hz); C6H5N3O (MW, 135.12), LCMS (EI) m/e 136 (M++H) and (M++Na) m/e 158.
Benzamidine hydrochloride (4.0 g, 0.25 mol) was dissolved in 64 ml of ethanol. To this 8.0 ml of a 25 wt percent solution of sodium methoxide was added. Reaction was then stirred at room temperature for 5 hrs, and filtered. Filtrate was then added to ethyl-2-cyano-4, 4-diethoxybutyrate (4.80 g, 0.21 mol). This solution was refluxed for 5 hrs.Half of solvent was removed under reduced pressure, then 80 ml of ice water was added, and the pH was adjusted to 7 with acetic acid. Material was then chilled for 6 hrs and product was isolated by vacuum filtration
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).
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