There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 623-47-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a) A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
94%
at 20 - 30℃; for 4 h;
A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
90%
at 20 - 30℃; for 3 h;
Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
90%
at 20℃; for 3 h;
Example 15.[00151] Example 15 presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6,7-dihydro-4H-pyrazolo[4',3':5,6]oxepino[4,3-d][1 ,3]thiazol-2-amine (Table II,Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
Reference：
[1] Patent: US2014/364412, 2014, A1, . Location in patent: Paragraph 0729; 0730
[2] Patent: WO2014/195402, 2014, A1, . Location in patent: Page/Page column 232
[3] Green Chemistry, 2009, vol. 11, # 2, p. 156 - 159
[4] Patent: WO2012/6760, 2012, A1, . Location in patent: Page/Page column 47
[5] Patent: WO2012/8999, 2012, A2, . Location in patent: Page/Page column 47
[6] Angewandte Chemie - International Edition, 2017, vol. 56, # 22, p. 6294 - 6297[7] Angew. Chem., 2017, vol. 129, # 22, p. 6391 - 6394,4
2
[ 80-11-5 ]
[ 623-47-2 ]
[ 5932-27-4 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 14, p. 5814 - 5823
3
[ 80-11-5 ]
[ 623-47-2 ]
[ 5932-27-4 ]
[ 88529-79-7 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 14, p. 5814 - 5823
4
[ 186581-53-3 ]
[ 623-47-2 ]
[ 5932-27-4 ]
Reference：
[1] Nucleosides and Nucleotides, 1999, vol. 18, # 2, p. 203 - 216
5
[ 623-47-2 ]
[ 13599-24-1 ]
Yield
Reaction Conditions
Operation in experiment
50%
With 2,2'-azobis(isobutyronitrile); iodine; tetrabutylammonium periodite In dichloromethane at 20℃; for 10 h; Irradiation; Inert atmosphere
General procedure: N-Hydroxy-1-phenylmethanesulfonamide (0.2 mmol), n-Bu4NIO4 (0.2 mmol), I2 (0.1 mmol) and AIBN (10percent) were added to a 25 mL roundbottom flask. A solution of the alkene (excess) or alkyne (0.2 mmol) in anhydrous CH2Cl2 (2 mL) was injected via a syringe and the mixture was stirred under visible-light irradiation for 10 h at r.t. The mixture was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaCl (2 10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification was accomplished by column chromatography on silica gel H with petroleum ether/ethyl acetate (20:1) as the eluent to give the pure product.
INTERMEDIATE 54 - PREPARATION OF ethyl S-phenylisoxazole-δ-carboxylate. ; A mixture of ethyl propriolate (0.657 ml 6.43 mmol), (E)-N-hydroxybenzimidoyl chloride (0.500 g; 3.21 mmol) and sodium bicarbonate (0.818 g; 9.64 mmol) in a mixture of ethyl acetate (16 ml.) and water (1 ml.) was stirred at room temperature, overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 80percent dichloromethane in heptane) to furnish 0.295 g (42percent) of ethyl 3-phenylisoxazole-5- carboxylate.ESI/APCI(+): 218 (M+H).
General procedure: To a solution of the appropriate aldoxime (1.2 mmol, 1.0 equiv) in ethyl methyl ketone (10 mL) was added appropriately substituted alkyne (1.32 mmol, 1.1 equiv) followed by alkyl nitrite 4 (1.32 mmol,1.1 equiv). After 5 min stirring at r.t., the turbid reaction mixture became a clear solution and the reaction mixture was stirred at 65 °C until the aldoxime had been consumed. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (EtOAc–n-hexane, 1:9 v/v) to afford the desired compound.
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1952, vol. <8> 13, p. 39,40
13
[ 622-42-4 ]
[ 623-47-2 ]
[ 13599-24-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1978, vol. 26, # 10, p. 3254 - 3256
14
[ 2365-48-2 ]
[ 623-47-2 ]
[ 5118-06-9 ]
Yield
Reaction Conditions
Operation in experiment
49.1%
Stage #1: at 20℃; for 1 h; Cooling with ice Stage #2: at -10 - 45℃; for 17 h;
Methyl 2-mercaptoacetate (4.31 mL, 47.1 mmol) was added to MeOH (94 mL) and cooled in an ice bath. Following, sodium hydride (3.39 g, 85 mmol) was slowly added and the reaction was stirred for 1 hour at room temperature. The reaction was cooled to -10 C and ethyl propiolate (5.01 mL, 48.0 mmol) was slowly added. The reaction was stirred at 0 °C for 1 hour, room temperature for 1 hour, and heated to 45 °C for three hours. (0342) Following, the reaction was heated for 12 hours at 35 °C. All reaction solvent was evaporated and the reaction was redissolved in water, neutralized to pH 7, and extracted 10 times with 3: 1 chloroform/IPA. The organic extracts were combined, evaporated, and dissolved in EtOAc. The EtOAc/reaction mixture was filtered through a pad of silica and washed with EtOAc. The organic was collected and condensed to generate methyl 3- hydroxythiophene-2-carboxylate (3.66 g, 49.1percent).
On a Vapourtec R2+/R4 flow system equipped with three PTFA reactor coils (a 10 mL) and a 250 psi back pressure regulator, ethyl propiolate and trimethylsilyl azide were injected via 2 mL loops. The flow rate was set to 0.5 mL/min, with a residence time of 1.5 h. The system was heated to 140 °C. Injections were performed every 40 min. The solvent used was acetonitrile. The total mixture coming out of the reactor was collected. In total, 5 injections were performed. The mixture was collected, and acetonitrile removed in vacuo (the collector of the rotary evaporator was filled with sat. aq. NaHC03 to quench any potentially formed HN3). The remaining solid was dissolved in EtOAc, and the organic phase washed with brine (3x), dried over Na2S04, filtered, and evaporated. The crude product was stirred in a minimal amount of Et20, filtered, and dried, to give the title compound (8.65 g, 81percent) as a white solid. MS (ESI): m/z = 142.1 [M+H]+.
Reference：
[1] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 1, p. 131 - 133
[2] Patent: WO2017/89389, 2017, A1, . Location in patent: Page/Page column 35
17
[ 623-47-2 ]
[ 40594-98-7 ]
Reference：
[1] Organic Letters, 2011, vol. 13, # 14, p. 3746 - 3749
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 627 - 630
[3] Tetrahedron, 2017, vol. 73, # 20, p. 2878 - 2885
18
[ 79-24-3 ]
[ 623-47-2 ]
[ 63366-79-0 ]
Reference：
[1] Tetrahedron, 2003, vol. 59, # 29, p. 5437 - 5440
[2] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 11, p. 3296 - 3303
[3] Chemical and Pharmaceutical Bulletin, 1978, vol. 26, # 10, p. 3254 - 3256
A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1 .00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane ( 1 0 g, 1 21 equiv) was stirred under nitrogen overnight at 110 "C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.41 -8.44 (m, 1H), 7.71 (d. J = 18 Hz, 1H), 5.88 (d, J = 8. 1Hz, 1H), 5.77 (m, 1H)
36%
at 110℃; Inert atmosphere
A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1 .00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane ( 1 0 g, 1 21 equiv) was sti rred under nitrogen overnight at 1 1 0 "C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown sol id1HNMR ( 300 MHz, DMSO-d6) δ 1 2.04 (s, 1H), 8.41 -8.44 (m, 1H), 7.71 (d. J = 18 Hz, 1H ), 5.88 (d, J = 8. 1Hz, 1H), 5.77 (m, 1H)
36%
at 110℃; Inert atmosphere
A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1 .00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane ( 1 0 g, 1 21 equiv) was stirred under nitrogen overnight at 110 "C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.41 -8.44 (m, 1H), 7.71 (d. J = 18 Hz, 1H), 5.88 (d, J = 8. 1Hz, 1H), 5.77 (m, 1H)
36%
at 110℃; Inert atmosphere
0217] Step 1. 4H-Pyrazolor 5-alpyrimidin-5-one. A solution of lH-pyrazol-3-ylamine (7 g, 84.24 mmol, 1.00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirred under nitrogen overnight at 110 °C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid. 1H NMR (300 MHz, DMSO-J6) δ 12.04 (s, 1H), 8.41-8.44 (m, 1H), 7.71 (d, J = 1.8 Hz, 1H), 5.88 (d, J = 8.1 Hz, 1H), 5.77 (m, 1H).
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 41, p. 6168 - 6178
[2] Patent: WO2013/127266, 2013, A1, . Location in patent: Page/Page column 142
[3] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 93
[4] Patent: WO2013/127268, 2013, A1, . Location in patent: Page/Page column 68
[5] Patent: WO2013/130943, 2013, A1, . Location in patent: Paragraph 0217
31
[ 89464-32-4 ]
[ 623-47-2 ]
[ 29274-22-4 ]
Yield
Reaction Conditions
Operation in experiment
36%
at 110℃; Inert atmosphere
[0209] Step 1. 4H-Pyrazolo[1,5-alpyrimidin-5-one. A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1.00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirred under nitrogen overnight at 110 °C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid. ‘H NMR (300 MHz, DMSO-d6) ö 12.04 (s, 1H), 8.41-8.44 (m, 1H), 7.71 (d, J= 1.8 Hz, 1H), 5.88 (d, J= 8.1 Hz, 1H), 5.77 (m, 1H).
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 14, p. 5814 - 5823
35
[ 623-47-2 ]
[ 64951-07-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 22, p. 4837 - 4843
36
[ 108-89-4 ]
[ 623-47-2 ]
[ 51135-70-7 ]
Yield
Reaction Conditions
Operation in experiment
53%
Stage #1: With mesitylenesulfonylhydroxylamine In dichloromethane at 0℃; for 2 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h;
General procedure: These were made using MSH or DNPH as detailed below, unless otherwise stated. A fresh solution of MSH23 in CH2Cl2 (1 equiv) was added to the substituted pyridine (1 equiv) in CH2Cl2 (10 mL) at 0 °C. After 2 h, the solvent was removed in vacuo. Alternatively, a solution of DNPH12 (1 equiv) and the substituted pyridine (1 equiv) in MeCN (40 mL) was heated at 40 °C for 18 h. The solvent was removed in vacuo. The method continues by taking the residue from either method in dry DMF (8 mL), and then ethyl propiolate (1 equiv) and K2CO3 (2 equiv) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient, unless otherwise stated) gave the pyrazolo[1,5-a]pyridine.
53%
Stage #1: With mesitylenesulfonylhydroxylamine In dichloromethane at 0℃; for 2 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h;
Step 2.1 : A fresh solution of O-(mesitylsulfonyl)hydroxylamine in CH2CI2 (6.0 ml_, 0.44 mol L"1, 2.6 mmol) [T. Eichenberger et al., HeIv. Chim. Acta 1986, 69(6), 1521] was added to 4-methylpyridine (1: X = Me) (248 mg, 2.66 mmol) in CH2CI2 (10 mL) at 0 0C. After 2 h, the solvent was removed in vacuo. The residue was taken up in dry DMF (8 mL), then ethyl propiolate (0.25 mL, 2.5 mmol) and K2CO3 (450 mg, 3.26 mmol) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with hexanes: EtOAc 97:3 to 95:5 to 9:1) gave ethyl 5-methyl- pyrazolo[1 ,5-a]pyridine-3-carboxyIate (4: X = Me) as a pale brown solid (175 mg, 53percent). 1H NMR δ (400 MHz, CDCI3) 8.39 (d, J 7.1 Hz, 1 H)1 8.34 (s, 1H), 7.93 (s, 1H), 6.76 (dd, J 7.1 , 1.9 Hz, 1 H), 4.38 (q, J 7.1 Hz, 2H), 2.47 (s, 3H), 1.41 (t, J 7.1 Hz, 3H). LCMS (APCI+) 205 (MH+, 100percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 69 - 85
[2] Patent: WO2009/8748, 2009, A1, . Location in patent: Page/Page column 56
Propiolic acid (310 μL, 5 mmol; Alfa Aesar, Ward Hill, Mass.; catalog No. A13245) was dissolved in 13 mL of ethanol, giving a colorless solution, to which concentrated sulfuric acid (139 μL, 2.5 mmol) was added. The resulting mixture was heated to reflux for 24 h, and then treated with 13 mL of water before being extracted with dichloromethane (10 mL; three times). The combined organic layers were washed with water (10 mL; three times) and brine (10 mL), and then dried over anhydrous Na2SO4 (Thermo Fisher Scientific, Pittsburgh, PA; catalog No. S421-3). Removal of the solvent under vacuum afforded the product as a light yellow color oil (177 mg, 36percent yield). 1H NMR (400 MHz, CDCl3, δ): 4.26 (q, 3JH-H=7.1 Hz, CH2, 2H), 2.92 (s, C≡CH, 1H), 1.33 (t, 3JH-H=7.2 Hz, CH3, 3H).
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, p. 3965
[2] Patent: US2016/264506, 2016, A1, . Location in patent: Paragraph 0035
[3] Chemische Berichte, 1926, vol. 59, p. 1689
[4] Nippon Kagaku Zasshi, 1956, vol. 77, p. 1689,1691[5] Chem.Abstr., 1959, p. 5163
[6] Chemische Berichte, 1882, vol. 15, p. 2702
[7] Journal of the Chemical Society, 1907, vol. 91, p. 834
[8] Chemische Berichte, 1885, vol. 18, p. 677[9] Chemische Berichte, 1889, vol. 22, p. 69
[10] Journal of Fluorine Chemistry, 1993, vol. 62, # 2-3, p. 217 - 241
[11] Tetrahedron Letters, 2005, vol. 46, # 15, p. 2547 - 2549
[12] Patent: US8569361, 2013, B1, . Location in patent: Paragraph 0108-0109
39
[ 764-01-2 ]
[ 1972-28-7 ]
[ 108-95-2 ]
[ 13610-09-8 ]
[ 623-47-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
With triphenylphosphine In tetrahydrofuran; benzene
But-2-ynyloxy-benzene To a solution of 6.14 g (23.40 mmol) of triphenylphosphine dissolved in 100 mL of benzene and 50 mL of THF was added 1.75 mL (23.40 mmol) of 2-butyn-1-ol. After five minutes 2.00 g (21.28 mmol) of the phenol, dissolved in 10 mL of THF, was added to the reaction followed by 3.69 mL (23.40 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluding with ethyl acetate/hexanes (1:10) to provide 2.18 g (70percent) of the desired propargylic ether as a clear liquid. EI Mass Spec: 146.0 M+
Reference：
[1] Patent: US6358980, 2002, B1,
40
[ 107-19-7 ]
[ 1972-28-7 ]
[ 287108-60-5 ]
[ 623-47-2 ]
[ 287108-61-6 ]
Yield
Reaction Conditions
Operation in experiment
71%
With triphenylphosphine In tetrahydrofuran; benzene
EXAMPLE 5 5-Bromo-3-methyl-2-[methyl-(4-prop-2-ynyloxy-benzenesulfonyl)-amino]-benzoic acid methyl ester To a solution of 0.317 g (1.208 mmol) of triphenylphosphine dissolved in 5 mL of benzene and 2 mL of THF was added 0.070 mL (1.208 mmol) of propargyl alcohol. After five minutes 0.500 g (1.208 mmol) of the product of Example 4, dissolved in 2 mL of THF, was added to the reaction followed by 0.190 mL (1.208 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluding with ethyl acetate/hexanes (1:10) to provide 0.389 g (71percent) of the desired propargylic ether as a white solid. Electrospray Mass Spec: 451.8 (M+H)+
Reference：
[1] Patent: US6277885, 2001, B1,
41
[ 924-44-7 ]
[ 623-47-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 34, p. 7602 - 7611
42
[ 541-41-3 ]
[ 74-86-2 ]
[ 623-47-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 16, p. 4154 - 4158[2] Angew. Chem., 2014, vol. 126, # 16, p. 4238 - 4242,5
[3] Chemical Communications, 2015, vol. 51, # 65, p. 13004 - 13007
Reference：
[1] Zhurnal Obshchei Khimii, 1950, vol. 20, p. 1729,1731;engl.Ausg.S.1787,1789
48
[ 38391-86-5 ]
[ 7732-18-5 ]
[ 623-47-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1950, vol. 20, p. 1729,1731;engl.Ausg.S.1787,1789
49
[ 623-73-4 ]
[ 623-47-2 ]
[ 37687-24-4 ]
Reference：
[1] Chemistry Letters, 2007, vol. 36, # 1, p. 60 - 61
[2] Green Chemistry, 2009, vol. 11, # 2, p. 156 - 159
[3] Chemical Communications, 2004, # 4, p. 394 - 395
[4] Tetrahedron Letters, 2010, vol. 51, # 45, p. 5915 - 5918
[5] Tetrahedron Letters, 2008, vol. 49, # 48, p. 6768 - 6772
50
[ 876726-66-8 ]
[ 623-47-2 ]
[ 37687-24-4 ]
Reference：
[1] Green Chemistry, 2009, vol. 11, # 2, p. 156 - 159
51
[ 623-47-2 ]
[ 41658-03-1 ]
Yield
Reaction Conditions
Operation in experiment
58%
Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h;
Reaction Step 1. Synthesis of ethyl 3-bromopropiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane Rf=0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30° C.) to afford an oil.
58%
Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h;
Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane, Rf = 0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25– 30 °C) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3- bromopropiolate (10.0 g, 58percent) as a yellow oil. LCMS m/z = 176.91 (M+1).
58%
Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h;
Reaction step 1. Synthesis of e propiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane, Rf = 0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25– 30 °C) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58percent) as a yellow oil. LCMS m/z = 176.91 (M+1).
58%
Stage #1: With silver nitrate In acetone for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h;
Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.0 g, 102 mmol, 1.0 eq) in acetone (200 mE) at room temperature. The resulting reaction mixture was stirred for 5 mm, then N135 (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 hr at room temperature. After completion of the reaction (monitored by TEC, 5percent ethyl acetate-hexane, R1=0. 55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30° C.) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58percent) as a yellow oil. ECMS mlz=176.91 (M+1).
58%
Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h;
Reaction Step 1 Synthesis of ethyl 3-bromopropiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane, Rf=0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30° C.) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58percent) as a yellow oil. LCMS m/z=176.91 (M+1).
Reference：
[1] Organic Letters, 2017, vol. 19, # 19, p. 5042 - 5045
[2] Journal of the American Chemical Society, 2007, vol. 129, # 2, p. 441 - 449
[3] Journal of Organic Chemistry, 1996, vol. 61, # 8, p. 2885 - 2887
[4] Organic Letters, 2015, vol. 17, # 5, p. 1320 - 1323
[5] Organic Letters, 2018, vol. 20, # 8, p. 2365 - 2368
[6] Chemistry--A European Journal, 2014, vol. 20, # 35, p. 11101 - 11110,10
[7] Patent: US2015/252051, 2015, A1, . Location in patent: Paragraph 0169; 0170
[8] Patent: WO2016/14913, 2016, A1, . Location in patent: Paragraph 129; 130
[9] Patent: WO2016/14916, 2016, A1, . Location in patent: Paragraph 124; 125
[10] Patent: US2017/298060, 2017, A1, . Location in patent: Paragraph 0136; 0137
[11] Patent: US2016/24056, 2016, A1, . Location in patent: Paragraph 0230
[12] Journal of Organic Chemistry, 2002, vol. 67, # 19, p. 6841 - 6844
[13] European Journal of Organic Chemistry, 2010, # 17, p. 3224 - 3228
[14] Organic Letters, 2010, vol. 12, # 15, p. 3328 - 3331
[15] European Journal of Organic Chemistry, 2011, # 20-21, p. 3837 - 3848
[16] Canadian Journal of Chemistry, 2011, vol. 89, # 12, p. 1494 - 1505
52
[ 623-47-2 ]
[ 7341-96-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
at -78 - 20℃; for 5 h;
To a solution of liquid NH3 (50 ml.) at -78°C was added dropwise ethyl 2-propynoate (1 1 g, 0.11 mol). The mixture was stirred at -78°C for 2 hours, then for 3 hours at room temperature. The remaining residue was concentrated under vacuum to give the title compound which was used in the next step without further purification (8 g, quantitative yield).
74%
at -10℃; for 1 h; Inert atmosphere
Ethyl propiolate (4.0 mL, 40 mmol) was added to aqueous ammonia (25percent w/w; 130 mL) at −10 °C and the reaction was stirred at −10 °C (1 h). The reaction mixture was poured onto ethyl acetate (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (4 x 100 mL) and the combined organic extracts were dried over MgSO4. The solvent and unreacted ethyl propiolate were removed in vacuo to give the crude title compound (2.02 g, 74percent) as an off-white solid, which was used without further purification.
72%
With ammonium hydroxide In water at 0℃; for 5.5 h;
Propynamide: To a solution of 30 mL of water and 9.19 g (135 mmol) ammonia (25-28 wt percent) is added dropwise 9.81 g (100 mmol) ethyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 5 h at 0° C., then acetic acid (3 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×40 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (5.0 g, yield 72percent, purity 99percent by GC). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (1H, s), 7.61 (1H, s), 4.05 (1H, s).
72%
With ammonia In water at 0℃; for 5.5 h;
To a solution of 30 mL of water and 9.19 g (135 mmol) ammonia (25-28 wt percent) is added dropwise 9.81 g (100 mmol) ethyl propiolate at 0 °C for 30 mins. The mixture was stirred for 5 h at 0 °C, then acetic acid (3 mL) was added. The mixture was stirred for another 10 mins and saturated with NaCI, followed by extraction with ethyl acetate (3 χ 40 mL). The combined organic phase was washed with saturated aqueous solution of NaHC03 (20 mL), dried over Na2S04, and removed by rotary evaporation to give product (5.0 g, yield 72percent, purity 99percent by GC).1H NMR (400 MHz, DMSO-d6) δ 8.07 (1 H, s), 7.61 (1 H, s), 4.05 (1 H, s).
Reference：
[1] Patent: WO2009/56556, 2009, A1, . Location in patent: Page/Page column 43
[2] Magnetic Resonance in Chemistry, 1997, vol. 35, # 9, p. 571 - 576
[3] Tetrahedron Letters, 2016, vol. 57, # 29, p. 3113 - 3116
[4] Patent: US2014/66655, 2014, A1, . Location in patent: Paragraph 0043; 0044
[5] Patent: WO2014/37308, 2014, A1, . Location in patent: Page/Page column 7
[6] European Journal of Organic Chemistry, 2011, # 34, p. 6957 - 6964
[7] Nippon Kagaku Zasshi, 1956, vol. 77, p. 1689,1691[8] Chem.Abstr., 1959, p. 5163
[9] Patent: US2004/14776, 2004, A1, . Location in patent: Page/Page column 38
[10] Patent: US2014/94456, 2014, A1, . Location in patent: Paragraph 0586-0587
[11] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0337
[12] Patent: WO2009/121812, 2009, A1, . Location in patent: Page/Page column 75
Reference：
[1] Canadian Journal of Chemistry, 1974, vol. 52, p. 3569 - 3576
57
[ 623-47-2 ]
[ 74-88-4 ]
[ 4341-76-8 ]
[ 74460-85-8 ]
[ 74460-84-7 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
[2] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
[3] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
[4] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
[5] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
[6] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1592 - 1596
58
[ 623-47-2 ]
[ 74-88-4 ]
[ 4341-76-8 ]
[ 5717-41-9 ]
[ 74460-85-8 ]
[ 74460-84-7 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
[2] Journal of the Chemical Society, Chemical Communications, 1980, # 4, p. 188 - 189
59
[ 637-87-6 ]
[ 623-47-2 ]
[ 20026-96-4 ]
Yield
Reaction Conditions
Operation in experiment
61%
Stage #1: With copper(l) iodide; caesium carbonate In tetrahydrofuran at 20℃; for 0.0833333 h; Inert atmosphere Stage #2: at 35℃; Inert atmosphere
a) (4-Chloro-phenyl)-propynoic acid ethyl ester (Va) Under argon atmosphere, a four neck flask was charged with 1-chloro-4-iodo-benzene (130.0 g, 0.55 mol), bis(triphenylphosphine) palladium(II) chloride (7.57 g, 10.8 mmol, 2 mol percent), copper(I) iodide (4.19 g, 22.0 mmol, 4 mol percent) and dry THF (1.4 l). At r.t., cesium carbonate (355.3 g, 1.09 mol, 2 eq.) was added over 5 min. Afterwards propynoic acid ethyl ester (111.3 ml, 1.09 mol, 2 eq.) was added, and the reaction mixture was stirred overnight at 35° C. An additional portion of propynoic acid ethyl ester (11.1 ml, 0.11 mol, 0.2 eq.) was added, and the reaction was stirred for another 3 h at 35° C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (0.5 l) and heptane (1 l). The resulting suspension was stirred at 40° C. for 1 h and filtered over celite. The filtrate was concentrated, and the product purified by silica gel filtration (toluene/heptane 1:2) to yield 72.6 g (61percent) of Va as a light yellow solid.
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 7, p. 2470 - 2483
63
[ 100-52-7 ]
[ 100-46-9 ]
[ 623-47-2 ]
[ 120533-76-8 ]
Yield
Reaction Conditions
Operation in experiment
46.3%
for 0.416667 h; Heating
General procedure: A mixture of aromatic aldehyde (0.05 mol), ethyl propiolate (0.10 mol), amine (0.05 mol), and 5.0 mL of acetic acid was heated in a steam bath for 25 min [16, 17]. The product was crystallized from methanol : water, 4 : 1 and then recrystallized from acetone : hexane, 1 : 1.
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 17, p. 5496 - 5504
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 22, p. 4729 - 4732
[3] European Journal of Medicinal Chemistry, 2001, vol. 36, # 4, p. 367 - 374
[4] European Journal of Organic Chemistry, 2000, # 2, p. 245 - 249
[5] Monatshefte fur Chemie, 2001, vol. 132, # 12, p. 1551 - 1555
[6] Chemical Biology and Drug Design, 2013, vol. 82, # 5, p. 567 - 578
[7] Russian Journal of General Chemistry, 2016, vol. 86, # 12, p. 2891 - 2899[8] Zh. Obshch. Khim., 2016, vol. 86, # 12, p. 2891 - 2899,9
[9] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14, p. 4983 - 4990
64
[ 3287-99-8 ]
[ 100-52-7 ]
[ 623-47-2 ]
[ 120533-76-8 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 9, p. 1017 - 1023[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, # 9, p. 1232 - 1238
Reference：
[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 1, p. 43 - 46
[2] Org. Process Res. Dev., 2011, vol. 15, # 5, p. 1073 - 1080
69
[ 98262-66-9 ]
[ 623-47-2 ]
[ 86477-10-3 ]
[ 86477-09-0 ]
Yield
Reaction Conditions
Operation in experiment
57%
at 120 - 122℃; for 12 h;
A solution of 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (13.5 g, 0.107 mole, crude, from example 4) and ethyl propiolate (15.8 g, 16.3 ml, 0.16 mole) in dry N,N-dimethylformamide (50 ml) is stirred and heated to 120-122° C. under a nitrogen atmosphere for a period of 12 hours. The reaction is monitored for completion by HPLC [Prodigy ODS3 4.6.x.150 mm column, with a 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02percent trifluoroacetic acid. Retention times under these conditions were: 2.6-2.7 min for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the desired, more polar isomer) and 2.8-2.9 min for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the less polar, undesired isomer). The UV detector was set at 215 nm, because at 254 nm the two isomers absorbed very differently, and the undesired isomer was almost undetectable). The mixture is then evaporated to a dark syrup under oil pump vacuum using a bath temperature up to 50° C. The ratio of the esters in the dark syrup is determined by NMR, as 2.13 to 1 in favor of the desired ester, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. The dark syrup is diluted with toluene and the solution is applied to a column of silica gel (500 mL) prepacked in hexanes by washing onto the column with hexanes. Elution is with hexanes-ethyl acetate mixture (4:1) followed by hexanes-ethyl acetate (1:1). Fractions are monitored by HPLC (same conditions as above). Fractions that contained both esters are combined and chromatographed once more. Fractions containing only ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate are combined and concentrated to give 11 g (57percent) of the pure ester as white crystals, m. p. 41-43° C. Similarly, 6.5 g (33.7percent) of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate is obtained as white crystals, m.p. 35-37° C.
41%
at 120 - 125℃; for 8 - 11 h;
The 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (971 g, 7.70 mol, made as in example 2) and 1,2-diethoxyethane (DEE, 2913 mL) are charged to a multinecked 12 L round bottom flask, is equipped with a water cooled condenser, and purged with nitrogen. The stirred solution is heated to 120-125° C. under a nitrogen atmosphere and ethyl propiolate (971 g, 9.90 mol) is added dropwise over a period of 3 hours (carbon dioxide evolution). The reaction is held at 120-125° C. for about 5 hours until the conversion is >99percent (<1percent of residual 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide, by GC-MS analysis). The mixture is then concentrated under oil pump vacuum using a rotary evaporator with a bath temperature up to 70° C. to a residue. About 1.5 kg of toluene is then added to the residue and the mixture is concentrated once more. A dark oil is obtained [1218 g, 46.9percent strength, (HPLC) in 41percent (real yield of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide]. [TABLE-US-00001] Ratio of 2- Ylide, Ester to 3- Addition Hold 3, Product 2-Ester Ester Time Time starting Crude 2-Ester percent Yield by GC-MS Solvent Temp° C. (hours)* (hours)** (g) (g) Wt percent (crude to real) (Area percent) DEE 120-125 3 5 971 1218 46.9 41 58/42 DEE 120-125 3 6.2 1400 1988 48.2 47 60/37 DEE 120-125 3 8 827 1075 45.5 42 57/40 *Addition time is the time taken to add the reagent, ethyl propiolate. **Hold time is the time the reaction is allowed to run beyond the addition time. The total reaction time is the sum of the addition time and the hold time.
42 %Chromat.
at 120 - 125℃; for 5 h;
To 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium Ylide (29.3 g, 0.232 mol prepared as in example 2) and chlorobenzene (97.2 g) under a nitrogen atmosphere at 120-125° C. is added dropwise ethyl propiolate (29.3 g, 0.299 mol) over a period of about 2 hours (carbon dioxide evolution). The reaction is held for about 3 hours until the conversion is >99percent (<1percent residual according to GC-MS analysis). The GC-MS ratio of the desired isomer, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, to the undesired isomer, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate, is 59/41 The mixture is then washed with water (50 mL). The organic phase is concentrated under oil pump vacuum up to a bath temperature of about 70° C. to afford a residue as a dark oil [39.1 g, 45.3percent strength (HPLC) in ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, 42percent (real yield of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide)]. The oil is characterized by HPLC, NMR.
Reference：
[1] Patent: US2004/242874, 2004, A1, . Location in patent: Page 13-14
[2] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 2, p. 169 - 175
[3] Patent: US2004/242874, 2004, A1, . Location in patent: Page 12-13
[4] Patent: US2004/242874, 2004, A1, . Location in patent: Page 13
[5] Organic Process Research and Development, 2006, vol. 10, # 4, p. 712 - 716
A mixture of 3,5-dichloro-6-methyl-[1 ,4]oxazin-2-one (45.5 g, 253 mmol) and ethyl propiolate (74.4 g, 758 mmol) in toluene (135 mL) is stirred under nitrogen at 80 0C for 23 h. The reaction is then cooled down to room temperature and the solvents are removed by rotary evaporation. The residue is treated with hexanes (400 mL), and the somewhat cloudy solution is decanted from a dark red residue containing undesired impurities. The hexanes are removed by rotary evaporation. The crude is then cooled to 0 0C, and the flask is swirled occasionally until the crude oil solidifies. The solid is then washed with small amounts of pentane. The cooled filtrate is filtered again, resulting in removal of additional yellow solid, which is the undesired regioisomer (16 g). The filtrate is then concentrated down to dryness by rotary evaporation and purified by silica gel chromatography (9:1 heptane / dichloromethane) to yield a clear liquid which solidifies upon standing (15.4 g, 65.8 mmol, 26percent). MS(ESI) m/z 234.16 (M+1 ). 1H NMR (400 MHz, CDCI3) δ ppm 7.55 (s, 1 H), 4.39 (q, J=7.07 Hz, 2 H), 2.53 (s, 3 H), 1.39 (t, J=7.14 Hz, 3 H).
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 5, p. 1380 - 1386
76
[ 623-47-2 ]
[ 89102-73-8 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: With sodium hydroxide; hydroxylamine hydrochloride In ethanol; water at 20℃; for 48 h;
To a solution of 30 g (0.306 mol) of ethyl propiolate in 600 mL of ethanol, 85 g (1.223 mol) of hydroxylamine hydrochloride in 1.1 L of a 10percent sodium hydroxide solution were added in an argon atmosphere. The mixture was stirred at room temperature for 48 h, and then acidified to a pH = 2-3 by addition of concentrated hydrochloric acid. The reaction mixture was extracted three times with diethyl ether, and the combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was extracted with hot hexane, and then the solvent was evaporated under reduced pressure. 9.0 g (yield = 35percent) of a white crystalline solid corresponding to the title compound was obtained. Mass spectrum (m/e): 83 (M+).
Reference：
[1] Organic Process Research and Development, 2006, vol. 10, # 4, p. 712 - 716
81
[ 1067233-79-7 ]
[ 623-47-2 ]
[ 231285-86-2 ]
[ 852228-09-2 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 4049 - 4064
82
[ 172095-72-6 ]
[ 623-47-2 ]
[ 85614-89-7 ]
Yield
Reaction Conditions
Operation in experiment
78.5%
Stage #1: With triethylamine In toluene at 20℃; for 2 h; Stage #2: at 85℃; for 70 h;
ii) 6-Hydroxy-5-methyl-nicotinic acid ethyl ester At RT, a solution of propionyl chloride (1.55 mL, 17.4 mmol) in 3.5 mL of toluene was added drop-wise to a solution of N-tert-butyldimethylsilyl isopropyl formimidate (3.51 g, 17.4 mmol) and triethylamine (12.2 mL, 87 mmol) in 10 mL of toluene. The resulting mixture was stirred at RT for 2 hours and then 10 mL of hexanes was added. The precipitate was removed by filtration and washed with hexanes (3 x 5 mL). The solution was concentrated in vacuo to afford a clear oil. This oil was solubilised in toluene (15 mL) and ethyl propiolate (1.2 mL, 11.6 mmol) was added. The resulting mixture was stirred at 85°C for 70 hours. The mixture was concentrated in vacuo and then diluted with HCI 2N. The aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo to afford a crude yellow paste (3.5 g). The crude product was purified by flash chromatography over silica gel using Hexanes/EtOAc (75/25 to 0/100) as solvent gradient to afford 6-hydroxy-5-methyl-nicotinic acid ethyl ester (1.65 g, 78.5percent) as a yellow powder. (ES- MS: m/z 182.1 [M+H]+, tR 3.28 min (system 2)).
With methanol; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; copper(l) chloride; sodium t-butanolate In tetrahydrofuran at 20℃; for 24 h; Inert atmosphere
General procedure: CuCl (1.5 mg, 0.015 mmol), NaOt-Bu (2.9 mg, 0.03 mmol), and Xantphos ligand (8.7 mg, 0.015 mmol) were placed in an oven-dried Schlenk tube under nitrogen and THF (0.45 mL) were added. The reaction mixture was stirred for 30 min at room temperature and then bis(pinacolato)diboron (127 mg, 0.5 mmol) in THF (0.3 mL) was added. The reaction mixture was stirred for 10 min and α,β-acetylenic ester 2 (0.5 mmol) was added, followed by MeOH (40 μL, 1 mmol). The reaction tube was washed with further THF (0.2 mL), sealed, and stirred until no starting material was detected by TLC. The reaction mixture was filtered through a pad of Celite and concentrated. The product was purified by silica gel chromatography.
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8903 - 8925,23
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 26, p. 7136 - 7139
[3] New Journal of Chemistry, 2018, vol. 42, # 21, p. 17346 - 17350
[4] Chemical Communications, 2008, # 6, p. 733 - 734
[5] Tetrahedron, 2012, vol. 68, # 17, p. 3444 - 3449
[6] Organic Letters, 2010, vol. 12, # 5, p. 1024 - 1027
84
[ 623-47-2 ]
[ 909717-95-9 ]
Yield
Reaction Conditions
Operation in experiment
850 mg
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: at 20℃; for 16 h;
To a solution of the product from step 1(1.50 g, 4.9 mmoi) in I)MF (2() mL) was added K2C03 (1.4 g, 98 mmoi). The mixture was stirred at ()°C for 10 minutes, then ethylpropiolate (480 mg, 4.9 mmoi) was added. The mixture was stirred at RT for i6hours, dilutedwith water and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vaeuo. The residue was purified by PrepHPLC to give the title compound (850 mg) as yellow oil. LRMS m/z (M-f-H) 221.1 found, 221 .1 required.
With potassium carbonate In N,N-dimethyl-formamide for 0.166667 h;
Compound 64.3. Ethyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate. Into a 250-mL three neck round-bottom flask, was placed a solution of l-amino-4-bromopyridin-l- ium iodide (compound 64.2, 15 g, -50percent purity, 24.9 mmol) in N.N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (1 1.7 mL, 1 15 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (300 mg, 6percent).
300 mg
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Compound 64.3. Ethyl 5-bromopyrazolo[l,5-]pyridine-3-carboxylate. Into a 250-mL three neck round-bottom flask, was placed a solution of l-amino-4-bromopyridin-l- ium iodide (compound 64.2, 15 g, -50percent purity, 24.9 mmol) in N,N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (11.7 mL, 115 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3 x 50 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (300 mg, 6percent).
Stage #1: With mesitylenesulfonylhydroxylamine In N,N-dimethyl-formamide at 0 - 40℃; for 16 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 6 h;
To a stirred solution of 4-bromopyridine (64.0 g, 40.5 mmol) in DME (200 mL) at 0 °0 was added O-(mesitylsulfonyl)hydroxylamine (80.0 g, 37.1 mmol) portion wise over a period of 20 mm. The resultant reaction mixture was allowed to warm to room temperature and maintained at 40°C for 16 h. The reaction mixture was cooled toO °0, diluted with DME (200 mL), K2003 (128 g, 92.7 mmol) followed by ethyl propiolate (43.07 mL, 42.5 mmol) were added and the resulting reaction mixture was stirred at rt for 6 h. The reaction mixture was poured on to ice-cold water, extracted with ethyl acetate (2 x 1000 mL). The ethyl acetate layer was washed with water, brine, dried over anhyd. Na2SO4 and concentrated. The crude compound was purified by column chromatography over silica gel (100—200 mesh) using a solvent gradient mixture of 7percent ethyl acetate in pet-ether to afford 3.5 g (3percent) of ethyl 5-bromopyrazolo[1 , 5-a]pyridine-3-carboxylate 94-1 as a light brown solid. ESI-LC/MS: m/z269.2 (M+H) & 271.2 [(M+2)+H]; R = 3.46 mm [Agilent [C with Ion trap Detector; Symmetry 018,3.5 pm, 4.6 X 75mm column; gradient of 50:50 H20 (0.1percent H000H): CH3CN (0.1percent H000H) to 10:90 H20 (0.1percent H000H):CH3CN (0.1percent H000H) in 4.0 mm and hold for 3.0 mm with flow rate of 1.0 mL/min].
With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and airdried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ‘H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75percent w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ‘H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer).
21 g
With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
Preparation of Ethyl 6-bromo-4-methoxypyrazolo|"l,5-a"|pyridine-3- carboxylate and Ethyl 4-bromo-6-methoxypyrazolo|"l,5-a"|pyridine-3-carboxylate. To a magnetically stirred white suspension of l-amino-3-bromo-5-methoxypyridin-l-ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4: 1 (by MR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75percent w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H MR (CDCh) δ 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer).
Reaction Step 1.Synthesis of ethyl 3-bromopropiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane Rf=0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30 C.) to afford an oil.
58%
Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2h at room temperature. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf = 0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25- 30 C) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10% diethyl ether in hexanes to afford ethyl 3- bromopropiolate (10.0 g, 58%) as a yellow oil. LCMS m/z = 176.91 (M+1).
58%
Reaction step 1. Synthesis of e propiolateSilver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2h at room temperature. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf = 0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25- 30 C) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10% diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58%) as a yellow oil. LCMS m/z = 176.91 (M+1).
58%
Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.0 g, 102 mmol, 1.0 eq) in acetone (200 mE) at room temperature. The resulting reaction mixture was stirred for 5 mm, then N135 (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 hr at room temperature. After completion of the reaction (monitored by TEC, 5% ethyl acetate-hexane, R1=0. 55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30 C.) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10% diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58%) as a yellow oil. ECMS mlz=176.91 (M+1).
58%
Reaction Step 1 Synthesis of ethyl 3-bromopropiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf=0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30 C.) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10% diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58%) as a yellow oil. LCMS m/z=176.91 (M+1).
With N-Bromosuccinimide; silver nitrate; In acetone; at 0 - 20℃;
To a solution of ethyl propionate (A-3) (26.3 g, 0.268 mol) and AgNCb (4.56 g, 26.8 mmol) in anhydrous acetone (300 mL) was added NBS (52.6 g, 0.295 mol) in several small portions at 0 C and stirred at room temperature overnight. The mixture was filtered. The filtrate was diluted with H2O (500 mL) and extracted with n-hexane (500 mL x 3). The combined extracts were washed with an aqueous HC1 solution (10%, 500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature (ESI) m/z: non- ionizable compound under routine conditions used; -NMK (CDCb, 400 MHz): d (ppm) 1.32 (t, J= 7.2 Hz, 3H), 4.25 (q, J= 7.2 Hz, 2H).
With N-Bromosuccinimide; silver nitrate; In acetone; at 20℃;
At room temperature, ethyl propionate (12.0 g, 122 mmol), NBS (26.2 g, 147 mmo) and AgNO3 (10.4 g, 61 mmol) were dissolved in acetone (400 mL) and stirred at room temperature overnight. After the reaction was monitored by TLC, the reaction was suction filtered, and the filtrate was concentrated to obtain the crude product 99-1, which was used in the next reaction without purification.
With potassium hydroxide; In ethanol; at 60 - 70℃; for 3h;
Step 3:[00342] To a hot (60 C) solution of <strong>[3599-89-1]propionamidine hydrochloride</strong> prepared instep 2 (54.3 g, O.Smol) and propynoic acid ethyl ester (53.9 g, 0.55 mol) in absolute alcohol (1L) was added dropwise a solution of KOH (70 g, 80%, 1 mol) in absolute alcohol (300 mL) during 3 hours. The temperature was kept between 60 C and 70 C during the addition. The solvent was removed in vacua and the residue was dissolved in water. The aqueous solution wasacidified to pH 5 with HC1 (6 M), extracted with ethyl acetate for at least 15 times. The organic layer was dried over NaaSCU and then filtered. The filtrate was evaporated under reduced pressure and the residue was recrystallized with acetonitrile to afford 2-ethyl-3H-pyrimidin-4-one as light yellow crystals (14 g, 23 %).[00343] 'H-NMRXCDCB) 5 8.00-7.98 (d, 1H, J = 6.8 Hz), 6.34-6.33 (d, 1H, J =6.8 Hz), 2.77-2.71 (q, 2H), 1.37-1.33 (t, 3H). MS (ESI) m/e (M+l) 125.2.
With potassium hydrogencarbonate; In ethanol; water; for 5.0h;
Dibromoformaldoxime (407 mg, 2.07 mmol) (prepared via the procedure of JC Rohloff, et. al., Tetrahedron Lett 1992, 33 : 3113-6), and ethyl propiolate (311 mg, 3.17 mmol) were dissolved in 10 ml of 50percent aqueous ETOH. While stirring, a solution of 243 mg (2.43 mmol) of potassium bicarbonate in 5 ml of water was added dropwise over 1 h. The resulting solution was stirred for an additional 4 h, diluted with 25 ml of water, and extracted with CHLOROFORM (3 x 25 ml). The combined organic extract was dried over sodium sulfate and concentrated in vacuo to a colourless oil, 345 mg (78percent yield) as a 7: 1 mixture of the 5-and 4- carboxylates. H NMR (CDC11. 34 (t, 3H, J = 7.16Hz), 4.30 4.37 (2q, 2H, J = 7.16 Hz), 6.92 8.81 (2s, IH, ratio 7: 1).
With acetic acid; lithium diisopropyl amide; In tetrahydrofuran; heptane-tetrahydrofuran-ethylbenzene; water;
(a-2) To a solution of ethyl propiolate (1.2 ml, 12.0 mmole) in tetrahydrofuran (20 ml) was added at -65 C. under the argon atmosphere a solution of 2.0M lithium diisopropylamide in a mixed solvent of heptane-tetrahydrofuran-ethylbenzene (6.0 ml, 12.0 mole), and the mixture was stirred for 20 minutes. A solution of <strong>[20357-22-6]4-methyl-2-nitrobenzaldehyde</strong> (1.65 g, 10 mmole) in tetrahydrofuran (10 ml) was added, and the reaction mixture was further stirred at 65 C. for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution (20 ml) or a solution of acetic acid (13.0 ml, 220 mmole) in tetrahydrofuran (20 ml), followed by water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate as an oil (2.60 g). 1 H-NMR (CDCl3): delta1.31 (1H, t), 2.46 (3H, s), 3.37 (1H, d), 4.24 (2H, q), 6.10 (1H, d), 7.51 (1H, dd), 7.78 (1H, d), 7.86 (1H, d). FDMS: m/z 264 (M+ +1).
With n-butyllithium; acetic acid; In tetrahydrofuran; hexane; water;
Starting from <strong>[20357-22-6]4-methyl-2-nitrobenzaldehyde</strong> and ethyl propiolate, ethyl 4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate was prepared with the following reagents instead of a solution of 1.56N butyllithium in hexane. (a-1) To a solution of ethyl propiolate (6.6 ml, 65 mmole) in tetrahydrofuran (70 ml) was added at -65 C. under the argon atmosphere a solution of 1.0M lithium bistrimethylsilylamide in tetrahydrofuran (65 ml, 65 mmole), and the mixture was stirred for 20 minutes. A solution of <strong>[20357-22-6]4-methyl-2-nitrobenzaldehyde</strong> (8.3 g, 50 mmole) in tetrahydrofuran (30 ml) was added, and the reaction mixture was further stirred at 65 C. for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution (80 ml) or a solution of acetic acid (13.0 ml, 220 mmole) in tetrahydrofuran (20 ml), followed by water, and the aqueous layer was extracted with ethyl acetate.
A solution of 2-methylfuran (6.56 g) in CH2 Cl2 (120 ml) was added, at about 20 C. to a mixture of ethyl propiolate (7.84 g) and anhydrous AlCl3 (10.64 g) in CH2 Cl2. The reaction mixture was allowed to stand at room temperature for 30 min with occasional shaking and was then shaken vigorously with cold water. The organic layer was extracted with 5% NaOH solution (3*10 ml), and the combined aqueous layer was acidified and extracted with ethyl acetate (3*20 ml). The combined organic layer was washed with water, brine-dried and partitioned with aqueous NaHCO3 (3*10 ml). The bicarbonate-soluble fraction, after reacidification and extraction with ether, gave 15a (1.9 g) as a colorless solid; mp 181-183 (lit 185) (McCulloch (1971), supra). 1 H NMR (CD3 OD):delta2.48 (s,3H), 6.88 (dd, J1 -3 Hz, J2 =8.2 Hz, 1H), 7.09 (d, J=8 Hz, 1H) and 7.36 (d, J=2.8 Hz, 1H).
With methanol; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; copper(l) chloride; sodium t-butanolate; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;
General procedure: CuCl (1.5 mg, 0.015 mmol), NaOt-Bu (2.9 mg, 0.03 mmol), and Xantphos ligand (8.7 mg, 0.015 mmol) were placed in an oven-dried Schlenk tube under nitrogen and THF (0.45 mL) were added. The reaction mixture was stirred for 30 min at room temperature and then bis(pinacolato)diboron (127 mg, 0.5 mmol) in THF (0.3 mL) was added. The reaction mixture was stirred for 10 min and alpha,beta-acetylenic ester 2 (0.5 mmol) was added, followed by MeOH (40 muL, 1 mmol). The reaction tube was washed with further THF (0.2 mL), sealed, and stirred until no starting material was detected by TLC. The reaction mixture was filtered through a pad of Celite and concentrated. The product was purified by silica gel chromatography.
Step 6. [4-amino-7-(beta-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-propynoic acid ethyl ester To a solution of the product from Step 5 (61 mg, 0.156 mmol) in DMF (2 mL) were added CuI (6 mg, 0.032 mmol) and TEA (45 muL, 0.323 mmol). The mixture was degassed with argon under sonication for 2-3 minutes and Pd(PPh3)4 (18 mg, 0.016 mmol) was added and the resulting mixture was heated at 55 C. for 15 min. Ethyl propiolate (4*5 muL, 0.197 mmol) was added to the reaction mixture at 55 C. in 30 minutes intervals. The crude mixture was concentrated and purified on silica gel with CH2Cl2/MeOH (100/1, 50/1, 25/1) as the eluents to afford 36 mg (64%) of the target compound. 1H NMR (Acetone-d6): delta 8.18 (s, 1H), 8.06 (s, 1H), 6.4 (br, 2H), 6.05 (d, 1H, J=6.2 Hz), 5.27 (br, 1H), 4.77 (m, 1H), 4.38 (m, 1H), 4.27 (q, 2H, J=7.1 Hz 1H), 3.79 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). MS: m/z=363.7 (M+1).
2,4-Dinitrophenylhydroxylamine (13.00 g, 65.3 mmol) was added to a 500 mL vial, dissolved in 200 mL of acetonitrile, and 4-methylpyridine (9.12 g, 97.9 mmol) was added at room temperature for 12 h at room temperature. The solution was spun dry, 200 mL of DMF and potassium carbonate (27.07 g, 195.9 mmol) were added, ethyl propiolate (9.60 g, 97.9 mmol) was added in one portion, and reacted at room temperature for 10 h. The reaction was completed by TLC, and 300 mL of water and EA, liquid separation, water layer was extracted with 300 mL of EA, and the organic phase was combined, washed with 300 mL of brine, dried over anhydrous sodium sulfate, filtered and evaporatedElution with PE/EA=20/1-10/1 gave 7.97 g of pale yellow solid, yield 59.8percent.
53%
General procedure: These were made using MSH or DNPH as detailed below, unless otherwise stated. A fresh solution of MSH23 in CH2Cl2 (1 equiv) was added to the substituted pyridine (1 equiv) in CH2Cl2 (10 mL) at 0 °C. After 2 h, the solvent was removed in vacuo. Alternatively, a solution of DNPH12 (1 equiv) and the substituted pyridine (1 equiv) in MeCN (40 mL) was heated at 40 °C for 18 h. The solvent was removed in vacuo. The method continues by taking the residue from either method in dry DMF (8 mL), and then ethyl propiolate (1 equiv) and K2CO3 (2 equiv) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient, unless otherwise stated) gave the pyrazolo[1,5-a]pyridine.
53%
Step 2.1 : A fresh solution of O-(mesitylsulfonyl)hydroxylamine in CH2CI2 (6.0 ml_, 0.44 mol L"1, 2.6 mmol) [T. Eichenberger et al., HeIv. Chim. Acta 1986, 69(6), 1521] was added to 4-methylpyridine (1: X = Me) (248 mg, 2.66 mmol) in CH2CI2 (10 mL) at 0 0C. After 2 h, the solvent was removed in vacuo. The residue was taken up in dry DMF (8 mL), then ethyl propiolate (0.25 mL, 2.5 mmol) and K2CO3 (450 mg, 3.26 mmol) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with hexanes: EtOAc 97:3 to 95:5 to 9:1) gave ethyl 5-methyl- pyrazolo[1 ,5-a]pyridine-3-carboxyIate (4: X = Me) as a pale brown solid (175 mg, 53percent). 1H NMR delta (400 MHz, CDCI3) 8.39 (d, J 7.1 Hz, 1 H)1 8.34 (s, 1H), 7.93 (s, 1H), 6.76 (dd, J 7.1 , 1.9 Hz, 1 H), 4.38 (q, J 7.1 Hz, 2H), 2.47 (s, 3H), 1.41 (t, J 7.1 Hz, 3H). LCMS (APCI+) 205 (MH+, 100percent).
On a Vapourtec R2+/R4 flow system equipped with three PTFA reactor coils (a 10 mL) and a 250 psi back pressure regulator, ethyl propiolate and trimethylsilyl azide were injected via 2 mL loops. The flow rate was set to 0.5 mL/min, with a residence time of 1.5 h. The system was heated to 140 °C. Injections were performed every 40 min. The solvent used was acetonitrile. The total mixture coming out of the reactor was collected. In total, 5 injections were performed. The mixture was collected, and acetonitrile removed in vacuo (the collector of the rotary evaporator was filled with sat. aq. NaHC03 to quench any potentially formed HN3). The remaining solid was dissolved in EtOAc, and the organic phase washed with brine (3x), dried over Na2S04, filtered, and evaporated. The crude product was stirred in a minimal amount of Et20, filtered, and dried, to give the title compound (8.65 g, 81percent) as a white solid. MS (ESI): m/z = 142.1 [M+H]+.
a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a) A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
94%
In tetrahydrofuran; at 20 - 30℃; for 4h;
A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
90%
In tetrahydrofuran; at 20 - 30℃; for 3h;
Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
90%
In hexane; at 20℃; for 3h;
Example 15.[00151] Example 15 presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6,7-dihydro-4H-pyrazolo[4',3':5,6]oxepino[4,3-d][1 ,3]thiazol-2-amine (Table II,Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
<strong>[144649-99-0]5-Bromo-2-methoxy-benzonitrile</strong> (25.00 mmol, 5.73 g) was dissolved in ethanol (35 mL) and treated with ethyl propiolate (28.75 mmol, 2.93 g). The reaction mixture was heated at 60° C. for 30 minutes and then treated with a solution of potassium hydroxide (28.75 mmol, 1.63 g) in ethanol (35 mL). The reaction mixture was then heated at reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and taken up in water 300 mL. The mixture was adjusted to pH 4 with conc hydrochloric acid and the resultant solid was filtered off and washed with water. The solid was transferred to a round bottom flask, suspended in toluene and evaporated to dryness twice to provide the title compound as an off white solid. Yield=4.4 g, 63percent. Analytical LCMS method 2, retention time 4.28 min, M+H=281. 1H NMR: (CDCl3) delta: 11.0 (br, s, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.61 (dd, 1H), 6.95 (d, 1H), 6.37 (d, 1H), 4.04 (s, 3H).
4-(3-chloro-phenyl)-2-(methoxy-methyl-amino)-4-oxo-but-2-enoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Intermediate 10.3: 4-{3-Chloro-phenyl)-2-{methoxy-methyl-amino)-4-oxo-but-2- enoic acid ethyl ester; To a solution of ethyl propiolate (1.0 ml, 10.0 mmol, 2.0 equiv.) in anhydrous THF (10 ml) was added LiHMDS (1M in THF, 10.0 ml, 10.0 mmol, 2.0 equiv.) dropwise at -78C (dry ice / acetone bath). The reaction mixture was stirred at -780C for 30 min before a solution of Intermediate 10.4 (1.0 g, 5.0 mmol, 1.0 equiv.) in anhydrous THF (5 ml) was added slowly. The resulting mixture was stirred at -78C for 10 min then allowed to warm to - 400C during 1 h and stirred at that temperature for additional 30 min. The reaction mixture was quenched by the addition of HCI 2M in water (5 ml), then diluted into Et2O (200 ml) and washed with water (2 x 80 ml). The organic layer was dried over Na2SO4, filtered and evaporated. The resulting residue was purified by Combi-Flash Companion (Isco Inc.) column chromatography (SiO2; gradient elution, heptane / AcOEt 95:5? 6:4) to yield the title compound as an orange oil. TLC: RF = 0.26 (heptane / AcOEt 7:3); LCMS: cW = 2.23 min; MS: m/z 298.0 [M+H]+ ; 1H NMR (400 MHz, CDCI3) delta 1.41 (t, J = 7.1 , 3H), 3.19 (s, 3H), 3.76 (s, 3H), 4.47 (q, J = 7.1 , 2H), 5.99 (s, 1H), 7.38 (m, 1 H), 7.48 (m, 1H), 7.79 (m, 1H), 7.89 (m, 1H).
Step-2: 2-(5-Ethoxycarbonyl-isoxazol-3-yl)-pyridine:To a mixture of pyridin-2-imidoyl chloride (15 gm), triethylamine (25 ml) in toluene (150 ml) was added ethyl propiolate (10 gm) stirred at 30C over a period of 0.5 h. The reaction was monitored by TLC. The reaction mixture was quenched with water (100 ml). The layers were separated. The organic layer was dried over sodium sulfate. It was evaporated under vacuum to provide a crude mass. Crude mass was purified by using silica gel column chromatography to provide title compound in 8.2 gm quantity (62%) as a liquid. The compound was characterized by proton NMR.H'-NM (CDCI3) delta: 1.39-1.42 (t, 3H), 4.41-4.46 (q, 2H), 7.34-7.37 (m, 1H), 7.55 (s, 1H), 7.78-7.82 (dt, 1H), 8.08-8.1 (d, 1H), 8.67-8.68 (d, 1H).
In neat (no solvent); at 100℃; for 0.25h;Microwave irradiation; Sealed tube;
General procedure: A mixture of benzotriazole 1 (0.06 g, 5 mmol) and methyl propiolate 2 (0.8 g, 1.0 ml, 0.01 mol) was made in a dried heavy wall Pyrex tube. The tube was sealed and then exposed to microwave oven. After 15 min irradiation at 200 W (100 °C) power, the mixture was cooled to room temperature. The residue of compounds was evaporated under air and reduced pressure. An off-white solid was afforded. The product 3 can be recrystallized from dried diethyl ether.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: Potassium carbonate (6.10 g, 44.14 mmol) was added to a stirred solution of 1- aminopyridinium iodide (6.57 g, 29.59 mmol) in anhydrous N,N-dimethylformamide (44 mL) at 0 00. Ethyl propiolate (3 mL, 29.7 mmol) was then added dropwise and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between water and chloroform. The organic phase was separated, washedwith water and brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (5.51 g, 96percent) as a red oil.LRMS (mlz): 191 (M+1).1H-NMR (300 MHz, 0D013): 1.4 (t, 3H), 4.4 (q, 2H), 7.0 (td, 1H), 7.4 (ddd, 1H), Obtained as a solid (54percent) from 1-amino-4-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (Preparation 2a) and ethyl propiolate following the experimental procedure as described in Preparation la followed by purification of the crude product by flash chromatography (hexanes/ethyl acetate).LRMS (mlz): 205 (M+1).1H-NMR (300 MHz, CDCI3): 1.38 -1.42 (t, 3H), 2.46 (s, 3H), 4.34 -4.40 (q, 2H),6.75 - 6.77 (d, 1 H), 7.92 (s, 1 H), 8.33 (s, 1 H), 8.37 - 8.39 (d, 1 H).
General procedure: To a 10 mL Schlenk charged with CF3CH2NH2·HCl (82 mg, 0.6 mmol) and NaNO2 (42 mg, 0.6 mmol) was added 1.0 mL of toluene and 50 muL of distilled H2O, and the resultant mixture was stirred at 0 oC for 0.5 h. Then, the alkyne 1 (0.2 mmol, 1.0 equiv.) was added to the in situ prepared CF3CHN2 solution, and the resulting mixture was stirred vigorously at room temperature for 0.5 to 1.0 h. After completion of the reaction, the mixture was quenched with distilled water (10 mL), and ethyl acetate (10 mL) was added, and filtered. The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried anhydrous Mg2SO4 and then concentrated in vacuo. The pure product was obtained by flash column chromatography on silica gel with hexane/ethyl acetate (15/1 to 10/1, v/v) to afford the 3-trifluoromethylpyrazole 2.
1-amino-3-bromo-5-methoxypyridin-1-ium 2.4.6-trimethylbenzenesulfonate[ No CAS ]
[ 623-47-2 ]
[ 1207557-36-5 ]
4-bromo-6- methoxypyrazolo[1,5-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and airdried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer).Independently the original aqueous reaction mixture filtrate was extracted with EtOAc(2 x 500 mL). The combined organic extracts were dried (Na2504), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[ 1,5 -a]pyridine (Intermediate P1) as white solid (upperRf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2) also as white solid (lower Rf spot,1.32 g). MS (apci) mlz = 226.9, 228.9 (M+H). ?HNIVIR (CDC13) 8.02 (m, 1H), 7.85 (d, 1H),7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and air- dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer; The i someric mixture of ethyl 6-bromo-4- methoxypyrazolo[ 1,5 -a]pyridine-3 -carboxyl ate and ethyl 4-bromo-4-methoxypyrazolo[ 1,5 - a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80 C for 90 mm followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2504, filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine as a beige solid (about 98:2 6-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H). ?H NMR (CDC13) 8.26 (m, 1H),7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently the original aqueous reactionmixture filtrate was extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo- 4-methoxypyrazolo[1,5-a]pyridine (Intermediate P1) as white solid (upperRf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[ 1, 5-a]pyridine (Intermediate P2) also as white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). ?H NMR (CDC13) 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
Preparation of 6-bromo-4-methoxypyrazolorL5-a1pyridine (PI) and 4- bromo-6-methoxypyrazolo[L5-alpyridine. The isomeric mixture of ethyl 6-bromo-4- methoxypyrazolo[l,5-a]pyridine-3-carboxylate and ethyl 4-bromo-4-methoxypyrazolo[l,5- a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80 C for 90 min followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2S04, filtered and concentrated in vacuo to yield 6-bromo-4- methoxypyrazolo[l,5-a]pyridine as a beige solid (about 98:2 6-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H). NMR (CDCh) delta 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently the original aqueous reaction mixture filtrate was extracted with EtOAc. The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50%) EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[l,5- a]pyridine (Intermediate PI) as white solid (upper Ri spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[l,5-a]pyridine (Intermediate P2) also as white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). NMR (CDCh) delta 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium-2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H NMR (CDCl3) delta 3.98 (6-Br isomer) vs.3.83 (4-Br isomer). The isomeric mixture of ethyl-6-bromo-4- methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl-4-bromo-6-methoxypyrazolo[1,5- a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80C for 90 min, followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine as a beige solid (about 98:2 6-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H). 1H NMR (CDCl3): delta 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently, the original aqueous reaction mixture filtrate was extracted with EtOAc (2 × 500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo- 4-methoxypyrazolo[1,5-a]pyridine (Intermediate 1) as a white solid (upper Rf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine also as a white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H).1H NMR (CDCl3): delta 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
1.32 g
To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air- dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H NMR (CDCl3) delta 3.98 (6-Br isomer) vs.3.83 (4-Br isomer).; The isomeric mixture of ethyl 6-bromo-4- methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 4-bromo-4-methoxypyrazolo[1,5- a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80C for 90 min followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate A1) as a beige solid (about 98:26-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H).1H NMR (CDCl3) delta 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). (1120) [00593] Independently the original aqueous reaction mixture filtrate was extracted with EtOAc (2 × 500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate A1) as white solid (upper Rf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate A2) also as white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). 1H NMR (CDCl3) delta 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
2.06 g; 1.32 g
To a magnetically stirred white suspension of1 -amino-3-bromo-5-methoxypyridin-1 -ium 2,4,6-trimethyl- benzenesulfonate (2a) (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). Afier vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with compound 3a as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in the next step without further purification. MS (apci) mlz=298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) oe 3.98 (3a) vs. 3.83 (4a).The isomeric mixture of ethyl-6-bromo-4- methoxypyrazolo[1 ,S-a]pyridine-3-carboxylate (3a) and ethyl-4-bromo-4-methoxypyrazolo[1 ,5-a]pyridine-3-car- boxylate (4a) described above (15 g, 50.1 mmol) was added to 48% HEr (114 mE) while stirring, tben beated at 80 C. for 90 mm, followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTEE and vacuum filtered to remove insoluble impurities. The MTEE filtrate was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 6-bromo-4- methoxypyrazolo[1 ,5-a]pyridine (5A) as a beige solid (about 98:2 6-14-Br; 5.08 g). MS (apci) mlz=226.9, 228.9 (M+H). ?H NMR (CDC13): oe 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently, the original aqueous reaction mixture filtrate was extracted with EtOAc (2x500 mE). The combined organic extracts were dried (Na2504), filtered, and concentrated in vacuo. The crude residue was taken up in DCM (50 mE) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[ 1 ,5-a]pyridine (5A) as white solid (upper Rf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1 ,5-a]pyridine (SC), also as white solid (lower Rf spot, 1.32 g). MS (apci) mlz=226.9, 228.9 (M+H). ?H NMR (CDC13) oe 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
ethyl 6-chloro-4-(2-fluorophenyl)quinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With tert-butylammonium hexafluorophosphate(V); calcium(II) trifluoromethanesulfonate; In neat (no solvent); at 110℃; for 2.5h;Green chemistry;
General procedure: A mixture of suitable 2-amino benzophenone (1.0 mmol) and ethyl propiolate 2a (1.2 mmol) was heated at 110 oC in the presence of Ca(OTf)2/Bu4NPF6 (10/10 mol%) for 3h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with EtOAc thrice; the combined organic layers were washed with brine solution and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the desired product 3a in 76% yield.
ethyl 3-(5-bromopyrazin-2-yl)prop-2-ynoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); triethylamine; zinc dibromide; In 1,4-dioxane; at 80℃; for 0.166667h;
Into a 20-L 4-necked round-bottom flask was placed a solution of TEA (682.5 g, 6.74 mol) in 1, 4-dioxane (8.5 L) , dibromozinc (374.5 g, 1.69 mol) , tetrakis (triphenylphosphane) palladium (82.5 g, 71.39 mmol) , ethyl prop-2-ynoate (345 g, 3.52 mol) , and a solution of <strong>[622392-04-5]2-bromo-5-iodopyrazine</strong> (400 g, 1.40 mol) in 1, 4-Dioxane (500 mL) . The resulting mixture was stirred for 10 min at 80 C, then diluted with 30 L of water/ice, and extracted with 2 x 10 L of ethyl acetate. The combined organic layers were dried in an oven under reduced pressure and concentrated under vacuum. The resulting residue was purified on a silica gel column with ethyl acetate/petroleum ether (1: 30) to provide the title compound.
With hydrazine hydrate; In methanol;Cooling with ice;
Under the ice bath,Hydrazine hydrate in a 100 mL single-mouth bottle(0.75 mL, 15 mmol) A solution of ethyl propiolate (1.5 mL, 15 mmol) in methanol (15 mL).TLC detection, the raw material reaction is complete, spin dry methanol,A yellow viscous liquid was obtained and the next step was taken directly.
With sodium ethanolate; In ethanol; at 22℃; for 13.5h;Inert atmosphere;
In a 25 mL three-necked flask, equipped with a bubble counter, a rubber septum and a thermometer, was dissolved under nitrogen 1.0 g (98 % purity, 5.46 mmol, 1.0 eq) of ethyl 3-amino-4,4,4-trifluoro-crotonate in 4.0 mL of sodium ethoxide (21 w% in ethanol) at 22 C. Afterwards 0.83 mL (99% purity, 8.19 mmol, 1.5 eq) of ethyl propiolate was dosed over 1.5 h at 22 C. The dark red solution was stirred for 12 h at this temperature until a HPLC measurement indicated complete conversion of starting materials. The reaction solution was then treated with aqueous HC1 (20 w%) until pH 4 was reached, which led to product precipitation. The solid was filtered, washed with -heptane / ethyl acetate 80:20 (v/v) and dried in vacuum at 22 C to leave 550 mg (99% purity, 2.34 mmol, 43% yield) of a white solid. 1 H-NMR (400 MHz; DMSO-d6) d = 8.02 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.28 (q, J = 8.0 Hz, 2H), 1.28 (t, J = 8.0 Hz, 3H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
