* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In methanol at 5 - 95℃; for 2.15 - 5 h;
Example 2: At 5 °C, a solution of MAA (46.9 g 0.40 mol) in MeOH (144.0 g) was treated with EO (25.0 g, 1.4 eq.) and then with triethylamine (TEA, 40.7 g, 1.0 eq.). The reaction mixture was heated to 60 °C within 0.5 h and kept at this temperature for 2.5 h. Quantitative GC analysis indicated that 50.8percent of MAA had been transformed into ABL with a selectivity of 72.9percent. Example 4: At 5 °C, a solution of MAA (47.0 g, 0.40 mol) in MeOH (144 g) was treated with EO (35.3 g, 2.0 eq.) and then with triethylamine (TEA) (42.4 g, 1.0 eq.). The reaction mixture was heated to 60 °C within 0.5 h and kept at this temperature for 4.5 h. Quantitative GC analysis indicated that 67.7percent of MAA had been transformed into ABL with a selectivity of 75.0percent. Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1. Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent. Example 28: Example of best mode of a series of reactions with TEA as compound of formula IV: 37 g MeOH were placed in a 250 mL autoclave, pressurized with 2-3 bar nitrogen gas and heated. After reaching 65 °C solution of MMA (39.9 g, 0.34 mol, 1 eq.) and TEA (34.4 g, 0.34 mol, 1 eq.) in methanol (27. g) and EO (30.1 g, 0.68 mol, 2 eq.) were simultaneously fed using two pumps within 11 min. After 2 h additional reaction time ABL was formed (GC analysis) with a selectivity of 77percent, corresponding to 52.3percent based on added MMA. Covered ranges in the series, carried out analogously: Temperature: 65 to 95 °CAddition time: 9 to 13 min.MMA added based on totally added solvent: 1.3 to 2.1 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.7 to 1.3EO/MMA molar ratio added to the reaction mixture: 1.7 to 2.2 Results within the series of Example 28: MMA conversion: 65.6 to 85.0percentSelectivity of ABL formation: 47.5 to 77.4percentABL yield based on MAA: 40.4 to 52.3percent
30.8%
With N,N,N',N'-tetramethylguanidine In methanol at 5 - 65℃; for 1.15 - 6.18333 h;
Example 1: At 5 °C, a solution of methyl acetoacetate (MAA, 46.7 g, 0.40 mol) in methanol (MeOH, 144.0 g) was treated with ethylene oxide (EO, 17.5 g, 1.0 eq.) and then with 1,1,3,3-tetramethylguanidine (TMG, 46.1 g, 1.0 eq.). The reaction mixture was heated to 40 °C within 0.5 h and kept at this temperature for 4.5 h. Quantitative GC analysis indicated that 53.7percent of MAA had been transformed into α-acetylbutyrolactone (ABL) with a selectivity of 75.2percent. Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1.Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent. Example 29: Example of best mode of a series of reactions with TMG as compound of formula IV: 37 g MeOH were placed in a 250 mL autoclave, pressurized with 2-3 bar nitrogen gas and heated. After reaching 45 °C solution of MMA (35.2 g, 0.30 mol, 1 eq.) and TMG (41.5 g, 0.36 mol, 1.2 eq.) in methanol (27. g) and EO (16.3 g, 0.37 mol, 1.2 eq.) were simultaneously fed using two pumps within 10 min. After 6 h additional reaction time ABL was formed (GC analysis) with a selectivity of 60.4percent, corresponding to 46.0percent total yield based on added MMA. Covered ranges in the series, carried out analogously: Temperature: 45 to 65 °CAddition time: 9 to 11 min.MMA added based on totally added solvent: 1.5 to 1.9 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.8 to 1.2EO/MMA molar ratio added to the reaction mixture: 0.8 to 1.2 Results within the series of Example 29: MMA conversion: 39.5 to 65.0percentSelectivity of ABL formation: 63.8 to 81.2percentABL yield based on MAA: 30.8 to 46.0percent
30.3%
With trimethylamine In methanol at 60 - 90℃; for 1.3 - 4 h;
Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1. Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent. Example 30: Example of best mode of a series of reactions with TMA as compound of formula IV using a microreactor: A solution A was prepared consisting of MMA (44.6 g, 0.384 mol, 1.0 eq.), TMA (16.8 g, 0.284 mol, 0.74 eq.) and MeOH (81.3 g). 30.6 g/h EO (0.695 mol/h, 1.495 eq.) and 172.8 g/h of solution A (0.465 mol/h MMA) were simultaneously fed using two pumps to a microreactor adjusted to 90 °C, said microreactor having 9.8 mL internal volume, and is acting as mixing and reaction zone. The residence time of the reaction mixture in the microreactor under the current flows was about 2.5 min. After passing through the microreactor the reaction mixture was collected in an autoclave, containing 250 mL MeOH at 60 °C and 2-3 bar under nitrogen gas. After about 1.3 h additional reaction time in the autoclave ABL was formed (GC analysis) with a selectivity of 74.8percent, corresponding to a total yield of 34.8percent based on added MMA, or yield of 61.9percent based on added TMA. 46.6percent MMA has been converted to ABL. Covered ranges in the series, carried out analogously: Temperature of the microreactor: 73 to 107 °CTemperature of the autoclave: 43 to 77 °CDosage rate Solution A: 48.7 to 172 g/hDosage rate EO: 8.6 to 30.6 g/hMMA added based solvent injected to the microreactor: 1.9 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.75EO/MMA molar ratio added to the reaction mixture: 1.5 Results within the series of Example 30: MMA conversion: 38.7 to 66.3percentSelectivity of ABL formation: 50.5 to 78.3percentABL yield based on MAA: 30.3 to 39.7percent
(1) The reactor slow heating to 75 °C, adding γ - butyrolactone, ethyl acetate and sodium ethoxide, reflux reaction 10 h after, shall be α - acetyl - γ - butyrolactone sodium salt and the by-product ethanol, wherein γ - butyrolactone and ethyl acetate increase mole ratio of 1:4, γ - butyrolactone and sodium ethoxide in a molar ratio of 1: 1.4;(2) Step (1) the resultant product distillation, to remove the excess of ethanol and ethyl acetate, the residue is dissolved in dilute sulfuric acid to adjust the pH to 4, standing minute fluid minute to the aqueous phase, the organic phase in the pressure is -0.1 mpa, temperature is 70 °C under the condition of reduced pressure distillation shall be α - acetyl γ - butyrolactone.
83%
Stage #1: at 50 - 100℃; for 5 h; Autoclave Stage #2: at -5 - 5℃; for 5 h;
100 g of ethyl acetate was added to a 500 ml reaction flask, and after warming to 50 ° C, 80 g of solid sodium methoxide was added simultaneously.The mixture was mixed with 86 g of ethyl acetate and 100 g of γ-butyrolactone, and the temperature of the system was maintained at 50 ° C, and the addition was completed within 2 hours. After the addition of the material, stirring was continued rapidly for 1 h at 60 °C. Discharge, the above liquid material is added to a 500ml autoclave, high pressure reaction at 100 ° C for 2h, the pressure gauge shows a small pressure, the pressure range is 0.1-1MPa, the reaction is completed, cooling, discharge, using 20g ethyl acetate wash reaction The kettle and the washing liquid were combined into the reaction liquid and used. The above materials were transferred to a 500 ml reaction flask, distilled under reduced pressure at 60 ° C (vacuum degree 0.09 MPa - 0.1 MPa), and concentrated to near dryness. The precipitated solid was a solid of α-acetyl-γ-butyrolactone sodium salt.The material was washed with 280 ml of ethyl acetate in a solid of α-acetyl-γ-butyrolactone sodium salt, filtered, and washed twice.Adding 260 ml of ethyl acetate to the above α-acetyl-γ-butyrolactone sodium salt solid.Cooling, temperature control at -5-5 °C, withThe 70percent ethyl acetate solution was adjusted to pH 6-7, stirred for 5 hours, filtered, and the filter cake was washed with 20 ml of ethyl acetate. The filtrate was transferred to a 500 ml single-mouth bottle and distilled under reduced pressure at 70 ° C (vacuum degree 0.09 MPa - 0.1 MPa). After the low-boiling substance was distilled, the concentrated liquid in the bottle was further heated to 95 ° C under reduced pressure (vacuum degree). ≤ 50 Pa), 104.7 g of α-acetyl-γ-butyrolactone was obtained, and the purity was 98.7percent, and the yield was 83.0percent by gas chromatography.
Reference：
[1] Patent: CN107857745, 2018, A, . Location in patent: Paragraph 0022-0047
[2] Patent: CN108129423, 2018, A, . Location in patent: Paragraph 0019-0021
[3] Chemical Papers, 2013, vol. 67, # 6, p. 624 - 630
3
[ 75-21-8 ]
[ 141-97-9 ]
[ 517-23-7 ]
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[1] Australian Journal of Chemistry, 1993, vol. 46, # 11, p. 1657 - 1672
[2] Patent: US5183908, 1993, A,
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 20, p. 4601 - 4602
8
[ 75-21-8 ]
[ 1007476-32-5 ]
[ 517-23-7 ]
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[1] Yakugaku Zasshi, 1942, vol. 62, p. 417,443;dtsch.Ref.S.122,125[2] Chem.Abstr., 1951, p. 4724
[3] Helvetica Chimica Acta, 1952, vol. 35, p. 2401,2405
[4] Doklady Akademii Nauk SSSR, 1934, p. I 314[5] Chem. Zentralbl., 1934, vol. 105, # II, p. 2381
9
[ 64620-59-3 ]
[ 517-23-7 ]
[ 62-53-3 ]
Reference：
[1] Journal of Pharmaceutical Sciences, 1990, vol. 79, # 2, p. 138 - 146
10
[ 64-17-5 ]
[ 1007476-32-5 ]
[ 107-07-3 ]
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Reference：
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To a solution of sodium (55.6 g, 2.4 mol) in ethanol (1000 ml) was added slowly 2-acetylbutyrolactone 155 g, 1.2 mol) after which thiourea (128 g, 1.65 mol) was added in small portions. The mixture was heated under reflux for 16 h, then concentrated, water (800 ml) was added and acidified slowly with concentrated hydrochloric acid (200 ml). The precipitate was collected and washed with water, isopropyl alcohol and petroleum ether. Yield 125 g (56%) of a white solid.
With hydrogenchloride at 70 - 80℃; for 1.5h; Reflux;
1.1; 2.1; 3.1; 4.1; 5.1; 6-12 Example 4
(1) To a 1000 ml four-necked flask equipped with a mechanical stirrer, a thermometer, and a reflux trap, 608 g (3.0 mol) of hydrochloric acid having a mass concentration of 18% was added, and the mixture was stirred and added dropwise to the α-acetyl-γ-butane. The ester was 128.5 g (1.0 mol), the reaction temperature was controlled at 70-80 ° C, and the reaction was carried out for 1.5 h, and then the temperature was raised and subjected to distillation treatment. The water and 5-chloro-2-pentanone were azeotropically distilled off, and the water was refluxed to the reaction flask.Obtained 116.5 g of 5-chloro-2-pentanone, and the content of gas chromatographic analysis was 96.24%.The molar yield was 93.02%;
70%
With hydrogenchloride; Sodium hydrogenocarbonate; sodium chloride In hexane; lithium hydroxide monohydrate at 110 - 115℃; for 10h; Large scale;
70%
With hydrogenchloride In lithium hydroxide monohydrate for 10h; Reflux;
64%
With hydrogenchloride In lithium hydroxide monohydrate at 100℃; for 0.166667h;
2.2.2. Preparation of 5-chloro-2-pentanone
A mixture of 12 ml conc. HCl, 14 ml H 2 O, and 10 g (78.13 mmol) -acetyl- -butyrolactone were placed in a two necked distilling flask equipped with a condenser and the receiver was immersed in an ice-bath. The entire reaction vessel was quickly immersed into the oil bath preheated at 100 °C. After about 10 min the color was changed from yellow to orange and then to black. After 20 ml of distillate have been collected, 7 ml H 2 O was added to the distill- ing flask and another 5 ml of distillate was collected. Afterwards, the yellow organic layer was separated and the aqueous layer was extracted with dichloromethane and dried over Na 2 SO 4 , and the solvent was evaporated. An amount of 6 g 5-chloro-2-pentanone was obtained as yellow, viscous oil in 64 % yield [43] .
2-(1,1-dioxido-1,2-benzisothiazol-3(2H)-ylidene)-1-(dihydro-2-oxo-2(3H)-furan-3-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: 3-acetyl-2-oxo-4,5-dihydrofuran; methyl 2-(aminosulfonyl)benzoate With N,N,N,N,-tetramethylethylenediamine; lithium diisopropyl amide In tetrahydrofuran at 0℃; for 3.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran
With calcium hydroxide; In ethanol; water; at 20℃; for 48h;
To a solution of O-methylisourea hydrogen sulfate (17.2 g, 0.1 mol) in water (90 ml) was added calcium hydroxide (8.14 g, 0.11 mol) followed by a solution of 2-acetylbutyrolactone (10.7 ml, 0.1 mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vaccuum and purified by flash chromatografy (dichloromethane/methanol=95/5). Yield 2.6 g (14%) of a white solid.
3-[1-[[3-[[dimethyl(1,1-dimethylethyl)silyloxy]methyl]-2-pyridinyl]amino]ethylidene]dihydro-2(3H)-furanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.1 parts (68.1%)
In ethanol; hexane;
b) A mixture of 5.5 parts of intermediate (1), 4.93 parts of dihydro-3-(1-oxoethyl)-2(3H)-furanone, a pinch of 4-methylbenzenesulfonic acid and 34.4 parts of a mixture of xylenes was stirred for 18 hours at reflux temperature using a water separator. After cooling, there were added 26.1 parts of methylbenzene. The whole was washed successively with water, sodium hydrogen sulfite and NaCl (sat.), and was then dried, filtered and evaporated. The residue was stirred in hexane. The solvent was decanted and, after cooling in a mixture of ethanol and dry ice, the precipitate was filtered off and dried, yielding 6.1 parts (68.1%) of 3-[1-[[3-[[dimethyl(1,1-dimethylethyl)silyloxy]methyl]-2-pyridinyl]amino]ethylidene]dihydro-2(3H)-furanone (interm. 2).
3-(2-chloroethyl)-7-methoxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10 parts (30.4%)
With ammonium hydroxide; trichlorophosphate; In hexane; ethyl acetate;
a) A mixture of 17 parts of 5-methoxy-2-pyridinamine, 61 parts of phosphoryl chloride and 348 parts of methylbenzene was stirred for 2 hours at 60° C. 18 Parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added and the reaction mixture was stirred overnight at 90° C. The whole was poured into crushed ice and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in a mixture of hexane and ethyl acetate (50:50 by volume). The precipitated product was filtered off and dried, yielding 10 parts (30.4percent) of 3-(2-chloroethyl)-7-methoxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one; mp. 150° C. (intermediate 3)
With thionyl chloride; sulfuric acid; magnesium; In tetrachloromethane; ethanol; toluene;
(A) A mixture of 8.0 g of magnesium turnings, 33 g of anhydrous ethanol and 3 ml of carbon tetrachloride was allowed to react on standing for several minutes. After the exothermic reaction had subsided, 250 ml of anhydrous toluene was slowly added under stirring, and the reaction mixture was stirred at 30-35 C for an additional 3 hours. To the resulting suspension of magnesium ethoxide, a solution of 84.6 g of alpha-acetyl-gamma-butyrolactone in 100 ml of anhydrous toluene was added dropwise under cooling at 0-5 C. After the resulting mixture was stirred at room temperature for one hour, crude 4-fluoro-2-nitrobenzoyl chloride, prepared from 55.5 g of <strong>[394-01-4]4-fluoro-2-nitrobenzoic acid</strong> and 170 ml of thionyl chloride, in 100 ml of anhydrous toluene was added dropwise at 20-25 C and stirred for an additional 3 hours. After 700 ml of 5% sulfuric acid was added to the resulting mixture under cooling with an ice-salt bath, the organic layer was separated, and the aqueous layer was extracted with portions of toluene. The resulting organic layer contained alpha-acetyl-alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone as the main product. The combined organic layer was washed with water and aqueous saturated sodium chloride solution and extracted with three portions of cold 5% aqueous ammonium hydroxide solution.
With boron trifluoride diethyl etherate In isopropyl methanesulfonate at 20℃; for 72.25h;
1
Example 1. (R)-5-Methyl-8-[2,2,2-trifluoro-l-phenylethyl]-7,8-dihydro-6H- pyrrolo [3,2e] [l,2,4]-triazolo[l,5-a]pyrimidine [Compound 1].(A) Intermediate (A) may be synthesised by the method of Y. Sato et al., J. Med. Chem. (1980) 23, 927-937 .6- (2-Hydroxyethyl)-5-methyl[l,2,4] triazolo [l,5- ]pyrimidin-7(4H)-oneA mixture of 3-aminotriazole (350g, 4.1mol) and -acetyl-y-butyrolactone (524.8g, 4.1mol) was stirred in IMS (2.8L) and BF .Et20 (85mL, 0.6mol) added over 15 min. After 3 days stilling at ambient temperature the solid was collected by filtration and dried on the filter. 1H NMR (d6-DMSO) δ 13.6 (1H, br), 10.37 (1H, s), 8.40 (1H, s), 4.30 (2H, t), 2.88 (2H, t) and 2.50 (3H, s).
With boron trifluoride diethyl etherate In isopropyl methanesulfonate at 20℃; for 72.25h;
1
Synthetic Example(S)-8-[l-(4-Fluorophenyl)ethyl]-5-methyl-7,8-dihydro-6H-pyrrolo [3,2] [1,2,4] triazolo[l,5-a]pyrimidine [Compound 1](A)Intermediate (A) may be synthesised by the method of Y. Sato et al., J. Med. Chem. (1980) 23, 927-937 .1. 6-(2-Hydroxyethyl)-5-methyl[l,2,4] triazolo [l,5-a]pyrimidin-7(4H)-oneA mixture of 3-aminotriazole (350g, 4.1mol) and a-acetyl-y-butyrolactone (524.8g, 4.1mol) was stirred in IMS (2.8L) and BF3.Et20 (85mL, 0.6mol) added over 15 min. After 3 days stirring at ambient temperature the solid was collected by filtration and dried on the filter. 1H NMR (d6-DMSO) δ 13.6 (1H, br), 10.37 (1H, s), 8.40 (1H, s), 4.30 (2H, t), 2.88 (2H, t) and 2.50 (3H, s).
With hydrogenchloride; hydrogen; trichlorophosphate; In cyclohexane; acetic acid; toluene;
Example-1 Preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. (formula-7) To a solution of 2-Amino-3-benzyloxypyridine (formula-2) (20 grams) in toluene (40 ml) added 2-acetyl gammabutyro lactone (formula-3) (16.6 grams), stirred for 15 min and added phosphorus oxychloride (0.27 ml). The reaction mixture was refluxed for 12 hours and water was removed azeotropically. Then the reaction mixture was cooled to 70-80 C., added phosphorus oxychloride (11.9 ml) and then heated to 90-95 C. and stirred for 8 hr. The solvent was distilled off under reduced pressure and concentrated hydrochloric acid (70 ml) was added to the reaction mixture followed by toluene (100 ml) and stirred at 65-70 C. for 9 hours. The reaction mixture was cooled to 0-5 C. and the solid formed was filtered, washed with toluene and acetic acid. The wet solid was taken in autoclave along with acetic acid (110 ml), added Pd/C and applied 3.0-3.5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 50-60 C., stirred for 8 hrs, then cooled to 25 C. and quenched with water. The reaction mixture was filtered and the pH of the filtrate was adjusted to 11 using aqueous sodium hydroxide solution. Extracted the reaction mixture with ethyl acetate. The ethyl acetate layer was treated with basic carbon, filtered and distilled off under reduced pressure. The solid formed was taken in cyclohexane (45 ml) and stirred for 60 min at 25 C. The solid was filtered, washed with cyclohexane and dried to provide the title compound. Yield: 11.0 grams.
With toluene-4-sulfonic acid In ethanol Reflux; regioselective reaction;
4.4. General procedure for the synthesis of 6-(2-hydroxyethyl)-5-methyl-2-substituted-pyrazolo[1,5-a]pyrimidin-7(4H)-one 20 and/or (3Z)-3-{1-[(5-substituted-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuranone 19
General procedure: A mixture of 3-substituted-5-amino-1H-pyrazoles 1a-h (1 mmol), 2-acetylbutyrolactone 18 (1 mmol) and 4-toluensulfonic acid (∼0.01 mmol) in ethanol (15 mL) was heated under reflux with magnetic stirring until TLC showed the absence of the starting material (18-24 h). After the reaction mixture was cooled down to room temperature, the solvent was removed under reduced pressure, and the resulting solid was purified by recrystallization from DMF to give compounds 19 and/or 20 (see Scheme 4).
General procedure: A mixture of 3-substituted-5-amino-1H-pyrazoles 1a-h (1 mmol), 2-acetylbutyrolactone 18 (1 mmol) and 4-toluensulfonic acid (∼0.01 mmol) in ethanol (15 mL) was heated under reflux with magnetic stirring until TLC showed the absence of the starting material (18-24 h). After the reaction mixture was cooled down to room temperature, the solvent was removed under reduced pressure, and the resulting solid was purified by recrystallization from DMF to give compounds 19 and/or 20 (see Scheme 4).
General procedure: A mixture of 3-substituted-5-amino-1H-pyrazoles 1a-h (1 mmol), 2-acetylbutyrolactone 18 (1 mmol) and 4-toluensulfonic acid (∼0.01 mmol) in ethanol (15 mL) was heated under reflux with magnetic stirring until TLC showed the absence of the starting material (18-24 h). After the reaction mixture was cooled down to room temperature, the solvent was removed under reduced pressure, and the resulting solid was purified by recrystallization from DMF to give compounds 19 and/or 20 (see Scheme 4).
With toluene-4-sulfonic acid In ethanol Reflux; regioselective reaction;
4.4. General procedure for the synthesis of 6-(2-hydroxyethyl)-5-methyl-2-substituted-pyrazolo[1,5-a]pyrimidin-7(4H)-one 20 and/or (3Z)-3-{1-[(5-substituted-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuranone 19
General procedure: A mixture of 3-substituted-5-amino-1H-pyrazoles 1a-h (1 mmol), 2-acetylbutyrolactone 18 (1 mmol) and 4-toluensulfonic acid (∼0.01 mmol) in ethanol (15 mL) was heated under reflux with magnetic stirring until TLC showed the absence of the starting material (18-24 h). After the reaction mixture was cooled down to room temperature, the solvent was removed under reduced pressure, and the resulting solid was purified by recrystallization from DMF to give compounds 19 and/or 20 (see Scheme 4).
15 6.1.1.3 Procedure P3 (18, 20)
General procedure: To a solution of 3-acetyl-dihydrofuran-2(3H)-one (1 equiv) in toluene, an appropriate amine (1 equiv) was added. The mixture was refluxed and the water azeotropically removed (Dean-Stark apparatus). The solvent was evaporated and a solid residue was recrystallized from i-PrOH.
[Cu(2-acetylbutyrolactonate)(N,N,N',N'-tetramethylethylenediamine)]ClO4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.7%
General procedure: To an ethanolic solution of 5 mmol of an appropriate CuX2.nH2O (X = ClO4-1 or NO3-1), a solution of HAcBL ligand in 20 mL ethanol was added dropwise with a continuous stirring, meanwhile 10 mmol of anhydrous Na2CO3 was added in small portions. The mixture was continuously stirred for about 30 min. until a greenish solution was obtained and then filtered. A solution of 5 mmol of the secondary diamine or diimine ligand (L) in 10 mL EtOH was added dropwise to the filtrate with continues stirring for an additional half an hour. Either, a solution or a precipitate that filtered off and left to stand overnight. The chelates obtained were re-crystallized from CH2Cl2 solvent and stored in a desiccator over CaCl2.
(±)-3-acetyl-3-(pent-4-yn-1-yl)dihydrofuran-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: 3-acetyl-2-oxo-4,5-dihydrofuran With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;
Stage #2: 5-iodopent-1-yne In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil
6-chloro-3-(2-chloroethyl)-2-methyl-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate at 120℃; for 1.5h;
3.3A.3A.8
To a mixture of 6-chloro-4-(trifluoromethyl)pyridin-2-amine (2, 2.2 g, 1.0 mmol) in phosphorous oxychloride (5 mL), 3-acetyldihydrofuran-2(3H)-one (2a, 0.256 g, 2.0 mmol) is added at room temperature followed by heating and stirring at 20 °C for 1.5 h. After completion, the reaction mixture is poured into crushed ice & extracted with ethyl acetate. Organic layer is dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to afford 6-chloro-3-(2-chloroethyl)-2-methyl-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3).
6-(2-chloroethyl)-7-methyl-2-phenyl-5H-[1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With trichlorophosphate for 2h; Reflux;
4.1.1 General procedure for the synthesis of compound (2a-c)
General procedure: A mixture of compounds 1a, 1b or 1c (0.05mol), 2-acetylbutyrolactone (0.05mol) and POCl3 (15mL) was heated under reflux for 2h. then excess POCl3 was distilled under reduced pressure and the residue was triturated with ice water. The obtained suspension was neutralized with 2M ammonia; crude product was filtered, dried, and crystallized from ethanol.
6-(2-chloroethyl)-2-(4-chlorophenyl)-7-methyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With trichlorophosphate for 2h; Reflux;
4.1.1 General procedure for the synthesis of compound (2a-c)
General procedure: A mixture of compounds 1a, 1b or 1c (0.05mol), 2-acetylbutyrolactone (0.05mol) and POCl3 (15mL) was heated under reflux for 2h. then excess POCl3 was distilled under reduced pressure and the residue was triturated with ice water. The obtained suspension was neutralized with 2M ammonia; crude product was filtered, dried, and crystallized from ethanol.
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