* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 1.5 h; Stage #2: With magnesium chloride In acetonitrile at 20℃;
X. Methyl 5-methoxy-3-oxopentanoate CDl (3.24 g, 20.0 mmol) was added portionwise to a stirred suspension of 3-methoxypropanoic acid (1.81 mi, 19.2 mmol) in anhydrous MeCN (80 mL). The mixture was allowed to stir at rt for 1.5 hrs. A powdered mixture of magnesium chloride (1.57 g, 16.5 mmol) and methyl potassium maionate (4.5 g, 28.8 mmol) was added portionwise (note CO2 gas evolved). The mixture was allowed to stir at rt. Volatiies were removed in vacuo and hydrochloric acid (2M, 105 mL) was added. The solution was stirred at rt for 1 hr and extracted with DCM (3 x 100 mL). The organics were dried over magnesium sulfate, filtered and solvent removed in vacuo to afford methyl 5-methoxy-3-oxopentanoate (2.69 g, 87percent yield).
With potassium <i>tert</i>-butylate; water In ethanol at 40℃; Inert atmosphere
General procedure: According to the literature procedure,10e a 250 mL, two-necked, round-bottomed flask was charged with diethyl malonate (40.0 mmol), water (40.0 mmol), and ethanol (45 mL), the mixture was stirred in 40 °C oil bath for 2 h. After that, a solution of potassium tert-butoxide (40.0 mmol) in ethanol (45 mL) was added slowly over 30 min. After completion of addition, the reaction mixture was stirred in 40 °C oil bath until consumption of the starting material (monitored by GC analysis). After removing the ethanol solvent by slow evaporation on rotary evaporator, 20 ml diethyl ether was added. The resulting solid was collected by filtration, washed sequentially with 1:1 mixture of diethyl ether and ethanol (5 mL.x.2) and diethyl ether (10 mL.x.3), transferred to a round-bottomed flask and dried under vacuum at 50 °C for 10 h to provide ethyl potassium malonate in 85percent yield.
82.8%
With potassium hydroxide In methanol at 10 - 68℃; for 3.5 h;
To the reaction flask was added 100 g of dimethyl malonate (0.757 mol) and 350.0 g of anhydrous methanol, and the mixture was completely mixed and dissolved, and a methanol solution of potassium hydroxide was slowly added dropwise at 10 to 35 ° C (potassium hydroxide: 42.3 G (0.754 mol), methanol: 350.0 g),Gradually there is a white solid precipitation process. After dripping,The reaction solution was further stirred at 10 to 35 ° C for about 3.5 hours.The temperature was raised to 65 to 68 ° C. The system was refluxed and filtered while hot to remove dipotassium malonate. The resulting filtrate was cooled to 0 ° C and filtered to give the monomethyl methyl malonate salt.After the filtrate was concentrated and further about 550 g of methanol was distilled off, the resulting concentrate was cooled to 0 ° C and filtered, and the resulting two partsPotassium monoglyceride potassium salt combined, vacuum drying, the final monomethyl methacrylate potassium salt 98.78g (HPLC purity:99.1percent yield: 82.80percent).
76%
With potassium hydroxide In methanol
Comparison Example 2 Preparation of Potassium Monomethyl Malonate (KMM) 111.6 g of KOH (1.8 mol) are dissolved in 500 g of methanol, and the solution is added to 264.2 g of dimethyl malonate (2 mol) in the course of 2 h at room temperature. The KPG agitator is operated during this at 50 rpm. This mixes the reaction suspension inadequately, broad edge zones remain virtually unmixed. The reaction suspension is then filtered and the filtration residue is washed with methanol and dried in vacuo. 214.2 g of KMM are is obtained, equivalent to a yield of 76percent of theory having a DKM content of <0.2percent by weight.
65%
With potassium hydroxide In methanol for 16 h;
To a water-cooled solution of dimethylmalonate (132 g, 1 mol) in MeOH (500 mL) was added KOH (56 g, 1 mol) portionwise. The reaction mixture was stirred for 16 h, the solid was filtered off, and the filtrate was condensed TO-100 mL. Ether was added to precipitate out the solid, which was filtered and washed with ether, then dried to yield a white solid (102 g, 65percent).
Reference：
[1] Tetrahedron, 2012, vol. 68, # 9, p. 2113 - 2120
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4470 - 4474
[3] Patent: CN106467492, 2017, A, . Location in patent: Paragraph 0129; 0130; 0131
[4] Journal of Physical Chemistry, 1987, vol. 91, # 19, p. 5129 - 5134
[5] Patent: US6172257, 2001, B2,
[6] Organic Syntheses, 1986, vol. 64, p. 144 - 144
[7] Canadian Journal of Chemistry, 2001, vol. 79, # 8, p. 1238 - 1258
[8] Journal of Medicinal Chemistry, 2009, vol. 52, # 4, p. 1204 - 1208
[9] Patent: WO2004/106296, 2004, A2, . Location in patent: Page 37
[10] Journal of Organic Chemistry, 1980, vol. 45, # 12, p. 2536 - 2538
[11] Heterocycles, 1991, vol. 32, # 2, p. 245 - 251
[12] Patent: US2015/210662, 2015, A1, . Location in patent: Paragraph 0070; 0071
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 10 - 35℃; for 2 h; Inert atmosphere Stage #2: With magnesium chloride In tetrahydrofuran at 10 - 35℃; Inert atmosphere
A) methyl 3-oxo-3-(pyridin-2-yl)propanoate To a solution of picolinic acid (3.08 g) in tetrahydrofuran (62.5 mL) was added 1,1'-carbonyldiimidazole (4.86 g) at room temperature. The reaction mixture was stirred under an argon atmosphere at room temperature for 2 hr. To the reaction mixture were added monomethylmonopotassium malonate (3.90 g) and magnesium chloride (2.38 g) at room temperature, and the mixture was stirred under an argon atmosphere at room temperature overnight. The reaction mixture was neutralized with 2M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.48 g). MS (API+): [M+H]+180.1.
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 1868 - 1897
[2] Patent: US2016/159808, 2016, A1, . Location in patent: Paragraph 1405; 1406
12
[ 38330-80-2 ]
[ 100312-28-5 ]
[ 75418-74-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 23, p. 4960 - 4964
Stage #1: With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5 h; Stage #2: With magnesium chloride In acetonitrile for 2 h; Reflux
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and methyl potassium malonate (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5percent aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81percent) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33percent) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65percent).
Stage #1: With triethylamine In acetonitrile at 30 - 50℃; for 8.3 h; Stage #2: With 1,1'-carbonyldiimidazole In acetonitrile at 30℃; for 3.5 h;
Step-1: Preparation of Methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate (Formula III)Monomethylmalonate potassium salt (MMMKS; 122.8 g), triethylamine (264 ml) and acetonitrile (1200 ml) were charged to a 3L round bottom flask (RBF) fitted with condenser, nitrogen inlet, thermometer pocket and overhead stirrer. MgCl2 (65.2 g) was added lot- wise to the above mixture over a period of 15-20 min at 30°C and the mixture was stirred for 10 min. The reaction mixture was heated to 50°C for 8 h at same temperature. After 8 hours, the reaction mixture was cooled to 30°C and marked as Part A. Ι, -carbonyldiimidazole (CDI) (1 10 g) and acetonitrile (250 ml) were charged to a 2L RBF fitted with nitrogen inlet, thermometer pocket, addition funnel and overhead stirrer. To this, a solution of 2,4,5-trifluorophenyl acetic acid (100 g) in acetonitrile (600 ml) was added slowly over a period of a 30 min at 30 °C and the reaction mixture was stirred at 30 °C for 3 h. This solution was marked as part B.The Part B solution was added drop-wise to part-A slurry over a period of 2 hour at 30 °C and the mixture was stirred. The progress of the reaction was monitored by TLC (Mobile phase: n-Hexane: ethyl acetate; 50:50). After 12 h, TLC analysis indicated <5percent of un-reacted starting material. The reaction mixture was concentrated under reduced pressure at 50-55°C to get a thick slurry. To this, water (1000 ml) was added and the mixture was cooled to 10-15°C and cone. HC1 (220.6 ml) was added slowly, below 20°C. MTBE (700 ml) was added to the mixture and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with MTBE (200 ml). The combined organic layers were washed with 7 percent aqueous NaHC03 solution (400 ml) followed by washing with brine (200 ml). The organic layer was dried over sodium sulphate and concentrated under vacuum at 50°C to get an oil (120 g). The obtained oil was diluted with isopropyl alcohol (400 ml) and cooled to 20°C. To this water (800 ml) was added slowly over a period of 4 hours at 18-20°C. The slurry was then stirred for 4 hours and filtered. The obtained cake was washed with water (100 ml) and then suck dried to obtain free solid of titled product.Yield: 115 g (83 percent); m.p.: 37-39°C; HPLC Purity : > 95 percent.H NMR (CDCI3): 3.64 (s, 3H), 3.75 (s, 2H), 3.85 (s, 2H), 6.88-7.11 (m, 2H).Mass spectrum: 247 [M+l] +.
83%
Stage #1: With triethylamine; magnesium chloride In acetonitrile at 30 - 50℃; Inert atmosphere Stage #2: With 1,1'-carbonyldiimidazole In acetonitrile at 30℃; for 5.5 h; Inert atmosphere
Example 1 Step-1 Preparation of Methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate (Formula III) [0156] Monomethylmalonate potassium salt (MMMKS; 122.8 g), triethylamine (264 ml) and acetonitrile (1200 ml) were charged to a 3 L round bottom flask (RBF) fitted with condenser, nitrogen inlet, thermometer pocket and overhead stirrer. MgCl2 (65.2 g) was added lot-wise to the above mixture over a period of 15-20 min at 30° C. and the mixture was stirred for 10 min. The reaction mixture was heated to 50° C. for 8 h at same temperature. After 8 hours, the reaction mixture was cooled to 30° C. and marked as Part A. 1,1′-carbonyldiimidazole (CDI) (110 g) and acetonitrile (250 ml) were charged to a 2 L RBF fitted with nitrogen inlet, thermometer pocket, addition funnel and overhead stirrer. To this, a solution of 2,4,5-trifluorophenyl acetic acid (100 g) in acetonitrile (600 ml) was added slowly over a period of a 30 min at 30° C. and the reaction mixture was stirred at 30° C. for 3 h. This solution was marked as part B. [0157] The Part B solution was added drop-wise to part-A slurry over a period of 2 hour at 30° C. and the mixture was stirred. The progress of the reaction was monitored by TLC (Mobile phase: n-Hexane: ethyl acetate; 50:50). After 12 h, TLC analysis indicated <5percent of un-reacted starting material. The reaction mixture was concentrated under reduced pressure at 50-55° C. to get a thick slurry. To this, water (1000 ml) was added and the mixture was cooled to 10-15° C. and conc. HCl (220.6 ml) was added slowly, below 20° C. MTBE (700 ml) was added to the mixture and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with MTBE (200 ml). The combined organic layers were washed with 7percent aqueous NaHCO3 solution (400 ml) followed by washing with brine (200 ml). The organic layer was dried over sodium sulphate and concentrated under vacuum at 50° C. to get an oil (120 g). The obtained oil was diluted with isopropyl alcohol (400 ml) and cooled to 20° C. To this water (800 ml) was added slowly over a period of 4 hours at 18-20° C. The slurry was then stirred for 4 hours and filtered. The obtained cake was washed with water (100 ml) and then suck dried to obtain free solid of titled product. [0158] Yield: 115 g (83percent); m.p.: 37-39° C.; HPLC Purity: ≧95percent. [0159] 1H NMR (CDCl3): 3.64 (s, 3H), 3.75 (s, 2H), 3.85 (s, 2H), 6.88-7.11 (m, 2H). [0160] Mass spectrum: 247[M+1]+.
2-Oxo-hexahydro-furo[2,3-b]pyran-3-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With ammonium cerium (IV) nitrate; In acetonitrile; at 0℃; for 2h;Inert atmosphere; ultrasonic bath;
Example 1C Under a nitrogen atmosphere 5.43 mL (59.4 mmol) 3,4-dihydro-2H-pyran, 23.2 g (149 mmol) potassium methyl malonate and 200 mL acetonintrile were combined and 65.2 g (119 mmol) ceric (IV) ammonium nitrate were added. The flask with the reaction mixture was immersed in an ultrasonic bath for 2 h at 0° C. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water and the aqueous phase extracted with dichloromethane. The organic layer was dried and evaporated under reduced pressure. The residue was purified by filtration over silica gel (eluent: dichloromethane). 5.50 g (46percent) of the product were obtained.MS (ESI pos): m/z=201 (M+H)+
With potassium tert-butylate; water; In ethanol; at 40℃;Inert atmosphere;
General procedure: According to the literature procedure,10e a 250 mL, two-necked, round-bottomed flask was charged with diethyl malonate (40.0 mmol), water (40.0 mmol), and ethanol (45 mL), the mixture was stirred in 40 C oil bath for 2 h. After that, a solution of potassium tert-butoxide (40.0 mmol) in ethanol (45 mL) was added slowly over 30 min. After completion of addition, the reaction mixture was stirred in 40 C oil bath until consumption of the starting material (monitored by GC analysis). After removing the ethanol solvent by slow evaporation on rotary evaporator, 20 ml diethyl ether was added. The resulting solid was collected by filtration, washed sequentially with 1:1 mixture of diethyl ether and ethanol (5 mL×2) and diethyl ether (10 mL×3), transferred to a round-bottomed flask and dried under vacuum at 50 C for 10 h to provide ethyl potassium malonate in 85% yield.
82.8%
With potassium hydroxide; In methanol; at 10 - 68℃; for 3.5h;
To the reaction flask was added 100 g of dimethyl malonate (0.757 mol) and 350.0 g of anhydrous methanol, and the mixture was completely mixed and dissolved, and a methanol solution of potassium hydroxide was slowly added dropwise at 10 to 35 C (potassium hydroxide: 42.3 G (0.754 mol), methanol: 350.0 g),Gradually there is a white solid precipitation process. After dripping,The reaction solution was further stirred at 10 to 35 C for about 3.5 hours.The temperature was raised to 65 to 68 C. The system was refluxed and filtered while hot to remove dipotassium malonate. The resulting filtrate was cooled to 0 C and filtered to give the monomethyl methyl malonate salt.After the filtrate was concentrated and further about 550 g of methanol was distilled off, the resulting concentrate was cooled to 0 C and filtered, and the resulting two partsPotassium monoglyceride potassium salt combined, vacuum drying, the final monomethyl methacrylate potassium salt 98.78g (HPLC purity:99.1% yield: 82.80%).
76%
With potassium hydroxide; In methanol;
Comparison Example 2 Preparation of Potassium Monomethyl Malonate (KMM) 111.6 g of KOH (1.8 mol) are dissolved in 500 g of methanol, and the solution is added to 264.2 g of dimethyl malonate (2 mol) in the course of 2 h at room temperature. The KPG agitator is operated during this at 50 rpm. This mixes the reaction suspension inadequately, broad edge zones remain virtually unmixed. The reaction suspension is then filtered and the filtration residue is washed with methanol and dried in vacuo. 214.2 g of KMM are is obtained, equivalent to a yield of 76% of theory having a DKM content of <0.2% by weight.
65%
With potassium hydroxide; In methanol; for 16h;
To a water-cooled solution of dimethylmalonate (132 g, 1 mol) in MeOH (500 mL) was added KOH (56 g, 1 mol) portionwise. The reaction mixture was stirred for 16 h, the solid was filtered off, and the filtrate was condensed TO-100 mL. Ether was added to precipitate out the solid, which was filtered and washed with ether, then dried to yield a white solid (102 g, 65%).
With potassium hydroxide; In methanol; at 20℃; for 2h;Large scale;
2 kg (14.83 mol, 98%) of dimethyl malonate are charged at 20 C. without solvent and to this are added 967.85 g (14.83 mol, 86%) of KOH (dissolved in 4.89 kg of methanol) over 1 hour. The mixture is then stirred for 1 hour at 20 C. and subsequently methanol is distilled off under reduced pressure at an internal temperature of ca. 35 C. The residue is dewatered to remove methanol and water residues under reduced pressure by azeotroping with ca. 4 kg of xylene at 40 to 56 C. The residual xylene suspension is reacted directly in the following step.
General procedure: In brief: 32.80 g <strong>[38330-80-2]methyl potassium malonate</strong> (0.21 mol) was placed in a 1l flask under an Ar blanket. 300 ml MeCN was added and the mixture stirred and cooled to 10-15 °C. To this mixture 44.36 ml dry Et3N (32.40 g, 0.32 mol) was added followed by 23.81 g anhydrous MgCl2 (0.25 mol) and stirring continued at 20-25 °C for 2.5 h. The resulting slurry was recooled to 0 °C and the respective acid chloride (0.1 mol) added dropwise over 25min followed by the addition of 3 ml Et3N. The mixture was allowed to stir over night at 20-25 °C and then concentrated in vacuum to remove the MeCN. The residue was suspended in100 ml toluene and the resulting sludge reconcentrated in vacuum. Again 150 ml toluene was added and the mixture cooled to 10-15 °C. 150 ml aqueous HCl (13percent) was added cautiously while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed twice with 40 ml of 13percent aq. HCl and 40 ml water. The solution was then concentrated in vacuum to give the crude product which was purified by distillation or recrystallisation. The purity was checked by HPLC/MS.
The alpha-hydromuconic acid used in the present invention was prepared by chemical synthesis. First, 1.5 L of super-dehydrated tetrahydrofuran (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 13.2 g (0.1 mol) of succinic acid monomethyl ester (manufactured by Wako Pure Chemical Industries, Ltd.), and 16.2 g (0.1 mol) of carbonyldiimidazole (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto with stirring, followed by stirring the resulting mixture under nitrogen atmosphere for 1 hour at room temperature. To this suspension, 15.6 g (0.1 mol) of <strong>[38330-80-2]malonic acid monomethyl ester potassium salt</strong> and 9.5 g (0.1 mol) of magnesium chloride were added. The resulting mixture was stirred under nitrogen atmosphere for 1 hour at room temperature, and then stirred at 40 C. for 12 hours. After the reaction, 0.05 L of 1 mol/L hydrochloric acid was added to the mixture, and extraction with ethyl acetate was carried out. By separation purification by silica gel column chromatography (hexane:ethyl acetate=1:5), 13.1 g of pure 3-oxohexanedicarboxylic acid dimethyl ester was obtained. Yield: 70%.
70%
First, 1.5 L of super-dehydrated tetrahydrofuran (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 13.2 g (0.1 mol) of succinic acid monomethyl ester (manufactured by Wako Pure Chemical Industries, Ltd.), and 16.2 g (0.1 mol) of carbonyldiimidazole (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto with stirring, followed by stirring the resulting mixture under nitrogen atmosphere at room temperature for 1 hour. To this suspension, 15.6 g (0.1 mol) of <strong>[38330-80-2]malonic acid monomethyl ester potassium salt</strong> and 9.5 g (0.1 mol) of magnesium chloride were added. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 hour, and then stirred at 40 C. for 12 hours. Afier completion of the reaction, 0.05 L of 1 mol/L hydrochloric acid was added to the mixture at room temperature, and extraction with ethyl acetate was carried out. By separation and purification by silica gel column chromatography (hexane:ethyl acetate=1:5), 13.1 g of pure 3-oxohexanedicarboxylic acid dimethyl ester was obtained. Yield: 70%.
Add 30g of monomethyl succinate and 260mL of tetrahydrofuran to a 500mL three-neck round bottom flask and add in batches.40.5 g of carbonyl diimidazole, stirred at room temperature for 1 hour,Then, 35.46 g of <strong>[38330-80-2]monomethyl malonate potassium salt</strong> and 21.62 g of magnesium chloride were added, and the reaction was stirred at 40 C for 15 hours. After the TLC detection reaction was completed, the solvent was distilled off.Adding 180 mL of acetic acid for acidification,The salt is removed by filtration to give an acetic acid solution of the compound of formula III.
Boc-glycine (175.2 kg, 1000.0 mol, 1 eq) was dissolved in 1750 kg of tetrahydrofuran at room temperature and stirred.Dissolved, added magnesium chloride (95.2 kg, 1000 mol, 1 eq) and N,N'-carbonyldiimidazole (162.1 kg, 1000 mol, 1 eq),The <strong>[38330-80-2]monomethyl malonate potassium salt</strong> (234.3 kg, 1500 mol, 1.5 eq) was added in portions, and the temperature was raised to 45 ° C to reflux until the reaction was complete.The solvent was removed, and after adding 875 kg of water, it was extracted 2-4 times with 1750 kg of ethyl acetate, and the organic phase was 875 kg of 10percent sodium hydrogencarbonate.The solution was washed, and the washed organic phase was heated to remove the solvent, and dried to obtain 210 kg of Compound B in a yield of 91.6percent.
76%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
General procedure: In brief: 32.80 g <strong>[38330-80-2]methyl potassium malonate</strong> (0.21 mol) was placed in a 1l flask under an Ar blanket. 300 ml MeCN was added and the mixture stirred and cooled to 10-15 °C. To this mixture 44.36 ml dry Et3N (32.40 g, 0.32 mol) was added followed by 23.81 g anhydrous MgCl2 (0.25 mol) and stirring continued at 20-25 °C for 2.5 h. The resulting slurry was recooled to 0 °C and the respective acid chloride (0.1 mol) added dropwise over 25min followed by the addition of 3 ml Et3N. The mixture was allowed to stir over night at 20-25 °C and then concentrated in vacuum to remove the MeCN. The residue was suspended in100 ml toluene and the resulting sludge reconcentrated in vacuum. Again 150 ml toluene was added and the mixture cooled to 10-15 °C. 150 ml aqueous HCl (13percent) was added cautiously while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed twice with 40 ml of 13percent aq. HCl and 40 ml water. The solution was then concentrated in vacuum to give the crude product which was purified by distillation or recrystallisation. The purity was checked by HPLC/MS.
Step-1: Preparation of Methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate (Formula III)Monomethylmalonate potassium salt (MMMKS; 122.8 g), triethylamine (264 ml) and acetonitrile (1200 ml) were charged to a 3L round bottom flask (RBF) fitted with condenser, nitrogen inlet, thermometer pocket and overhead stirrer. MgCl2 (65.2 g) was added lot- wise to the above mixture over a period of 15-20 min at 30C and the mixture was stirred for 10 min. The reaction mixture was heated to 50C for 8 h at same temperature. After 8 hours, the reaction mixture was cooled to 30C and marked as Part A. Iota, -carbonyldiimidazole (CDI) (1 10 g) and acetonitrile (250 ml) were charged to a 2L RBF fitted with nitrogen inlet, thermometer pocket, addition funnel and overhead stirrer. To this, a solution of 2,4,5-trifluorophenyl acetic acid (100 g) in acetonitrile (600 ml) was added slowly over a period of a 30 min at 30 C and the reaction mixture was stirred at 30 C for 3 h. This solution was marked as part B.The Part B solution was added drop-wise to part-A slurry over a period of 2 hour at 30 C and the mixture was stirred. The progress of the reaction was monitored by TLC (Mobile phase: n-Hexane: ethyl acetate; 50:50). After 12 h, TLC analysis indicated <5% of un-reacted starting material. The reaction mixture was concentrated under reduced pressure at 50-55C to get a thick slurry. To this, water (1000 ml) was added and the mixture was cooled to 10-15C and cone. HC1 (220.6 ml) was added slowly, below 20C. MTBE (700 ml) was added to the mixture and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with MTBE (200 ml). The combined organic layers were washed with 7 % aqueous NaHC03 solution (400 ml) followed by washing with brine (200 ml). The organic layer was dried over sodium sulphate and concentrated under vacuum at 50C to get an oil (120 g). The obtained oil was diluted with isopropyl alcohol (400 ml) and cooled to 20C. To this water (800 ml) was added slowly over a period of 4 hours at 18-20C. The slurry was then stirred for 4 hours and filtered. The obtained cake was washed with water (100 ml) and then suck dried to obtain free solid of titled product.Yield: 115 g (83 %); m.p.: 37-39C; HPLC Purity : > 95 %.H NMR (CDCI3): 3.64 (s, 3H), 3.75 (s, 2H), 3.85 (s, 2H), 6.88-7.11 (m, 2H).Mass spectrum: 247 [M+l] +.
83%
Example 1 Step-1 Preparation of Methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate (Formula III) [0156] Monomethylmalonate potassium salt (MMMKS; 122.8 g), triethylamine (264 ml) and acetonitrile (1200 ml) were charged to a 3 L round bottom flask (RBF) fitted with condenser, nitrogen inlet, thermometer pocket and overhead stirrer. MgCl2 (65.2 g) was added lot-wise to the above mixture over a period of 15-20 min at 30 C. and the mixture was stirred for 10 min. The reaction mixture was heated to 50 C. for 8 h at same temperature. After 8 hours, the reaction mixture was cooled to 30 C. and marked as Part A. 1,1?-carbonyldiimidazole (CDI) (110 g) and acetonitrile (250 ml) were charged to a 2 L RBF fitted with nitrogen inlet, thermometer pocket, addition funnel and overhead stirrer. To this, a solution of 2,4,5-trifluorophenyl acetic acid (100 g) in acetonitrile (600 ml) was added slowly over a period of a 30 min at 30 C. and the reaction mixture was stirred at 30 C. for 3 h. This solution was marked as part B. [0157] The Part B solution was added drop-wise to part-A slurry over a period of 2 hour at 30 C. and the mixture was stirred. The progress of the reaction was monitored by TLC (Mobile phase: n-Hexane: ethyl acetate; 50:50). After 12 h, TLC analysis indicated <5% of un-reacted starting material. The reaction mixture was concentrated under reduced pressure at 50-55 C. to get a thick slurry. To this, water (1000 ml) was added and the mixture was cooled to 10-15 C. and conc. HCl (220.6 ml) was added slowly, below 20 C. MTBE (700 ml) was added to the mixture and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with MTBE (200 ml). The combined organic layers were washed with 7% aqueous NaHCO3 solution (400 ml) followed by washing with brine (200 ml). The organic layer was dried over sodium sulphate and concentrated under vacuum at 50 C. to get an oil (120 g). The obtained oil was diluted with isopropyl alcohol (400 ml) and cooled to 20 C. To this water (800 ml) was added slowly over a period of 4 hours at 18-20 C. The slurry was then stirred for 4 hours and filtered. The obtained cake was washed with water (100 ml) and then suck dried to obtain free solid of titled product. [0158] Yield: 115 g (83%); m.p.: 37-39 C.; HPLC Purity: ?95%. [0159] 1H NMR (CDCl3): 3.64 (s, 3H), 3.75 (s, 2H), 3.85 (s, 2H), 6.88-7.11 (m, 2H). [0160] Mass spectrum: 247[M+1]+.
General procedure: In brief: 32.80 g <strong>[38330-80-2]methyl potassium malonate</strong> (0.21 mol) was placed in a 1l flask under an Ar blanket. 300 ml MeCN was added and the mixture stirred and cooled to 10-15 °C. To this mixture 44.36 ml dry Et3N (32.40 g, 0.32 mol) was added followed by 23.81 g anhydrous MgCl2 (0.25 mol) and stirring continued at 20-25 °C for 2.5 h. The resulting slurry was recooled to 0 °C and the respective acid chloride (0.1 mol) added dropwise over 25min followed by the addition of 3 ml Et3N. The mixture was allowed to stir over night at 20-25 °C and then concentrated in vacuum to remove the MeCN. The residue was suspended in100 ml toluene and the resulting sludge reconcentrated in vacuum. Again 150 ml toluene was added and the mixture cooled to 10-15 °C. 150 ml aqueous HCl (13percent) was added cautiously while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed twice with 40 ml of 13percent aq. HCl and 40 ml water. The solution was then concentrated in vacuum to give the crude product which was purified by distillation or recrystallisation. The purity was checked by HPLC/MS.
With piperidine; pyridine hydrochloride; In pyridine; at 120℃; for 2.5h;
D1. METHVL3- (4-METHOXVPVRIDIN-2-Y ACRVLATE; A mixture of 45 g OF 4-METHOXYPYRIDINE-2-CARBALDEHYDE (Ashimori et AL., Chem. Pharm. Bull. 38,2446- 2458 (1990) ), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are slowly heated, with stirring, to 120°C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120°C for a further 2.5 hours, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl ACETATE/WATER and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2: 1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m. p. of 80-82°C. The mass spectrum shows the molecular peak MH+ at 194 Da
With piperidine; pyridine hydrochloride; In pyridine; at 120℃; for 2.5h;
D1. METHYL 3- (4-METHOXVAVRIDIN-2-VL) ACRVLATE A mixture of 45 g of <strong>[16744-81-3]4-methoxypyridine-2-carbaldehyde</strong> (Ashimori et AL., Chem. Pharm. Bull. 38, 2446- 2458 (1990) ), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 mi of piperidine in 700 mi of pyridine are slowly heated, with stirring, to 120°C. WHEN the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120°C for a further 2.5 hours, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2: 1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m. p. of 80-82°C.
With piperidine; pyridine hydrochloride; In pyridine; at 120℃; for 2.5h;
D1. METHVL 3-F4-METHOXYPVRIDIN-2-VL) ACRVLATE A mixture of 45 g OF 4-METHOXYPYRIDINE-2-CARBALDEHYDE (ASHIMORI et AL., Chem. Pharm. Bull. 38,2446- 2458 (1990) ), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are slowly heated, with stirring, to 120°C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120°C for a further 2.5 hours, and the pyridine IS-THEN distilled off under reduced pressure. The residue is partitioned between ethyl acetatelwater and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2: 1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m. p. of 80-82°C. The mass spectrum shows the molecular peak MH+ AT 194 Da.
With piperidine; pyridine hydrochloride; In pyridine; at 120℃; for 2.5h;
A mixture of 45 G of 4-METHOXYPYRIDINE-2-CARBALDEHYDE (Ashimori et AL., Chem. Pharm. Bull. 38, 2446- 2458 (1990) ), 75.80 G of pyridine hydrochloride, 102.45 G of monomethyl malonate potassium salt and 4.1 mi of piperidin in 700 ML of pyridine are slowly heated, with stirring, to 120 C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120 C for a further 2.5 h, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chroma- tographed on a silica gel column using ethyl ACETATE/PETROLEUM ether 2: 1. This initially gives 43.2 G of the title compound as a yellow oil which crystallizes on standing and then shows a m. p. of 80-82 C. The mass spectrum shows the molecular peak MHD AT 194 DA.
Step 2 In a 50 ml three neck balloon provided with a magnetic stirrer, an addition bulb and a thermometer, <strong>[38330-80-2]methyl potassium malonate</strong> (10.27 g; 65.76 mmols) is solubilized in 10 ml water. The reaction mixture is cooled by means of an ice bath and 5.5 ml concentrated hydrochloric acid are slowly added. The reaction mixture is filtered and the KCl precipitate is washed with ether (3*10 ml). The filtrate is allowed to settle and the aqueous phase is extracted with ether (3*10 ml). The combined ether phases are dried on anhydrous MgSO4, filtered and concentrated to give the methyl malonic acid (7.42 g; 96percent) in the form of a colourless oil.
84.8%
With hydrogenchloride; In hexane; dichloromethane;
EXAMPLE 24 Monomethyl malonic acid A 4 liter flask was changed with 90 g (0.576 moles) of methyl malonate potassium salt, about 540 ml of 1N HCl (to a pH of 1.0), and 2 liters of methylene chloride. The solution was transferred to a continuous extractor which contained an additional two liters of methylene chloride. After 4 hours extraction, no product remained in the aqueous layer (TLC on silica gel with 1:1 hexane:ethyl acetate) and the product layer was separated and dried over MgSO4. Removal of the solvent at reduced pressure gave 57.7 g (84.8percent yield) of the title compound. Alternatively, prepare the title compound by substituting the sodium salt for the potassium salt.
Compound 209c (1.9 g, 16.1 mmol) was dissolved in THF (50 mL), CDI (12.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. MgCl2 (1.5 g, 16.1 mmol) and KOCOCH2CO2Me (3.8 g, 24.2 mmol) were added, the resulting mixture was stirred at room temperature overnight. EtOAc (100 mL), water (50 mL) were added. The aqueous layer was separated and extracted with EtOAc. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated. The residue was separated by silica gel chromatography, with Biotage 40S+column, eluted with EtOAc: hexanes, 1:10, to give 2.1 g (74percent) yellow liquid as Compound 209d.
Compound 271d (2.40 g, 14.0 mmol) dissolved in THF (50 mL), CDI (2.48 g, 15.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. MgCl2 (1.5 g, 15.3 mmol) and KOCOCH2CO2Me (3.3 g, 20.9 mmol) were added, the resulting mixture was stirred at room temperature overnight. EtOAc (100 mL), water (50 mL) were added. The aqueous layer was separated and extracted with EtOAc. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated. The residue was filtered through a pad of silica gel, eluted with EtOAc: hexanes, 1:3, to give 2.2 g (69percent) yellow liquid as Compound 270e.
To a mixture of 3, 4,5-trimethoxybenzoic acid (24.7 g, 116 mmol) and carbonyldiimidazole (20.8 g, 128 mmol) was added dry THF (300 mL) (Caution: gas evolution). The reaction mixture was stirred at room temperature for 4 h, then the Part A compound (20 g, 128 mmol) AND MGCL2 (12.2 g, 128 mmol) were added portionwise. The reaction mixture was stirred at 40°C for 2 days. The resulting precipitate was removed by filtration, and the filtrate was diluted with water and acidified with 1N HC1 until PH-4. The mixture was extracted with ether (200 mL) and washed with water (2 x 100 mL), aq. NAHC03 AND water, then dried over MGS04. Evaporation provided a crude product which was purified with flash chromatography on silica, eluting with a gradient OF 0percent to 50percent EtOAc/hexane to give the beta-keto ester (18 g, 58percent) as a white solid. MS (ES+) m/z (M+Na) += 291.22. 1H NMR (400 MHz, CDC13) : 8 3.76 (s, 3H), 3.92 (s, 6H), 3.93 (S, 3H), 3.98 (s, 2H), 7.22 (s, 2H). HPLC: Retention time = 2.26 min (Method C).
3-(5-Bromo-thiophen-2-yl)-3-oxo-propionic acid methyl ester (39); [00170] Carbonyldiimidazole (9.7 g, 59.9 mmol) is added portion-wise to a suspension of delta-bromo-thiophen^-carboxylic acid (10.3, 49.8 mmol) in 75 ml of acetonitrile, and the reaction mixture is stirred at 200C for 1 h. To the formed solution, a mixture of <strong>[38330-80-2]monomethyl monopotassium malonate</strong> (8.91 g, 55 mmol) and MgCI2 anhydrous (5.22 g, 55 mmol) is added; the mixture is stirred at 2O0C for 18 h. Acetonitrile is evaporated under reduced pressure and water (100 ml) is added, the resulting suspension is acidified with 10percent HCI to pH 4.5; the mixture is extracted with DCM (2x200 ml). The organic phase is washed with concentrated NaHCO3 solution (2x80 ml), water (100 ml), dried over Na2SO4. After evaporation of solvent 12.14 g (92.3percent) of the title compound is obtained. 1H NMR (CDCI3, 400 MHz), delta (ppm): 3.75 (s, 3H); 3.85 (s, 2H); 7.1 (d, 1 H); 7.5 (d, 1 H).
20.3 g (0.13 mol) of <strong>[38330-80-2]monomethyl malonate potassium salt</strong> was dissolved in 125 mL of DMF, heated to 35 ° C, 12.9 g (0.12 mol) of methyl chloroacetate was added dropwise, and stirred at 35 ° C for 8 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 20.1 g of methyl ethyl malonate, the yield is 81.3percent
80%
In N,N-dimethyl-formamide; at 35℃;
Example 4; To a suspension of 78.9 g of potassium monoethylmalonate in 500 ml of dimethylformamide are added dropwise, at 35° C., 55 g of methyl chloroacetate and the mixture is stirred at 35° C. for 8 hours. The solvent is removed under reduced pressure and the residue is admixed with 100 ml of water and 100 ml of toluene. The phases are separated and the aqueous phase is washed with 100 ml of toluene. The combined organic phases are dried over magnesium sulphate and concentrated under reduced pressure. 77.6 g of methyl 2-methoxy-2-oxoethylpropanedicarboxylate are obtained in a purity of 98percent (this corresponds to 80percent yield).1H NMR (CDCl3, 298 K) delta: 3.51 s (2H), 3.77 s (3H), 3.78 s (3H), 4.69 s (2H)
With tetrabutylammomium bromide; In toluene; at 50℃;
11.95 g (75.7 mmol) of commercially supplied potassium methyl malonate are dissolved/suspended in 71.25 g of various solvents/solvent mixtures, which were varied with regard to temperatures and catalyst addition according to Table 1. [0078] Subsequently 8.23 g (75.0 mol) of methyl chloroacetate are added and the mixtures obtained stirred at room temperature.
To a 500 mL round bottom flask containing phenylcyclopentane carboxylic acid 1 (14 g, 73 mmol) was added anhydrous THF (200 mL). Carbonyldiimidazole (12.5 g, 77 mmol) was added to the reaction mixture, which was then allowed to stir for 2 hr. at room temperature. A mixture of magnesium chloride (7.7 g, 81 mmol) and potassium monomethylmalonate (12.6 g, 81 mmol) was added, and the solution was heated to 50° C. and stirred overnight. The solid was filtered off and washed with THF. The filtrate was evaporated then dissolved in ethyl acetate. The mixture was washed with 1N HCl (1.x.) and 5percent aqueous sodium bicarbonate (2.x.). The combined organic layers were then dried over anhydrous magnesium sulfate, filtered, and concentrated to give a waxy pale yellow solid (11.7 g, 65percent yield) which was used without further purification. 1H NMR (CDCl3, 400 MHz): delta=7.34 (m, 2H), 7.27 (m, 3H), 3.63 (s, 3H), 3.28 (s, 2H), 2.53-2.47 (m, 2H), 1.98-1.90 (m, 2H), 1.72 (m, 4H).
Example 2 Alternate synthesis of 5-(2-bromo-5-fluorophenyl)-l-ter/-butyl-4-iodo-lH-pyrazole[0235] Readily available <strong>[394-28-5]2-bromo-5-fluorobenzoic acid</strong> was converted to methyl 3-(2- bromo-5-fluorophenyl)-3-oxopropanoate using condensation with 3-methoxy-3- oxopropanoate. Subsequent de-carboxylation gave l-(2-bromo-5-fluorophenyl)ethanone, which was then converted to 5-(2-bromo-5-fluorophenyl)-l-tert-butyl-4-iodo-lH- pyrazole as described in Example 1.
Phenylacetyl chloride (4.44 gr, 28.7 mmol) is added to a cooled (0 0C) mixture of monomethyl monopotassium malonate (8.96 gr, 57.4 mmol, 2.0 equiv.), magnesium chloride (6.00 gr, 63 mmol, 2.2 equiv.) and triethylamine (17.5 ml, 126 mmol, 4.4 equiv.) in acetonitrile (100 ml). The mixture is stirred at 00C for 3 h then aqueous 2N HCI is added and the mixture is stirred for another hour. The layers are separated and the aqueous layer is extracted with EtOAc (2x). The combined organic layers are washed with brine, dried over Na2SO4 and concentrated to dryness. The oily residue is purified by flash column chromatography (10-30% EtOAc in heptane) to afford 2.62 gr (47%) of a yellow oil.
With 1,1'-carbonyldiimidazole; magnesium chloride; In tetrahydrofuran; at 20℃; for 12h;
To the three-necked reaction flask was added 50 g (0.43 mol) of <strong>[6540-33-6]cyclobutylacetic acid</strong>, 73.4 g (0.47 mol) of potassium monomethyl maleate and 300 mL of tetrahydrofuran, and 103.7 g (0.64 mol) of carbonylimidazole was added thereto with stirring ), And 15 g of magnesium chloride was added to form a reaction solution. After completion of the reaction, the reaction solution was allowed to react at room temperature for 12 hours, Then, 100 mL of water was added to the reaction solution, stirring was continued for 0.5 h, The organic phase was washed with 50 mL of saturated brine once, dried, Concentrated to give 66.5 g of methyl 4-cyclobutyl-3-oxo-butyric acid methyl ester of formula A, Yield 89.2%
To a suspension of CDI (389 mg, 2.4 mmol) in THF (5 mL) was added a solution of 3-(3-chloro-2-fluorobenzyl)-2,6-difluorobenzoic acid 6 (602 mg, 2.0 mmol) in THF (5 mL) dropwise, the mixture was stirred at rt for 2 h. After a mixture of potassium 3-methoxy-3-oxopropanoate (374 mg, 2.4 mmol) and MgCl2 (228 mg, 2.4 mmol) in THF (10 mL) stirring at 50 °C for 2 h was added the above solution. The resulting mixture was stirred at 50 °C overnight, filtrated. The filtrate was diluted with water (5 mL) and acidified with 4 M HCl to pH 56. The mixture was extracted with ethyl acetate (15 mL) and washed with water (5 mL), satd aq NaHCO3 (5 mL), and brine (5 mL), then dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 15:1, v/v) to give the desired compound 7 as a colorless oil (320 mg, 45percent): keto form/enol form = 2.3:1; keto form 1H NMR (CDCl3) delta 3.75 (s, 3H, CH3), 3.95 (s, 2H, CH2), 4.03 (s, 2H, CH2), 6.91-6.96 (m, 1H, ArH), 7.02-7.12 (m, 2H, ArH), 728-7.34 (m, 2H, ArH); Enol form 1H NMR (CDCl3) delta 3.83 (s, 1.3H, CH3), 4.03 (s, 0.9H, CH2), 5.44 (s, 0.4H, OH), 6.89-6.96 (m, 0.4H, ArH), 7.02-7.12 (m, 0.9H, ArH), 7.21-7.34 (m, 0.9H, ArH), 12.31 (s, 0.4H, CH); MS (ESI) m/z 357 [M+H]+.
320 mg
General procedure: To a suspension of CDI (389 mg, 2.4 mmol) in THF (5 mL) was added a solution of 7a-b (2.0 mmol) in THF (5 mL) dropwise. The resulting mixture was stirred at room temperature for 2 h, and then potassium 3-methoxy-3-oxopropanoate (374 mg, 2.4 mmol) and MgCl2 (228 mg, 2.4 mmol) were added portion-wise. The reaction mixture was stirred at 60 °C overnight. The resulting precipitate was removed by filtration, and the filtrate was diluted with water (5 mL) and acidified with 2 M HCl to pH 6-7. The mixture was extracted with ethyl acetate (15 mL) and washed with water (5 mL), satd aq NaHCO3 (5 mL), and brine (5 mL), then dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20/1 to 15/1, v/v) to give the desired compound.
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
General procedure: A solution of N-(tert-butoxycarbonyl)-beta-alanine (6.00 g, 31.71 mmol) in anhydrous tetrahydrofuran (100 mL) under an argon atmosphere was treated with N,N'-carbonyldiimidazole (7.24 g, 38.05 mmol). After stirring at room temperature for 1 h, previously mixed magnesium chloride (3.00 g, 31.51 mmol) and <strong>[38330-80-2]monomethyl monopotassium malonate</strong> (9.84 g, 63.02 mmol) were added. The resulting mixture was kept under an argon atmosphere and was stirred at room temperature for an additional 18 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (100 mL) and washed with 5% aqueous KHSO4 (2*50 mL), 5% aqueous NaHCO3 (2*50 mL) and brine (2*50 mL). The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure to afford 6 as a pale yellow oil (7.70 g, 31.39 mmol). The crude compound was dissolved in anhydrous acetonitrile (100 mL), under an argon atmosphere, and 3-carboxybenzenesulfonyl azide (7.84 g, 34.53 mmol) was added in one portion, followed by triethylamine (13.13 mL, 94.17 mmol). The resulting mixture was stirred at room temperature for 1 h. The solvent was concentrated in vacuo and the residue was dissolved in diethyl ether (100 mL) and washed with saturated aqueous NaHCO3 (2*50 mL), and saturated aqueous NH4Cl (2*50 mL). The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure to afford 7 as an orange oil (8.35 g, 30.78 mmol) that was taken on without further purification. It was dissolved in anhydrous toluene (300 mL), under an argon atmosphere, and Rh2(OAc)4 (0.068 g, 0.15 mmol) was added. The reaction mixture was heated at 85-90 C for approximately 30 min in a preheated oil bath. The solvent was evaporated to dryness and the residue was purified by column chromatography (eluent: hexanes/ethyl acetate 3:1) to afford pure 5 as a white solid (7.41 g, 30.47 mmol, 96% overall yield). Mp 56 C. IR (neat) nu 2979, 1772, 1745, 1707 cm-1. 1H NMR (CDCl3, 400 MHz) delta 1.39, 1.46 (two s, 9H), 2.59-2.76 (dd, 2H, J=8.4, 6.8 Hz), 3.66-3.94 (m, 5H), 4.46, 4.54 (two s, 1H). 13C NMR (CDCl3, 100 MHz) delta (duplicate signals are observed for most carbons) 28.09, 28.19; 36.37, 37.06; 41.52, 42.17; 52.86, 53.00; 65.20, 65.60; 81.15; 153.75; 166.69; 204.52. HRMS (ESI) C11H17NNaO5 [M+Na]+: calcd 266.0999, found 266.1004.
With dmap; bis(eta3-allyl-mu-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,3,5-trimethyl-benzene; at 140℃; for 20h;Inert atmosphere;
General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 °C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.
With dmap; bis(eta3-allyl-mu-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,3,5-trimethyl-benzene; at 140℃; for 20h;Inert atmosphere;
General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 °C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.
A) methyl 3-oxo-3-(pyridin-2-yl)propanoate To a solution of picolinic acid (3.08 g) in tetrahydrofuran (62.5 mL) was added 1,1'-carbonyldiimidazole (4.86 g) at room temperature. The reaction mixture was stirred under an argon atmosphere at room temperature for 2 hr. To the reaction mixture were added monomethylmonopotassium malonate (3.90 g) and magnesium chloride (2.38 g) at room temperature, and the mixture was stirred under an argon atmosphere at room temperature overnight. The reaction mixture was neutralized with 2M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.48 g). MS (API+): [M+H]+180.1.
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
To a solution of 1,1?-carbonyldiimidazole (1.73 g, 10.67 mmol) in tetrahydrofuran (45mL) under nitrogen is added solid 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid 91a (1.93 g, 8.89 mmol) and the mixture is stirred for 4 hours. Magnesium chloride (850 mg, 8.88mmol) and methyl potassium malonate (2.77 g, 17.77 mmol) are then added and the mixture is stirred overnight. The mixture is diluted with water and 1 M HCl. The aqueous phase is extracted with ethyl acetate (3x). The combined organic phase is washed with 1 M HCl (1x), brine (1x), dried over Na2SO4 and concentrated in vacuo to afford methyl 5-(tertbutoxycarbonylamino)-5-methyl-3-oxohexanoate 91b as a light yellow oil: ESI-MS calcd. for C13H24NO5 ([M+H]+) 274.2, found 274.1. The product is used without further purification.
Asuspension of magnesium chloride (6.96 g, 73.0 mmol) and methyl malonate potassiumsalt (17.66 g, 113.2 mmol) was stirred in THF (280 ml) at 50 oc, under a nitrogenatmosphere for 6 h. To a solution of N-(tert-butoxycarbonyi)-L-phenylalanine (20.0 g,75.4mmol) in THF (200 ml) in a separate flask, under nitrogen and at 0 oc was addedportionwise 1,1 '-carbonyldiimidazole (18.34 g, 113.1 mmol) and the reaction stirred atambient temperature for 2 h, then added to the cooled malonate suspension. Thereaction mixture was then stirred at room temperature for 17 h. Most of the THF wasremoved in vacuo. To the residue was added saturated potassium hydrogen sulphate(300 ml) and ethyl acetate (300 ml). The layers were separated then the aqueous layerwas extracted twice more with ethyl acetate. The combined organic layers were washedwith saturated sodium bicarbonate (2x300 ml) and brine (300 ml), dried andconcentrated in vacuo to give methyl 4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpentanoate (22.22 g, 92percent) as a pale viscous oil which solidified. 1H NMR (400MHz, CDCb) o 7.33-7.08 (m, SH), 5.20-4.80 (m, 1 H), 4.62-4.48 (m, 1 H), 3.69 (s, 3H),3.52 (d, J=16.0 Hz, 1 H), 3.45 (d, J=16.0 Hz, 1 H), 3.25-2.88 (m, 2H), 1.39 (s, 9H). 13CNMR (100 MHz, CDCI3) o 201.8, 167.3, 155.2, 136.1, 129.2, 128.6, 126.9, 80.1, 60.4,52.3, 46.5, 36.7, 28.2. ElMS: m/z 321 [Mt HRMS calcd for C17H23N05 321.1576, found321.1555.
87%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
methyl (R)-4-[(tert-butoxycarbonyl)amino]-3-oxo-4-phenylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
methyl (S)-7-[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-3-oxoheptanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
methyl (S)-8-[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-3-oxooctanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
7-tert-butyl 1-methyl (S)-4-[(benzyloxy)carbonyl]amino}-3-oxoheptanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
methyl (S)-4-[(benzyloxy)carbonyl]amino}-5-(tert-butoxy)-3-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
methyl (R)-4-[(tert-butoxycarbonyl)amino]-6-(methylthio)-3-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and methyl potassium malonate (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
methyl 4-(2-[(benzyloxy)carbonyl]amino}acetamido)-3-oxo-5-phenylpentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
General procedure: 4.2. Synthesis of beta-keto esters from N-protected amino acids-general procedure 1 (GP1). To a solution/suspension of N-protected amino acid (10 mmol) in anhydrous THF (50 mL) under argon was added CDI (2.01 g, 12.00 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h, followed by the addition of a solid mixture of MgCl2 (0.95 g, 9.80 mmol) and <strong>[38330-80-2]methyl potassium malonate</strong> (2.37 g, 15.00 mmol). The reaction mixture was stirred at room temperature for additional 24 h. Volatile components were evaporated in vacuo, the residue was dissolved in EtOAc (150 mL) and washed with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq. satd, 50 mL), NaHCO3 (aq. satd, 20 mL), and NaCl (aq. satd, 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo.
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and <strong>[38330-80-2]methyl potassium malonate</strong> (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5percent aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81percent) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33percent) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65percent).
General procedure: To a solution of 1,1?-carbonyldiimidazole (1.73 g, 10.67 mmol) in tetrahydrofuran (45mL) under nitrogen is added solid 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid 91a (1.93 g, 8.89 mmol) and the mixture is stirred for 4 hours. Magnesium chloride (850 mg, 8.88mmol) and methyl potassium malonate (2.77 g, 17.77 mmol) are then added and the mixture is stirred overnight. The mixture is diluted with water and 1 M HCl. The aqueous phase is extracted with ethyl acetate (3x). The combined organic phase is washed with 1 M HCl (1x), brine (1x), dried over Na2SO4 and concentrated in vacuo to afford methyl 5-(tertbutoxycarbonylamino)-5-methyl-3-oxohexanoate 91b as a light yellow oil.
methyl 6-(4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)phenyl)-3-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
To an acetonitrile solution (0.05 M) of 4-(4-((l -ethoxy-2-methyl-l -oxopropan-2- yl)oxy)phenyl)butanoic acid (1 eq.) from the previous step was added CDI (1.1 eq.). The resulting yellow solution was then allowed to stir at RT for 2.5 h before it was added dropwise, over a period of 1.5 h, into a white suspension of potassium 3-methoxy-3-oxopropanoate (2.1 eq.), magnesium chloride (2.5 eq.) and triethylamine (3.2 eq.). The resulting suspension was then stirred at RT for 16 h and finally heated at reflux for another 24 h. The crude reaction suspension thus obtained was cooled to RT and diluted with EtOAc. The insolubles were then removed via filtration and rinsed further with EtOAc and DCM. The filtrate thus obtained was concentrated in vacuo, re-taken up in EtOAc and washed sequentially with 10percent aq. HCl, water and brine. The organic extract was then dried over Na2S04 and filtered. Concentration of the filtrate in vacuo affored the desired product as a golden oil (96percent yield) which can be used without further purification
2-(hydroxydiphenylmethyl)-1-ethyl-1H-benzo[d]imidazole-6-carboxylic acid[ No CAS ]
[ 38330-80-2 ]
methyl 3-(1-ethyl-2-(hydroxydiphenylmethyl)-1H-benzo[d]imidazol-6-yl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
[0425j Step A: Preparation of methyl 3 -(1 -ethyl-2-(hydroxydiphenylmethyl)- 1H- benzo [d]imidazol-6-yl)-3 -oxopropanoate: A solution of 2-(hydroxydiphenylmethyl)- 1-ethyl- 1H-benzo[d]imidazole-6-carboxylic acid (0.15 g, 0.4 mmol) and CDI (0.078 g, 0.48 mmol) in THF (15 mL) was stirred at ambient temperature for 2 hours. Potassium 3-methoxy-3- oxopropanoate (0.075 g, 0.48 mmol) and magnesium chloride (0.046 g, 0.48 mmoL) were added. The reaction mixture was stirred at 70 °C overnight. After cooling to ambient temperature, the solid was removed by filtration. Water was added to the filtrate and acidified with 2 N HC1 to pH6-7. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give methyl 3 -(1 -ethyl-2-(hydroxydiphenylmethyl)- 1H-benzo [d]imidazol-6-yl)-3 - oxopropanoate (0.14 g, 82percent) as solid.
General procedure: In brief: 32.80 g <strong>[38330-80-2]methyl potassium malonate</strong> (0.21 mol) was placed in a 1l flask under an Ar blanket. 300 ml MeCN was added and the mixture stirred and cooled to 10-15 °C. To this mixture 44.36 ml dry Et3N (32.40 g, 0.32 mol) was added followed by 23.81 g anhydrous MgCl2 (0.25 mol) and stirring continued at 20-25 °C for 2.5 h. The resulting slurry was recooled to 0 °C and the respective acid chloride (0.1 mol) added dropwise over 25min followed by the addition of 3 ml Et3N. The mixture was allowed to stir over night at 20-25 °C and then concentrated in vacuum to remove the MeCN. The residue was suspended in100 ml toluene and the resulting sludge reconcentrated in vacuum. Again 150 ml toluene was added and the mixture cooled to 10-15 °C. 150 ml aqueous HCl (13percent) was added cautiously while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed twice with 40 ml of 13percent aq. HCl and 40 ml water. The solution was then concentrated in vacuum to give the crude product which was purified by distillation or recrystallisation. The purity was checked by HPLC/MS.
General procedure: In brief: 32.80 g <strong>[38330-80-2]methyl potassium malonate</strong> (0.21 mol) was placed in a 1l flask under an Ar blanket. 300 ml MeCN was added and the mixture stirred and cooled to 10-15 °C. To this mixture 44.36 ml dry Et3N (32.40 g, 0.32 mol) was added followed by 23.81 g anhydrous MgCl2 (0.25 mol) and stirring continued at 20-25 °C for 2.5 h. The resulting slurry was recooled to 0 °C and the respective acid chloride (0.1 mol) added dropwise over 25min followed by the addition of 3 ml Et3N. The mixture was allowed to stir over night at 20-25 °C and then concentrated in vacuum to remove the MeCN. The residue was suspended in100 ml toluene and the resulting sludge reconcentrated in vacuum. Again 150 ml toluene was added and the mixture cooled to 10-15 °C. 150 ml aqueous HCl (13percent) was added cautiously while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed twice with 40 ml of 13percent aq. HCl and 40 ml water. The solution was then concentrated in vacuum to give the crude product which was purified by distillation or recrystallisation. The purity was checked by HPLC/MS.
General procedure: In brief: 32.80 g <strong>[38330-80-2]methyl potassium malonate</strong> (0.21 mol) was placed in a 1l flask under an Ar blanket. 300 ml MeCN was added and the mixture stirred and cooled to 10-15 °C. To this mixture 44.36 ml dry Et3N (32.40 g, 0.32 mol) was added followed by 23.81 g anhydrous MgCl2 (0.25 mol) and stirring continued at 20-25 °C for 2.5 h. The resulting slurry was recooled to 0 °C and the respective acid chloride (0.1 mol) added dropwise over 25min followed by the addition of 3 ml Et3N. The mixture was allowed to stir over night at 20-25 °C and then concentrated in vacuum to remove the MeCN. The residue was suspended in100 ml toluene and the resulting sludge reconcentrated in vacuum. Again 150 ml toluene was added and the mixture cooled to 10-15 °C. 150 ml aqueous HCl (13percent) was added cautiously while keeping the temperature below 25 °C. The aqueous layer was separated and the organic layer washed twice with 40 ml of 13percent aq. HCl and 40 ml water. The solution was then concentrated in vacuum to give the crude product which was purified by distillation or recrystallisation. The purity was checked by HPLC/MS.
[00459] To the solution of 2-chloroisonicotinic acid (5 g, 31.7 mmol) in ACN (30 mL) was added CDI (11.6 g, 71.4 mmol) and the mixture was stirred at 25C for lh. potassium 3-methoxy-3- oxopropanoate (5.4 g, 31.7 mmol) and MgCl2 (2.9 g, 31.7 mmol) were added then the mixture was stirred at 25 C for 12hrs. After removal of the solvent, the residue was extracted with EtOAc (20 mLX3). The organic layer was dried over Na2SO4, concentrated and purified by column chromatography to give compound I. (4.2 g, yield: 58.3%). 1H NMR (400 MHz, DMSO- : delta 12.32 (s, 1H), 8.63 (d, J= 4.8 Hz, 2H), 8.52 (d, J= 5.2 Hz, 1H), 7.93 (s, 2H), 7.87 (s, 1H), 7.79- 7.84 (m, 1H), 6.22 (s, 1H), 4.22-4.28 (m, 4H), 4.10-4.15 (m, 4H), 4.01-4.08 (m, 2H), 1.98 (s, 3H), 1.25-1.29 (m, 3H), 1.20-1.23 (m, 6H).
(S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
To a mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (200 g, 0.985 mol) in THF (1 L) was added 1,1?-carbonyldiimidazole (176 g, 1.084 mol) at room temperature. The mixture was stirred at room temperature for 1 h. Then magnesium chloride (101 g, 1.084 mol) and potassium 3-methoxy-3-oxopropanoate (169 g, 1.084 mol) were added. After addition, the mixture was stirred at 50° C. for 3 h. TLC (petroleum ether:ethyl acetate=5:1) showed the starting material was consumed. The mixture was cooled and filtered; the filter cake was washed with THF (300 mL) and filtered. The combined filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (1 L) washed with water (800 mL), brine (800 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45percent) as a yellow oil, which was used in the next step directly without further purification.
45%
To a mixture of (S)-2-((tert-butoxycarbonyl)amino)bu- tanoic acid (200 g, 0.985 mol) in THF (1 L) was added 1,1?-carbonyldiimidazole (176 g, 1.084 mol) at rt.mixture was stirred at it for 1 h. Then magnesium chloride(101 g, 1.084 mol) and potassium 3-methoxy-3-oxopro- panoate (169 g, 1.084 mol) were added. After addition,mixture was stirred at 50° C. for 3 h. TLC (petroleum ether:ethyl acetate=5: 1) showed the starting material was consumed. The mixture was cooled and filtered; the filtercake was washed with THF (300 mE) and filtered.combined filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (1 E) washed with water (800 mE), brine (800 mE), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45percent) as a yellow oil, which was used in the next step directly without thrther purification.
[0089] To a mixture of (lS')-2-((ieri-butoxycarbonyl)amino)butanoic acid (200 g, 0.985 mol) in THF (1 L) was added Iota,Gamma-carbonyldiimidazole (176 g, 1.084 mol) at rt. The mixture was stirred at rt for 1 h. Then magnesium chloride (101 g, 1.084 mol) and potassium 3- methoxy-3-oxopropanoate (169 g, 1.084 mol) were added. After addition, the mixture was stirred at 50 °C for 3 h. TLC (petroleum ether: ethyl acetate = 5: 1) showed the starting material was consumed. The mixture was cooled and filtered; the filter cake was washed with THF (300 mL) and filtered. The combined filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (1 L) washed with water (800 mL), brine (800 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (^-methyl 4-((ieri-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45percent) as a yellow oil, which was used in the next step directly without further purification.
X. Methyl 5-methoxy-3-oxopentanoate CDl (3.24 g, 20.0 mmol) was added portionwise to a stirred suspension of 3-methoxypropanoic acid (1.81 mi, 19.2 mmol) in anhydrous MeCN (80 mL). The mixture was allowed to stir at rt for 1.5 hrs. A powdered mixture of magnesium chloride (1.57 g, 16.5 mmol) and methyl potassium maionate (4.5 g, 28.8 mmol) was added portionwise (note CO2 gas evolved). The mixture was allowed to stir at rt. Volatiies were removed in vacuo and hydrochloric acid (2M, 105 mL) was added. The solution was stirred at rt for 1 hr and extracted with DCM (3 x 100 mL). The organics were dried over magnesium sulfate, filtered and solvent removed in vacuo to afford methyl 5-methoxy-3-oxopentanoate (2.69 g, 87percent yield).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
General procedure: A mixture of proline methyl ester hydrochloride (4, 100?720 mg, 0.6?4.3 mmol), methyl potassiummalonate (0.1?1.0 g, 0.9?6.5 mmol), DIPEA (0.5?3.7 mL, 3.0?22 mmol) and HBTU (0.3?2.5 g, 0.9?6.5 mmol) in THF (2.1?15 mL) was stirred overnight at room temperature. The solvent was thenevaporated under reduced pressure and ethyl acetate (8 mL) was added to the crude product. Themixture was washed with water (8 mL) and brine (2×8 mL), dried (Na2SO4) and concentrated invacuo. The crude product was purified by column chromatography (33?100percent ethyl acetate inpetroleum ether) to give the product as a yellow oil.
(R)-methyl 1-(3-methoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
General procedure: A mixture of proline methyl ester hydrochloride (4, 100?720 mg, 0.6?4.3 mmol), methyl potassiummalonate (0.1?1.0 g, 0.9?6.5 mmol), DIPEA (0.5?3.7 mL, 3.0?22 mmol) and HBTU (0.3?2.5 g, 0.9?6.5 mmol) in THF (2.1?15 mL) was stirred overnight at room temperature. The solvent was thenevaporated under reduced pressure and ethyl acetate (8 mL) was added to the crude product. Themixture was washed with water (8 mL) and brine (2×8 mL), dried (Na2SO4) and concentrated invacuo. The crude product was purified by column chromatography (33?100percent ethyl acetate inpetroleum ether) to give the product as a yellow oil.
6-[4-(3-methoxy-3-oxopropanoyl)-N-tosylpyrrol-2-yl]-1,1-dimethoxy-4,4-dimethyl-5-nitrohexan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With 1H-imidazole; dicobalt octacarbonyl; palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; magnesium chloride; In tetrahydrofuran; at 65℃; for 72h;Inert atmosphere; Sealed tube;
A mixture of compound 1 (1.34 g, 2.50 mmol), <strong>[38330-80-2]methyl potassium malonate</strong> (585 mg, 3.80 mmol), Xantphos (725 mg, 1.30 mmol), MgCl2 (357 mg,3.80 mmol) and imidazole (330 mg, 5.00 mmol) was placed in a 50-mL Schlenk flask and charged with argon. THF (25.0 mL) was added followed with addition of Et3N (520 L, 3.80 mmol). The mixture was degassed by freeze-pump-thaw cycle. Then, Pd(OAc)2 (280 mg, 1.30 mmol) and Co2(CO)8 (430 mg, 1.30 mmol) was added. The flask was sealed immediately and heated at 65 °C for 48 h and progress was monitored by TLC analysis. If reaction is not completed, Pd(OAc)2 (140 mg, 0.65 mmol) and Co2(CO)8 (215 mg, 0.65 mmol) was added and the reaction was continued for another 24 h. The reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The filtrate was washed with brine and water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (silica, ethyl acetate) to give a light-yellow solid (1 .10 g, 80percent): mp138?140 °C; ?H NMR (300 MHz) oe 1.14 (s, 3H), 1.23 (s, 3H), 2.45 (s, 3H), 2.57?2.73 (AB,2J 18.6 Hz, 2H), 3.11?3.17 (ABX, 2J= 16.0 Hz, 1H), 3.35?3.45 (ABX, 2J 16.0 Hz, 3J12.3 Hz, 1H), 3.42 (s, 6H), 3.73 (s, 3H), 3.75 (s, 2H), 4.37 (s, 1H), 5.21?5.26 (ABX, 2J12.0 Hz, 3J= 2.1 Hz, 111), 6.42 (d, J= 1.5 Hz, 1H), 7.37?7.40 (d, J 8.2 Hz, 2H), 7.70?7.73(d, J?= 8.2 Hz, 2H), 7.93 (d, J= 1.8 Hz, 1H); ?3C NMR (75 MHz) 21.8, 23.8, 24.0, 26.3,36.4, 44.5, 46.6, 52.5, 55.1, 92.8, 104.7, 112.5, 126.1, 127.1, 128.0, 130.7, 130.9, 134.8,146.5, 167.5, 186.5, 203.1; ESI-MS obsd 533.1846, calcd 533.1850 [(M+H), M =c251132N2o,os].
To a mixture of 10 g of <strong>[1702-17-6]3,6-dichloropyridine-2-carboxylic acid</strong> and 52 mL of toluene, 9.8 mL of thionyl chloride was added at room temperature.The reaction mixture was heated and stirred at 110 C. for 4 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain an oily substance. To a mixture of 6.9 g of anhydrous magnesium chloride and 104 mL of THF was added 11 g of potassium methyl malonate at room temperature. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, the whole amount of the oily substance obtained in the above Production Example 13 (1) and 14 mL of triethylamine were successively added under ice cooling. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. 300 mL of 2N hydrochloric acid was added to the resulting reaction mixture under ice cooling, and the mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography to obtain 7.9 g of an intermediate (13-2)
To a mixture of 30 g of 3-chloro-5- (trifluoromethyl) pyridine-2-carboxylic acid and 130 mL of toluene, 25 mL of thionyl chloride and 1.6 mL of DMF were added successively at room temperature. The reaction mixture was stirred at 110 C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain an oily substance.32 g of potassium methyl malonate was added to a mixture of 22 g of anhydrous magnesium chloride and 270 mL of THF at room temperature. The reaction mixture was stirred at 50 C. for 1 hour. To the reaction mixture, the whole amount of the oily substance obtained in the above Production Example 28 (1) and 65 mL of triethylamine were successively added under ice cooling. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. 400 mL of 2 N hydrochloric acid was added to the obtained reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography to obtain 29 g of an intermediate (28-2)
2-(1-methyl-1H-[1,2,3]triazol-4-yl)cyclopropanecarboxylic acid[ No CAS ]
[ 38330-80-2 ]
methyl 3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
42d) 3-[2-(1 -Methyl-1 H-[1 , 2, 3]triazol-4-yl)-cyclopropyl]-3-oxo-propionic acid methyl ester 1 ,10-carbonyldiimidazole (0.109 g, 0.67 mmol) was added portionwise over 5 min to a stirred solution of 2-(1 -methyl-1 H-[1 ,2,3]triazol-4-yl)-cyclopropanecarboxylic acid (0.1 OOg, 0.61 mmol) in anhydrous THF (2 ml_) under argon. After 1 h, a mixture of MgCI2 (0.1 16 g, 1 .22 mmol) and potassium hydrogen methyl malonate (0.285 g, 1 .83 mmol) was added. After 24 h the mixture was concentrated under vacuum and diluted with ethyl acetate. The mixture was then washed with aqueous NaHS04 (1 M) and brine, and the organic phase dried over Na2S04, filtered, and concentrated to dryness to give the product, used without further purification (0.187g, quantative). LC-MS /z 224 (M + H) +, 0.68 (ret. time)
59.3%
To a solution of 2-Cl -methyl-l H-l ,2 ,3-triazol-4-yl)cyclopropanecarboxylic acid (24 g, 144mmol) in tetrahydrofuran (700 mL), was added CDI (30.3 g, 215 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then potassium 3-methoxy-3- oxopropanoate (67.3 g, 431 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and re-dissolved in ethyl acetate (200 mL). Then it was washed with 1 M KHSO4 (150 mL), saturated NaHCO3 (150 mL) andbrine (150 mL). The organic layer was dried with Na2SO4 and concentrated to obtain the title compound methyl 3-(2-(l -methyl-l H-l ,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate (20 g, 85 mmol, 59.3 percent yield) as an oil. LC-MS mlz 224.1 (M+H), 1.39 mm (ret. time).
Keep the internal temperature 10 ~ 25 ,100 g of the potassium monomethyl malonate obtained in Example 2 (HPLC purity: 99.1percent, 0.634 mol) and 750 g of acetonitrile were mixed in a reaction flask to maintain the internal temperature of the system at 10 ° C to 25 ° C,After adding 96.23 g of triethylamine (0.951 mol)72.40 g of a magnesium chloride solid (0.760 mol) was added slowly. After the addition is complete,Natural temperature, and keep the system temperature 20 ~ 25 insulation 2 to 3 hours.After cooling to 0 to 10 ° C, 70.10 g of dichloroacetyl chloride (0.476 mol) was slowly added dropwise. Drop finished,The temperature was naturally raised to 20 ° C to 25 ° C and held at that temperature for 18 hours.After completion of the reaction, 240 g of ethyl acetate was added to dilute the reaction solution. Cooling to 0 ~ 15 ,Slowly drop the concentration of 455g 5percentHydrochloric acid aqueous solution (said mass concentration refers to the mass of hydrogen chloride as a percentage of the total mass of the hydrochloric acid aqueous solution). After completion of the dropwise addition, the mixture was incubated at 0 to 15 ° C for 30 minutes,Dispensing. The obtained organic phase was an aqueous hydrochloric acid solution having a mass concentration of 5percent(200 g x 2). After the obtained organic phase was removed from the solvent,Get itMethyl dichloroacetoacetate76.95 g (GC purity: 97.5percent, yield: 85.2percent).
100 g of the potassium monomethyl malonate obtained in Example 2 (HPLC purity: & lt; RTI ID = 0.0 & gt;99.1percent, 0.634 mol) and 750 g of acetonitrile were mixed in a reaction flask to maintain the internal temperature of the system at 10 ° C to 25 ° CAfter adding 96.23 g of triethylamine (0.951 mol), 72.40 g of magnesium chloride solid (0.760 mol) was added slowly. FeedingAfter completion, the natural temperature, and keep the system temperature 20 ~ 25 insulation 2 to 3 hours. Cooling to 0 ~ 10 , slow dropAdd 86.55gTrichloroacetyl chloride (0.476 mol). Drop finished, naturally heated to 20 ~ 25 and 18 in the temperature insulationTime.After completion of the reaction, 240 g of ethyl acetate was added to dilute the reaction solution. Cooling to 0 ~ 15 , slowly dropping 455gOf the aqueous solution of hydrochloric acid having a mass concentration of 5percent (the mass concentration means that the mass of the hydrogen chloride accounts for the total amount of the aqueous hydrochloric acid solutionPercentage of mass). After completion of the dropwise addition, the mixture was incubated at 0 to 15 ° C for 30 minutes. The resulting organic phase uses a mass concentrationAnd washed twice with 5percent aqueous hydrochloric acid (200 g x 2). The organic phase was removed to remove the solvent to give methyl trichloroacetoacetate97.94 g (GC purity: 97.7percent, yield: 86.1percent).
With 1H-imidazole; magnesium chloride; In tetrahydrofuran; at 0 - 20℃; for 44h;Inert atmosphere;
Under a nitrogen atmosphere, the starting material of formula 3 (2.8297 g, 9.14 mmol) was dissolved in 36.56 ml of dry tetrahydrofuran,The reaction system was placed in an ice-water mixture and cooled to 0 C,Then, potassium monomethyl malonate (2.85 g, 18.28 mmol) was added,Imidazole (1.24 g, 18.28 mmol) and anhydrous magnesium chloride (1.74 g, 18.28 mmol)The reaction was carried out at room temperature for 44 h, quenched with saturated NH4Cl solution,Ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered,The crude product was distilled under reduced pressure and purified by silica gel column chromatography to give a yellow viscous compound of formula 41.2106g, yield 76%;
3-(3-tert-butoxycarbonylamino-cyclopentyl)-3-oxo-propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5 g
13a) 3-(3-tert-Butoxycarbonylamino-cyclopentyl)-3-oxo-propionic acid methyl ester A stirred mixture of 3-aminocyclopentanecarboxylic acid (4.00 g, 31 .0 mmol) in THF (20 ml_) was treated with NaOH (1 M aqueous, 57 ml_) followed by Boc anhydride (6.76 g, 31 .0 mmol). After 16 h the mixture was acidified with 2N HCI and then extracted with EtOAc (2x 70 ml_). The organic phases were combined, dried (MgS04), filtered, and concentrated to dryness. The residue was taken up into dry THF (70 ml_) and 1 ,1 '- carbonyldiimidazole (2.86 g, 17.6 mmol) was added and the mixture stirred for 1 h. A solid, powdered mixture of MgCI2 (2.10 g, 17.6 mmol) and potassium methyl malonate (5.05 g, 32.3 mmol) was added and the mixture stirred at room temperature for 18h. The mixture was concentrated and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc before the combined organic phase was washed with brine, dried (MgS04), filtered, and concentrated to dryness to give the product (5g, quantative) used directly in the next step without purification.
3-oxo-3-(3-phenyl-cyclobutyl)propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.63 g
49a) 1 -(3-Bromo-phenyl)-5-(3-phenyl-cyclobutyl)-1 H-pyrazole-4-carboxylic acid methyl ester Under argon, 1 ,1 -carbonyldiimidazole (552 mg 3.4 mmol) was added portionwise to a solution of <strong>[66016-28-2]3-phenyl-cyclobutanecarboxylic acid</strong> (500 mg, 2.84 mmol) in anhydrous THF (9 mL) and the mixture was stirred at room temperature for 1 hour. Then, a well homogenised and powdered solid mixture of MgCI2 (270 mg, 2.84 mmol) and potassium hydrogen methyl malonate (665 mg, 4.26 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The reaction was concentred under vaccum, ethyl acetate was added, and the organic layer was washed with NaHS04 (1 M, aqueous) and then brine. The organic phase was dried over anhydrous Na2S04, filtered, and the filtrate was concentrated to dryness under vacuum to give 3-oxo-3-(3-phenyl-cyclobutyl)- propionic acid methyl ester (0.63 g). A mixture of 3-oxo-3-(3-phenyl-cyclobutyl)-propionic acid methyl ester (0.63 g), dimethylformamide-dimethylacetal (1 .32 mL, 3.12 mmol) and TsOH (5 mg) was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and dissolved in acetonitrile (9 mL). Diisopropylamine (0.742 mL, 4.26 mmol) was added followed by 3-bromophenylhydrazine hydrochloride (712 mg, 3.12 mmol). The solution was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc and washed with water (x7). The organic phase was dried over MgS04, filtered, and concentrated under vacuum to afford the title compound (800 mg, 69%) which was used without further purification. LC-MS m/z 41 1 (M + H)+, 1 .61 (ret. time).
methyl 3-(2,2-difluorocyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
67a) Methyl 3-(2,2-difluorocyclopropyl)-3-oxopropanoate To a solution of 2,2-difluorocyclopropanecarboxylic acid (5.00 g, 41 .0 mmol) in Tetrahydrofuran (THF) (50 ml) was added CDI (7.97 g, 49.2 mmol), portionwise, and stirred at room temperature for 3 h. Then, the reaction was diluted with Tetrahydrofuran (THF) (25 ml) and magnesium chloride (5.15 g, 54.1 mmol) and potassium methyl malonate (12.79 g, 82 mmol) were added and the reaction was stirred for 18 h. Afterwards, the reaction was diluted with water (50.0 ml) and the pH was adjusted to pH = 7 with 1 M HCI (47.5 ml, 47.5 mmol). The aqueous layer was extracted with EtOAc (2X). The combined organics were washed with 1 N HCI and brine, dried with MgS04 and the solvent was concentrated. The residue was re-dissolved in EtOAc and washed with sat. K2C03 (3X), brine, dried with MgS04, and concentrated to provide the title compound (1 .86 g, 25% yield). 1H NMR (400 MHz, Chloroform-d) delta ppm 1 .72 - 1 .84 (m, 1 H) 2.21 - 2.32 (m, 1 H) 2.89 - 3.01 (m, 1 H) 3.57 - 3.68 (m, 2 H) 3.80 (s, 3 H).
2-(2,2-dibromovinyl)cyclopropanecarboxylic acid[ No CAS ]
[ 38330-80-2 ]
methyl 3-(2-(2,2-dibromovinyl)cyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
75c) Methyl 3-(2-(2,2-dibromovinyl)cyclopropyl)-3-oxopropanoate To a solution of 2-(2,2-dibromovinyl)cyclopropanecarboxylic acid (37.6 g, 139 mmol) in tetrahydrofuran (THF) (350 mL) was added CDI (33.9 g, 209 mmol). The mixture was stirred for 2 hours at room temperature, potassium 3-methoxy-3-oxopropanoate (65.3 g, 418 mmol) was added, followed by magnesium chloride (15.92 g, 167 mmol). The resulting reaction mixture was stirred overnight at room temperature. The mixture was neutralized with 6.0 N HCI and diluted with water, extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The residue was dissolved in DCM and purified on the Torrent flash column chromatography (750 g silica gel) eluting with a gradient of 0-25percent ethyl acetate in hexanes. The title compound was obtained as clear yellow oil (45.4 g, 139 mmol, 100 percent yield). LC-MS m/z 324.8 (M+H)+, 1 .0 min (ret. time)
100%
To a solution of 2-(2,2-dibromovinyl)cyclopropanecarboxylic acid (37.6 g, 139 mmol) in tetrahydrofuran (THF) (350 mL) was added CDI (33.9 g, 209 mmol). The mixture was stirred for 2 hours at room temperature, potassium 3-methoxy-3-oxopropanoate (65.3 g, 418 mmol) was added, followed by magnesium chloride (15.92 g, 167 mmol). The resulting reaction mixture was stirred overnight at room temperature. The mixture was neutralized with 6.0 N HC1 and diluted with water, extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The residue was dissolved in DCM and purified on the Torrent flash column chromatography (750 g silica gel) eluting with a gradient of 0- 25percent ethyl acetate in hexanes. The title compound was obtained as clear yellow oil (45.4 g, 139 mmol, 100 percent yield). LC-MS mlz 324.8 (M+H)+, 1.0 min (ret. time).
2-(5-methylisoxazol-3-yl)cyclopropanecarboxylic acid[ No CAS ]
[ 38330-80-2 ]
methyl 3-(2-(5-methylisoxazol-3-yl)cyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
159d) Methyl 3-(2-(1 -methyl-1 H-1 ,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate A solution of 2-(5-methylisoxazol-3-yl)cyclopropanecarboxylic acid (1650mg, 9.87 mmol) in tetrahydrofuran (THF) (200 mL) was added CDI (2087 mg, 14.81 mmol). The reaction mixture was stirred at 25 °C for 2 h. It was added potassium 3-methoxy-3-oxopropanoate (4625 mg, 29.6 mmol) and potassium 3-methoxy-3-oxopropanoate (4625 mg, 29.6 mmol). The reaction mixture was stirred at room temperature for 18 h. Then the solvent was evaporated and re-dissolved in ethyl acetate (20mL). The suspension thus obtained was washed with 1 M KHS04, saturated NaHC03, and brine. The organic layer was dried over Na2S04 and concentrated to obtain the title compound methyl 3-(2-(1 -methyl-1 H- 1 ,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate (2.1 g, 9.41 mmol, 95 percent yield) as an oil. LC-MS m/z 223.9 (M+H)+, 1 .52 min (ret. time).
methyl 3-(3-bromo-6-methylpyridin-2-yl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Under vacuum,Crystal water with a mass ratio of 40:60:8 g (36.1 mmol) of zinc chloride is heated to melt and remove water.Under nitrogen protection, 75 ml of 1,2-dichloroethane was added in sequence.Compound 3 is <strong>[717843-48-6]3-bromo-6-methyl-2-cyanopyridine</strong> 5.5g(27.9mmol),13 g (77 mmol) of monomethyl malonate potassium salt and 1.8 ml (11.0 mmol) of diisopropylethylamine were stirred and refluxed for 16 hours.After the system was cooled to room temperature, 20 ml of 6N hydrochloric acid was added.Returning again for 1 hour, separating the organic phase,The aqueous phase was extracted 3 times with dichloromethane.The organic phases were combined and dried over anhydrous magnesium sulfate.Remove organic solvent, purify,The compound 4 is obtained as methyl 3-(3-bromo-6-methylpyridine)-3-carbonylpropanoate, the yield is 82%, 6.6 g;
100.0 g of the compound represented by the Chemical Formula 1 -3 prepared in step 2, 61.9 g of carbonyldiimidazole and 1.0 L of acetonitrile were added to a flask, and then stirred at room temperature for 1 hour. 59.8 g of <strong>[38330-80-2]methyl potassium malonate</strong>, 36.4 g of anhydrous magnesium chloride, 1.0 L of acetonitrile and 38.8 g of triethylamine were added to another flask and then stirred at 20 to 30°C for 1 hour. The reactants of the two flasks were mixed and refluxed at an external temperature of 80°C for 1 hour to complete the reaction. After cooling to room temperature, purified water was added. After cooling the internal temperature to 5 to 10°C, stirring was carried out for I hour. The obtained solid was filtered under reduced pressure and washed with purified water. Since the obtained crystal is a magnesium salt, the following salt dissociation process was carried out.The magnesium salt prepared above, 1.5 L of ethyl acetate and 1.0 L of purified water were added to a flask and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N-HC1. The organic layer was extracted, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45°C to prepare 97.3 g of the compound represented by the Chemical Formula 1-4 (yield: 81.4percent).-NMR (500 MHz, CDC13): 7.26-7.30 (m, 1H), 6.85-6.92 (m, 2H), 5.83 (s, 1H), 5.64-5.65 (d, 1H), 3.67 (s, 3H), 3.38-3.52 (dd, 2H), 1.41 (s, 9H)
methyl 3-(2-bromo-4-chlorophenyl)-3-oxopropionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.8%
General procedure: A dry 200-mL three-necked flask equipped with a three-way valve was charged with 2-bromobenzoic acid (4b) (5.00 g, 21.6 mmol), CDI (3.86 g, 23.8 mmol), and CH3CN (100 mL). At the same time, another dry 300-mL three-necked flask equipped with a three-way valve was charged with methyl potassium malonate (4.23 g, 27.1 mmol), MgCl2 (2.27 g, 23.8 mmol), (C2H5)3N (9.06 mL, 65.0 mmol), and CH3CN (100 mL). After 8-h stirring at rt, the solution in the 200-mL flask was slowly cannulated into the 300-mL flask. The mixture was stirred at 50 °C for 24 h, and then cooled to rt. To the mixture was carefully added 2M aq HCl (30 mL). The aq layer was extracted with EtOAc (50 mL * 3) and the combined organic layers were washed with brine (30 mL). Dryness over Na2SO4 (ca. 20 g)/filtration/concentration afforded a yellow oil (ca. 5 g), which was purified by SiO2-chromatography (200 g, 4:1 hexane-EtOAc eluent) to give methyl 3-(2-bromo-4-methoxyphenyl)-3-oxopropionate (5b) (4.40 g, 82.0percent) as a yellow oil
methyl 3-(3,5-dichlorophenyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Monomethyl malonate potassium salt (4.06 g, 26 mmol),MgCl2 (2.48 g, 26 mmol) was stirred under reflux in THF (30 mL) overnight to give solution A; N,N'-carbonyldiimidazole (CDI, 3.94 g, 24 mmol)Slowly added to 3,5-dichlorobenzoic acid (3.82 g, 20 mmol) in THF (20 mL).Stir at room temperature for 1 hour to form solution B.Solution B was then slowly added dropwise to solution A at room temperature.After the completion of the dropwise addition, the reaction was stirred at room temperature overnight.It was quenched with 1 M EtOAc (50 mL).The organic phase was combined, washed with brine and dried over anhydrous sodium sulfate.Concentration under reduced pressure gave compound 34A (4.7 g, 95percent yield) as a yellow solid.
General procedure: The carboxylic acid (1 equiv) and CDI (1.1 equiv) were dissolved inanhydrous THF (0.5 M) and stirred at room temperature for 1 h.Monomethyl potassium malonate 6 (1.2 equiv) and anhydrous MgCl2 (1.5 equiv) were added and the reaction was stirred at room temperatureovernight. The reaction was treated with 1 M HCl (aq). The phaseswere separated and the aqueous phase was extracted with EtOAc. Thecombined organic phases were washed with water and brine, dried overNa2SO4, filtered and concentrated under reduced pressure. Purificationby flash column chromatography (2? 22% EtOAc in pentane) affordedbeta-ketoesters 8a-c. All 1H NMR spectra also showed trace amounts of theenol tautomer of the product.
General procedure: The carboxylic acid (1 equiv) and CDI (1.1 equiv) were dissolved inanhydrous THF (0.5 M) and stirred at room temperature for 1 h.Monomethyl potassium malonate 6 (1.2 equiv) and anhydrous MgCl2 (1.5 equiv) were added and the reaction was stirred at room temperatureovernight. The reaction was treated with 1 M HCl (aq). The phaseswere separated and the aqueous phase was extracted with EtOAc. Thecombined organic phases were washed with water and brine, dried overNa2SO4, filtered and concentrated under reduced pressure. Purificationby flash column chromatography (2? 22% EtOAc in pentane) affordedbeta-ketoesters 8a-c. All 1H NMR spectra also showed trace amounts of theenol tautomer of the product.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
