* 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.
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 20, p. 6389 - 6396
2
[ 53088-68-9 ]
[ 5182-44-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1959, vol. 32, p. 1135,1136
[2] Chemische Berichte, 1960, vol. 93, p. 1496 - 1506
3
[ 53088-68-9 ]
[ 14161-84-3 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 19, p. 7234 - 7242
[2] Patent: US2014/187538, 2014, A1,
4
[ 67-56-1 ]
[ 1878-65-5 ]
[ 53088-68-9 ]
Yield
Reaction Conditions
Operation in experiment
97.8%
at 0 - 20℃; for 3 h; Inert atmosphere; Schlenk technique
General procedure: Thionyl chloride (1.06 mL, 14.63 mmol) was added to dropwise the solution of phenyl aceticacid derivatives (1 g, 4.877 mmol) in methanol (10 mL) at 0 . The reaction was allowed to room temperature for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved ethyl acetate and water. The mixture was extracted with ethyl acetate and washed with sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6a-f.
Reference：
[1] Tetrahedron, 1997, vol. 53, # 38, p. 13149 - 13164
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2843 - 2866
[3] Journal of Medicinal Chemistry, 2001, vol. 44, # 17, p. 2701 - 2706
[4] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1679 - 1693
[5] Tetrahedron Letters, 2003, vol. 44, # 2, p. 331 - 334
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5515 - 5518
[7] Tetrahedron, 2002, vol. 58, # 51, p. 10113 - 10126
[8] Chemische Berichte, 1960, vol. 93, p. 1496 - 1506
[9] Journal of Medicinal Chemistry, 1993, vol. 36, # 23, p. 3738 - 3742
[10] Patent: US2012/252802, 2012, A1, . Location in patent: Page/Page column 77-78
[11] Advanced Synthesis and Catalysis, 2015, vol. 357, # 11, p. 2479 - 2484
[12] Synlett, 2015, vol. 26, # 13, p. 1880 - 1884
[13] Angewandte Chemie - International Edition, 2017, vol. 56, # 14, p. 3987 - 3991[14] Angew. Chem., 2017, vol. 129, # 14, p. 4045 - 4049,5
[15] Journal of Chemistry, 2017, vol. 2017,
[16] Angewandte Chemie - International Edition, 2018, vol. 57, # 32, p. 10357 - 10361[17] Angew. Chem., 2018, vol. 130, p. 10514 - 10518,5
[18] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 44, p. 11797 - 11805
5
[ 1878-65-5 ]
[ 74-88-4 ]
[ 53088-68-9 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 20℃; for 1 h; Stage #2: at 20℃; for 48 h;
General procedure: To 15 mmol of appropriate phenylacetic acid in 45 mL of dried toluene 15 mmol of DBU was added and the reaction mixture was stirred in roomtemperature for 1 h. After that time 15 mmol of iodomethane was added and stirring was continued for 2 days. Then, the solvent was evaporated, the residuewas dissolved in ethyl acetate and washed with 0.5percent NaOH and brine. Organic layer was dried over anhydrous Na2SO4. Finally, the solvent was evaporated togive the product as colorless oils. 1.2.1. Methyl 2-(3-chlorophenyl)acetate (4e)CAS: 53088-68-9. Colorless oil, yield 63percent, 1H NMR [DMSO-d6] : 7.29-7.34 (m, 3H, Ph-4,5,6-H), 7.20-7.23 (m, 1H, Ph-2-H), 3.71 (s, 2H, Ph-CH2), 3.60 (s, 3H,CH3).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 117 - 124
6
[ 1878-65-5 ]
[ 53088-68-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sulfuric acid In methanol; 1,1-dichloroethane
Example 84 4-[1-[3-chloro-4-[1N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic Acid To a stirred solution of 3-chlorophenylacetic acid (21.76 g, 127.6 mmol) in dichloroethane (100 ml) was added MeOH (15.6 ml, 383 mmol) and H2SO4 (1 ml) at room temperature. After 20 minutes stirring, the mixture was heated at 80° C. for 2 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq NaHCO3 and brine. After dried over Na2SO4, the extract was concentrated in vacuo to give methyl 3-chlorophenylacetate (25.4 g, 100percent) as a colorless oil. 1H-NMR (CDCl3) δ 3.60 (s,21), 3.70 (s, 3H), 7.15-7.26 (m, 4H).
With thionyl chloride; at 0 - 20℃; for 3h;Inert atmosphere; Schlenk technique;
General procedure: Thionyl chloride (1.06 mL, 14.63 mmol) was added to dropwise the solution of phenyl aceticacid derivatives (1 g, 4.877 mmol) in methanol (10 mL) at 0 . The reaction was allowed to room temperature for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved ethyl acetate and water. The mixture was extracted with ethyl acetate and washed with sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6a-f.
With thionyl chloride; at 0 - 80℃;
Thionyl chloride (11 g, 100 mmol) was added dropwise to a mixture of <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (1.7 g, 10 mmol) in methanol (20 mL) at 0 C. The resulting mixture was refluxed at 80 C. for 12 hours. The volatiles were removed under vacuum and the residue was diluted with water and extracted with ethyl acetate. The combined organic solution was washed with water, dried over sodium sulfate and the concentrated to give 1.5 g of methyl 2-(3-chlorophenyl)acetate as a yellow oil, which was used without further purification.Compound A20 was synthesized in 4 steps according to the procedure for compound A23, substituting the crude methyl 2-(3-chlorophenyl)acetate in place of methyl 4-chlorophenylacetate. The final product was purified by reverse phase flash chromatography (0 to 70% acetonitrile in aq. 0.01% ammonium bicarbonate) to give 19 mg of compound A20 as a white solid: >99.5% purity (HPLC); MS m/z: 514.1 (M+1); 1H NMR (CDCl3, 500 MHz) delta 8.37 (d, J=8.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.62 (t, JHF=54.0 Hz, 1H), 7.41 (m, 2H), 7.21 (m, 2H), 7.10 (s, 1H), 6.96 (m, 1H), 5.10 (s, 1H), 4.00-3.69 (m, 8H), 3.19 (s, 2H), 1.47 (s, 6H) ppm.
With sulfuric acid; for 5h;Reflux;
General procedure: (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.% sulfonic acid (0.28 mL) inmethanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted withsaturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combinedextracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (38) (1.13 g, 99% yield) as a colorless oil. The crude product was used without purification. (Step 2)10 A solution of 38 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide11 (1.16 g, 5.88 mmol) in acetonitrile(9.8 mL) was treated with DBU (1.10 mL, 7.36 mmol) at 0 C and the mixture was stirred for overnight at roomtemperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Theresidue was purified by chromatography on silica gel (n-hexane/ethyl acetate = 10/1 as the eluent) to afford 2a(1.22 g, 98% yield) as an orange solid.
With sulfuric acid; for 12h;Reflux;
General procedure: A mixture of 2-fluorobenzoic acid (5a)(1 g, 7.13mmol) in MeOH (20 mL) was stirred for a fewminutes. Concentrated H2SO4 (1 mL) was added, and themixture was refluxed for 12 h. The reaction was monitoredby TLC using -hexane, with ethyl acetate as a developingsystem.CH2Cl2 (30 mL) was then added, and the mixture wasextracted with distilled H2O (3 × 20 mL).The organic phasewas separated, dried on anhydrous Na2SO4, and evaporatedunder vacuum to afford corresponding ester 6a in almostquantitative yield in oil form (1.09 g).
With N-Bromosuccinimide; hydrogen bromide; In chloroform; for 72h;Heating / reflux;
EXAMPLE 96; Synthesis of (3-Chloro-phenyl)-[4-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperazin-1-yl]-acetic acid methyl ester; Step 1: A mixture of (3-Chloro-phenyl)-acetic acid methyl ester (2.0 g, 10.8 mmol), N-bromosuccinimide (1.95 g, 11.0 mmol) and 3 drops of hydrobromic acid (48% solution) in chloroform (100 mL) was heated under reflux for three days. Additional amounts of N-bromosuccinimide and hydrobromic acid were added to drive the reaction to completion. The reaction mixture was concentrated to dryness, taken up in methylene chloride and loaded onto a column of silica gel. Elution with 10% ethyl acetate/hexanes gave Bromo-<strong>[53088-68-9](3-chloro-phenyl)-acetic acid methyl ester</strong> (1.95 g, 69% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform;
REFERENCE EXAMPLE 30 Methyl (RS)-a-bromo-(3-chlorophenyl)acetate A mixture of Reference Example 29 (5.0 g), N-bromosuccinimide (5.3 g) and azobisisobutyronitrile (0.38 g) in dry chloroform (50 ml) was heated at reflux for 6 hours. The reaction mixture was washed four times with water (50 ml) and the organic phase dried over magnesium sulphate and evaporated. The residual oil was purified by flash chromatography on silica eluding with a mixture of ethyl acetate and pentane (5:95, v/v). Fractions homogenous in the required product were combined and evaporated to give the title compound (4.3 g) as an oil.
To a stirred mixture of methyl 3-clorophenylacetate (25.4 g, 128 mmol) in H2SO4 (44 ml) was added HNO3 (5.5 ml, 138 mmol) at 0 C. The reaction mixture was gradually raised to room temperature for 4 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with aq. NaHCO3 and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [1 kg, n-hexane/EtOAc (40/1)] to give methyl 3-chloro-4-nitrophenylacetate (11.4 g, 36%) as a yellow oil. 1H-NM (CDCl3) delta 3.69 (s, 2H), 3.74 (s, 3H), 7.33 (dd, J=8.3, 1.5 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H).
General procedure: Aryl acetate 1a (2.0 mmol, 1.0 equiv.), CuO (0.2 mmol, 0.1equiv.) and aq TBHP (6.0 mmol, 3.0 equiv.) were added to aflask connected to a reflux condenser. The flask was heated at 110 C for 4.5 h and then cooled to room temperature.Pyridine (0.5 mL, 3.0 equiv.) was added and the mixture washeated to 50 C and stirred for 4.0 h. Thereafter, an aqueoussolution of Na2S2O3 (0.5 mol L-1, 10.0 mL) was added, andthe mixture was extracted with EtOAc (×3). The organiclayers were combined, washed with brine, dried overanhydrous Na2SO4, filtered, concentrated and purified byflash column chromatography over silica gel (200-300 mesh) using petroleum ether/EtOAc (25:1) to afford thedesired compound 2a (172.3 mg, 53% yield) as a colourlessoil.
List of Compounds 1: ... METHYL 4-FLUOROPHENYLACETATE METHYL 2-CHLORO-4-FLUOROPHENYL ACETATE METHYL 3-CHLOROPHENYLACETATE METHYL 3,4-DICHLOROPHENYLACETATE ...
66
[ 1878-65-5 ]
4-[1-[3-chloro-4-[1N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic Acid[ No CAS ]
[ 53088-68-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sulfuric acid; In methanol; 1,1-dichloroethane;
Example 84 4-[1-[3-chloro-4-[1N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic Acid To a stirred solution of 3-chlorophenylacetic acid (21.76 g, 127.6 mmol) in dichloroethane (100 ml) was added MeOH (15.6 ml, 383 mmol) and H2SO4 (1 ml) at room temperature. After 20 minutes stirring, the mixture was heated at 80 C. for 2 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq NaHCO3 and brine. After dried over Na2SO4, the extract was concentrated in vacuo to give methyl 3-chlorophenylacetate (25.4 g, 100%) as a colorless oil. 1H-NMR (CDCl3) delta 3.60 (s,21), 3.70 (s, 3H), 7.15-7.26 (m, 4H).
To a stirred mixture of methyl 3chlorophenylacetate (10.8 g, 47.1 mmol) in H2SO4 (15.1 ml) was added HNO3 (2.8 ml, 70.7 mmol) at 0 C. The reaction mixture was gradually raised to room temperature for 5.5 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq. NaHCO3 and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [500 g, n-hexane/EtOAc (10/1)] to give methyl 3-bromo-4-nitrophenylacetate (3.69 g, 29%) as a yellow oil. 1H-NMR (CDCl3) delta 3.68 (s, 2H), 3.73 (s, 3H), 7.38 (dd, J=8.3, 1.2 Hz, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1M).
To a solution of dimethyl methylphosphonate (4.32 mL, 40 mmol) in anhydrous THF (40 mL), cooled at-78 [C] was added [N-BULI] (1.6 M in hexane, 27.5 mL, 44 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 3-chlorophenylacetate (3.69 mL, 20 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at-78 [C,] gradually was warm to room temperature. The mixture was quenched with addition of 1N [HC1] to pH 4-5. The organic layer was separated, washed with brine and dried over [MGS04.] The residue was purified through flash chromatography on silica gel [(MEOH/CH2CL2] 1.5/98. 5) to give the product (1.43 g) with colorless oil in 26% [YIELD. LH-NMR (CDC13) delta 3.07 (d, J= 21 Hz, 2H), 3.750 (s, 3 H), 3.775 (s, 3H), 3.873 (s, 2H), 7.01 (t, J= 8.0 Hz, 1H), 7.19 (s, 1H), 7.28 (d, J= 8. 0 Hz, 2H).
With n-butyllithium; acetic acid; In tetrahydrofuran; ethyl acetate;
Preparation 5 [3-(3-Chloro-phenyl)-2-oxo-propyl]-phosphonic acid dimethyl ester To a solution of dimethyl methylphosphonate (17.93 g, 144 mmol) in THF (270 mL) at -78 C. was slowly added n-BuLi (2.5M, 64.2 mL, 160.6 mmol). The reaction mixture was stirred for 1 h and <strong>[53088-68-9](3-chloro-phenyl)-acetic acid methyl ester</strong> (26.93 g, 146 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred for 24 h. AcOH (15 mL) was added and the volatiles were removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed carefully with saturated aqueous NaHCO3 (3 times). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (20% EtOAc in hexanes to EtOAc) provided the title compound (9.28 g).
With n-butyllithium; acetic acid; In tetrahydrofuran; ethyl acetate;
Preparation 14 [3-(3-Chloro-phenyl)-2-oxo-propyl]-phosphonic acid dimethyl ester To a solution of dimethyl methylphosphonate (17.93 g, 144 mmol) in THF (270 mL) at -78 C. was slowly added n-BuLi (2.5M, 64.2 mL, 160.6 mmol). The reaction mixture was stirred for 1 h and <strong>[53088-68-9](3-chloro-phenyl)-acetic acid methyl ester</strong> (26.93 g, 146 mmol) 25 was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred for 24 h. Acetic acid (15 mL) was added and the volatiles were removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed carefully with saturated aqueous NaHCO3 (3 times). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (20% EtOAc in hexanes to EtOAc) provided the title compound (9.28 g).
REFERENCE EXAMPLE 29 Methyl 3-chlorophenylacetate A solution of 3-chlorophenylacetic acid (10.0 g) in methanol (80 ml) containing 2 drops of concentrated sulphuric acid was heated at reflux for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was dried over magnesium sulphate and evaporated to give the title compound (9.8 g) as a colourless oil.
methyl (3-chlorophenyl)(4,6-dimethoxypyrimidin-2-yl)-acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide;
EXAMPLE 1 Methyl (3-chlorophenyl)(4,6-dimethoxypyrimidin-2-yl) acetate Sodium hydride (6.0 g of 80% in oil) was added to a stirred solution of <strong>[53088-68-9]methyl (3-chlorophenyl)acetate</strong> (36.8 g) and 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (42.6 g) in dimethylformamide (250 ml) with water bath cooling. The resulting suspension was stirred at room temperature for 18 hours. The mixture was then poured onto water (1.5 l) and the resulting oil was extracted into ether. The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate, and evaporated to give a yellow oil, which was purified by chromatography to give 42.3 g of the desired product as a colourless oil.
β-(dimethylamino)-3-chloroatropic acid, methyl ester[ No CAS ]
[ 64124-05-6 ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide;
EXAMPLE 9 1,4-Bis-(3-chlorophenyl)-2-ethyl-3-pyrazolin-5-one A 17 gram portion of 3-chlorophenylacetic acid, methyl ester, was combined with 12 grams dimethylformamide dimethyl acetal in 100 ml. dimethylformamide and the mixture was heated in an open flask at the boiling temperature of the mixture for 6 hours. The hot reaction mixture was then poured over ice, and the aqueous mixture was filtered. The solids were recrystallized from benzene/hexane to produce 13 grams of beta-(dimethylamino)-3-chloroatropic acid, methyl ester, m.p. 84-86 C.
6-(3-chlorobenzyl)-1-(2,6-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
sodium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; mineral oil;
EXAMPLE 1 6-(3-Chlorobenzyl)-1-(2,6-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one 0.1 g (0.43 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 16A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.3 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The sodium chloride precipitated thereby is filtered off. The filtrate is concentrated in vacuo, and the remaining residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 mum; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 59 mg (37% of theory) of the product are obtained as a colourless solid. LC-MS (Method 2): Rt=4.20 min. MS (ESI pos): m/z=365 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=1.87 (s, 6H), 3.92 (s, 2H), 7.29 (m, 7H), 8.28 (s, 1H), 12.43 (s, 1H) ppm.
6-(3-chlorobenzyl)-1-(2,3-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium chloride; In ethanol; mineral oil;
EXAMPLE 2 6-(3-Chlorobenzyl)-1-(2,3-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one 0.1 g (0.43 mmol) of 5-amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 17A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.3 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The mixture of sodium chloride and the product precipitated thereby is filtered off and washed several times with water and diethyl ether. Drying under high vacuum results in 97 mg (61% of theory) of the product as colourless solid. LC-MS (Method 3): Rt=3.85 min. MS (ESI pos): m/z=365 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=1.82 (s, 3H), 2.32 (s, 3H), 3.92 (s, 2H), 7.31 (m, 7H), 8.23 (s, 1H), 12.40 (s, 1H) ppm.
6-(3-chlorobenzyl)-1-(4-methylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 3 6-(3-Chlorobenzyl)-1-(4-methylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one In analogy to the preparation of Example 2, 99 mg (69% of theory) of the desired product are obtained as a colourless solid starting from 0.88 g (0.41 mmol) of 5-amino-1-(4-methylphenyl)-1H-pyrazole-4-carboxamide (Example 18A), 0.22 g (1.2 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.16 g (4.09 mmol) of 60% sodium hydride. LC-MS (Method 3): Rt=4.03 min. MS (ESI pos): m/z=351 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=2.35 (s, 3H), 4.04 (s, 2H), 7.35 (m, 5H), 7.50 (s, 1H), 7.89 (d, 2H), 8.23 (s, 1H), 12.49 (s, 1H) ppm.
6-(3-chlorobenzyl)-1-(2,6-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 4 6-(3-Chlorobenzyl)-1-(2,6-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one In analogy to the preparation of Example 1, 104 mg (69% of theory) of the desired product are obtained as a colourless solid starting from 0.1 g (0.37 mmol) of 5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carboxamide (Example 19A), 0.2 g (1.1 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.14 g (3.6 mmol) of 60% sodium hydride. LC-MS (Method 3): Rt=3.77 min. MS (ESI pos): m/z=405 (M+H)+1H-NMR (300 MHz, DMSO-d6): delta=3.94 (s, 2H), 7.30 (m, 4H), 7.69 (m, 2H), 7.70 (s, 1H), 8.39 (s, 1H), 12.57 (s, 1H) ppm.
6-(3-chlorobenzyl)-1-(2,5-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 5 6-(3-Chlorobenzyl)-1-(2,5-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one In analogy to the preparation of Example 1, 35 mg (23% of theory) of the desired product are obtained as a colourless solid starting from 0.1 g (0.37 mmol) of 5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxamide (Example 20A), 0.2 g (1.1 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.14 g (3.6 mmol) of 60% sodium hydride. LC-MS (Method 2): Rt=4.20 min. MS (ESI pos): m/z=405 (M+H)+
6-(3-chlorobenzyl)-1-(2-aminophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 6 1-(2-Aminophenyl)-6-(3-chlorobenzyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one In analogy to the preparation of Example 1, 103 mg (63% of theory) of the desired product are obtained as a colourless solid starting from 0.1 g (0.46 mmol) of 5-amino-1-(2-aminophenyl)-1H-pyrazole-4-carboxamide (Example 22A), 0.25 g (1.4 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.18 g (4.6 mmol) of 60% sodium hydride. LC-MS (Method 6): Rt=3.32 min. MS (ESI pos): m/z=352 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=3.96 (s, 2H), 4.46 (s, 2H), 6.81 (t, 1H), 7.03 (d, 1H), 7.31 (m, 5H), 7.44 (s, 1H), 8.28 (s, 1H), 12.47 (s, 1H) ppm.
5-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carboxamide[ No CAS ]
[ 53088-68-9 ]
6-(3-chlorobenzyl)-1-(3-chloropyridin-2-yl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 8 6-(3-Chlorobenzyl)-1-(3-chloropyridin-2-yl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one In analogy to the preparation of Example 2, 85 mg (54% of theory) of the desired product are obtained as a colourless solid starting from 0.1 g (0.42 mmol) of 5-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carboxamide (Example 24A), 0.23 g (1.26 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.17 g (4.2 mmol) of 60% sodium hydride. LC-MS (Method 3): Rt=3.10 min. MS (ESI pos): m/z=372 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=4.01 (s, 2H), 7.34 (m, 4H), 7.49 (s, 1H), 7.69 (d, 1H), 7.91 (t, 1H), 8.27 (s, 1H), 12.57 (s, 1H) ppm.
6-(3-chlorobenzyl)-1-(3-fluorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 7 6-(3-Chlorobenzyl)-1-(3-fluorophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one In analogy to the preparation of Example 2, 125 mg (77% of theory) of the desired product are obtained as a colourless solid starting from 0.1 g (0.45 mmol) of 5-amino-1-(3-fluorophenyl)-1H-pyrazole-4-carboxamide (Example 23A), 0.25 g (1.36 mmol) of <strong>[53088-68-9]methyl 3-chlorophenylacetate</strong> and 0.18 g (4.5 mmol) of 60% sodium hydride. LC-MS (Method 3): Rt=3.98 min. MS (ESI pos): m/z=355 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=4.08 (s, 2H), 7.19 (m, 1H), 7.36 (m, 3H), 7.55 (m, 2H), 7.93 (m, 2H), 8.3 (s, 1H), 12.61 (s, 1H) ppm.
With sulfuric acid; In methanol; water; ethyl acetate;
Example 1 Preparation of Methyl-2-(3-Chlorophenyl) Acetate 3-chloro phenyl acetic acid (10.0 g) was added to a mixture containing methanol (50 mL) and sulfuric acid (2.0 mL) at 25-35 C. The mixture was heated to reflux temperature. The refluxing was continued till substantial completion of the reaction. The solvent in the reaction mass was distilled under reduced pressure at 55 C. Water (50 mL) was added and the pH of the mixture was adjusted to pH 8 with 20% sodium carbonate solution (50.0 mL). Ethyl acetate (100 mL) was charged and aqueous and organic layer were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The ethyl acetate layers were combined and washed with water (50 mL). The organic layer was distilled at 55 C. under reduced pressure to obtain the title compound. Yield: 10.3 g.
In N,N-dimethyl-formamide; at -10 - 20℃;Inert atmosphere;
General procedure: 5.2.1 5,6-Dichloro-1,3-dihydro-3-(4-chlorophenyl)-indole-2-one (3) Sodium hydrate 60% (2.85 g, 71.2 mmol) at -10 C and under nitrogen atmosphere was suspended in N,N-dimethylformamide (DMF) (45 ml) before being added to a solution of 1,2-dichloro-4-fluoro-5-nitrobenzene (5 g, 23.8 mmol) and methyl-4-chlorophenyl acetate (4.4 g, 23.8 mmol). in DMF (70 ml) The mixture was stirred at -5 C for 2 h and then allowed to warm up to room temperature. After quenching with ice, an aqueous solution of 10% NH4Cl was added and the mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using column chromatography on silica gel (hexane/EtOAc = 3/1) to give 1,2-dichloro-4-[2-(methy-l-4-chlorophenyl acetate)]-5-nitrobenzene (3.18 g, 36%) as a colourless oil.
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