* 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] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 20, p. 4560 - 4563
2
[ 1878-65-5 ]
[ 5182-44-5 ]
Yield
Reaction Conditions
Operation in experiment
55%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere
Example 86A 2-(3-chlorophenyl)ethanol To a mixture of 2-(3-chlorophenyl)acetic acid (11.4 g, 66.7 mmol) in 150 mL of THF was added LiAlH4 (3.04 g, 80.0 mmol) portionwise at 0° C. The resulting mixture was warmed to room temperature and stirred for 2 hours under N2 atmosphere. Then 2 N NaOH (30 mL) was added dropwise and extracted with EtOAc (2*150 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to provide the crude product which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=50:1-10:1) to obtain 4.96 g of the title compound as a colorless oil. Yield: 55percent.
55%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2 h;
2-(3-chlorophenyl)ethanol[113] To a mixture of 2-(3-chlorophenyl)acetic acid (11.4 g, 66.7 mmol) in 150 mL of THF was added LiAlH4 (3.04 g, 80.0 mmol) portionwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours under 2 atmosphere. Then 2 N NaOH (30 mL) was added dropwise and extracted with EtOAc (2 x 150 mL). The organic layers were combined, dried over anhydrous Na2S04; filtered, and concentrated to provide the crude product which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50: 1 - 10: 1) to obtain 4.96 g of the title compound as a colorless oil. Yield: 55percent.
18.3g
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; for 4 h;
Specific operations are as follows: 20g of m-chlorophenylacetic acid was added to 200ml of tetrahydrofuran, cooled to 0 ° C with stirring,At the beginning of batch addition of 8.9g of lithium aluminum hydride, the temperature was raised to 25 ~ 30 after the addition, the reaction 4h after the addition of water 300ml, dichloromethane400 ml of the mixture was separated, and the organic phase was added with 20 g of anhydrous sodium sulfate and dried under reduced pressure at 30-35 ° C. to obtain a pale yellow oil (S1-1): 18.3 g; Dropping phosphorus tribromide, the dropping temperature during the control at 0 ~ 10 ° C, dropping completed,After stirring for 10min, the temperature was raised to 75-80 ° C,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,The mixture was stirred for 20 minutes, and the filtrate was concentrated under reduced pressure at 40-45 ° C. to give a yellow liquid (intermediate S2): 22.4 g. Yield: 87.0percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 756 - 760
[2] Patent: US2013/131036, 2013, A1, . Location in patent: Paragraph 1585; 1586
[3] Patent: WO2013/62966, 2013, A2, . Location in patent: Paragraph 112; 113
[4] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479
[5] Journal of the American Chemical Society, 1978, vol. 100, p. 228 - 246
[6] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[7] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4321 - 4335
[8] Chemische Berichte, 1960, vol. 93, p. 1496 - 1506
[9] Patent: US4801593, 1989, A,
[10] Patent: WO2003/95444, 2003, A1, . Location in patent: Page/Page column 45
[11] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 7, p. 1906 - 1914
[12] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[13] Patent: CN106478506, 2017, A, . Location in patent: Paragraph 0113; 0114
3
[ 1878-65-5 ]
[ 16799-05-6 ]
Reference：
[1] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[2] Patent: CN106478506, 2017, A,
4
[ 1878-65-5 ]
[ 108-24-7 ]
[ 14123-60-5 ]
Reference：
[1] Archiv der Pharmazie, 1992, vol. 325, # 12, p. 751 - 760
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 17, p. 5309 - 5312[3] Angew. Chem., 2016, vol. 128, # 17, p. 5395 - 5398,4
5
[ 1878-65-5 ]
[ 621-37-4 ]
[ 100-51-6 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 852 - 858
6
[ 67-56-1 ]
[ 1878-65-5 ]
[ 538-86-3 ]
[ 621-37-4 ]
[ 100-51-6 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 852 - 858
7
[ 1878-65-5 ]
[ 14161-84-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 11, p. 1704 - 1711
[2] Patent: US2014/187538, 2014, A1,
8
[ 1878-65-5 ]
[ 74-88-4 ]
[ 14161-84-3 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 38, p. 13149 - 13164
[2] Journal of the American Chemical Society, 2017, vol. 139, # 44, p. 15632 - 15635
9
[ 1878-65-5 ]
[ 58357-84-9 ]
Reference：
[1] Archiv der Pharmazie, 1988, vol. 321, # 5, p. 265 - 272
[2] Journal of the American Chemical Society, 1984, vol. 106, # 11, p. 3344 - 3353
10
[ 1529-41-5 ]
[ 1878-65-5 ]
[ 58357-84-9 ]
Reference：
[1] Biocatalysis and Biotransformation, 2011, vol. 29, # 2-3, p. 54 - 59
11
[ 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
12
[ 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
13
[ 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 1-butyl-3-methylimidazolium hydrogen sulfate; water; at 60 - 65℃; for 1.4h;Green chemistry;
General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO4 and the reaction mixture was heated at 60-65 C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90%) in all cases. All final products obtained were found sufficiently pure so it didn?t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95% ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;
To a solution of <strong>[1878-65-5]2-<strong>[1878-65-5](3-chlorophenyl)acetic acid</strong></strong> (20.0 g, 0.12 mol) and DMF (0.2 mL) in DCM (100 mL) was added oxalyl chloride (45.7 g, 0.36 mol) dropwise and the mixture was stirred at RT for 1 h. The mixture was then concentrated under reduced pressure to give the title compound (10.0 g, 45%) as a red oil. LCMS-C: Rt2.03 min; m/z 185.0 [M- CI+MeO+H]+.
With thionyl chloride; for 1h;Heating / reflux;
A suspension of <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (2 mmole) in thionyl chloride (10 ml) was refluxed for 1 hour. The excess thionyl chloride was removed under reduced pressure to yield crude <strong>[1878-65-5]3-chlorophenyl acetic acid</strong> chloride. This crude residue was redissolved in dichloromethane (10 ml) and this solution was added to a solution of 4- (piperazin-1-yl)-6-chloro-pyrido[3,2-d]pyrimidine (2 mmole) in dichloromethane (10 ml). The resulting mixture was stirred at room temperature for 1 hour. The solvents were removed by evaporation in vacuo. The crude residue was purified by silica gel column chromatography, the mobile phase being a MeOH/dichloromethane mixture in a ratio of 1:40, affording the pure title compound (yield 60 %) as a yellowish solid which was characterized by its mass spectrum as follows: MS (m/z): 403.1 ([M+H]+, 100).
With thionyl chloride; for 3h;Heating / reflux;
3-Chlorophenylacetyl chloride 3-Chlorophenylacetic acid (19.7 g) in thionyl chloride (100 ml) was heated at reflux for 3 h. Volatiles were removed in vacuo and the obtained oily residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): 4.12 (s, 2H), 7.16 (d, 1H), 7.27-7.34 (m, 3H).
With thionyl chloride; for 3h;Heating / reflux;
3-Chlorophenylacetyl chloride.3-Chlorophenylacetic acid (19.7 g) in thionyl chloride (100 ml) was heated at reflux for 3 h.Volatiles were removed in vacuo and the obtained oily residue was used in the next step <n="32"/>without iurther purification. 1H NMR (500 MHz, CDCl3): 4.12 (s, 2H), 7.16 (d, IH), 7.27- 7.34 (m, 3H).
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 1h;
To a solution of <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (10.0 g) in THF (200 ml) was added DMF (5 drops) and then oxalyl chloride (8.0 ml) was added at room temperature, and the mixture was stirred for 1 hr. The mixture was concentrated in vacuo to give 3-chlorophenylacetyl chloride.Aluminum chloride (16 g) was added to a suspension of 2H-1, 4-benzoxazin-3 (4H) -one (8.0 g) in 1, 2-dichloroethane (100 ml) with ice-cooling and then 3-chlorophenylacetyl chloride obtained above was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hr, then poured into ice-cooled water (200 ml) and the resulting crystals were collected by filtration. The crystals were suspended in methanol (200 ml) and the mixture was refluxed for 2 hr. After cooling the mixture, the resulting crystals were collected by filtration. The title compound was obtained as crystals (14.9 g) .1H-NMR (300 MHz, DMSO-d6) delta: 4.35 (2H, s), 4.69 (2H, s) , 7.07 (IH, d, J = 8.3 Hz), 7.17 - 7.25 (IH, m) , 7.26 - 7.40 (3H, m) , 7.52 (IH, d, J = 1.9 Hz), 7.73 (IH, dd, J = 8.3, 1.9 Hz,), 10.89 (IH, s) .
With thionyl chloride; In dichloromethane; for 3h;Heating / reflux;
A solution of 3- chlorophenylacetic acid (0.85 g, 5.0 mmol) and thionyl chloride (3.0 mL) in CH2C12 (17.0 mL) was heated to reflux for 3 h, then cooled to room temperature and added to a suspension of aluminum chloride (1. 12 g, 8.4 mmol) in 1,2-dichloroethane (3. 0 mL) stirring at room temperature. After 15 min, a solution of 1-phenylsulfonylpyrrole (0.87 g, 4.2 mmol) in 1,2-dichloroethane (3.0 mL) was added, and the reaction mixture was stirred at room temperature. The reaction was monitored by thin layer chromatography. After 2 h, the mixture was poured over ice water and extracted with CH2C12 (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2S04, filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, EtOAc/hexane 15-30%) to afford 1.33 g (88%) of a white solid. M. p. 106-108 C ; 1H NMR (300 MHz, CDC13) 8 4.00 (s, 2H), 6.70 (dd, J = 1. 6, 3.3 Hz, 1H), 7.12 (m, 1H), 7.14 (dd, J= 2.2, 3.3 Hz, 1H), 7.24 (m, 3H), 7. 57 (m, 2H), 7.65 (m, 1H), 7.77 (t, J = 1. 9 Hz, 1H), 7.91 (m, 2H); MS (ESI) 381.8 (M+ + Na).
With thionyl chloride; for 1.5h;Heating / reflux;
A solution of 3- chlorophenylacetic acid (2.0 g) in 9 ml_ of thionyl chloride was refluxed for 1.5 h. The solution was cooled and concentrated in vacuo to afford the acid chloride as a yellow oil.
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h;
General procedure: To the various carboxylic acids (obtained from ASDI, Inc., 0.076 mmol, 1 equiv.) was added dry DCM (0.5 mL), oxalyl chloride (0.076 mmol, 1 equiv.), and then 2 drops of DMF. The reactions were placed in the shaker and reacted overnight at ambient temperature for 24 h. A solution of the hydrochloride salt of 3 (0.048 mmol, 1 equiv.) in 1.5 mL of DMF was added, followed by DIEA (0.240 mmol, 5 equiv.). The vials were agitated in the shaker for 24 h at ambient temperature. The solvent was removed in a Genevac HT24 centrifugal evaporator, and the crude intermediates were carried forward without purification. To each of the above crude products was added 10% TEA in MeOH (2 mL). The reaction vials were then placed in the shaker at 33 C overnight, and the solvent was evaporated. All the crude products were purified via preparative HPLC to >95% purity, and the desired products in the yields as described below.
With thionyl chloride; at 80℃; for 3h;
General procedure: For the synthesis of compounds 4a-4h and 5a-5h was depicted in Scheme 2. Firstly, 2-phenylacetic acid (1 mmol) and SOCl2 (4-6 mL) were refluxed at 80 C for 3 h. The reaction liquid was cooled to room temperature and then evaporated to give reactive acyl chloride. The product was obtained as an oil matter, which would be dissolved in acetone (5-6 mL) in the next step. Treatment of 3a (5-phenylthiazol-2-amine) with 2-phenylacetyl chloride in acetone for 5 h at ice-bath afforded the aimed amine. Meanwhile, K2CO3 (0.8 g) was added to the mixture. Then the mixture was evaporated under reduced pressure and the resulting solid was washed with diluted NaOH liquid. The aimed amide was extracted from the NaOH liquid with ethyl acetate for column chromatography. Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether to give the aimed amine (4a). Compounds of 4b-4h and 5a-5h could begot with corresponding acids by the procedures above.
With thionyl chloride; at 80℃; for 4h;Inert atmosphere;
General procedure: A dry flask containing the corresponding carboxylic acid (1 mmol) and SOCl2 (0.6 mL) was heated at 80 C for 4 h under a nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated under reduced pressure to remove the volatiles and then, the resultant crude reaction mixture was diluted with anhydrous DCM (2 mL). The DCM solution of corresponding acid chloride was slowly added to another RB flask containing the corresponding amine (1 mmol), Et3N (111 mg, 1.1mmol) and DCM (4 mL) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 12 h. After this period, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous NaHCO3 solution (twice). The combined organic layers were dried over anhydrous Na2SO4 and then, the solvent was evaporated in vacuo to afford a crude reaction mixture. Purification of the crude reaction mixture by column chromatography (neutral alumina (EtOAc/hexanes=25:75) furnished the corresponding products 1f-j.
With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 0℃; for 0.5h;Inert atmosphere;
General procedure: A carboxylic acid (0.75 mmol) was added into a dry double-neckflask, and 5 mL of dry THF was added to the flask. N,N-dimethylformamide(1.50 mmol, 0.15 mL) was added into the solutionunder nitrogen at 0 C. When the solids were completely dissolved,oxalyl chloride (3.75 mmol) was added slowly. After 30 min, thesolvent and excess oxalyl chloride were removed under reducedpressure to obtain an acyl chloride which was kept dry. 100 mg ofcompound 2-4 (0.53 mmol) was added into a dry double-neckflask, and 5 mL of dry THF was added to the flask. When thesewere completely dissolved, dry pyridine (1.06 mmol, 0.01 mL) wasadded under nitrogen at 0 C. The THF solution of an acyl chloride(0.793 mmol) was added into the mixture slowly. After 30 min,20 mL of saturated ammonium chloride solution was slowly addedinto the mixture, and the mixture was extracted with EtOAc(3 x 20 mL). The organic layer was dried over anhydrous Na2SO4,filtered and concentrated to dryness, then purified through silicagel column (EA: PE 2: 1) to give B-1~B-15.
With thionyl chloride; at 60℃; for 16h;
A solution of <strong>[1878-65-5]2-<strong>[1878-65-5](3-chlorophenyl)acetic acid</strong></strong> (50.0 g, 293.1 mmol, 1.0 eq) in SOCh (300.0 mL) was stirred at 60C for about 16 h. TLC (Petroleum ether/Ethyl acetate = 3/1) showed the starting material was consumed completely (quenched by methanol). Then the mixture was concentrated by rotary evaporator to give 2-(3-chlorophenyl)acetyl chloride (55.4 g, crude) as light yellow liquid.
With thionyl chloride; at 60℃; for 16h;
General procedure: A solution of <strong>[1878-65-5]2-<strong>[1878-65-5](3-chlorophenyl)acetic acid</strong></strong> (50.0 g, 293.1 mmol, 1.0 eq) in SOCh (300.0 mL) was stirred at 60C for about 16 h. TLC (Petroleum ether/Ethyl acetate = 3/1) showed the starting material was consumed completely (quenched by methanol). Then the mixture was concentrated by rotary evaporator to give 2-(3-chlorophenyl)acetyl chloride (55.4 g, crude) as light yellow liquid.
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 lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
Example 86A 2-(3-chlorophenyl)ethanol To a mixture of 2-(3-chlorophenyl)acetic acid (11.4 g, 66.7 mmol) in 150 mL of THF was added LiAlH4 (3.04 g, 80.0 mmol) portionwise at 0 C. The resulting mixture was warmed to room temperature and stirred for 2 hours under N2 atmosphere. Then 2 N NaOH (30 mL) was added dropwise and extracted with EtOAc (2*150 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to provide the crude product which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=50:1-10:1) to obtain 4.96 g of the title compound as a colorless oil. Yield: 55%.
55%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; under 1520.1 Torr; for 2h;
2-(3-chlorophenyl)ethanol[113] To a mixture of 2-(3-chlorophenyl)acetic acid (11.4 g, 66.7 mmol) in 150 mL of THF was added LiAlH4 (3.04 g, 80.0 mmol) portionwise at 0C. The resulting mixture was warmed to room temperature and stirred for 2 hours under 2 atmosphere. Then 2 N NaOH (30 mL) was added dropwise and extracted with EtOAc (2 x 150 mL). The organic layers were combined, dried over anhydrous Na2S04; filtered, and concentrated to provide the crude product which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50: 1 - 10: 1) to obtain 4.96 g of the title compound as a colorless oil. Yield: 55%.
With hydrogenchloride; In water;
(b) Lithium aluminium hydride (19 g,) was suspended in dry ether (300 ml) and 3-chlorophenylacetic acid (58 g,) in dry ether (600 ml) was added dropwise to the stirred suspension over 1 hr. The mixture was then heated at reflux for 2 hr. when tlc indicated completion of reaction. Excess lithum aluminium hydride was carefully decomposed with water (500 ml). The ether layer was separated off and 2M hydrochloric acid was used to break up the gelatinous aqueous layer which was then extracted with ether (2*400 ml). The combined ether layers were washed with water (300 ml), dried (sodium sulphate) and evaporated in vacuo to give 2-(3-chlorophenyl)ethanol as a pale yellow oil (53.1 g) characterised by its nmr spectrum.
With borane-THF; In tetrahydrofuran; at 0℃; for 4h;
In a flame-dried three-neck 1000 mL round-bottom flask equipped with a reflux condenser and an argon line, the appropriate carboxylic acid (21-26) (1 eq. ) was placed and was dissolved in THF. To this solution, a solution of 1M BH3. THF was added via cannula (2 eq. ) at 0C. The reaction mixture was kept at OOC for 4 hours and monitored by TLC. The reaction mixture was diluted with cold H20, washed with a saturated solution of NaHCO3 and extracted with ether. The combined organic layers were then washed with brine (1 x 25 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to give 21a-26a in 58-88% yield. m-Chlorophenethyl alcohol (21a) in NMR (CDC13) : o 7.21-7. 19 (q, 3H), 7.12 (t, lH), 3.76 (t, 2H), 2.78 (t, 2H). 13CNMR (CDC13) : 8 140.90, 134.14, 129.69, 129.06, 127.02, 126.45, 62.96, 38.69. IR (liquid film) 3464,2948, 2879,1598, 1574,1429, 1096,1047, 958 FT-ICR MS : m/z 157 (M. +H).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4.5h;Reflux;
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
18.3g
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 30℃; for 4h;
Specific operations are as follows: 20g of m-chlorophenylacetic acid was added to 200ml of tetrahydrofuran, cooled to 0 C with stirring,At the beginning of batch addition of 8.9g of lithium aluminum hydride, the temperature was raised to 25 ~ 30 after the addition, the reaction 4h after the addition of water 300ml, dichloromethane400 ml of the mixture was separated, and the organic phase was added with 20 g of anhydrous sodium sulfate and dried under reduced pressure at 30-35 C. to obtain a pale yellow oil (S1-1): 18.3 g; Dropping phosphorus tribromide, the dropping temperature during the control at 0 ~ 10 C, dropping completed,After stirring for 10min, the temperature was raised to 75-80 C,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,The mixture was stirred for 20 minutes, and the filtrate was concentrated under reduced pressure at 40-45 C. to give a yellow liquid (intermediate S2): 22.4 g. Yield: 87.0%.
EXAMPLE 6 2-(3-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (3-Chloro-phenyl)-acetic acid (6.03 g, 0.03 mol) was dissolved in ethanol (37.7 mL) and treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-chloro-phenyl)-acetic acid ethyl ester (6.10 g, 86.8%) as a clear oil: EI-HRMS m/e calcd for C10H11ClO2 (M+) 198.0448, found 198.0442.
86.8%
sulfuric acid; In ethanol;
EXAMPLE 6 2-(3-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (3-Chloro-phenyl)-acetic acid (6.03 g, 0.03 mol) was dissolved in ethanol (37.7 mL) and treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 12 h. The reaction was concentrated in. vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-chloro-phenyl)-acetic acid ethyl ester (6.10 g, 86.8%) as a clear oil: EI-HRMS m/e calcd for C10H11ClO2 (M+) 198.0448, found 198.0442.
To a solution of 3-chlorophenylacetic acid (0.5 g, 2.93 mmol) and DMAP (0.36 g, 2.93 mmol) in dichloromethane (30 mL) was added ethyl 4-aminobutyrate hydrochloride (0.49 g, 2.93 mmol) at room temperature. After stirring for 10 min, EDCI (0.56 g, 2.93 mmol) was added portionwise to the mixture at room temperature. The reaction was stirred for 12 h. A 1 N aqueous HCl solution (20 mL) was poured into the reaction mixture, and 4- [2-(3-chlorophenyl)acetylamino]butyric acid ethyl ester was extracted with ether (30 mL). The ether solution was washed with water (50 mL), dried over Na2SO4, and concentrated. To the residue dissolved in ethanol (10 mL) was added 1 N aqueous NaOH solution (6 mL), and after 12 h of stirring at room temperature, the product was extracted with dichloromethane (30 mL). The organic solution was washed with water (30 mL), dried over Na2SO4, and concentrated to give 4-[2-(3-chlorophenyl)acetylarnino]butyric acid (0.6 g, 80%). A mixture of this acid (0.6 g, 2.35 mmol), K2CO3 (0.49 g, 3.52 mmol), and 1-bromopentane (0.53 g, 3.52 mmol) in DMF (20 mL) was stirred overnight at room temperature. The product was extracted with ether (40 mL), and the ether solution was washed with water (50 mL), dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography (hexane:ethyl acetate = 3:1) to afford 988 as an oil (0.74 g, 97%): 1H NMR (CDCl3) 0.91 (3H, t, J = 6.9 Hz), 1.26-1.33 (4H, m), 1.59-1.63 (2H, m), 1.80 (2H5 quint, J = 6.9 Hz), 2.31 (2H, t, J = 6.9 Hz), 3.27 (2H, q, J = 6.9 Hz), 3.52 (2H, s), 4.04 (2H, t, J = 6.9 Hz), 5.72 (IH, s), 7.13-7.17 (2H, m), 7.27-7.30 (2H, m); LC-MS (ESI) m/z calcd for Ci7H24ClNO3 [M + H]+ 326.14, found [M + H]+ 326.15. Anal. (C17H24ClNO3) C, H, N. [0210] Compounds 837 and 1068 were prepared with the same method used for the preparation of compound 988 using 1-adamantylacetic acid or adamantane-1-carboxylic acid instead of 3-chlororhohenylacetic acid. Compound 837: IH NMR (CDC13) 0.91 (3H, t, J = 6.9 Hz), 1.29-1.35 (4H, m), 1.35-1.72 (14H, m), 1.84 (2H, quint, J = 6.9 Hz), 1.91 (2H5 s), 1.97 (3H, m), 2.37 (2H, t, J = 6.9 Hz), 3.29 (2H, q, J = 6.9 Hz), 4.07 (2H, t, J = 6.9 Hz), 5.66 (IH, s); LC-MS (ESI) m/z calcd for C21H35NO3 [M + H]+ 350.26, found [M + H]+ 350.29. Anal. (C21H35NO3) C5 H5 N. EPO <DP n="66"/>[0211] Compound 1068: 1HNMR (CDCl3) 0.91 (3H, t, J = 6.9 Hz), 1.29-1.35 (4H, m), 1.60-1.86 (16H, m), 2.03 (3H, m), 2.35 (2H, t, J = 6.9 Hz), 3.29 (2H, q, J = 6.9 Hz), 4.07 (2H, t, J = 6.9 Hz), 5.85 (IH, s); LC-MS (ESI) m/z calcd for C20H33NO3 [M + H]+ 336.25, found [M + H]+ 336.34. Anal. (C20H33NO3) C, H, N.
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).
With hydrogenchloride In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
28.A (A)
(A) {2-12-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic Acid Ethyl Ester A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to -78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting reaction solution was stirred at -78° C. for 1 h. Iodomethylcyclopentane (4.64 g, 22.08 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at -78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. The solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1*150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2(M+) 252.0917, found 252.0915.
72.9%
With hydrogenchloride In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
120 6-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic Acid
EXAMPLE 120 6-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic Acid A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to -78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting solution was stirred at -78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (4.64 g, 22.08 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at -78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1*150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2(M+) 252.0917, found 252.0915.
72.9%
With hydrogenchloride In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
120 6-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid
EXAMPLE 120 6-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to -78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting solution was stirred at -78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (4.64 g, 22.08 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at -78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1*150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0915.
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.
a) rac-2-(3-Chloro-phenyl)-5,5,5-trifluoro-pentanoic acid <n="188"/>To a stirred solution of m-chlorophenylacetic acid (2.38 g, 14 mmol) in tetrahydrofuran (85 ml) was added at -78 0C lithium diisopropylamide solution (31 ml IM in THF, 31 mmol). After stirring the mixture for 20 min l-iodo-3,3,3-trifluoropropane (4.38 g, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. Water (5 ml) was added followed by 2N hydrochloric acid (10 ml). The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSCU and evaporated and the residue was purified by column chromatography (Sitheta2, heptane/EtOAc= 9:1) to yield a colourless oil, (1.75 g, 47 %); MS (EI): 264.9 (M+ ).
A solution of diisopropylamine (7.87 mL, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to -78 C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0 C. and stirred for 15 min. The solution was re-cooled to -78 C. and treated, via cannula, with a solution of <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25 C. where it was stirred for 45 minutes and was then re-cooled to -78 C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via cannula, and the resulting mixture was stirred at -78 C. for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×30 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid as a white solid. HRMS: calcd for C14H17ClO3, 268.0866; found (ESI_FT), 291.0748.
96%
A solution of diisopropylamine (7.87 mL, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to-78 C and treated dropwise with a solution of n- butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0 C and stirred for 15 min. The solution was re-cooled to-78 C and treated, via canula, with a solution of <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25 C where it was stirred for 45 minutes and was then re-cooled to-78 C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via canula, and the resulting mixture was stirred at-78 C for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1 x 30 mL). The aqueous layer was then acidified to pH = 1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3 x 30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenyl) hvdroxvcvclohexvl) acetic acid as a white solid. HRMS: calcd for C14H17CIO3, 268.0866 ; found (ESI-FT), 291. 0748.
Step 2; To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (36.64 mg, 0.15 mmol, 1.0 equiv) in methanol (2.0 mL) was added cyclohexanecarbaldehyde (25.80 mg, 27.08 muL, 0.23 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (3-chloro-phenyl)-acetic acid (34.12 mg, 0.20 mmol, 1.33 equiv; [CAS RN 1878-65-5]) and cyclohexyl isocyanide (16.38 mg, 18.41 muL, 0.15 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 15.7 mg (21%) of the title compound. MS (ISP): 500.2 [M+H]+.
With bis-triphenylphosphine-palladium(II) chloride; tetraethylammonium chloride; sodium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; at 80℃; under 11251.1 Torr; for 20h;Autoclave;
General procedure: The carbonylation reaction was performed in a 150 mL polytetrafluoroethylene(PTFE)-lined autoclave equipped witha magnetic stir bar. In a typical experiment, the substituted benzyl chloride (0.01 mol), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), NaOH (4 M, 8 mL) and DMB (10 mL)were placed in the autoclave. The autoclave was purged three times with N2 and three times with CO, and then heated to 80 C. During the reaction, the CO pressure was maintained at 1.5 MPa. When the reaction was complete,the autoclave was cooled to room temperature in ice water,and the CO was discharged to atmospheric pressure. The mixture was then adjusted to pH 2 with HCl (12 M), and the solid was collected via filtration and air-dried. The crude product was recrystallised in MeOH/H2O (1:1, v/v) to obtain 2,4-DCPA. The remaining commercially available catalysts were evaluated under the same conditions. The percent conversion and yield were quantified by the method reported by Lei et al.
81%
General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15%), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 C and adjusted to pH=1-2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized.
81%
With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide; In methanol; at 180℃; under 11251.1 Torr; for 6h;Autoclave;
312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,Palladium acetate 1.37g,Adding to the autoclave reaction vessel, stirring for 5 minutes to dissolve the catalyst, replacing the air in the kettle three times with CO, raising the temperature to 180 C, flushing the CO to a pressure of 1.5 MPa. Within 1 hour,At the same time, 64.4 g (0.4 mol) of m-chlorobenzyl chloride and 160 g (1.2 mol) of 30% NaOH were added dropwise to the reaction vessel.After reacting for 5 hours, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, the catalyst was filtered off, and the pH was adjusted to 1 by adding 30% hydrochloric acid, and filtered.Dry to obtain m-chlorophenylacetic acid,The purity was 99.28% and the yield was 81%.
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
4-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid (23)Preparation of (S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)thiazol-4-yl]ethanamine hydrobromide salt (22): A mixture of (S)-tert-butyl 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2- ylcarbamate, 7, (7.74g, 20mmol), and thiophene-2-carbothioic acid amide (3.14g, 22mmol) in CH3CN (200 mL) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 7.14 g (87 % yield) of the desired product. ESI+ MS 332 (M+l).Preparation of 2-(3-chlorophenyl)-Lambda/-{(5)-2-(4-nitrophenyl)-l-[2-(thiophen-2-yl)thiazol- 4-yl]ethyl}acetamide (23): To a solution of 2-(4-nitrophenyl)-l-(2-thiophene2-ylthiazol-4- yl)ethylamine, 22, (0.41 g, lmmol) <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (0.17Og, lmmol) and 1- hydroxybenzotriazole (HOBt) (0.07Og, 0.50mmol) in DMF ( 5 mL) at 0 0C, is added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.19Og, lmmol) followed by triethylamine (0.42mL, 3mmol). The mixture is stirred at 0 0C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60 % yield) of the desired product which is used without further purification. ESI- MS 482 (M-I).Preparation of {4-[2-(3-chlorophenyl)acetylamino]-2-(2-thiophen-2-ylthiazol-4- yl)ethyl]phenyl} sulfamic acid (24): 2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-l-[2- (thiophene2-yl)thiazol-4-yl]ethyl}acetamide, 23, (0.290 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with Stheta3-pyridine (0.157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.078 g of the desired product as the ammonium salt. 1H NMR (CD3OD) delta 7.61 (d, IH, J = 3.6Hz), 7.58 (d, IH, J = 5.1Hz), 7.41-7.35 (m, IH), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, IH, J = 6.6Hz), 3.70 (d, 2H, J = 3.9Hz), 3.23 (IH, A of ABX, J = 6.6, 13.8Hz), 3.07 (IH, B of ABX, J = 8.1, 13.5Hz).
60%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
Preparation of 2-(3-chlorophenyl)-Lambda/-{(5)-2-(4-nitrophenyl)-l-[2-(thiophen-2-yl)thiazol- 4-yl]ethyl}acetamide (23): To a solution of 2-(4-nitrophenyl)-l-(2-thiophene2-ylthiazol-4- yl)ethylamine, 22, (0.41 g, lmmol) <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (0.17Og, lmmol) and 1- hydroxybenzotriazole (HOBt) (0.07Og, 0.50mmol) in DMF ( 5 mL) at 0, is added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.19Og, lmmol) followed by triethylamine (0.42mL, 3mmol). The mixture is stirred at 0 0C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60 % yield) of the desired product which is used without further purification. ESI- MS 482 (M-I).
60%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.5h;
To a solution of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41 g, 1 mmol) <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (0.170 g, 1 mmol) and 1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at 0 C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190 g, 1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture is stirred at 0 C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60% yield) of the desired product which is used without further purification. ESI-MS 482 (M-1).
60%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
To a solution of 2-(4-nitrophenyl)- 1 -(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41 g, lmmol) <strong>[1878-65-5]3-chlorophenylacetic acid</strong> (0. 170g, lmmol) and 1-hydroxybenzotriazole (HOBt) (0.070g, 0.SOmmol) in DMF ( 5 mL) at 0C, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0. 190g, lmmol)followed by triethylamine (0.42mL, 3mmol). The mixture is stirred at 0 C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HC1, 5 % aqueous NaHCO3, water and brine, and dried over Na2504. The solvent is removed in vacuo to afford 0.290 g (60 % yield) of the desired product which is usedwithout further purification. ESI- MS 482 (M-1).
60%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.5h;
To a solution of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41 g, 1mmol) 3-chlorophenylaceticacid (0.170g, 1mmol) and 1-hydroxybenzotriazole (HOBt) (0.070g, 0.50mmol) in DMF (5 mL) at 0 C, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190g, 1mmol) followed by triethylamine (0.42mL, 3mmol). Themixture is stirred at 0 C for 30 minutes then at room temperature overnight. The reaction mixture is diluted with waterand extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5 % aqueous NaHCO3, waterand brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60 % yield) of the desired productwhich is used without further purification. ESI- MS 482 (M-1).
6-(2-(3-chlorophenyl)acetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.3%
Stage #1: 3,4-dihydro-3-oxo-2H-1,4-benzoxazine; 3-chlorophenylacetic acid With phosphoric acid; trifluoroacetic anhydride at 0 - 20℃; Inert atmosphere;
Stage #2: With sodium hydrogencarbonate In water at 0℃; Inert atmosphere;
4.1.7.1. Typical procedure for the synthesis 6-phenylacetyl-4H-benzo [1,4]-oxazin-3-one
General procedure: Phosphoric acid (3.15 g, 0.032 mol) and TFAA (21.8 mL, 0.104 mol) were added to the mixture of 4H-Benzo [1,4]oxazin-3-one (4 g, 0.026 mol) and substituted phenylacetic acid (1.1eq), at 0 °C. After completion of addition, the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and adjusted the pH to 7 by adding the saturated NaHCO3 solution. The precipitated solid was filtered, washed with water and dried to give the desired product.
82.3%
With phosphoric acid; trifluoroacetic anhydride at 0 - 20℃; for 1h; Inert atmosphere;
Stage #1: 3-chlorophenylacetic acid With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.583333h; Inert atmosphere;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78 - 25℃; for 2h; Inert atmosphere;
Stage #1: 3-chlorophenylacetic acid With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.66667h;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78 - 25℃; for 5.17h;
1.A Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone
Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 117 mL) was slowly added to a -78° C. solution of 2-(3-chlorophenyl) acetic acid (10 g, 58.6 mmol) in tetrahydrofuran (58 mL) over 1 hour. After stirring at -78° C. for 40 minutes, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in tetrahydrofuran (35 mL) was added over a period of 10 minutes. The reaction was stirred at -78° C. for 3 hours then allowed to warm to 25° C. After two hours at 25° C., the reaction was quenched with saturated aqueous ammonium chloride solution, and most of the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate (2*100 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated. The product was recrystallized from ether/pentane to provide the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6, δ ppm): 8.05 (m, 2H), 7.62 (m, 2H), 7.33 (m, 3H), 7.21 (br d, J=7.3 Hz, 1H), 4.45 (s, 2H). MS (ESI)=265.1 [M+H]+.
Stage #1: 3-chlorophenylacetic acid With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.66667h;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78℃; for 3.16667h;
Step A Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone
Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone [0245] [0246] Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 117 mL) was slowly added to a -78° C. solution of 2-(3-chlorophenyl) acetic acid (10 g, 58.6 mmol) in tetrahydrofuran (58 mL) over 1 hour. After stirring at -78° C. for 40 minutes, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in tetrahydrofuran (35 mL) was added over a period of 10 minutes. The reaction was stirred at -78° C. for 3 hours then allowed to warm to 25° C. After two hours at 25° C., the reaction was quenched with saturated aqueous ammonium chloride solution, and most of the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated. The product was recrystallized from ether/pentane to provide the title compound as a white solid.
Stage #1: 3-chlorophenylacetic acid With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.66667h;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78 - 25℃; for 5h;
A Step A. 2-(3-Chlorophenyl)-l-(4-chlorophenyl)ethanone
Step A. 2-(3-Chlorophenyl)-l-(4-chlorophenyl)ethanone Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 1 17 mL) was slowly added to a -78 °C solution of 2-(3-chlorophenyl) acetic acid (10 g, 58.6 mmol) in tetrahydrofuran (58 mL) over 1 hour. After stirring at -78 °C for 40 minutes, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in tetrahydrofuran (35 mL) was added over a period of 10 minutes. The reaction was stirred at -78 °C for 3 hours then allowed to warm to 25 °C. After two hours at 25 °C, the reaction was quenched with saturated aqueous ammonium chloride solution, and most of the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate (2 χ 100 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated. The product was recrystallized from ether/pentane to provide the title compound as a white solid. lH NMR (500 MHz, DMSO-i/6, δ ppm): 8.05 (m, 2H), 7.62 (m, 2H), 7.33 (m, 3H), 7.21 (br d, J= 7.3 Hz, 1H), 4.45 (s, 2H). MS (ESI) = 265.1 [M + H]+.
Stage #1: 3-chlorophenylacetic acid With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.66h;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78 - 25℃; for 5.16h;
1.A Step A. 2-(3-Chlorophenyl)-l-(4-chlorophenyl)ethanone
Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 117 mL) was slowly added to a -78 °C solution of 2-(3-chlorophenyl) acetic acid (10 g, 58.6 mmol) in tetrahydrofuran (58 mL) over 1 hour. After stirring at -78 °C for 40 minutes, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in tetrahydrofuran (35 mL) was added over a period of 10 minutes. The reaction was stirred at -78 °C for 3 hours and then allowed to warm to 25 °C. After two hours at 25 °C, the reaction was quenched with saturated aqueous ammonium chloride solution, and most of the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate (2 c 100 mL). The combined organic layers were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated. The product was recrystallized from ether/pentane to provide the 2-(3-chlorophenvD-l-(4- chlorophenvDethanone as a white solid.
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.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;
General procedure for the synthesis of 2-phenyl-N-(4-phenylthiazol-2-yl) acetamide derivatives 3a-3l and 4a-4l
General procedure: For the synthesis of compounds 3a-3h, 3j, 3k, 4a-4h, 4j, 4k, a mixtureof corresponding acids (1 mmol), 4-phenylthiazol-2-ylamine derivatives (2a or 2b, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.5 mmol), 1-hydroxybenzotrizole (HOBt, 0.05 mmol) in CH2Cl2 (20-30mL) was stirred at room temperature for 24 h. After that, the solvent was removed in vacuo to afford a residue, which was extracted with EtOAc (3 ×20mL). The combined organic phases were dried with anhydrous Na2SO4. Removal of all the solvent in vacuo resulted in a residue, which was purified with recrystallization to give target products.
With water; sodium hydroxide; In 1,4-dioxane; at 60℃; for 2h;pH 10 - 14;
m-Chlorotoluene (1.89 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120 C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 82 mg ethyl m-chlorophenylacetate was obtained by column chromatography, in a yield of 83%. 1HNMR (400 MHz, CDCl3) delta 1.24 (t, J=7.2 Hz, 3H), 3.58 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 7.15-7.18 (m, 1H), 7.24-7.26 (m, 1H), 7.29 (s, 1H); 13CNMR (100 MHz, CDCl3) delta 14.2, 40.9, 61.1, 127.3, 127.5, 129.5, 129.8, 134.3, 135.9, 170.9; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0342. The ethyl m-chlorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60 C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 64 mg product m-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.
2-(3-chlorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h;
General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%).
With ammonium acetate; oxygen; copper diacetate; In 1-methyl-pyrrolidin-2-one; at 120℃; under 760.051 Torr; for 20h;
Adding reaction bottle 1a (2mmol, 394 mg), 2e (4mmol, 678 mg), ammonium acetate (4mmol, 308 mg), copper acetate (20mol %, 80 mg) and NMP (10 ml). Oxygen is then used to replace the three times in the oxygen atmosphere of the reaction system, the 120 C heating reaction 20 hours. After the reaction is finished first quenching with saturated sodium carbonate solution, then using ethyl acetate extraction, anhydrous sodium sulfate for drying, after decompression turns on lathe does solvent, petroleum ether and ethyl acetate mixed solvent for carrying out simple column chromatography to get product 3ae, the yield is 97%. White solid
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.
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 0.5% 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 63%, 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).
Stage #1: 3-chlorophenylacetic acid With sodium hydrogencarbonate In water at 60℃;
Stage #2: copper(II) sulfate In water for 3h;
Stage #3: 1,10-Phenanthroline In water for 3h;
Synthesis of 1 and 2
General procedure: One-pot synthesis scheme was employed for synthesis of both complexes by subsequent addition of NaHCO3 (0.42 g, 5.0 mmol) to 3-chlorophenylacetic acid (0.85 g,5.0 mmol) in distilled water at 60 °C with continuous stirring.When effervescence was stopped in the reaction mixture aqueous solution of copper sulphate (0.72 g, 2.5mmol) was added drop wise and mixture was stirred for next three hours. After that, 1,10-phenanthroline (0.49 g,2.5 mmol) for complex 1 and 2,2’-bipyridine (0.40 g, 2.5mmol) for complex 2 was added in reaction mixture and stirring was continued for next three hours. Precipitates of both complexes were separated from the reaction mixture by filtration and washed thoroughly with distilled water and air dried. Later on both complexes were recrystallizedfrom chloroform and analyzed by FT-IR and X-ray single crystal analyses Dark blue crystals (1); yield (75%). Anal. Calcd. forC56H40Cl4Cu2N4O8(%): calc. C, 57.64%; H, 3.43%; N,4.80%; found: C, 56.45%; H, 3.23%; N, 4.54%; m.p.171-172 °C; FT-IR (cm-1): 1625 ν (OCO)asym, 1427ν (OCO)sym, Δν = 198, 2980 ν(Ar-H), 1519, 1562νAr(C=C), 723 ν (Ar-Cl), 611 ν (Cu-O), 482 ν (Cu-N); ε= 93.4 L mol-1 cm-1.
Stage #1: 3-chlorophenylacetic acid With sodium hydrogencarbonate In water at 60℃;
Stage #2: copper(II) sulfate In water for 3h;
Stage #3: [2,2]bipyridinyl In water for 3h;
Synthesis of 1 and 2
General procedure: One-pot synthesis scheme was employed for synthesis of both complexes by subsequent addition of NaHCO3 (0.42 g, 5.0 mmol) to 3-chlorophenylacetic acid (0.85 g,5.0 mmol) in distilled water at 60 °C with continuous stirring.When effervescence was stopped in the reaction mixture aqueous solution of copper sulphate (0.72 g, 2.5mmol) was added drop wise and mixture was stirred for next three hours. After that, 1,10-phenanthroline (0.49 g,2.5 mmol) for complex 1 and 2,2’-bipyridine (0.40 g, 2.5mmol) for complex 2 was added in reaction mixture and stirring was continued for next three hours. Precipitates of both complexes were separated from the reaction mixture by filtration and washed thoroughly with distilled water and air dried. Later on both complexes were recrystallizedfrom chloroform and analyzed by FT-IR and X-ray single crystal analyses
Multi-step reaction with 2 steps
1: sulfuric acid / 12 h / Reflux
2: hydrazine / ethanol; water / 10 h / Reflux
Multi-step reaction with 2 steps
1: sulfuric acid / Reflux
2: hydrazine hydrate / acetonitrile / 3 h / Reflux
Multi-step reaction with 3 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C
1.2: 16 h / 20 °C
2.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 1.5 h / 20 °C
3.1: triethylamine / 0.5 h / 20 °C
With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide; In methanol; at 180℃; under 11251.1 Torr; for 6h;Autoclave;
312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,1.37 g of palladium acetate was added to the autoclave reactor.Stir the catalyst for 5 minutes, displace the air in the kettle 3 times with CO, raise the temperature to 180 C, and flush the CO to the pressure to 1.5 MPa. Within 1 hour,At the same time, 82.2 g (0.4 mol) of m-chlorobenzyl bromide and 160 g (1.2 mol) of 30% NaOH were added dropwise to the reaction vessel.After reacting for 5 hours, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, the catalyst was filtered off, and the pH was adjusted to 1 by adding 30% hydrochloric acid, and filtered.Dry to obtain m-chlorophenylacetic acid, the purity is:99.28%, the yield was 87%.
4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl 2-(3-chlorophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1.
2-(3-chlorophenyl)-N-(4-methylthiazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With HATU; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;
4.1.42. 4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methylthiazol-2-yl)-3-(trifluoromethyl)benzamide (51a)
General procedure: To a solution of 50 (1 g, 2.3 mmol) in DMF (20 mL) were addedK2CO3 (3.2 g, 23 mmol), 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (0.84 g, 2.8 mmol) and HATU (1.1 g,3 mmol) in batches, and the reaction was allowed to be stirred at rtfor 8h. The mixture was extracted by DCM (100 mL 3) andwashed with water (100 mL 2) followed by brine (100 mL). Theorganic layers were dried over sodium sulfate, filtered, concentratedand purified by silica gel column chromatography (elutingwith 0e30% EtOAc in heptane) to afford 51a as a white solid (0.72 g,72%).
methyl 3-[2-(3-chlorophenyl)acetamido]pyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: 2-(3-chlorophenyl)acetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 3-amino-isonicotinic acid methyl ester In N,N-dimethyl-formamide at 20℃;
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