* 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 Medicinal Chemistry, 1981, vol. 24, # 2, p. 140 - 145
6
[ 106-39-8 ]
[ 27329-70-0 ]
[ 34035-03-5 ]
Yield
Reaction Conditions
Operation in experiment
63%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 60℃; for 2 h;
General procedure: To a solution of 1-bromo-4-chlorobenzene (478 mg, 2.50 mmol) in a mixture of DME (7.5 mL) and EtOH (5.0 mL) were added PdCl2(PPh3)2 (36.5 mg, 52.0 μmol), 5-formyl-2-furanboronic acid (365 mg, 2.61 mmol), and 2 M aqueous Na2CO3 solution. The reaction mixture was stirred for 2 h at 60 °C, then cooled to room temperature, and volatile materials were removed under reduced pressure. To the obtained residue was added H2O and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to afford 19e (323 mg, 63percent) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 9.64 (1H, s), 7.73 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.30 (1H, d, J = 3.6 Hz), 6.81 (1H, d, J = 3.6 Hz); MS (FAB) m/z 207 (M+H)+.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6384 - 6393,10
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 36, p. 7402 - 7417
Reference：
[1] Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10251 - 10263
[2] Journal of the American Chemical Society, 1998, vol. 120, # 26, p. 6621 - 6622
Stage #1: With iodine; magnesium In tetrahydrofuran; ethylene dibromide at 20℃; for 2 h; Stage #2: at 20℃; for 2 h;
To a stirred suspension of magnesium (5.37 g, 223.75 mmol, 3 equiv) in dry THF (60 mL) under argon atmosphere was added iodine (2 crystals), 1,2-dibromo ethane (2 drops). 1-bromo-4-chlorobenzene (25.76 g, 134.39 mmol, 1.8 equiv) was then added dropwise for 1 h at room temperature. The reaction mixture was stirred at room temperature for 1 h. A solution of picolinaldehyde (8 g, 74.68 mmol) in dry THF (19 mL) was added drop wise at room temperature and stirred for 2 h. After completion of reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extract was washed with water, brine, dried over sodium sulfate, filteredand concentrated under reduced pressure. Purification using silica gel column chromatography (40percent EtOAc/hexanes as eluent) afforded 12.26 g of (4-chlorophenyl) (pyridin-2-yl) methanol (yield = 75percent). ESI + MS: m/z 220 ([M + Hj).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 12, p. 3044 - 3047
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 219 - 232
[3] Patent: WO2016/100823, 2016, A1, . Location in patent: Page/Page column 115; 116
[4] Patent: US2006/100243, 2006, A1, . Location in patent: Page/Page column 7; sheet 1
Reference：
[1] Chemical Communications, 2014, vol. 50, # 59, p. 7941 - 7944
16
[ 106-39-8 ]
[ 1159-54-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 18, p. 4069 - 4081
[2] Chemistry - A European Journal, 2013, vol. 19, # 30, p. 10024 - 10029
[3] Canadian Journal of Chemistry, 1982, vol. 60, p. 716 - 722
[4] Macromolecules, 2012, vol. 45, # 7, p. 2981 - 2988
17
[ 108-86-1 ]
[ 106-39-8 ]
[ 106-46-7 ]
[ 694-80-4 ]
[ 106-37-6 ]
[ 108-90-7 ]
[ 583-53-9 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 609 - 615[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 4, p. 681 - 688
18
[ 106-39-8 ]
[ 17729-59-8 ]
[ 140-53-4 ]
Reference：
[1] Chemistry Letters, 1984, p. 1511 - 1512
19
[ 106-39-8 ]
[ 75-05-8 ]
[ 140-53-4 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 13, p. 3377 - 3386
20
[ 106-39-8 ]
[ 1210469-45-6 ]
[ 17721-06-1 ]
[ 183676-87-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
[2] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
21
[ 106-39-8 ]
[ 1318073-66-3 ]
[ 17721-06-1 ]
[ 183676-87-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
22
[ 106-39-8 ]
[ 78756-27-1 ]
[ 17721-06-1 ]
[ 183676-87-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
23
[ 106-39-8 ]
[ 1318073-67-4 ]
[ 17721-06-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
24
[ 106-39-8 ]
[ 1210469-45-6 ]
[ 17721-06-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
25
[ 106-39-8 ]
[ 17721-06-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
26
[ 106-39-8 ]
[ 1318073-65-2 ]
[ 17721-06-1 ]
[ 183676-87-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 981 - 985
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4149 - 4152
33
[ 106-39-8 ]
[ 1511-62-2 ]
[ 43141-66-8 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 38, p. 12543 - 12548[2] Angew. Chem., 2018, vol. 130, p. 12723 - 12728,6
34
[ 106-39-8 ]
[ 41513-04-6 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 17, p. 7912 - 7918
35
[ 106-39-8 ]
[ 41513-04-6 ]
[ 16588-24-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1915, vol. 34, p. 220
36
[ 106-39-8 ]
[ 14472-80-1 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026,4
[2] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026
[3] Journal of the American Chemical Society, 2012, vol. 134, # 49, p. 20208 - 20208
[4] Patent: WO2012/153162, 2012, A1,
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 10, p. 1299 - 1312
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 49, p. 14748 - 14752[7] Angew. Chem., 2015, vol. 127, # 49, p. 14961 - 14965,5
37
[ 106-39-8 ]
[ 4619-18-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 35, p. 8114 - 8117
38
[ 106-39-8 ]
[ 106-41-2 ]
[ 2050-47-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 9, p. 1591 - 1600
39
[ 106-39-8 ]
[ 66-25-1 ]
[ 7295-50-3 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 32, p. 10510 - 10511
40
[ 106-39-8 ]
[ 16588-24-2 ]
Reference：
[1] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[2] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
41
[ 106-39-8 ]
[ 41513-04-6 ]
[ 16588-24-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1915, vol. 34, p. 220
42
[ 106-39-8 ]
[ 95-92-1 ]
[ 34966-48-8 ]
Yield
Reaction Conditions
Operation in experiment
22%
Stage #1: With iodine; magnesium In tetrahydrofuran at 40℃; Inert atmosphere Stage #2: at -45 - 20℃; Inert atmosphere
Reference Example-1 A solution of 1-bromo-4-chlorobenzene (15.0 g, 38.4 mmol) in THF was added dropwise to a suspension of magnesium (2.1 g, 86.2 mmol) in THF at 40° C. (oil bath temperature) in the presence of a catalytic amount of iodine in an argon gas atmosphere, whereby a Grignard reagent was prepared. The Grignard reagent was added dropwise to a solution of diethyl oxalate (17.7 g, 94.2 mmol) in THF at -45° C., and the temperature was slowly raised to room temperature, followed by stirring for 18 hours. After the reaction was completed, the reaction solution was poured into ice, then, acidified with concentrated hydrochloric acid, and the resultant product was extracted with ether (100 mL*2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby a yellow oily crude product (14.8 g) was obtained. This was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), whereby ethyl 2-(4-chlorophenyl)-2-oxoacetate (4.68 g, yield: 22percent) was obtained as a yellow oily material. 1H-NMR (400 MHz, CDCl3): δ1.43 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H).
Reference：
[1] Organic Letters, 2014, vol. 16, # 13, p. 3528 - 3531
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 10, p. 2249 - 2252
[3] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 3990 - 3998
[4] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 6, p. 1470 - 1479
[5] Patent: US2016/24110, 2016, A1, . Location in patent: Paragraph 0420; 0421
[6] Patent: EP1486483, 2004, A1, . Location in patent: Page 32
[7] Chemical Communications, 2013, vol. 49, # 32, p. 3300 - 3302
43
[ 106-39-8 ]
[ 75716-82-4 ]
[ 34966-48-8 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 1, p. 211 - 213
44
[ 106-39-8 ]
[ 105-53-3 ]
[ 19677-37-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 25 h;
EXAMPLE 6 Coupling of 4-chlorobromobenzene with diethyl malonate to give diethyl 2-(4-chlorophenyl) malonate 191.5 mg of 4-chlorobromobenzene (1 mmol) and 160 mg of diethyl malonate (1 mmol) were dissolved in 5 ml of N,N-dimethylformamide under protective gas, admixed with 652 mg of cesium carbonate (2 mmol) and stirred for 1 h. 17.9 mg (4 mol percent) of the HBPNS ligand and 9.0 mg of palladium(II) acetate (4 mol percent) were then added, and the mixture was heated to 80° C. for 24 h. For workup, 5 ml of water and 10 ml of toluene were added, the mixture was shaken, and the lower water phase was discharged and washed once again with 5 ml of water to remove residual dimethylformamide. After removal of the toluene on a rotary evaporator, 230 mg (0.85 mmol, 85percent) of the product were obtained.
Reference：
[1] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[2] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
55
[ 106-39-8 ]
[ 1073-70-7 ]
Yield
Reaction Conditions
Operation in experiment
88.1%
Stage #1: With hydrazine hydrate; copper(II) sulfate; cobalt(II) chloride In propylene glycol at 152℃; for 10 h; Stage #2: With hydrogenchloride In water
The reaction vessel was charged with reaction materials: 98.25 g of p-bromochlorobenzene and 3.3 equivalents of hydrazine hydrate, hydrazine hydrateThe degree is 71percent, adding 10percent by weight of a phase transfer catalyst (PEG400), 3 times by weight of a solvent (propylene glycol), and 20percent by weight of a catalyst (3:1 mass ratio of copper sulfate and cobalt chloride). The reaction; the reaction process includes: slowly warming and control the temperature to 152 ° C, normal pressure reflux or packing pressure reaction, maintaining the temperature reaction 10h, sampling HPLC detection of p-chlorophenylhydrazone no longer increase, that is, stop the reaction.After the reaction was completed, the solid was separated by filtration and the filtrate was distilled to remove the solvent.To the residue obtained in Step B was added 30percent hydrochloric acid, the pH was adjusted to 3, and the mixture was thoroughly stirred and filtered.The filter residue was washed with water and dried at 55°C to obtain p-chlorophenylhydrazine hydrochloride. In this example, the yield of p-chlorophenylhydrazine hydrochloride was 88.1percent, and the HPLC content was 99.29percent.
86.3%
Stage #1: With 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin; hydrazine hydrate; copper(I) bromide In propylene glycol; water at 172℃; for 5 h; Stage #2: With hydrogenchloride In water at 70℃;
in an equivalent ratio of 1: 2.8 for p-bromochlorobenzene, hydrazine hydrate as the reaction raw material, The reaction was carried out by adding a phase transfer catalyst (benzo-18-crown-6), a solvent (90percent aqueous solution of propylene glycol) and a catalyst (cuprous bromide), wherein the concentration of hydrazine hydrate was 59.5percent phase transfer catalyst, The weight ratio of the catalyst is 1: 0.15: 0.2, the weight ratio of bromochlorobenzene to the solvent is 1: 16.6; The reaction process involves slowly raising the temperature and controlling the temperature to 172 °C,Holding pressure reaction, keep the temperature reaction 5h, Sampling HPLC was detected until p-chlorophenylhydrazine was no longer increased, ie, the reaction was stopped. After completion of the reaction, the solid was separated by filtration and the filtrate was distilled off to remove the solvent. To the residue obtained in step B was added 24.8percent hydrochloric acid, adjusted to pH 1.8, And then fully stirred and filtered. the filter residue washed, 70 °C to obtain p-chlorophenylhydrazine hydrochloride. In this example, the yield of p-chlorophenylhydrazine hydrochloride was 86.3percent and the HPLC content was 99.2percent.
80%
Stage #1: With potassium phosphate; N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide; cetyltrimethylammonim bromide; copper(I) bromide In water at 110℃; for 0.166667 h; Sealed tube; Inert atmosphere Stage #2: With hydrazine hydrate In water at 110℃; for 1.5 h; Sealed tube; Inert atmosphere Stage #3: With hydrogenchloride In dichloromethane; water
General procedure: CuBr (36 mg, 0.25 mmol, 2.5 mol percent), L3 (110 mg, 0.4 mmol,4 mol percent), H2O (0.5 mL), and K3PO4 (254 mg, 1.2 mmol) were mixedin a 15 mL screw cap test tube. After STAC (110 mg, 0.3 mmol,3 mol percent) and aryl bromide (10 mmol) were added, the resulting mixture was stirred at 80-110° C (bath temperature) for 10 min.Then K3PO4 (2.29 g, 10.8 mmol) and N2H4*H2O (1 g, 20 mmol) were added and argon (flow rate 5-7 mL/min) was bubbled through thereaction mixture for 5 min.28 The reaction mixture was stirred ina closed test tube at 80-110° C (bath temperature) for 1-2 h until complete consumption of starting material was observed as monitoredby TLC (eluentehexane), then cooled to room temperatureand diluted with SH2Cl2 (50 mL). The resulting solutionwas filteredand washed with brine (225 mL). Aq HCl (37percent) was added to the CH2Cl2 solution dropwise until pH 3-4. The formed precipitate was filtered, washed with SH2Cl2 (15 mL) and dried atroom temperature. NMR spectra of certain synthesized aryl hydrazine hydrochlorides showed that they contained 1-5 mol percent of the corresponding aniline hydrochlorides as impurities (see Supplementary data). Analytical samples of aryl hydrazine hydrochlorides were purified via precipitation from methanol solution by adding 2-3 volumes of diethyl ether.
Reference：
[1] Patent: CN105968048, 2016, A, . Location in patent: Paragraph 0030-0054; 0055-0059; 0060-0069
[2] Patent: CN106045876, 2016, A, . Location in patent: Paragraph 0055; 0056; 0057; 0058; 0059
[3] Chinese Journal of Chemistry, 2018, vol. 36, # 11, p. 1003 - 1006
[4] Tetrahedron, 2014, vol. 70, # 26, p. 4043 - 4048
56
[ 106-39-8 ]
[ 785051-54-9 ]
Reference：
[1] Patent: KR2015/24669, 2015, A,
57
[ 106-39-8 ]
[ 86-74-8 ]
[ 785051-54-9 ]
Reference：
[1] Patent: KR2015/84657, 2015, A,
58
[ 106-39-8 ]
[ 918516-27-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 3, p. 963 - 969
Reference Example-1 A solution of 1-bromo-4-chlorobenzene (15.0 g, 38.4 mmol) in THF was added dropwise to a suspension of magnesium (2.1 g, 86.2 mmol) in THF at 40 C. (oil bath temperature) in the presence of a catalytic amount of iodine in an argon gas atmosphere, whereby a Grignard reagent was prepared. The Grignard reagent was added dropwise to a solution of diethyl oxalate (17.7 g, 94.2 mmol) in THF at -45 C., and the temperature was slowly raised to room temperature, followed by stirring for 18 hours. After the reaction was completed, the reaction solution was poured into ice, then, acidified with concentrated hydrochloric acid, and the resultant product was extracted with ether (100 mL*2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby a yellow oily crude product (14.8 g) was obtained. This was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), whereby ethyl 2-(4-chlorophenyl)-2-oxoacetate (4.68 g, yield: 22%) was obtained as a yellow oily material. 1H-NMR (400 MHz, CDCl3): delta1.43 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H).
Reference Production Example 8 In 140 ml of tetrahydrofuran were added 40.0 g of 4-bromochlorobenzene and 5.33 g of magnesium under nitrogen atmosphere, and stirred to prepare Grignard reagent. In 750 ml of tetrahydrofuran was dissolved 49.3 g of diethyl oxalyl, and the Grignard reagent was added dropwise at -70C over 30 minutes. The reaction mixture was warmed to room temperature over 2 hours, and stirred at room temperature for 2 hours. After addition of ice water and saturated ammonium chloride aqueous solution, the organic solvent was removed by distillation under reduce pressure from the reaction mixture. The residue was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 22.1 g of ethyl 2-(4-chlorophenyl)-2-oxoacetate. 1H-NMR (CDCl3, TMS) d (ppm): 7.98-8.01 (2H, m), 7.48-7.51 (2H, m), 3.98 (3H, s)
To a stirred suspension of magnesium (5.37 g, 223.75 mmol, 3 equiv) in dry THF (60 mL) under argon atmosphere was added iodine (2 crystals), 1,2-dibromo ethane (2 drops). 1-bromo-4-chlorobenzene (25.76 g, 134.39 mmol, 1.8 equiv) was then added dropwise for 1 h at room temperature. The reaction mixture was stirred at room temperature for 1 h. A solution of picolinaldehyde (8 g, 74.68 mmol) in dry THF (19 mL) was added drop wise at room temperature and stirred for 2 h. After completion of reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extract was washed with water, brine, dried over sodium sulfate, filteredand concentrated under reduced pressure. Purification using silica gel column chromatography (40percent EtOAc/hexanes as eluent) afforded 12.26 g of (4-chlorophenyl) (pyridin-2-yl) methanol (yield = 75percent). ESI + MS: m/z 220 ([M + Hj).
The compounds of the present invention were synthesized according to the procedure, which is illustrated schematically in FIG. 1 for three MPH alkyl analogs. Referring to FIG. 1, para-bromochlorobenzene 1 was converted into a Grignard reagent with Mg/THF which was then reacted with the pyridine-2-carboxaldehyde 2 to produce the alcohol 3. The alcohol 3 was oxidized with pyridinium chlorochromate in CH2Cl2 to produce the ketone 4. The ketone 4 was then reacted with a Grignard reagent that contains the required R group to produce the alcohol 5. After dehydration with refluxing HCl, the resulting Z and E olefin mixture 6 was hydrogenated with 10percent Pt/C in HOAc containing 3percent CF3COOH to produce the final compounds 7 with a ratio of about 40:60 of the R,R/S,S and R,S/S,R racemates for the ethyl compound. The racemates were separated by column chromatography and their relative configurations were determined by x-ray crystallography.
170 g
Into a 3 lit RB Flask, 22.28 gm of Magnesium turnings was added. 200 ml of Tetrahydrofuran and 400 ml of Toluene were added which was then heated to 65°C and reaction was initiated and added 214.4 gm of 4-Bromochlorobenzene solution in 440 ml of Toluene. After careful addition and maintenance of reaction at 75-90°C for 1 hr 30 min, cooled the contents of the reaction to 45°C. A solution of 100 gm of Pyridine-2-carbaldehyde dissolved in 200 ml Toluene was added at 48-52°C and maintained the reaction mass for 1 hr at 45-55°C, the reaction was decomposed by the addition of above reaction mass to 1 lit of 33percent Ammonium chloride solution, followed by extraction with Toluene. The Toluene layer was distilled under vacuum and the product was isolated by Hexane. Yield: 160-170 gm
With sodium borohydrid; magnesium; In methanol; diethyl ether; cyclohexane; ethyl acetate;
a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm3 of diethyl ether is poured slowly into a suspension, cooled to 10 C. of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm3 of anhydrous ethyl ether. After refluxing for one hour, the mixture is cooled to 10 C., supplemented slowly with 40 cm3 of methanol and then filtered on supercel. 4.54 g of sodium borohydride are added under argon and in small fractions over 15 minutes and then the reaction medium is stirred for 20 hours at 20 C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 C. under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 5 cm, height 42 cm), eluding under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane ({fraction (4/6)} by volume) and collecting 100-cm3 fractions. Fractions 6 to 12, concentrated to dryness, correspond to 13 g of imine in the form of a yellow oil which is taken up in 100 cm3 of methanol. The solution obtained is supplemented with 2.4 g of sodium borohydride and stirred for one hour at 5 C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 C. under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 40 cm), eluding under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane ({fraction (4/6)} by volume) and collecting 60-cm3 fractions. 11.0 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine are obtained in the form of a yellow oil.
With sodium borohydrid; magnesium; In methanol; diethyl ether; cyclohexane; ethyl acetate;
a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm3 of ethyl ether is poured slowly into a suspension, cooled to 10 C., of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm3 of anhydrous ethyl ether. After refluxing for one hour, the mixture is cooled to 10 C., supplemented slowly with 40 cm3 of methanol and then filtered on supercel. 4.54 g of sodium borohydride are added under argon and in small fractions over 15 minutes and then the reaction medium is stirred for 20 hours at 20 C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 C. under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 5 cm, height 42 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) as eluent and collecting 100 cm3 fractions. Fractions 6 to 12, concentrated to dryness, correspond to 13 g of imine in the form of a yellow oil which is taken up in 100 cm3 of methanol. The solution obtained is supplemented with 2.4 g of sodium borohydride and stirred for one hour at 5 C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 C. under reduced pressure (2.7 Kpa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 40 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) as eluent and collecting 60 cm3 fractions. 11.0 g of [(4-chloro-phenyl)(thien-2-yl)methyl-(RS)]amine are obtained in the form of a yellow oil.
3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide hydrochloride[ No CAS ]
[ 247940-06-3 ]
N-[1-(4-Chloro-phenyl)-piperidin-4-yl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane;
(iii) N-[1-(4-Chloro-phenyl)-piperidin-4-yl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide A mixture of 100 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide hydrochloride (0.2 mmol), 62 mg (0.33 mmol) 4-Bromochlorobenzene, 73 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised. The product was obtained as its trifluroacetate salt.
1-(4-chlorophenyl)-4-(1,4-dioxa-8-spiro[4.5]decyl)cyclohexanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium chloride; iodine; magnesium; In tetrahydrofuran;
a) 4.53 mg of magnesium shavings and a granule of iodine were treated with 150 ml of tetrahydrofuran while stirring and gassing with nitrogen. Subsequently, the mixture was treated dropwise within 20 minutes with a solution of 38.4 g of 4-bromo-1-chlorobenzene in 150 ml of tetrahydrofuran and boiled at reflux for 1.25 hours. Thereafter, the reaction mixture was cooled to 0° C. and treated dropwise within 30 minutes at 0°-5° C. with a solution of 35.7 g of 8-(4-oxocyclohexyl)-1,4-dioxaspiro-[4.5]decane in 240 ml of tetrahydrofuran. The reaction mixture was stirred for a further 4 hours without cooling, then treated within 10 minutes with 240 ml of 10 percent ammonium chloride solution and extracted with diethyl ether. The ether phases were washed twice with water, dried over sodium sulfate, filtered and concentrated. There were thus obtained 54.7 g of 1-(4-chlorophenyl)-4-(1,4-dioxa-8-spiro[4,5]decyl)cyclohexanol as beige crystals.
[Li(TMP)Zn(tBu)2] 1 was made according to the literature procedure2 on a 0.4 mmol scale in THF solution. To this 1-methyl-1,2,3-triazole (0.015 mL, 0.2 mmol) was added and the resultant light yellow solution was allowed to stir at room temperature for 2 hours. This solution was then transferred to a THF (1 mL) solution of Pd[P(tBu)3]2 (10.2 mg, 2.5 mol percent) and 1-bromo-4-chlorobenzene (38.3 mg, 0.2 mmol) to give a heterogeneous orange solution. The reaction mixture was then reacted in the microwave at 100°C for 10 minutes. The reaction was then quenched with saturated NH4Cl solution (2 mL) and extracted with DCM (3 x 1 mL). The organic fractions were combined and dried by passing through a phase separator cartridge with a hydrophobic frit and the solvent removed under reduced pressure. The residue was purified by column chromatography using a 4 g silica cartridge and eluent EtOAc:Heptane (50:50 to 60:50) to give 14b as a light yellow oil 40 mg (51percent yield) 1H NMR (400 MHz, CDCl3) delta ppm 4.00 (s, 3 H) 7.48 - 7.55 (m, 2 H) 7.61 - 7.69 (m, 2 H) 7.94 (s, 1 H)
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82% yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil.
With C30H21F6N2NiO2P; In tetrahydrofuran; at 70℃; for 24h;Schlenk technique; Inert atmosphere;
General procedure: A Schlenk flask was charged with an appropriate amount of complex 2b (0.016mmol, 2.0mol%) and the corresponding bromo or iodo arene (0.77mmol). The flask was cycled with nitrogen and vacuum. Afterwards a THF solution of benzylzinc bromide (2.2mL, 1.1mmol, 0.5M in THF) was added. The flask was sealed and heated at 70C for 24h. After that time, the mixture was cooled, and dichloromethane and water were added. The aqueous layer was extracted with dichloromethane and the collected organic layers were washed with water and dried with Na2SO4. The coupling product was confirmed by GC-MS (with n-dodecane as internal standard) and NMR analysis. The analytical properties of the products are in agreement with literature data [6a,24].
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 6h;Inert atmosphere;
General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; at 140℃; for 3h;
A 50 mL of flask was charged with 2.87 g of 4-chlorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N'-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2*50 mL) and brine (2*50 mL). The organics were dried over MgSO4 and concentrated under reduced pressure. The residued was purified via flash column chromatography on silica gel (0-25percent EtOAc in hexanes) to get the desired product (1.25 g, 50percent).
In accordance with the process of the present invention, the compound represented by the formula V is first obtained by reacting a compound of the formula VI with a compound of the formula VII to give a compound of the formula V, wherein the compound represented by the formula VI (p-bromochlorobenzene) Add to the reactor, in the argon protection, adding anhydrous tetrahydrofuran as a solvent, cooled to -75 C, slowly dropping 1.5 M 2M butyl lithium solution, reaction, 6 hours, adding anhydrous methanol quenched by adding two The organic layer was dried over anhydrous sodium sulfate and dried. After the dried intermediate, palladium acetate and an appropriate amount of anhydrous potassium acetate were directly added. The reaction was continued for 11 hours, followed by spotting. After the completion of the reaction, Dichloromethane extraction, organic layer dried with anhydrous sodium sulfate and dried, with methylene chloride / petroleum ether (volume ratio of 1: 5) through the column, spin-dried 4-azafluorenone
With copper(l) iodide; ethylenediamine; sodium t-butanolate; In toluene; at 100℃; for 4.0h;
General procedure: CuI (10mol%) and EDA (10mol%) were added to a mixtureof O-alkyl carbamate (1mmol), NaOtBu (1.5mmol) and aryl halide (1mmol) in 2mL toluene and the mixture wasstirred for the appropriate time, which was determined byTLC monitoring, at 100C. After completion of the reaction,the catalyst was removed by filtration and 20mL H2Owas added to the filtrate. The resultant mixture was extractedwith CHCl3.Then the organic phase was washed with water(2 × 10mL) and dried over anhydrous Na2SO4.After evaporationof CHCl3under reduced pressure, the correspondingcrude product was purified by flash chromatography to givethe desired pure cross-coupling product in good to excellentyield. In the case of using arylboronic acids as couplingpartners, Cu(OAc)2 was employed instead of CuI.
5-(4-chlorophenyl)-1-methyl-1H-imidazole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With trifuran-2-yl-phosphane; palladium diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h;Inert atmosphere;
1-bromo-4-chlorobenzene (1.5 mmol),Pd(OAc)2 (0.05 mmol), P(2-furyl)3 (0.1 mmol) and K2CO3 (2.0 mmol) were placed in a reaction vessel under astream of nitrogen. Deaerated 13 (1.0 mmol) and anhydrous N,N-dimethylformamide (5 mL) were then addedand the resulting mixture was stirred at 110 oC for 48 h, monitoring the reaction by TLC (CH2Cl2/MeOH 95:5).Once the reaction was complete, the mixture was cooled to rt, diluted with EtOAc/CH2Cl2 (1:1, 30 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by flash chromatography with CH2Cl2/MeOH 95:5 as the eluent. The product was obtained as a pale yellow solid. Yield: 40%. 1H NMR (300 MHz, CDCl3) deltaH 9.80 (1H, s, CHO), 7.62 (1H, s, CH aromatic), 7.50 (2H, d, 3JHH 8.43 Hz, CHaromatic), 7.36 (2H, d, 3JHH 8.43 Hz, CH aromatic), 3.59 (3H, s, CH3) ppm. 13C NMR (75 MHz, CDCl3) deltaC 185.36,149.25, 137.87, 131.12, 129.54, 129.33, 128.06, 125.98, 33.78 ppm. MS (ESI): m/z calcd for C11H9ClN2NaO[M+Na]+: 243.03; found 243.1.
1-tert-butyl 2-methyl (2R)-4-(4-chlorophenyl)piperazine-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 80℃; for 18.0h;Inert atmosphere;
1-tert-butyl 2-methyl (2R) -piperazine-1, 2-dicarboxylate (500 mg)1-Bromo-4-chlorobenzene (383 mg), palladium (II) acetate(15 mg), BINAP (75 mg),And sodium tert-butoxide (442 mg) were added toluene in a nitrogen stream, and the mixture was stirred at 80 C. for 18 hours.The reaction solution was cooled to room temperature, filtered through celite with ethyl acetate,The solvent was evaporated under reduced pressure to obtain a residue,Silica gel column chromatography (hexane-ethyl acetate)Made,1-tert-butyl 2-methyl (2R) -4- (4-chlorophenyl)Piperazine-1, 2-dicarboxylate240 mg (yield 34%) was obtained
40 g (208.93 mmol) of 1-bromo-4-chloro-benzene was dissolved in 400 ml of tetrahydrofuran, and 5.08 g (208.93 mmol) of magnesium was added thereto at 0 C under nitrogen injection. The resulting mixture was refluxed for 3 hours . After the completion of the reaction, 38.6 g (208.93 mmol) of 2- (chloromethyl)benzoic acid methyl ester in 200 ml of tetrahydrofuran was slowly added dropwise at 0 C. The mixture was stirred for 30 minutes. And the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction product is slowly added dropwise to the reaction solution, quenched, extracted with ethyl acetate and distilled water, and subjected to anhydrous magnesium sulfate treatment. Crystallization with dichloromethane and hexane gave 29.9 g (55 wt%) of intermediate compound [138-1] as a white solid.
29.9 g
In a 2 L reaction flask, 40 g (208.93 mmol) was dissolved in 400 ml of tetrahydrofuran.After 1-bromo-4-chloro-benzene, under the condition of injecting nitrogen at a temperature of 0 C,After adding 5.08 g (208.93 mmol) of magnesium, the mixture was stirred at reflux for 3 hours.After completion of the reaction, 38.6 g (208.93 mmol) of methyl 2-chloromethylbenzoate was slowly added dropwise to 200 ml of tetrahydrofuran at a temperature of 0 C. The mixture was stirred for 30 minutes.Stir at room temperature for 24 hours. After the reaction,The reaction was slowly added dropwise to the water for quenching, and then extracted with ethyl acetate and distilled water.It was filtered through anhydrous magnesium sulfate.Crystallization using dichloromethane and hexane,Thus prepared 29.9 g (55 wt%)Intermediate compound of white solid [138-1].
With sodium hydroxide; In toluene; at 30 - 113℃; for 4.5h;
After reducing the solution containing pyrazol in step (2) to 30 ° C, adding 45.18 g of toluene, stirring for 0.5 h, increasing the temperature of the mixture and refluxing the water to a moisture content of 0.08percent in the mixture. The temperature of the mixture was lowered to 40 ° C, 58.01 g (99percent, 0.3 mol) of p-bromochlorobenzene and 16.16 g (99percent, 0.4 mol) of sodium hydroxide were added, and the temperature of the mixture was raised to 110 ° C. After refluxing for 4 hours, the mixture was detected by liquid phase method multiple times. When the pyrazole peak disappeared, the reaction was stopped. After the temperature of the mixed solution was lowered to 40 ° C, 50 g of water was added to the mixture, and the mixture was dropped. Add hydrochloric acid to the pH of the mixture = 3, then raise the temperature of the mixture to 95 ° C, distill off the toluene, finally reduce the temperature of the mixture to 30 ° C, and suction to obtain 1-(4-chlorophenyl)-3-pyrazolol.Using this method, 31.96 g of 1-(4-chlorophenyl)-3-pyrazol was obtained in content of 97percent, yield 80percent.
General procedure: To a mixture of aryl halide (0.3 mmol), NiCl2(H2O)1.5 [1] (0.0075 mmol, 2.5 mol percent), was charged dry THF (1 mL). The mixture was pumped and refilled with nitrogen for three times. The resulting mixture was stirred at -10 under nitrogen for 30 min. The reaction mixture was quenched through the addition of ice MeOH, then poured into a separatory funnel containing saturated aqueous NH4Cl (ca. 5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine and dried over Na2SO4. The crude product was purified by column chromatography. Extent of isomerization can be easily determined via 1H NMR spectroscopy by comparison of the intergral of the singlet from the t-butyl group (1.3-1.4 ppm, 9H) to the integral of the doublet from the benzylic S3 protons of the i-butyl group (2.4-2.5 ppm, 2H). The doublet from the methyls of the i-butyl group could additionally be used (ca. 0.8 ppm, 6H).
Under argon protection, mix chlorobromobenzene, cuprous iodide, solid base and benzene, control the reaction temperature to 142 C, the reaction pressure is 4 atm, stir for 62 min, add the mixture M1, add dropwise After completion, the reaction temperature was controlled to be 163 C, the reaction pressure was 6 atm, and the reaction was completed at 1.5 h to obtain a mixture M2.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; for 12h;Reflux;
30.29 g (105 mmol) of 3- (9H-carbazole-9-yl) phenyl boronic acid and 20 g (105 mmol) of 1-Bromo-4-chlorobenzene,Pd (PPh 3) 4 0.03 eq,K 2 CO 3 2 eq was suspended in THF and distilled water and stirred under reflux for 12 hours.After the completion of the reaction, the mixture was extracted, and the organic layer was concentrated and subjected to silica gel column to obtain 35 g (yield: 94%) of the intermediate compound B.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
