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Limited Quantity
USD 15-60
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Structure of 611-19-8 * Storage: {[proInfo.prStorage]}
* 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] Green Chemistry, 2018, vol. 20, # 20, p. 4729 - 4737
[2] Tetrahedron Letters, 1988, vol. 29, # 45, p. 5783 - 5786
[3] Journal of Organic Chemistry, 2017, vol. 82, # 5, p. 2407 - 2413
[4] Journal of the American Chemical Society, 1949, vol. 71, p. 2644,2646
[5] Helvetica Chimica Acta, 1957, vol. 40, p. 1639,1650
[6] Justus Liebigs Annalen der Chemie, 1926, vol. 446, p. 225
[7] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1903, vol. 136, p. 242
[8] Journal of the American Chemical Society, 1932, vol. 54, p. 647,656
2
[ 81067-96-1 ]
[ 5219-70-5 ]
[ 611-19-8 ]
Reference：
[1] Liebigs Annalen der Chemie, 1982, # 1, p. 121 - 136
3
[ 89-98-5 ]
[ 56427-98-6 ]
[ 611-19-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2342 - 2347
4
[ 89-98-5 ]
[ 611-19-8 ]
Reference：
[1] Organic Preparations and Procedures International, 2007, vol. 39, # 4, p. 412 - 415
5
[ 17849-38-6 ]
[ 611-19-8 ]
Reference：
[1] Journal of the Chemical Society, 1935, p. 1815,1818
[2] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 307
[3] Australian Journal of Chemistry, 1970, vol. 23, p. 329 - 339
[4] Journal of Pharmaceutical Sciences, 1984, vol. 73, # 3, p. 374 - 377
6
[ 133-59-5 ]
[ 611-19-8 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 2042,2046
7
[ 108-88-3 ]
[ 611-19-8 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 5, p. 2407 - 2413
8
[ 100-44-7 ]
[ 104-83-6 ]
[ 611-19-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 420
9
[ 17849-38-6 ]
[ 609-65-4 ]
[ 611-19-8 ]
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 34, p. 10145 - 10149[2] Angew. Chem., 2016, vol. 128, # 34, p. 10300 - 10304,5
10
[ 7791-25-5 ]
[ 95-46-5 ]
[ 94-36-0 ]
[ 95-49-8 ]
[ 611-19-8 ]
[ 578-51-8 ]
[ 3433-80-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2940
11
[ 708-65-6 ]
[ 128408-26-4 ]
[ 611-19-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1163 - 1169
12
[ 191402-57-0 ]
[ 128408-30-0 ]
[ 611-19-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1163 - 1169
13
[ 7553-56-2 ]
[ 100-44-7 ]
[ 104-83-6 ]
[ 611-19-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 420
14
[ 10026-13-8 ]
[ 611-19-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1926, vol. 449, p. 264
15
[ 7647-18-9 ]
[ 100-44-7 ]
[ 104-83-6 ]
[ 611-19-8 ]
[ 3290-01-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1932, vol. 493, p. 153,156, 164
16
[ 7553-56-2 ]
[ 100-44-7 ]
[ 13911-02-9 ]
[ 13911-07-4 ]
[ 104-83-6 ]
[ 611-19-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1932, vol. 493, p. 153,156, 164
17
[ 611-19-8 ]
[ 7499-08-3 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 334 - 343
18
[ 611-19-8 ]
[ 13078-80-3 ]
Reference：
[1] Tetrahedron, 1977, vol. 33, p. 581 - 588
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 2644,2646
27
[ 611-19-8 ]
[ 6305-95-9 ]
Reference：
[1] Journal of the American Chemical Society, 1961, vol. 83, p. 1691 - 1697
28
[ 611-19-8 ]
[ 75-36-5 ]
[ 6305-95-9 ]
Reference：
[1] Synthesis, 2010, # 5, p. 882 - 891
29
[ 611-19-8 ]
[ 2856-63-5 ]
Yield
Reaction Conditions
Operation in experiment
22 %Chromat.
With palladium diacetate; sodium carbonate; triphenylphosphine In 1-methyl-pyrrolidin-2-one at 140℃; for 10 h; Inert atmosphere
General procedure: 0.06 mmol PPh3, 0.02 mmol Pd(OAc)2, and 0.4 mL NMP were added into a dried 20 mL tube under a dry nitrogen atmosphere. After the mixture was stirred at room temperature for about 5 min to give a homogeneous solution, 0.3 mmol K4[Fe(CN)6], 1.5 mmol Na2CO3, 1 mmol benzyl chloride, and 0.4 mL NMP were added under a dry nitrogen atmosphere. The reaction tube was sealed with a septum and placed in a constant-temperature oil bath set at 140(+/-5) °C to perform the reaction for 10 h. Once the reaction time was reached, the mixture was cooled to room temperature, then acetophenone was added as an internal standard. GC analysis of the mixture provided the yield of the product (note: in order to decrease the analysis error, the mixture after the reaction was not purified or concentrated). The cyanation product was purified by column chromatography and identified by 1H NMR, 13C NMR or GC-MS data.
Reference：
[1] Helvetica Chimica Acta, 2002, vol. 85, # 7, p. 2089 - 2104
[2] Tetrahedron, 1977, vol. 33, p. 581 - 588
[3] Australian Journal of Chemistry, 1970, vol. 23, p. 329 - 339
[4] Journal of the American Chemical Society, 1961, vol. 83, p. 1691 - 1697
31
[ 151-50-8 ]
[ 611-19-8 ]
[ 2856-63-5 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 776 - 794
[2] Bulletin de la Societe Chimique de France, 1966, p. 1956 - 1966
32
[ 54903-50-3 ]
[ 611-19-8 ]
[ 53885-35-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: at 60℃; for 1 h; Stage #2: With hydrogenchloride In dichloromethane
In a 500 ml three-necked flask, 12.7 g (0.1 mol) of 2-thiophenethylamine,9 g (0.3 mol) of formaldehyde, 50 g of dichloromethane and 50 g of dichloroethane,S2O82- / SnO2-Fe2O3 solid super acid 12 grams,Turn on stirring, and heated to 60 ° C for 5 hours after the reaction was stopped heating,The reaction solution was then cooled to room temperature,19.3 g (0.12 mol) of 2-chlorobenzyl chloride and 10.1 g of solid base-III were further added to the reaction mixture,Continue to heat and make it at 60 temperature for 1 hour, stop heating and stirring,Let stand, filtered to remove residue, the filtrate was passed into hydrogen chloride gas to give 26.1 g of triclopyridine hydrochloride, yield 87percent.
With hydrogenchloride; sodium hydrogencarbonate In ethanol
d 5-(2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride 26.1 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 80 ml of ethanol and 19 g of sodium bicarbonate are charged into a 250-ml three-necked round bottom flask fitted with a thermometer, a condenser and a mechanical stirrer. 30.2 g of o-chlorobenzyl chloride are then added and the mixture is heated to about 75°-80° C. during 1 hour. The reaction mixture is evaporated down and the residue is taken up with 200 ml of isopropyl ether. The 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine obtained is then added to 100 ml of ethanol. After adding 20 ml of concentrated hydrochloric acid to the ethanolic solution, heating to reflux and cooling the mixture, 46.6 g of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, which crystallises, are obtained. M.p.: 210° C. Yield: 83percent. 1 H NMR spectrum (CDCl3) (300 MHz) δ=3.1-4.9 (8H,m); 6.6 (2H,d); 7.8 (4H,m) ppm.
Reference：
[1] Patent: US5132435, 1992, A,
34
[ 30433-91-1 ]
[ 2053-29-4 ]
[ 611-19-8 ]
[ 53885-35-1 ]
Yield
Reaction Conditions
Operation in experiment
84%
With hydrogenchloride; formaldehyd; potassium carbonate In tetrahydrofuran; methanol; water; toluene
8A. FORMULA IV WHERE R1,R2,R3,R4,R5,R6,R7AND R8ARE HYDROGEN, AND R9IS CHLORO. A solution of 37percent aqueous formaldehyde (23.1kg) was added to 2-(2--thienyl)ethylamine (35kg) dissolved in toluene (60kg). The mixture was refluxed with stirring for 4hrs. After the reflux the mixture was kept under an inert atmosphere, allowed to cool and the aqueous layer was removed. The solvent was removed from the organic layer yielding the desired formimine (a compound of Formula 5) of 2-(2-thienyl)ethylamine as a monomer [N-formylidene-2-(2-thienyl)ethylamine] or as a trimer [1,3,5-tris-(2-(2-thienyl)ethyl)-hexahydro-s-triazine]. The formimine was dissolved in tetrahydrofuran (57kg). A solution of tetrahydrofuran and hydrogen chloride (g) was prepared by adding hydrogen chloride (g) (12.3kg) to tetrahydrofuran (57kg) at -5°C to 0°C. While under an inert atmosphere, the hydrogen chloride solution in tetrahydrofuran was added to the formimine solution and stirred for 4hrs at 5°C to 0°C yielding the cyclic amine (a compound of Formula 6). An aqueous solution of potassium carbonate was prepared by dissolving potassium carbonate (76kg) in water (70kg). The aqueous potassium carbonate solution and o-chlorobenzylchloride (45.2kg) was then added to the mixture. The mixture was heated to 95°C to 100°C, allowed to cool and refluxed at 70°C to 75°C for 3hrs. After reflux, the reaction mixture was allowed to cool, extracted with toluene (1x55kg, 2x42.5kg), filtered, and washed with toluene yielding the desired product in toluene. The toluene was removed under reduced pressure yielding (a compound of Formula IV), 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine, ticlopidine free base. A methanolic solution of hydrogen chloride was prepared by adding hydrogen chloride (g) (12.5kg) to methanol (28kg). The ticlopidine free base was dissolved in toluene (44kg) and the methanolic solution of hydrogen chloride was added. Ticlopidine hydrochloride (84percent) was isolated from the solution by centrifugation, washed with methanol/toluene (9:1) at 0°C and dried.
Stage #1: With sodium carbonate In water at 85℃; for 2 h; Large scale Stage #2: at 85℃; Large scale
1000 kg of water was charged to a 4000 L reactor, then 460 kg of 4, 4-dimethyl-3-isoxazolidinone was added. The resulting solution was stirred at room temperature for 1 h. Thereafter, 383 kg of Na2C03 was added in small portions. The temperature of the resulting mixture was raised to 85°C and the mixture stirred at this temperature for 2 h. Thereafter, 672 kg of 2-chlorobenzyl chloride was added dropwise over a period of 5 h at 85°C. After the addition was completed, the resulting solution was stirred at the same temperature until the reaction had completed. The resulting mixture was cooled to room tempertaure and 800 kg of dichloromethane was added to the reactor. The resulting mixture was stirred at room temperature for 15 h. Thereafter, the aqueous phase was separated, extracted with dichloromethane (3 times). Dichloromethane was recovered by distillation and then 2000 kg of hexane was added into the reactor. The resulting mixture was refluxed for 1 h, then cooled to 10 to 15°C and stirred for another 1 h. The solid material was isolated by filtration. The solid was washed with hexanes several times and dried under high vacuum to give pure clomazone Technical (815 kg, Purity: 96percent). Similar results are obtained using sodium hydroxide as the base, in place of sodium carbonate.
Reference：
[1] Patent: WO2015/353, 2015, A1, . Location in patent: Page/Page column 16; 17
[2] Patent: CN106749072, 2017, A, . Location in patent: Paragraph 0018; 0021; 0024; 0027
37
[ 4300-97-4 ]
[ 611-19-8 ]
[ 81777-89-1 ]
Reference：
[1] Patent: CN108774186, 2018, A, . Location in patent: Page/Page column 5; 6; 7
3C. Ticlopidine Free Base To a suspension of sodium hydride (0.42 g, 8.6 mmole) in THF (5.0 ml) is added a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 7.2 mmole), prepared, for example, as described in Example 3B, in THF (10 ml). The mixture is stirred under a nitrogen atmosphere at room temperature for 30 minutes and o-chlorobenzyl chloride (1.74 g, 10.8 mmole) is added. After stirring at room temperature for 90 minutes, toluene (15 ml) is added and the mixture is heated to reflux for 15 to 20 hours. Disappearance of starting material is confirmed by TLC. The mixture is then cooled to room temperature and acidified with 40 ml 1N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of toluene. The aqueous layer is then separated and basified with dilute aqueous sodium hydroxide to pH 13-14. The product is extracted into methylene chloride (3*40 ml). The methylene chloride extracts are washed (1*50 ml water) and (1*50 ml salt solution) then dried over anhydrous magnesium sulfate and concentrated to give the desired product. Following the above procedure, there was obtained 1.5 g (80%) of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (ticlopidine free base) as a light yellow oil. NMR (CDCl3) delta: 7.7-7.15 (m, 4H), 7.05 (d, 1H), 6.65 (d, 1H), 3.8 (s, 2H), 3.6 (s, 2H), 2.85 (br.s, 4H).
In tetrahydrofuran; toluene;
A-3. Ticlopidine Free Base To a suspension of sodium hydride (0.42 g, 8.6 mmole) in THF (5.0 ml) is added a solution of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.0 g, 7.2 mmole), prepared, for example, as described in Example A-2, in THF (10 ml). The mixture is stirred under a nitrogen atmosphere at room temperature for 30 minutes and o-chlorobenzyl chloride (1.74 g, 10.8 mmole) is added. After stirring at room temperature for 90 minutes, toluene (15 ml) is added and the mixture is heated to reflux for 15 to 20 hours. Disappearance of starting material is confirmed by TLC. The mixture is then cooled to room temperature and acidified with 40 ml 1N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of toluene. The aqueous layer is then separated and basified with dilute aqueous sodium hydroxide to pH 13-14. The product is extracted into methylene chloride (3*40 ml). The methylene chloride extracts are washed (1*50 ml water) and 1*50 ml salt solution) then dried over anhydrous magnesium sulfate and concentrated to give the desired product. Following the above procedure, there is obtained 1.5 g (80%) of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (ticlopidine free base) as a light yellow oil. Reported NMR (CDCl3) w: 7.7-7.15 (m,4H), 7.05 (d,1H), 6.65 (d,1H), 3.8 (s,2H), 3.6 (s,2H), 2.85 (br.s,4H).
f. contacting 4,5,6,7-tetrahydrothieno[3,2-c]pyridine with sodium hydride followed by o-chlorobenzyl chloride to give 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, and
Stage #1: Indole-3-carboxaldehyde With caesium carbonate In acetonitrile at 60℃; for 2h;
Stage #2: 1-chloro-2-(chloromethyl)benzene In acetonitrile at 60℃; for 1h;
5.1.3 General procedure A for the synthesis of 7a-42a
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
72.3%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide Reflux;
General Procedure for the Preparation of 3a-3i.
General procedure: Indole-3-carboxaldehyde (1, 5 mmol) was dissolved in appropriate quantity of dimethylformamide (DMF) and 2.4 ml of 1,8-Diazabicycloundec-7-ene was added. Further, 6 mmol appropriate benzyl chloride (2) was added slowly to the mixture and refluxed for >20 hours [21]. The product was extracted by fractionation from ethyl acetate and water. The organic layer was concentrated to give crude product which was then purified using column chromatography (petroleum ether: ethyl acetate).
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
Stage #1: Indole-3-carboxaldehyde With potassium carbonate In acetone for 0.0833333h;
Stage #2: 1-chloro-2-(chloromethyl)benzene In acetone at 50℃;
4.2.1. Synthesis of variedly substituted benzyl-1H-indole-3-carbaldehyde (3a-i)
General procedure: A mixture of indole-3-carbaldehyde (1) (0.35 g, 2.5 mmol) andpotassium carbonate (5 mmol) in acetone (10 ml) was stirred for5 min. Next, variedly substituted benzyl chlorides (2a-i) (2.5mmol) were added into the reaction mixture and stirred at 50 C.Completion of reaction was monitored by TLC. After completionof reaction, the mixture was filtered to remove K2CO3 and concentratedunder vacuum. Obtained crude product was dried andrecrystallized with diethyl ether to afford the pure product (3a-i).
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
Stage #1: carbon monoxide With C28H22CoN4O6 In butan-1-ol at 60℃; for 2h; Glovebox; High pressure; Green chemistry;
Stage #2: 1-chloro-2-(chloromethyl)benzene With tetra-(n-butyl)ammonium iodide; sodium hydroxide In butan-1-ol at 60℃; for 22h; Glovebox; High pressure; Green chemistry; regioselective reaction;
4.4 Synthesis of 2a-u
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.
88%
With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide In methanol at 180℃; for 6h; Autoclave;
6; 10
312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,1.37 g of palladium acetate was added to the autoclave reactor.The catalyst was dissolved by stirring for 5 minutes, and the air in the kettle was replaced with CO three times, and the temperature was raised to 180 ° C.Rush into the CO until the pressure rises to 1.5 MPa. Within 1 hour,At the same time, 64.4 g (0.4 mol) of o-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 o-chlorophenylacetic acid, the purity is:99.35%, the yield was 88%.
85%
With bis-triphenylphosphine-palladium(II) chloride; tetraethylammonium chloride; sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene at 80℃; for 20h; Autoclave; regioselective reaction;
Catalytic experiments
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.
76%
With sodium hydroxide In toluene at 85 - 95℃; for 6.5h;
96 %Chromat.
With water; palladium diacetate at 110℃; for 4h; Ionic liquid;
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In DMF (N,N-dimethyl-formamide); at 60℃; for 4h;
To a mixture of part C compound (205 mg, 0.83 mmol), potassium carbonate (900 g, 6.64 mmol) and Bu4NI (cat) in dry DMF (3.4 mL) was added 2-chlorobenzylchloride (0.42 mL, 3.32 mmol). The reaction mixture was heated at 60 C. for 4 hr and partitioned between water (25 mL) and Et2O (3×60 mL). The organic extracts were washed with water (3×25 mL) and brine (25 mL) and dried (MgSO4) to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as a white solid (392 mg, 95%), mp 100-101 C.
With hydrogenchloride; potassium hydroxide; sodium ethanolate; In ethanol; n-heptane; water;
EXAMPLE 1 Preparation of 1-(2-carboxyethyl)-2-chlorobenzene A solution of 171.0 g (2.51 mol) of sodium ethoxide in ethanol is admixed with 149.2 g (932 mmol) of diethyl malonate. 50.0 g (311 mmol) of 2-chlorobenzyl chloride are added to this reaction mixture, and after the addition is complete the reaction mixture is refluxed for three hours. After cooling to room temperature, 480 g (1.71 mol) of a KOH solution are added and the mixture is subsequently refluxed for another hour. The ethanol is then distilled off and the residue is subjected to an aqueous work-up and extracted three times with 100 ml each time of diethyl ether. The organic phase is discarded and the aqueous phase is brought to a pH of 1 using concentrated HCl. The mixture is subsequently extracted three times with 100 ml each time of diethyl ether. The combined organic phases are washed with 100 ml of water and then with 100 ml of a saturated NaCl solution. After drying over magnesium sulfate, the solvent is removed in an oil pump vacuum. The residue is taken up in heptane and subsequently heated to 180 C. After gas evolution has ceased, the solvent is removed in an oil pump vacuum. 43.8 g (91%) of the desired product are isolated. The product prepared is used without further purification for the next step.
6 1-Chloro-2-(4-fluorophenyl)-3-(2-chlorophenyl)propan-2-ol
1-Chloro-2-(4-fluorophenyl)-3-(2-chlorophenyl)propan-2-ol 170 g (1.0 mol) of 2-chlorobenzyl chloride dissolved in 400 ml of diethyl ether were added to 36.0 g (1.5 mol) of magnesium turnings in 200 ml of diethyl ether. 155 g (0.9 mol) of para-fluoro-ω-chloroacetophenone, dissolved in 450 ml of diethyl ether, were subsequently added dropwise at -10° C., and the mixture is then stirred for a further 2 hours at 25° C. 49.0 g (0.5 mol) of concentrated sulfuric acid in 300 ml of diethyl ether are then added dropwise at -10° C. The mixture is allowed to warm to 25° C., and the precipitated salt is filtered off with suction. The crude ether solution of the chlorohydrin is then employed further.
With magnesium In diethyl ether; toluene
1 1-Chloro-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-propanol
1-Chloro-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-propanol 30 g (1.25 mol) of magnesium turnings are introduced into 100 ml of diethyl ether at room temperature, and 17 g (0.1 mol) of 2-chlorobenzyl chloride are added dropwise within 4 to 5 minutes. After the Grignard reaction has started, a further 153 g (0.95 mol) of 2-chlorobenzyl chloride in 800 ml of diethyl ether are added dropwise at the reflux temperature within about one hour. After a further 30 minutes, the Grignard solution is cooled and added dropwise at 0° to 2° C. to 157 g (0.91 mol) of 4-fluoro-ω-chloroacetophenone in 250 ml of toluene, and the mixture is then stirred at 0° C. for 1 to 2 hours and worked up in a conventional manner.
Stage #1: 1-chloro-2-(chloromethyl)benzene With magnesium In diethyl ether at 20℃; Reflux;
Stage #2: 2-Chloro-4'-fluoroacetophenone In diethyl ether; toluene at 0 - 2℃; for 2h;
1.1; 1.2; 1.3; 2.1; 2.2; 2.3; 3.1; 3.2; 3.3 Example 3
(1) Add 37.5 g of magnesium turnings to 100 mL of diethyl ether.15 g of 2-chlorobenzyl chloride was added dropwise at room temperature.After 4-5 minutes, after the addition is completed,Warming reflux to obtain A solution;(2) 150 g of a solution of 2-chlorobenzyl chloride dissolved in 900 mL of diethyl ether was added dropwise to the solution A.After the addition is completed within 75 minutes,Reflux for 30 minutes to obtain a solution B;(3) 150 g of 4-fluorochloroacetophenone was mixed with 250 mL of toluene, and the temperature was lowered to 0-2 ° C.Add B solution dropwise, and control the temperature at 0 ° C for 2 hours.Obtaining 1-chloro-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-propanol;
With hydrogenchloride; triethylamine In water; acetonitrile
2.b (b)
(b) Production of di-tert-butyl-N-[(2-chlorophenyl)methyl]-3,3'-iminodipropionate 45.06 g (0.27 mol) of 2-chlorobenzylchloride and 51 g (0.19 mol) of di-tert-butyl-3,3'-iminodipropionate were dissolved in 350 ml of acetonitrile, mixed with 28.3 g (0.28 mol) of triethylamine and refluxed. After 5 hours, 8.85 g (0.06 mol) of 2-chlorobenzylchloride and 9.34 g (0.09 mol) of triethylamine were again added. After being refluxed for 15 hours, the reaction mixture was concentrated by evaporation. The residue was taken up in 300 ml of water, 100 ml of HCl 5n and 300 ml of ether. The acidic water phase was made basic with NaOH (20 percent) and extracted three times with 100 ml of ether. 67.7 g (91 percent) of the subtitle compound (noted above) was obtained from the ether phase. Data concerning the compound was: 1 H-NMR: (CDCl3, 300 MHz); 7.5 (dd, J=8.0 Hz, 1.5 Hz, 1H); 7.32 (dd, J=8.0 Hz, 1.5 Hz, 1H); 7.26-7.14 (m, 2H); 3.7 (s, 2 H); 2.82 (t, J=7.5 Hz, 4H); 2.41 (t, J=7.5 Hz, 4H); 1.44 (s, 18H);
With hydrogenchloride; sodium hydrogencarbonate; In ethanol;
d 5-(2-Chlorobenzyl)-<strong>[54903-50-3]4,5,6,7-tetrahydrothieno[3,2-c]pyridine</strong> hydrochloride 26.1 g of <strong>[54903-50-3]4,5,6,7-tetrahydrothieno[3,2-c]pyridine</strong>, 80 ml of ethanol and 19 g of sodium bicarbonate are charged into a 250-ml three-necked round bottom flask fitted with a thermometer, a condenser and a mechanical stirrer. 30.2 g of o-chlorobenzyl chloride are then added and the mixture is heated to about 75-80 C. during 1 hour. The reaction mixture is evaporated down and the residue is taken up with 200 ml of isopropyl ether. The 5-(2-chlorobenzyl)-<strong>[54903-50-3]4,5,6,7-tetrahydrothieno[3,2-c]pyridine</strong> obtained is then added to 100 ml of ethanol. After adding 20 ml of concentrated hydrochloric acid to the ethanolic solution, heating to reflux and cooling the mixture, 46.6 g of 5-(2-chlorobenzyl)-<strong>[54903-50-3]4,5,6,7-tetrahydrothieno[3,2-c]pyridine</strong> hydrochloride, which crystallises, are obtained. M.p.: 210 C. Yield: 83%. 1 H NMR spectrum (CDCl3) (300 MHz) delta=3.1-4.9 (8H,m); 6.6 (2H,d); 7.8 (4H,m) ppm.
8-(2-chlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dimethyl sulfoxide; mineral oil;
Preparation 11 A 60% dispersion of sodium hydride in mineral oil (1.87 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (6.3 g) in dimethyl sulfoxide (63 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 2-chlorobenzyl chloride (7.54 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of diethyl ether and n-hexane to give 8-(2-chlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (7.75 g). mp: 97 to 98 C. IR (Nujol): 1535, 1280, 1260, 1100 cm-1 NMR (CDCl3, δ): 2.46 (3H, s), 5.41 (2H, s), 6.26-6.73 (2H, m), 7.05-7.50 (4H, m), 7.52-7.83 (2H, m).
N-[1-(2-Chlorobenzyl)-4-piperidyl]-N-(1H-5-indazolyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; acetic acid; In methanol; acetonitrile;
Example 134 N-[1-(2-Chlorobenzyl)-4-piperidyl]-N-(1H-5 indazolyl)amine 2-Chlorobenzyl chloride (81 mg), <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> (77 mg), and potassium carbonate (138 mg) were dissolved in acetonitrile (1 ml), and the mixture was then stirred at room temperature for 18 hr. The reaction mixture was filtered through Celite, and the filtrate was then concentrated to give an intermediate. This intermediate, 5-aminoindazole (53 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (109 mg, yield 80%). 1H-NMR (CDCl3, 400 MHz): 1.47 - 1.60 (m, 2H), 2.06 - 2.16 (m, 2H), 2.25 - 2.36 (m, 2H), 2.87 - 2.97 (m, 2H), 3.30 - 3.40 (m, 1H), 3.67 (s, 2H), 6.78 - 6.84 (m, 2H), 7.16 - 7.34 (m, 4H), 7.35 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.88 (s, 1H) Mass spectrum (ESI-MS, m/z): 341 (M++1)
To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF (120 mL) at 0 C. was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol). The mixture was stirred at 0 C. for 15 minutes before the addition of 2-chlorobenzylchloride (12.3 g, 76.4 mmol). After stirring at 55 C. overnight, the mixture was poured into ice-water and washed with Et2O twice. The aqueous layer was acidified and filtration of the resulting precipitate gave compound 16 (14.7 g, 85%).
Stage #1: 1-chloro-2-(chloromethyl)benzene With magnesium In diethyl ether Reflux;
Stage #2: 2-chloro-1-(3-fluorophenyl)ethanone In diethyl ether; toluene at 0 - 20℃;
Stage #3: With water; ammonium chloride In diethyl ether; toluene at 0℃;
a
a) Synthesis of 1-chloro-2-(3-fluorophenyl)-3-(2-chlorophenyl)propan-2-ol Magnesium turnings (1.09 g, 44.8 mmol) were added to a solution of ortho-chlorobenzyl chloride (0.1 ml, 0.8 mmol) in anhydrous diethyl ether (20 ml) and iodine. Once the exothermal reaction had started, further benzyl chloride (7.10 g, 44.0 mmol) was added dropwise to the reaction solution under reflux. The mixture was stirred under reflux for a further two hours and then cooled to 0° C., and a solution of 2-chloro-1-(2-chlorophenyl)ethanone (3.87 g, 22.4 mmol) in anhydrous toluene (10 ml) was added dropwise. The mixture was then stirred at room temperature for three hours and again cooled to 0° C., and aqueous ammonium chloride solution (10 ml) was added. The aqueous phase was extracted repeatedly with ethyl acetate, the combined organic phases were dried (sodium sulfate) and the solvent was distilled off. The residue (about 8.6 g) was used without purification for the next reaction step.
4-benzyloxy-l-(2-chloro-benzyl)-lH-pyridin-2-oneA solution of 4~benzyloxy-lH-pyridone(300mg, 1.49mmol) and NaH(60mg,1.49mmol) in solvent of DMF was stirred for 30min followed by adding 2-chlorobenzyl chloride(240mg, 1.49mmol) further stirring for 30min at room temperature. The resulting solution was worked up with Water and dichloromethane and purified by column chromatography(ethyl acetate/hexane, 1:1) to obtain the titled compound(320mg, 67%).1H NMR (CDCl3, 300 MHz) delta 5.00 (s, 2H), 5.20 (s, 2H), 5.97 (dd, IH), 6.04 (d, IH),7.17-7.39 (m, 10H)
Stage #1: 3,5-dimethyl-1H-pyrazole With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1.5h;
Stage #2: 1-chloro-2-(chloromethyl)benzene In dimethyl sulfoxide for 1.75h;
Powdered potassium hydroxide (1.751 g, 31.2 mmol) was added to a solution of 3,5-dimethylpyrazole (2 g, 20.81 mmol) in anhydrous DMSO (10.40 ml) and the resulting heterogeneous solution was stirred for 1.5 hr at 80 °C before being cooled to roomtemperature. 2-Chloro benzylchloride (2.64 ml, 20.81 mmol) was then added in 6 M DMSO over 15 min, and the solution was stirred for a further 1.5 hrs. Upon completion as observed by TLC, the reaction was poured over water and the resulting aqueous phase was extracted with two 20 mL portions of CHCI3. The combined organic layers were washed with 100 mL of water, dried with anhydrous MgS04 and concentrated under reduced pressure to yield 4.55 g (99%) of l-(2-chlorobenzyl)-3,5-dimethyl-lH-pyrazole as a clear liquid. 1H NMR (300 MHz, CDCI3) δ 7.41 - 7.31 (m, 1H), 7.24 - 7.09 (m, 2H), 6.59 - 6.50 (m, 1H), 5.90 (s, 1H), 5.31 (s, 2H), 2.26 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCI3) δ 148.32, 139.96, 135.46, 131.96, 129.42, 128.76, 127.72, 127.48, 105.84, 50.12, 13.80, 11.15. HRMS (m z): [MNa]+ calc for C12Hi3ClN2Na+ 243.07; found 243.0651.
99%
Stage #1: 3,5-dimethyl-1H-pyrazole With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1.5h; Inert atmosphere;
Stage #2: 1-chloro-2-(chloromethyl)benzene In dimethyl sulfoxide at 20℃; for 1.25h; Inert atmosphere;
1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazole
Powdered potassium hydroxide (1.751 g, 31.2 mmol) was added to a solution of 3,5-dimethylpyrazole (2 g, 20.81 mmol) in anhydrous DMSO (10.40 ml) and the resulting heterogeneous solution was stirred for 1.5 hr at 80° C. before being cooled to room temperature. 2-Chloro benzylchloride (2.64 ml, 20.81 mmol) was then added in 6 M DMSO over 15 min, and the solution was stirred for a further 1.5 hrs. Upon completion as observed by TLC, the reaction was poured over water and the resulting aqueous phase was extracted with two 20 mL portions of CHCl3. The combined organic layers were washed with 100 mL of water, dried with anhydrous MgSO4 and concentrated under reduced pressure to yield 4.55 g (99%) of 1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazole as a clear liquid. 1H NMR (300 MHz, CDCl3) δ 7.41-7.31 (m, 1H), 7.24-7.09 (m, 2H), 6.59-6.50 (m, 1H), 5.90 (s, 1H), 5.31 (s, 2H), 2.26 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.32, 139.96, 135.46, 131.96, 129.42, 128.76, 127.72, 127.48, 105.84, 50.12, 13.80, 11.15. HRMS (m/z): [MNa]+ calc for C12H13ClN2Na+ 243.07. found 243.0651.
87%
Stage #1: 3,5-dimethyl-1H-pyrazole With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1.5h;
Stage #2: 1-chloro-2-(chloromethyl)benzene In dimethyl sulfoxide at 20℃; for 1.75h;
4.1.3. General procedure for the synthesis of compound 3a-d
3,5-dimethyl-1H-pyrazole (1000 mg, 10.40 mmol) and KOH(1675 mg, 10.40 mmol) were dissolved in DMSO and the resultingheterogeneous solution was stirred for 1.5 h at 80C before beingcooled to room temperature. Benzyl chloride (6 M) in 50 mL DMSOwas then added over 15 min, and the reaction mixture was stirredfor a further 1.5 h. Upon completion as observed by TLC. The reac-tion was poured over water, and the resulting aqueous phase wasextracted with two 20 mL portions of CHCl3. The combined organiclayers were washed with 100 mL of water, dried with anhydrousNa2SO4 and concentrated under reduced pressure. The residue waspuried by ash chromatography on silica-gel with 20% ethyl ac-etate in petroleum ether. Yielding 87% compound 3a (1999 mg) as ayellow oil. Compounds 3b-d were synthesized following the pro-cedure of preparation 3a.
82%
Stage #1: 3,5-dimethyl-1H-pyrazole With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1h; Inert atmosphere;
Stage #2: 1-chloro-2-(chloromethyl)benzene In dimethyl sulfoxide at 20℃; for 2h; Inert atmosphere;
Stage #1: 3,5-dimethyl-1H-pyrazole With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1.5h;
Stage #2: 1-chloro-2-(chloromethyl)benzene In dimethyl sulfoxide for 2.75h;
1.3
(1000mg, 10.40mmol) and KOH (1675mg, 10.40mmol) was dissolved in DMSO, and the resulting heterogeneous solution was stirred at 80 1.5h, then cooled to room temperature. Then, added over 15 minutes a solution of 6M DMSO (876mg, 15.61mmol), and the reaction mixture was stirred for 2.5 hours. TLC observation to monitor whether the reaction is complete. The reaction was dissolved in water, the aqueous phase with CHCl3 extraction. The combined organic layers were washed with 100ml of water, dried over anhydrous Na2SO4, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in petroleum ether. To give a yellow oil.
Stage #1: 3,5-dimethyl-1H-pyrazole With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1.5h;
Stage #2: 1-chloro-2-(chloromethyl)benzene In dimethyl sulfoxide at 20℃; for 2.75h;
1.3
3,5-Dimethyl-1H-pyrazole (1000 mg, 10.40 mmol) and KOH (1675 mg, 10.40 mmol) were dissolved in DMSO, and the resulting heterogeneous solution was stirred at 80 ° C for 1.5 h, then cooled to room temperature. Then 6 M DMSO solution of o-chlorobenzyl chloride (876 mg, 15.61 mmol) was added over 15 min and the reaction mixture was stirred for additional 2.5 h. TLC was observed to monitor whether the reaction was complete. The reaction was dissolved in water, aqueous phase was extracted with CHCl3. The combined organic layers were washed with 100ml of water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in petroleum ether to obtained as a yellow oil.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; manganese; palladium diacetate; magnesium chloride In N,N-dimethyl-formamide for 12h; Inert atmosphere; Schlenk technique;
62%
With (1,2-dimethoxyethane)dichloronickel(II); C15H27P*(x)BF4*H(1+); magnesium chloride; zinc In N,N-dimethyl-formamide at 20℃; Schlenk technique;
42%
With samarium; chloro-trimethyl-silane; tetra-(n-butyl)ammonium iodide In acetonitrile at 20℃; for 2h; Electrochemical reaction; Cooling with ice;
272 mg
Stage #1: 1-chloro-2-(chloromethyl)benzene With magnesium; lithium chloride; zinc(II) chloride In tetrahydrofuran at 25℃; for 1h;
Stage #2: carbon dioxide In tetrahydrofuran at 50℃; for 12h;
With palladium diacetate; sodium carbonate; triphenylphosphine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 10h;Inert atmosphere;
General procedure: 0.06 mmol PPh3, 0.02 mmol Pd(OAc)2, and 0.4 mL NMP were added into a dried 20 mL tube under a dry nitrogen atmosphere. After the mixture was stirred at room temperature for about 5 min to give a homogeneous solution, 0.3 mmol K4[Fe(CN)6], 1.5 mmol Na2CO3, 1 mmol benzyl chloride, and 0.4 mL NMP were added under a dry nitrogen atmosphere. The reaction tube was sealed with a septum and placed in a constant-temperature oil bath set at 140(+/-5) C to perform the reaction for 10 h. Once the reaction time was reached, the mixture was cooled to room temperature, then acetophenone was added as an internal standard. GC analysis of the mixture provided the yield of the product (note: in order to decrease the analysis error, the mixture after the reaction was not purified or concentrated). The cyanation product was purified by column chromatography and identified by 1H NMR, 13C NMR or GC-MS data.
1,1'-(2-(2,4-difluorophenyl)-2-hydroxypropane-1,3-diyl)bis(4-(2-chlorobenzyl)-1H-1,2,4-triazol-4-ium) chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.7%
In acetonitrile; at 80℃;
General procedure: To a solution of compound 6 (0.12 g, 0.4 mmol) in acetonitrile (10 mL) was added 1-butyl bromide (0.14 g, 1.0 mmol), 1-octyl bromide (0.19 g, 1.0 mmol), 1-dodecyl bromide (0.25 g, 1.0 mmol), or 1-hexadecyl bromide (0.30 g, 1.0 mmol) respectively. The mixture was stirred at 80 C. After the reaction came to the end (monitored by TLC, eluent, methanol/aqueous ammonia, 10/1, V/V), the solvent was evaporated under reduced pressure. The residue was washed three times with petroleum ether and dried in vacuum to give alkyl fluconazoliums 10a-d.
To a solution of 5-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (1.06 g, 4.5 mmol) in EtOH (20 mL) and H20 (20 mL) was added ]H-benzimidazoi-4-amine (0.6 g, 4.5 mmoi) and the mixture was heated at reflux overnight. The reaction mixture was concentrated, then dissolved in DMF (20 mL) and the mixture was stirred at 80 °C for 2 h. After cooling to r.t. l-chloro-2-(chlorornethyl)benzene (725 mg, 4.5 mmol) and K2CO3 (620 mg, 4.5 mmol) were added and the mixture was stirred at 80 °C for another 2 h. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by prep- HPLC to give 0.6 g (30percent) of 3-(benzy.oxy l-[ l -(2-chloroben2yl) H-benzimidazol-4-yl]pyridin-4(lH)- one. MS (ESI) (M+H)+ 442.1/ 444.1.
With trans-bis(dicyclohexylphenylphosphine)(2-methylphenyl)nickel(II) chloride; triethylamine In dichloromethane at 0 - 20℃; for 8h; regioselective reaction;
90%
With trans-bis(dicyclohexylphenylphosphine)(2-methylphenyl)nickel(II) chloride; triethylamine In dichloromethane at 20℃;
General procedure: Having established the competence of precatalyst 1 for this coupling reaction, the reaction was optimized, ultimately arriving at the conditions described in Table 1, with the conditions in entry 4 being chosen to utilize in additional reactions. The was investigated reaction under solvent-free (neat) conditions, and it was observed that these conditions performed quite poorly. This may be attributed to the low solubility of precatalyst 1 in triethylamine, which causes very slow activation. However, even in toluene, activation of the precatalyst is not facile, as entry 2 highlights: even after 1 hour, only 2 % of product has been produced, and although the reaction ultimately does reach completion, it requires nearly 24 hours to do so. The addition of COD to the reaction mixture was shown to again reduce the rate of reaction (entry 3). Changing the reaction solvent to dichloromethane facilitated rapid activation of the catalyst and a greatly accelerated coupling, requiring only 4 hours for the reaction to reach complete conversion (cf. entries 2 and 4), which corresponds approximately to a five-fold rate enhancement. The change from toluene to CH2CI2 also allowed for a reduction of the excess of alkene required (cf. entries 4-9). In toluene, changing from 5 to 2 equiv of alkene caused a marked decrease in the yield, even after 24 hours of reaction time (92% vs. 54%). However, in CH2CI2, changing from 5 to 2 equiv of alkene ultimately afforded the product in only a slightly diminished yield (96 vs. 84%), though the reaction rate was decreased. As the excess further decreases, however, the yield begins to drop considerably, ultimately to 68% when a 1 : 1 stoichiometry of benzyl chloride and alkene was used. Also interesting is the marked reduction in yield observed when Hiinig's Base (Et'P^N) is used instead of triethylamine (cf. entries 4 and 11). Though of similar thermodynamic basicity, this likely suggests that the sterically less hindered Et3N is capable of deprotonating the nickel hydride (formed after β-hydride elimination- FIG. 5, vide infra) much more efficiently. Prior to beginning this optimization process, one of the changes investigated was whether the use of dried and degassed solvents and reagents is necessary to obtain satisfactory results. Preliminary trials showed that using reagents and solvents "as received" had no negative effects on the yield of the reaction, however a direct comparison was carried out to rigorously verify this observation. As the comparison between entries 4 and 12 indicates, the reaction does appear to proceed more rapidly when purified and degassed reagents are employed, but ultimately the same yield is achieved in both cases. This difference in rate may be attributed to the oxygen mediated decomposition of some portion of the catalyst when unpurified reagents are employed, causing the effective catalyst loading to be slightly less than the nominal loading. Having verified the absence of negative effects, all further reactions were carried out without purification or degassing of any reagents, taking the conditions described in entry 4 as the optimized conditions. Having satisfactorily optimized the conditions for the coupling reaction, the scope of the reaction were examined, the results of which are shown in FIG. 2. In Fig. 2: Yields listed are isolated yields. Ratios reported represent the ratio of the major (branched) product to the sum of all other isomers as determined by GC.
With NHC-Pd(II)-Im; sodium hydroxide In water at 50℃; for 3h; Inert atmosphere; Schlenk technique;
Amination of benzyl chlorides 2 with dialkylformamides 3 in neat water catalysed by NHC-Pd(II)-Im complex 1; general procedure
General procedure: Under a N2 atmosphere, NaOH (3.0 equiv), NHC-Pd(II)-Im complex 1 (1.0 mol%), water (1.0 mL), benzyl chloride 2a (0.8 mmol), and N-formylmorpholine 3a (2.0 equiv) were successively added into a Schlenk reaction tube. The mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. Then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (eluent: PE/EA = 5:1) to give the pure products 4a. 4-(2-Chloro-benzyl)-morpholine (4m):20 Yellow liquid; 1H NMR (500 MHz): δ 7.47 (dd, J = 1.0, 7.5 Hz, 1H), 7.33 (dd, J = 1.5, 8.0 Hz,1H), 7.22 (td, J = 7.5, 1.5 Hz, 1H), 7.17 (td, J = 7.5, 2.0 Hz, 1H), 3.71 (t,J = 4.5 Hz, 4H), 3.61 (s, 2H), 2.50 (t, J = 4.5 Hz, 4H); 13C NMR (125 MHz): δ 135.3, 134.3, 130.6, 129.3, 128.1, 126.4, 66.9, 59.5, 53.5.
96%
With potassium hydroxide In water at 50℃; for 3h; Green chemistry;
4.2.1 General procedure for the reactions between (pseudo)halides 1 and formamides 2
General procedure: KOH (2.4mmol), H2O (1.0mL), (pseudo)halides 1 (0.8mmol), and formamides 2 (1.6mmol) were successively added into a reaction tube. Then the reaction mixture was stirred under the conditions shown in Tables 1-5. After the reactions were completed, the mixture was extracted by ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography to give products 3.
2-(2-chlorobenzyl)-decahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In acetonitrile; at 20℃;
General procedure: 1,2,3,4-Tetrahydro-isoquinoline(1g, 7.5 mmol) was dissolved in 5 mL of anhydrous acetonitrile. Then to thissolution was slowly added 2-chloro- or 2-bromo-benzyl compound (7.5 mmol) and the reaction was carried out overnight at room temperature. The solvent wasremoved under reduced pressure. The residue was resuspended in 1 ml of DMSO andpurified using C18 flash chromatography as described above.
General procedure: 1,2,3,4-Tetrahydro-isoquinoline(1g, 7.5 mmol) was dissolved in 5 mL of anhydrous acetonitrile. Then to thissolution was slowly added 2-chloro- or 2-bromo-benzyl compound (7.5 mmol) and the reaction was carried out overnight at room temperature. The solvent wasremoved under reduced pressure. The residue was resuspended in 1 ml of DMSO andpurified using C18 flash chromatography as described above.
2-(2-chlorobenzyl)-isoquinolinium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In acetonitrile; at 20℃;
General procedure: 1,2,3,4-Tetrahydro-isoquinoline(1g, 7.5 mmol) was dissolved in 5 mL of anhydrous acetonitrile. Then to thissolution was slowly added 2-chloro- or 2-bromo-benzyl compound (7.5 mmol) and the reaction was carried out overnight at room temperature. The solvent wasremoved under reduced pressure. The residue was resuspended in 1 ml of DMSO andpurified using C18 flash chromatography as described above.
With (1,3-dimesitylimidazolidin-2-yl)copper(I) chloride; potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere; Schlenk technique;
Cu-Catalyzed Carboboration of Alkenes: A General Procedure.
General procedure: A Schlenk tube equipped with a magnetic stirring bar was charged with SIMesCuCl (6.0 μmol), alkene 0.30 mmol), bis(pinacolato)diboron (0.39 mmol), a carbon electrophile (0.90 mmol), 1 M KOt-Bu in THF (0.45 mmol), and DMF (0.55 mL). The mixture was stirred at r.t. for the period specified in Tables 2-4, and diluted with EtOAc before filtration through a Celite plug. The organic solution was washed with brine (2 ×) and dried (MgSO4). Evaporation of the solvent followed by column chromatography (silica gel, hexane-EtOAc or hexane-CH2Cl2) or gel-permeation chromatography (CHCl3) gave the product.
4-((2-chlorobenzyl)oxy)-2-hydroxybenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.8%
With sodium hydrogencarbonate; potassium iodide In acetonitrile at 60 - 65℃;
5.7 General procedure for preparation of compounds 10a-g
General procedure: A mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 0.01 mol), substituted benzyl chloride (0.011 mol), NaHCO3 (1.26 g, 0.015 mol) and catalytic amount of potassium iodide in 20 mL acetonitrile was heated to 60 °C for 36 h and hot filtered, the filtrate was cooled to 10 °C and filtered, the filtrated cake was collected and recrystallized with EtOH to obtain compounds 10a-g.
66%
With potassium hydrogencarbonate; potassium iodide In acetonitrile at 70℃; for 2h;
General procedure: 2,4-Dihydroxybenzaldehyde(2.6 g, 15 mmol, 1 eq), KHCO3 (2.8 g, 33 mmol,2.2 eq), 3-nitrobenzyl chloride (1.7 g, 16.5 mmol, 1.1 eq), and anhydrousACN (50 mL) were added to a 100 mL round bottom flask. Thereaction proceeded under reflux condition for overnight. After cooling,the solvent was removed with reduced pressure evaporation. The crudeproduct was washed with DCM for 30 min and purified with reducedpressure flash column chromatography eluting with DCM. The product(1.8 g) was obtained as a white powder (Yield 47%). 1H NMR: (300 MHz,DMSO-d6) δ ppm 5.22 (s, 2H) 6.58 (s, 1H) 6.65 (d, J = 8.78 Hz, 1H)7.53-7.68 (m, 2H) 7.73-7.84 (m, 2H) 7.90 (s, 1H) 10.00 (s, 1H) 11.03 (s,1H)
66%
With potassium hydrogencarbonate; potassium iodide In acetonitrile at 70℃; for 2h;
General procedure: 2,4-Dihydroxybenzaldehyde(2.6 g, 15 mmol, 1 eq), KHCO3 (2.8 g, 33 mmol,2.2 eq), 3-nitrobenzyl chloride (1.7 g, 16.5 mmol, 1.1 eq), and anhydrousACN (50 mL) were added to a 100 mL round bottom flask. Thereaction proceeded under reflux condition for overnight. After cooling,the solvent was removed with reduced pressure evaporation. The crudeproduct was washed with DCM for 30 min and purified with reducedpressure flash column chromatography eluting with DCM. The product(1.8 g) was obtained as a white powder (Yield 47%). 1H NMR: (300 MHz,DMSO-d6) δ ppm 5.22 (s, 2H) 6.58 (s, 1H) 6.65 (d, J = 8.78 Hz, 1H)7.53-7.68 (m, 2H) 7.73-7.84 (m, 2H) 7.90 (s, 1H) 10.00 (s, 1H) 11.03 (s,1H)
With sodium carbonate; potassium iodide at 65℃; for 30h;
1000 kg of water was charged to a 4000 L reactor, then 460 kg of 4, 4-dimethyl-3-isoxazolidinone was added. The resulting solution was stirred at room temperature for 1 h. Thereafter, 383 kg of Na2C03 was added in small portions. The temperature of the resulting mixture was raised to 85C and the mixture stirred at this temperature for 2 h. Thereafter, 672 kg of 2-chlorobenzyl chloride was added dropwise over a period of 5 h at 85C. After the addition was completed, the resulting solution was stirred at the same temperature until the reaction had completed. The resulting mixture was cooled to room tempertaure and 800 kg of dichloromethane was added to the reactor. The resulting mixture was stirred at room temperature for 15 h. Thereafter, the aqueous phase was separated, extracted with dichloromethane (3 times). Dichloromethane was recovered by distillation and then 2000 kg of hexane was added into the reactor. The resulting mixture was refluxed for 1 h, then cooled to 10 to 15C and stirred for another 1 h. The solid material was isolated by filtration. The solid was washed with hexanes several times and dried under high vacuum to give pure clomazone Technical (815 kg, Purity: 96%). Similar results are obtained using sodium hydroxide as the base, in place of sodium carbonate.
With tetrabutylammomium bromide; sodium hydroxide; at 90℃; for 5.5h;
The reaction solution (containing 97.2% of 4,4-dimethylisoxazol-3-one) in the previous step was heated to 90 C,0.6 g of NaOH solids, 0.4 g of tetrabutylammonium bromide as a catalyst,16.1 g of o-chlorobenzyl chloride was added dropwise, 0.5h drop finishedThe 90 incubation reaction 5h.After completion of the reaction, the mixture was cooled to room temperature and extracted three times with 30 ml of ethyl acetate to remove the solvent in an oil phase to give a pale yellow oil,That isdifferentCrude oxalone crude. The yield was 94% and the total yield was 87.1%.
973 kg
With potassium carbonate; at 85℃; for 3h;pH 7;Large scale;
the crude isoxalinone in step 3, first dehydrated under reduced pressure, and then the dried oily mixture is cooled to 45 C, then passed through a dry hydrogen chloride gas, and maintained at this temperature for 3 h, Then, 10.5 kg of o-chlorobenzyl chloride, 9.57 kg of 30% by mass of liquid alkali, 2.9 kg of potassium carbonate solid were added to the reaction solution, and the pH was adjusted to 7.00, and then the temperature was raised to 85 C for 3 hours, and the amount of o-chlorobenzyl chloride was qualified. After standing, the layers were separated, the lower organic phase was separated, dehydrated under reduced pressure, and the oxaloxone product was distilled off under vacuum, and further purified by petroleum ether to obtain 973 kg of clomazone, content 98.1%. The yield (calculated as hydroxylamine hydrochloride) was 92.1%.
In toluene at 70℃; for 5h; Sonication; Green chemistry;
General Procedure for the Synthesis of N-alkylpyridazinium Halides 1-8 with Ultrasonic Irradiation
General procedure: Pyridazine (1.0 eq.) and an alkyl halide (1.1 eq.) were added totoluene (15 mL) and placed in a closed vessel and exposed to irradiation for 5 h at 70 °C in a sonicator until a precipitate was formed. The obtained solid was filtered and washed with ethyl acetate to afford the desired pyridazinium IL
6-[(2-chlorobenzyl)oxy]-1,3-benzothiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With 1,1'-[1,2-phenylenebis(nitrilomethylylidene)dinaphthalen-2-olato]uranyl(VI); bromine In dichloromethane at 20℃; for 0.583333h;
Halogen exchange reaction of alkyl halides with elemental halogens (general procedure)
General procedure: A solution of alkyl halide (1 mmol) in dichloromethane (5 mL) was added to a stirred solution of catalyst (0.1 mmol) in CH2Cl2 (5 mL) at room temperature followed by dropwise addition of a solution of elemental halogen (Br2 or I2) (2 mmol) in dichloromethane (5 mL) over 15 min. After completion of the reaction (TLC monitoring), the reaction mixture was filtered and the obtained organic solution was washed with 10% aqueous Na2S2O3 (2×10 mL) and water (2×10 mL).The aqueous layer was extracted with CH2Cl2 (2×10 mL) and the combined organic layers were dried with CaCl2. Removal of the solvent afforded pure target alkyl halides. Structures of the obtained alkyl halides were confirmed by a comparison with authentic samples prepared in accordance to the literature procedure.2
Stage #1: butan-1-ol With cobalt(II) acetate; cobalt(II) nitrate at 40℃; for 2h; Autoclave;
Stage #2: 1-chloro-2-(chloromethyl)benzene With sodium hydroxide In water at 40℃; for 12h; Autoclave;
7 Synthesis of O-chlorophenylacetic acid
To a 3000 L autoclaveAdding 1,200 kg of n-butanolAnd cobalt nitrate 0.2,Cobalt acetate 1.5kg, CO replacement after adjusting the pressure of 0.5MPa, The temperature was raised to 40 ° C for 2 hours.Pressure relief by adding sodium hydroxide 200kg and water 800kg,Through the CO adjustment pressure of 0.3MPa,Heating up to 40° C ,Slowly and slowly adding o-chlorobenzyl chloride 300kg,After the addition reaction was incubated for 12 hours.Cooling pressure after standing static stratification,Organic phase with water 400kg × 2 wash,Also said that the water twice cleaning,Collecting water,concentrate,With concentrated hydrochloric acid to adjust the PH 3,Cooling and drying products,The yield was 93.7%Purity of 99.6%.
3-chloro-2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-propan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.3%
First, tert-butyl methyl ether (690 mL) / 2-methyltetrahydrofuran (230 mL) mixed solvent was prepared for use.The three-neck round bottom flask was evacuated and replaced with nitrogen twice, and then at 25 C,Add 45.6g (1.9mol) magnesium powder, 0.25g (0.001mol) iodine, 15mL mixed solvent and 10g (0.06mol) o-chlorobenzyl chloride,Under low-speed stirring, until the color of iodine disappears and a slight boiling occurs, the remaining mixed solvent is added dropwise with 290 g (1.8 mol) of o-chlorobenzyl chloride.After the dropping was completed, the reaction was continued at 50 C for 0.5 h. The temperature was lowered to 25 C, and unreacted magnesium powder was filtered off to obtain an o-chlorobenzyl magnesium chloride solution.Raw material storage tanks 1,2 were added with a <strong>[120983-72-4]1-chloro-1-chloroacetylcyclopropane</strong> methyl tert-butyl ether solution (50% by mass) and an o-chlorobenzyl magnesium chloride solution,The flow rate of <strong>[120983-72-4]1-chloro-1-chloroacetylcyclopropane</strong> was controlled by a metering pump to 0.1 mol / min,The flow rate of o-chlorobenzylmagnesium chloride is 0.11 mol / min.The reaction temperature is 0 C and the residence time is 30s.Acidify the effluent at the outlet of the microchannel reactor with dilute hydrochloric acid (5% by mass) to neutrality, and separate the liquid.After the organic phase was dried over anhydrous sodium sulfate,Distillation gave 489.4 g of product 1- (2-chlorophenyl) -2- (1-chlorocyclopropyl) -3-chloro-2-propanol,Based on 1-chloro-1-acetylcyclopropane, the yield was 95.3% and the purity was 92.2%.
94%
First, a tert-butyl methyl ether (8L) / 2-methyltetrahydrofuran (2L) mixed solvent was prepared for use.Vacuum the 50L reactor,Nitrogen replacement 2 times,Then at 25 C,Add 444g (18.49mol) magnesium powder,2.5g (0.01mol) iodine,0.9L mixed solvent and 90g (0.056mol) o-chlorobenzyl chloride,When stirring at low speed, when the color of iodine disappears and a slight boiling occurs, the reaction is initiated.Mix the remaining mixed solvent with 2.91kg (18.07mol) o-chlorobenzyl chloride,Add dropwise and finish in about 4h.The reaction was continued at 50 C for 0.5 h.The temperature was lowered to 0 to 5 C, and 2.64 kg (17.26 mol) of 1-chloro-1-acetylcyclopropane was added dropwise.After dripping, the reaction was continued for 1 h.5% dilute hydrochloric acid was added dropwise to pH = 7, and the liquid was separated.The organic phase was washed twice with water, separated, and the organic phase was dissolved to obtain 5.27 kg of a crude Grignard product.Based on 1-chloro-1-acetylcyclopropane,The yield was 94% and the purity was 86.1%.
89%
In a 250mL round bottom three-necked flask equipped with a constant pressure titration funnel and condenser, a 10g (0.062mol) 2-chlorobenzyl chloride and 50mL THF solution were mixed under constant pressure and pressure drop In a funnel, 1.8 g (0.074 mol) of magnesium turnings and 10 ml of a THF solution and a small amount of iodine were added to a three-necked flask, and 2 ml of a 2-chlorobenzyl chloride solution in THF was dropped. The mixture was gently heated, The device was slowly added dropwise into the ice bath (drops / 3s) until the end drops, and then reacted dropwise 1h, the above Grignard reaction was slowly added dropwise 9.0g (0.058mol) 1-chloro-1-chloroacetyl The solution of methylcyclopropane in THF (30 mL) was slowly added dropwise (drop / 3 s) until dripping finished, and the reaction was continued for 1 hour at the end of dropping. The apparatus was kept in an ice bath. Finally slowly slowly adding the reaction solution to a saturated aqueous solution of NH4Cl ice to quench the reaction,The mixture was stirred for 1 hour. The organic phase was separated by a separatory funnel and dried over anhydrous sodium sulfate. THF was distilled off to obtain 14.45 g of the compound (II) as a light yellow oily liquid with a yield of 89%.
81%
Install a mechanical stirring, reflux condenser, constant pressure dropping funnel, and thermometer on a dry, anhydrous 1000 mL reaction flask, and install a desiccator on the top of the reflux condenser to feed the reaction flask at a flow rate of 7 to 10 mL/min. Replace N2 for more than 10 minutes.In the reaction bottle, ethylene glycol dimethyl ether 200g was added in sequence.Fresh magnesium turnings 12g, iodine 0.05g, quickly add o-chlorobenzyl chloride 6g, open the stirring, waiting for the Grignard reaction.After the Grignard reaction was initiated, a mixture of 62.4 g of o-chlorobenzyl chloride and 50 g of toluene was slowly added dropwise via a constant pressure dropping funnel. During the addition, the temperature in the reaction flask was controlled to be constant at 20 to 25 C. After 2 hours of dropping,A mixed solution of 58.5 g of 2-chloro-1-(1-chloro-cyclopropyl)-ethanone and 50 g of toluene was slowly added dropwise through another constant pressure dropping funnel, and the addition was completed 2 hours later.The reaction solution was cooled and cooled to <15C, and 550 g of a pre-cooled saturated aqueous ammonium chloride solution was added dropwise.Stand for stratification and remove the water layer. The organic layer was distilled under reduced pressure in a vacuum condition of -0.080 to -0.090 Mpa to recover the solvent.2-(1-Chloro-cycloprop-1-yl)-3-chloro-1-(2-chloro-phenyl)-2-propanol (99.8 g) was obtained as the target product.Gas chromatography analysis of the product content 81%.
In a 500 ml three-necked flask, 12.7 g (0.1 mol) of 2-thiophenethylamine,9 g (0.3 mol) of formaldehyde, 50 g of dichloromethane and 50 g of dichloroethane,S2O82- / SnO2-Fe2O3 solid super acid 12 grams,Turn on stirring, and heated to 60 C for 5 hours after the reaction was stopped heating,The reaction solution was then cooled to room temperature,19.3 g (0.12 mol) of 2-chlorobenzyl chloride and 10.1 g of solid base-III were further added to the reaction mixture,Continue to heat and make it at 60 temperature for 1 hour, stop heating and stirring,Let stand, filtered to remove residue, the filtrate was passed into hydrogen chloride gas to give 26.1 g of triclopyridine hydrochloride, yield 87%.
a. 500kg of hydroxylamine hydrochloride was formulated into 22% solution with water, put into the No. 1 reactor, together with the prepared first hydrochloric acid tank, start the reaction using a bipolar membrane electrodialysis unit, when the pH of the hydroxylamine hydrochloride solution reaches 7, start adding drop-wise equimolar chloropivaloyl chloride, maintain temperature at 15 C and pH 6.5, at the same time continue to separate hydrochloric acid by bipolar membrane electrodialysis unit, after the addition is completed, the temperature is raised at 25 C;b. Transfer the material obtained in step a into the second reactor, add 1000kg of dichloroethane, add 2000 kg of sodium chloride solution and raise the temperature at 45 C, together with the prepared second hydrochloric acid tank, using a bipolar membrane electrodialysis unit, continue to separate the hydrochloric acid, control pH at 8.5, the reaction time is 3h;c. Transfer the material obtained in step b into the third reactor, add equimolar o-chlorobenzyl chloride, and added 23 kg of tetrabutylammonium bromide, and temperature is raised at 85 C and kept for 3.5 h, and the temperature is stratified; transfer the sodium chloride solution obtained in the upper layer to a sodium chloride solution tank, measure and reuse to step b;d. The lower layer obtained by layering step c is dehydrated to obtain crude clomazone, the obtained crude content was 77.0%; the water layer obtained in the upper layer is reused in step b.
With sodium hydrogen sulfide In dimethyl sulfoxide at 180℃; for 2h;
1; 4-10 (Example 1)
1.3g (8.1mmol) of o-chlorobenzyl chloride was added in 20mL two-necked flask, 70% sodium hydrosulfide 0.97g (12mmol), 4mL dimethylsulfoxide, was stirred at 180 °C for 2 hours. The reaction was cooled to room temperature, methanol 2mL was added. The precipitated solid was filtered. The resulting solid was washed with water, washed with acetone, thus obtained 0.32g BTBT pale yellow crystals (yield 33%). HPLC purity (340nm) 99.77%.
3-(4-((2-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 1-chloro-2-(chloromethyl)benzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h;
Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃;
The invention relates to a method for synthesizing a propionate thiophene sitting continuous flow oxidation, comprising the following steps:In the first step, the synthesis of the intermediate 2 was carried out in a 1000 mL round bottom three-necked flask equipped with a constant pressure titration funnel and a condenser, and an anhydrous anaerobic operation was carried out. Under a nitrogen atmosphere, 28 g of o-chlorobenzyl chloride was mixed with a 150 mL mixed solvent. Evenly placed in a constant pressure dropping funnel, 5.4 g of magnesium shoulder, 30 mL of mixed solvent and iodine were added to a three-necked flask, and 2 mL of o-chlorobenzyl chloride solution was added dropwise thereto, and the temperature was controlled by micro-heating. After the initiation, the temperature was controlled at 30 C. Slowly add dropwise, 2 h drops, continue to react for 1 h after the completion of the drop;26.6 g of <strong>[120983-72-4]1-chloro-1-chloroacetylcyclopropane</strong> was mixed with 30 mL of mixed solvent and placed in a constant pressure titration funnel, and slowly dropped into Grignard reagent. After 2 h, the reaction was continued for 1 h after the completion of the dropwise addition. The magnesium shoulder was removed by filtration, saturated aqueous ammonium chloride solution was added thereto, the reaction was quenched, stirred for 0.5 h, and separated with a sep. funnel. The organic phase was dried over anhydrous sodium sulfate and evaporated to give 43.5 g of pale yellow oily liquid. Intermediate 2.In the second step, the synthesis of the intermediate 3, 6.12 g of the intermediate 2 and 9 mL of hydrazine hydrate were stirred at 100 C, and the reaction was monitored by HPLC until the intermediate 2 was completely converted, the reaction was stopped, and the reaction solution was cooled to room temperature with saturated salt. Water washing, toluene extraction 3 times, the organic phase was combined, 2.47 mL of 36% HCl aqueous solution was directly added, stirred for 0.5 h, and then allowed to stand until the solid was completely precipitated, filtered, and the filter cake was collected;5 g of the solid obtained in the previous step was mixed with 1.29 g of ammonium thiocyanate, 1.25 g of 40% aqueous formaldehyde solution and 35 mL of ethyl acetate. The reaction was stirred at 75 C, and monitored by HPLC. After completion of the reaction, it was cooled to room temperature and saturated. Washing with an aqueous solution of sodium chloride, separating the organic phase, the organic phase is dried over anhydrous sodium sulfate, and then evaporated to give a pale yellow solid intermediate 3;In the third step, prothioconazole was synthesized. 10 mmol/L of intermediate 3 acetone solution was placed in a liquid storage bottle, and 20 mmol/L aqueous ferric chloride solution was placed in a B liquid storage bottle, A, B. The medium solution was injected into the continuous flow microreactor according to the flow rate ratio of 1:1, and the temperature of the microchannel was controlled at 20 C. The reaction was monitored by HPLC. After the reaction was completed, the liquid product was collected and used.The mixture was extracted with ethyl acetate, and the extract was evaporated to dryness, and then directly recrystallized, filtered and dried to give a white solid.
2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazol-1-yl)-propane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
314 g
To a stirred mixture of magnesium flakes (29.0 g, 1,2 mol) and iodine (2.0 g, 0.0157 mol) in toluene (68 ml) and 2-methyl tetrahydrofuran (32 ml) was dropwise added a mixture of 2-chlorobenzylchioride (163.0 g, 1.0 moe) in toluene (230 mi) and 2- methy tetrahydrofuran (1 10 mi) at 20-30C. The reaction mixture was cooled to 0- 10C and l-chloro-l-chloroacetylcyclopropane (153 g, 0.95 mole) in 2-methyi tetrahydrofuran (40 ml) and toluene (120 ml) was dropwise added to it and the reaction was stirred for 2 hours. Mixture of toluene and 2-methy tetrahydrofuran was concentrated under reduced pressure and the reaction mass was cooled to 1GC. To the reaction mass was added water (350 ml) followed by hydrochloric acid (30%, 170 g) and was stirred for 3 hours at room temperature. The organic layer was separated, dried and concentrated under reduced pressure to obtain 247 g mixture of 2-(2-chlorobenzyi)-2-(1-ch[orocyclopropy) oxirane and 1-chioro-2-(1- chlorocyciopropyi)-3-(2-ehIorophenyi) propan-2-ol. Crude mass 247 g is analyzed as 54,02 % 2-(2-chlorobenzyl)-2-(1-chiorocyclopropyl) oxirane and 14,06% 1- chloro-2-(1-chlorocyciopropyl)-3-(2-chiorophenyl) propan-2-ol. Accordingly yield is 70,8% based on 1-chioro-1-chloroacetyFcyc(opropane. Dimer content: 3.5%. A mixture of 1 , 2, 4-triazole (431 g), potassium carbonate (861 g) in dimethylformamide (DMF) (704 g) is heated to 80-85 C for 1.0 hr. To this mixture is drop wise added 1-chioro-2-(1-chlorocyclopropyl)-3-(2-chiorophenyl)propa-2-ol and 2-(2-chlorobenzyi)-2-(1-qhforocyclopropyl) oxirane (577 g) in DMF (450 g) and the reaction mixture is heated to 80-85 C for 3 hrs. The mixture is then cooled to room temperature and filtered to obtain residue. The residue thus obtained is washed with the portions of DMF, and then the filtrate is concentrated under reduced pressure to obtain a crude mass. The crude mass is then dissolved in toluene (900 g) and water (700 g) with continuous stirring at 65-70 C for 1.0 hr. The resulting mixture is cooled and filtered off. The resulting filtrate is concentrated under reduced pressure and then crystallized in isopropanol to obtain 314 g of 2- (1-chlorocyciopropyf)-1-(2-chiorophenyl}-3-(1>2;4-trazol-1-yi)propan-2-ol.
3-chloro-2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-propan-2-ol[ No CAS ]
2-(1-chloro-cycloprop-1-yl)-2-(2'-chloro-benzyl)-oxirane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: A mixture of magnesium flakes (17,0 g, 0.708 mo) and iodine (0.5 g) is treated with toluene (80 mi), tetrahydrofuran {20 ml) and 2-chSorobenzylchlonde (1 g, 0.006 mole) at 20 C, A mixture of 2-chlorobenzyichloride {97.0 g, 0.60 mole) in toluene (338 ml) and tetrahydrofuran (42 mi) is drop-wise added to it in the course of 5 hours at 50-55 C. After completion of addition the mixture is allowed to react for 30 minutes 50-55 C. The reaction mixture was cooled to 20 C and un reacted magnesium is decanted. Into the decanted reaction mixture, t-chioro-1- chloroacetycyclopropane (89 g, 0.58 mole) in is dropwise added in the course of 45 minutes at 20-30 C and the reaction was further stirred for 30 minutes. The reaction mixture is poured into the solution of concentrated sulfuric acid (24 g) and water (170 g) in the course of 30 minutes at 0-20 C. The organic layer was separated and washed with water. The organic layer was dried and concentrated under reduced pressure to obtain a mixture of 2-(2-chlorobenzyi)-2-(1- chorocycfopropyl) oxirane and 1-chloro-2-(1-chlorocyclopropyi)-3-(2- chorophenyi) propan-2-ol. Crude mass 145 g is analyzed as 27.69% 2-(2- chforobenzy)-2-(1-chlorocyclopropyl) oxirane and 10.36% 1-chloro-2-{1- chlorocycSopropyl)-3-(2-chlorophenyl) propan-2-ol. Accordingly yield is 49.92% based on 1-ehloro-1~chforoacetyicyciopropane. Dimer content: 28.84%.
the temperature of the loop kettle is raised to 45 C,Start adding the liquid base with a mass fraction of 30% again.After the liquid base is 30%, the liquid alkali is kept for 2.5 hours.Then, 1.0 kg of a mixture of potassium chloride and tetrahydrofuran in a mass ratio of 0.8:1 was added as a catalyst, and the temperature was kept for 0.5 hour.After the middle control is passed, the stirring is stopped, and the 1,1-dichloroethane is separated and removed.The remaining water layer was heated to a temperature of 60 C and a small amount of 1,1-dichloroethane was removed under reduced pressure.The aqueous layer is then transferred to a synthesis kettle;Step 3: Synthesis reaction: 1.1kg phase transfer catalyst and 15.08kg potassium carbonate solid were put into the synthesis kettle, then 688kg o-chlorobenzyl chloride was added, the stirring temperature was raised to 68 C, and the temperature was kept for 5 hours. After the sampling was controlled, the temperature was lowered. At 55 C, the water layer was left to stand still, and the remaining reaction materials were transferred to a dehydration kettle, and the water was completely removed under reduced pressure to obtain 1028 kg of crude wasoxadione, the content was 88.6%;
1-(2-chlorobenzyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
In acetonitrile; at 80℃; for 48h;
General procedure: 5,6-Dimethoxy-2-[(pyridin-4-yl)methylene)-1-indanone (0.35 mmol) was dissolved in 4 cc acetone (for synthesis of 5a) or acetonitrile (for synthesis of 5b-o) under refux temperature, and then 1.05 mmol of appropriate alkyl halides was added. The reaction mixture was stirred for 48 h under refux condition. The precipitate was fltered and washed with appropriate solvent. The obtained solid was dried under reduced pressure to aford related compounds.
2-(1-chloro-cycloprop-1-yl)-2-(2'-chloro-benzyl)-oxirane[ No CAS ]
C12H12Cl3O(1-)*Cl(1-)*Mg(2+)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; magnesium; In 2-methyltetrahydrofuran; water; toluene; at 20 - 25℃;Inert atmosphere; Sealed tube;
(1) Replace the air in the system with high-purity nitrogen, and close all pipeline valves. (2) Add 161 g of o-chlorochlorobenzyl and 1127 g of methyltetrahydrofuran to the first storage bottle 1.1,The third storage bottle 2.2 was charged with 130.1 g of <strong>[120983-72-4]1-chloro-1-chloroacetylcyclopropane</strong> and 390 g of toluene,Add 650 mL of a 2M aqueous hydrochloric acid solution to the reaction quenching flask 3.1.The first tube reactor 1.3 was charged with 364 g of magnesium dust and fixed with a filter element. (3) Open the connection valve between the first liquid storage bottle 1.1 and the first tube reactor 1.3,The connection valve between the first tubular reactor 1.3 and the second storage bottle 1.4 is specifically to open the first connection valve 4.1,The second connection valve 4.2 and the third connection valve 4.3 turn on the first material pump 1.2,The material in the first storage bottle 1.1 was passed through the first tubular reactor 1.3 at 10 mL / min, and the reaction temperature in the first tubular reactor 1.3 was maintained at 20 to 25 C.The 2-chlorobenzylmagnesium chloride generated in the first tubular reactor 1.3 was received in the second storage bottle 1.4, and the GC was sampled to detect that the content of o-chlorochlorobenzyl was 0.17%.
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