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Structure of 3185-99-7 * 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.
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4 h; Heating / reflux
Example 211; l-(bromomethyl)-4-(methylsulfonyl)benzene; A stirred mixture of l-methanesulfonyl-4-methyl-benzene (1.30 g, 7.5 mmol), n- bromosuccinimide (1.30 g, 7.10 mmol), and benzoyl peroxide (70 mg, 0.30 mmol) in CCl4 (70 mL) was heated at reflux for 4 h. The reaction was cooled, filtered, and concentrated in vacuo. The combined organic phases were concentrated and the residue chromatographed eluting with 1 :9 ethyl acetate :hexane to afford the title compound as a white solid (0.700 g, 38percent). mp 99-101 0C; MS (ES) m/z 248.9..
Reference：
[1] Synlett, 2003, # 5, p. 702 - 704
[2] Patent: WO2008/49047, 2008, A2, . Location in patent: Page/Page column 121
[3] Zhurnal Obshchei Khimii, 1958, vol. 28, p. 488,494; engl. Ausg. S. 480, 484
[4] Journal of the Chemical Society, 1962, p. 1420 - 1427
[5] Journal of the Chemical Society, 1962, p. 1420 - 1427
[6] Journal of Organic Chemistry, 1975, vol. 40, # 25, p. 3778 - 3780
[7] Tetrahedron, 1984, vol. 40, # 10, p. 1863 - 1868
[8] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 1005 - 1010
[9] Organic Letters, 2013, vol. 15, # 16, p. 4194 - 4197
[10] European Journal of Organic Chemistry, 2014, vol. 2014, # 16, p. 3402 - 3410
2
[ 3185-99-7 ]
[ 1671-18-7 ]
Yield
Reaction Conditions
Operation in experiment
95.2%
at 52℃; for 3 h;
In 500ml four bottle add 100g of4-methylsulfonyltoluene and 156 g of 98percent sulfuric acid (ie 18.4 mol / L),Stirring temperature;Chlorine gas was Liquid chromatography to track the progress of the reaction; when the impurities introduced into the mixed solution at a rate of 18 m 3 / h at 52 ° C,in about 1percent stop chlorine, then the reaction qualified;After hydrolysis, and down to room temperature after filtration, and then washed, refined,Filtered to greater than 98percent content of 2-chloro-4-methylsulfonyl toluene.The final drying get2-Chloro-4-methylsulfone Toluene117g,The final molar yield of 2-chloro-4-methylsulfone toluene was 95.2percent.
93%
With chlorine In sulfuric acid; water
EXAMPLE 1 85.1 g (0.5 mol) of methyl 4-methylphenyl sulfone in 160 g of 96percent strength sulfuric acid are introduced into a 500 ml glass flask equipped with stirrer, condenser, gas inlet, thermometer and dropping funnel. At 80° C., about 75 g of chlorine are metered in over the course of 6 hours with vigorous stirring. After the reaction is completed, residual hydrogen chloride is eliminated by passing a N2 stream through the flask, 58 g of water are slowly added dropwise and the mixture is then allowed to cool to 20° C. in the course of 2 hours with stirring. The precipitated product is filtered off and washed with about 500 ml of water until free from acid. After drying at 50° C./100 mbar, 96.5 g of 3-chloro-4-methylphenyl methyl sulfone are obtained (content 98.6percent by weight, corresponding to a yield of 93.0percent of theory, melting point: 91.5° C.).
62.9%
With chlorine In sulfuric acid; water
EXAMPLE 4 85.1 g (0.5 mol) of methyl (4-methylphenyl) sulfone in 150 g of 10.6percent strength fuming sulfuric acid are introduced into a 500 ml glass flask equipped with stirrer, condenser, gas inlet, thermometer and dropping funnel. At 65° C., about 120 g of chlorine are metered in over the course of 5 hours with vigorous stirring. After the reaction is completed, residual hydrogen chloride is eliminated by passing a N2 stream through the flask, 69 g of water are added dropwise and the mixture is allowed to cool to 20° C. The precipitated product is filtered off and washed with about 500 ml of water until free from acid. After drying at 50° C./100 mbar, 65.4 g of 3-chloro-4-methylphenyl methyl sulfone are obtained (content 98.5percent by weight, corresponding to a yield of 62.9percent of theory, melting point: 89-91° C.).
Reference：
[1] Patent: CN104086466, 2017, B, . Location in patent: Paragraph 0017-0021; 0024; 0036
[2] Patent: US5241120, 1993, A,
[3] Patent: US5241120, 1993, A,
[4] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 415,417[5] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 734,735
[6] Chemical and Pharmaceutical Bulletin, 1962, vol. 10, p. 1001 - 1008
3
[ 3185-99-7 ]
[ 110964-79-9 ]
Yield
Reaction Conditions
Operation in experiment
90.2%
Stage #1: for 4.5 h; Large scale Stage #2: With nitric acid; vanadia In water at 142 - 145℃; for 38.5 h; Large scale
In the nitration reaction kettle adding 98percent concentrated sulfuric acid 1450 kg, P-methylsulfonyl toluene 355 kg, 4.5 hours the pumping 205 kg of 68percent nitric acid for nitration, keeping the heat after dropping 65 minutes, to obtain the nitrification; The nitrification liquid will be introduced into the oxidation reaction after the cauldron, adding 7.2 kg catalyst V2O5 and water 315 kg after, raising the temperature to 142 degrees, in the 21 hours the pumping is in the 68percent nitric acid 900 kg, at the same time control the reaction temperature is 145 degrees; then in 16 hours the pumping in the 350 - 370 kg of 50percent nitric acid, at the same time control the reaction temperature is 143 degrees; after dropping insulation 1.5 hours. The reaction liquid cooling to 100 degrees, then adding 900 kg after lowering the temperature to 49 degrees, then filter to obtain the oxidation product, water 1050 kg circulating rinsing oxidation product; adding NaOH to the oxidation product solution adjusting pH value to 8.5, in order to dissolve the oxidation product, in in the adding process control temperature is 57 °C; then is discharging centrifugal, instillment salt acid pH value adjusted to 1.5, at a temperature of 57 °C within the range of 40 minutes, cooling to 35 °C after centrifugal, rinsing, to obtain the purified 2 - nitro -4 - methylsulfonyl-benzoic acid, and the refined in the 65 °C drying; in acyl thionyl chloride is added in the reactor, and then put into the 2 - nitro -4 - methylsulfonyl benzoic acid, DMF in order to heating reflux reaction, reaction 12 hours after separating the distilled thionyl chloride, to obtain 2 - nitro -4 - methylsulfonyl benzoyl chloride. The obtained 2 - nitro -4 - methyl sulfonyl chloride product purity is 97.44percent, yield is 90.02percent.
90.77%
Stage #1: With sulfuric acid; nitric acid In water for 6.1 h; Heating; Industrial scale Stage #2: With boron nitride; vanadia In water at 142 - 146℃; for 29 h; Industrial scale
In the nitration reaction kettle adding 98percent concentrated sulfuric acid 1500 kg, P-methylsulfonyl toluene 350 kg and oxidation aqueous mother liquor 625 kg after, 5 hours the pumping is 210 kg of 68percent nitric acid for nitration, keeping the heat after dropping 70 minutes, to obtain the nitrification; The nitrification liquid will be introduced into the oxidation reaction after the cauldron, adding 5 kg catalyst V2O5 and 17 kg particle size is in the 1 - 10 micron boron nitride powder, raising the temperature to 142 degrees, in 16 hours the pumping is in the 68percent nitric acid 890 kg, at the same time control the reaction temperature is 146 degrees; then in 12 hours the pumping 350 kg of 68percent nitric acid, at the same time control the reaction temperature is 144 degrees; after dropping insulation 1 hours. The reaction liquid cooling to 100 degrees, adding water 1000 kg and then lowering the temperature to 50 degrees, then filter to obtain the oxidation product and oxidizing aqueous mother liquor, water 1100 kg circulating rinsing oxidation product; adding NaOH to the oxidation product solution pH value adjusted to 9.0, in order to dissolve the oxidation product, in in the adding process control temperature is 60 °C, and filter and isolate the nucleating agent; then is discharging centrifugal, instillment salt acid pH value adjusted to 2, at a temperature of 60 °C maintained under 30 minutes, cooling to 35 °C after centrifugal, rinsing, to get the purified 2 - nitro -4 - methylsulfonyl benzoic acid; five times will be refined in the 55 °C drying; in acyl thionyl chloride is added in the reactor, and then put into the 2 - nitro -4 - methylsulfonyl benzoic acid, DMF in order to heating reflux reaction, reaction 3 - 4 hours after the thionyl chloride is separated by distillation, to obtain 2 - nitro -4 - methylsulfonyl benzoyl chloride. The obtained 2 - nitro -4 - methyl sulfonyl chloride product purity is 91.46percent, the yield of 90.77percent.
Reference：
[1] Patent: CN106565561, 2017, A, . Location in patent: Paragraph 0012-0017; 0018; 0019; 0020
[2] Patent: CN106565557, 2017, A, . Location in patent: Paragraph 0017-0019
[3] Journal of Organic Chemistry, 1953, vol. 18, p. 1380,1400
[4] Patent: CN106380429, 2017, A, . Location in patent: Paragraph 0020; 0021; 0022; 0023; 0024; 0025; 0026-0058
[5] Patent: CN106432006, 2017, A, . Location in patent: Paragraph 0016; 0017; 0018; 0019; 0020; 0021; 0022
[6] Patent: CN106565560, 2017, A, . Location in patent: Paragraph 0021-0022
[7] Patent: CN106565556, 2017, A, . Location in patent: Paragraph 0023-0025
[8] Patent: CN106565558, 2017, A, . Location in patent: Paragraph 0021-0022
[9] Patent: WO2018/178860, 2018, A1,
With sulfuric acid; nitric acid In water at 100℃; Flow reactor; chemoselective reaction;
With sulfuric acid; nitric acid
In sulfuric acid
1.b b)
b) Preparation of 4-methylsulfonyl-2-nitrotoluene 68 g of 4-methylsulfonyltoluene in 400 ml of concentrated sulfuric acid were admixed at 0°-10° C. with a mixture of 80 ml of concentrated sulfuric acid and 31 ml of 65% strength by weight nitric acid. The reaction mixture was stirred at 10° C. for 2 hours and at room temperature for a further 2 hours. It was then poured onto about 1 kg of ice, and the solids were filtered off with suction, washed with water and dried at 50° C. under reduced pressure, to leave 85 g of 4-methylsulfonyl-2-nitrotoluene (melting point 112°-115° C.).
With sulfuric acid; nitric acid In water for 5.6h;
2
The nitrification reactor was added with 98% concentrated sulfuric acid (1500 kg), 350 kg of methylsulfonyl toluene and 625 kg of the oxidized aqueous mother liquor. After 5 hours, 210 kg of 68% nitric acid was uniformly added dropwise, and the mixture was incubated for 70 minutesliquid;After the nitrification solution was introduced into the oxidation reaction vessel, 5 kg of the catalyst V2O5 and 17 kg of the boron nitride powder having a particle size of 1 to 10 m were added. After the temperature was raised to 142 degrees, 890 kg of 68% nitric acid was uniformly added over 16 hours while controlling the reaction temperature 146 degrees; then within 12 hours evenly add 350kg of 68% nitric acid, while controlling the reaction temperature of 144 degrees; dripping after the end of 1 hour.The reaction solution is cooled to 100 degrees, then add 1000kg of water and then cooled to 50 degrees, and then filter to get the oxidation product and oxidation of the water mother liquor, with water 1100kg cycle rinse oxidation products; adding NaOH solution to the oxidation of pH value to 9.0, To dissolve the oxidation product, in the process of adding the control temperature of 60 , and filter to separate the nucleating agent; and then hot centrifuge, dropping hydrochloric acid to adjust the pH value to 2, at 60 for 30 minutes, After centrifugation at 35 ° C, rinsing, i.e., purified 2-nitro-4-methanesulfonylbenzoic acid was carried out. After five passes, it was dried at 55 ° C to give the 2-nitro-4-methanesulfonylbenzoic acid product The purity was 90.33% and the yield was 92.56%.
205 g
Stage #1: Methyl p-tolyl sulfone With sulfuric acid at 20℃; for 0.5h;
Stage #2: With fuming sulphuric acid; nitric acid at 10℃; for 10h;
1.2 Step 2: Synthesis of 2-nitro-p-methylsulfonyl toluene
170 g of p-Methylsulfonyl toluene obtained in step 1 was added in 100 g of sulphuric acid (98 %) and stirred at room temperature for 30 minutes and then cooled to 10 °C to obtain a reaction mixture. A mixture of 100 g of oleum (24 %) and 70 g of nitric acid (98%) was added over 4 hours at 10 °C to the reaction mixture to obtain a resultant mixture. The resultant mixture was stirred for 6 hours to obtain a reaction mass. The reaction mass was drowned into ice water, stirred, and filtered to obtain a cake containing 2-nitro-p- methylsulfonyl toluene. The so obtained cake was washed with water and dried in an oven at 80 °C to obtain 205 g of 2-nitro-p-methylsulfonyl toluene having HPLC purity of 99.38%.
124 kg
With sulfuric acid; nitric acid at -3 - 0℃; Large scale;
1; 2 Example 1:
A method for preparing 2-nitro-4-methylsulfonyltoluene in a continuous stream, with p-methylsulfonyltoluene, sulfuric acid and nitric acid are used as raw materials, and the reaction is carried out by continuously feeding the raw materials into a channel reactor. Achieve continuous preparation of 2-nitro-4-methylsulfonyltoluene, the production process device diagram is shown in Figure 1, and includes the following steps:(1) The molar ratio of p-methylsulfonyltoluene to sulfuric acid is 1:0.8, formulating a solution of p-methylsulfonyltoluene and 98% by mass of sulfuric acid into p-sulfone toluene/sulfuric acid; the molar ratio of nitric acid to sulfuric acid is 1:1.2, a nitric acid solution having a mass fraction of 68% and sulfuric acid having a mass fraction of 98% were formulated into a nitric acid/sulfuric acid preparation.(2) preparing a formulation of p-methylsulfonyltoluene/sulfuric acid prepared in the step (1) and a preparation solution of nitric acid/sulfuric acid at 57 kg/h, respectively. A rate of 50 kg/h is simultaneously continuously input into the cooling module 11 of the channel reactor for mixing, cooling and preliminary reaction to obtain a mixed solution. The temperature of the mixture was controlled at -3 °C.(3) The mixed liquid obtained in the step (2) was continuously fed into the fluid module 12 of the channel reactor to continue the reaction to obtain a reaction liquid in which the temperature of the reaction liquid was controlled at 0 °C.(4) The reaction product solution obtained in the step (3) is discharged through the outlet module 13 of the channel reactor, and the discharged reaction liquid is stored in the kettle 2, and when the reaction liquid is accumulated to 300 kg, Dropped into the crystallizer 3 containing 1000 kg of ice water, maintaining the temperature at 3 ° C, Stirring for 1 h to crystallize the product in the reaction mixture; Filtering the crystallized product after the stirring by the filtering device 4; The filter cake obtained by filtration is washed with water having a temperature of 4 ° C; Drying the filter cake obtained after washing with a drying device 5, Obtained 124 kg of white powdery crystals, The mass percentage (purity) of 2-nitro-4-methylsulfonyltoluene in the crystal is 99.3%. The content of 2,6-dinitro-4-methylsulfonyltoluene was 0.02%.
With nitric acid; vanadia; zirconium(IV) acetate at 120 - 160℃;
2-6
Dissolve 170g 4-methylsulfonyltoluene in 540g 70% nitric acid solution and place it in the first storage tank 1. Dissolve 0.5g vanadium pentoxide and 1.0g zirconium acetate in 1260g 90% nitric acid , And placed in the second storage tank 2. The first tubular reactor 3 is divided into two sections for temperature control,The first stage is 120°C and the second stage is 130°C. The temperature of the second tubular reactor 4 was set to 160°C.The flow rate of the first metering pump is 2mL/min, and the flow rate of the second metering pump is 6.3mL/min.The pressure is 1.5MPa.The residence time of the first tubular reactor 3 is 12 minutes, and the residence time of the second tubular reactor 4 is 80 minutes. The product in the collecting kettle 6 is vacuum-rotated to a paste state. Adjust the paste-like product to alkalinity with sodium hydroxide solution under fully stirring conditions, continue stirring for 20 minutes, and then filter. The filtrate is yellow. Add hydrochloric acid or dilute nitric acid recovered after distillation to the filtrate until the filtrate is acidic. At this time, a large amount of light yellow solid was precipitated, and 233 g of ochre solid was obtained after drying, with a single-pass yield of 95% and a purity of 98%.After alkaline washing, the filter cake was slurried and washed with a small amount of 65% nitric acid and filtered to obtain 10 g of white solid which was unreacted 2-nitro-4-methylsulfonyl toluene. The liquid phase was sampled at the outlet of the first tubular reactor 3, and the nitration yield of 4-methylsulfone toluene was 99%.
Stage #1: Methyl p-tolyl sulfone With sulfuric acid In water Cooling with ice;
Stage #2: With nitric acid In water at 45℃;
1.1-1.2; 2.1-2.2; 3.1-3.2; 4.1-4.2; 5.1-5.2 Example 1:
(1) At room temperature, mix and dissolve p-methylsulfonyl toluene and sulfuric acid in a mass ratio of 1:3, stir, and slowly add water dropwise under an ice water bath to make the sulfuric acid concentration respectively 70%, 75%, 80%, 85%, 90% to obtain a p-methylsulfonyl toluene sulfuric acid solution.(2) The p-methylsulfonyl toluene sulfuric acid solution and fuming nitric acid are respectively delivered to the two inlets of the microchannel reactor via a precisely controlled flow advection pump, and the molar ratio of p-methylsulfonyl toluene to fuming nitric acid is controlled to be 1: 1.2. At 45, the two liquids are mixed and contacted instantly in the microchannel reactor and reacted. The discharge port is controlled by a needle valve to control the discharge flow, thereby controlling the reaction pressure of the microreaction channel to 0.3MPa, and transferring the reaction liquid to the ice Filter in water, wash with ice water, and dry in vacuo to obtain 2-nitro-4-sulfonylmethyltoluene. The residence time of the reaction solution in the microchannel reactor is 2 minutes. The conversion rate and purity of 2-nitro-4-sulfonylmethyltoluene are shown in Table 1 and Figure 2.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Heating / reflux;
Example 211; l-(bromomethyl)-4-(methylsulfonyl)benzene; A stirred mixture of l-methanesulfonyl-4-methyl-benzene (1.30 g, 7.5 mmol), n- bromosuccinimide (1.30 g, 7.10 mmol), and benzoyl peroxide (70 mg, 0.30 mmol) in CCl4 (70 mL) was heated at reflux for 4 h. The reaction was cooled, filtered, and concentrated in vacuo. The combined organic phases were concentrated and the residue chromatographed eluting with 1 :9 ethyl acetate :hexane to afford the title compound as a white solid (0.700 g, 38%). mp 99-101 0C; MS (ES) m/z 248.9..
(S)-3-hydroxy-4-phenyl-1-(p-toluenesulfonyl)butan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: Methyl p-tolyl sulfone With n-butyllithium In tetrahydrofuran at -78 - 0℃;
Stage #2: (S)-methyl 2-hydroxy-3-phenylpropanoate In tetrahydrofuran at 0℃; for 1h;
A method for preparing 2-nitro-4-methylsulfonylbenzoic acid, the preparation method comprising the following steps: In the nitrification reactor, 1.0 ton of dichloromethane was added, 0.8 ton of p-methylsulfone toluene was added, and the mixture was cooled to 10 C. The concentrated nitric acid was added dropwise, and the sample was analyzed by hollow sampling. After the nitration reaction was completed, it was placed in an oxidation reactor. Heating, distilling off dichloromethane, then adding 70% sulfuric acid as solvent, adding catalyst vanadium pentoxide, heating to 140 C, adding 60% nitric acid for oxidation reaction, after the reaction is finished, cooling to 25 C, centrifugation, mother liquor Applying to the oxidation reaction, the crude product is put into the reaction tank again, water is added, and the alkali solution is added to adjust the alkaline pH to 11. After filtering the impurities, the mother droplet is diluted with sulfuric acid to adjust the pH to 1.9, cooled and centrifuged, and dried to obtain a fine product
90.2%
In the nitration reaction kettle adding 98% concentrated sulfuric acid 1450 kg, P-methylsulfonyl toluene 355 kg, 4.5 hours the pumping 205 kg of 68% nitric acid for nitration, keeping the heat after dropping 65 minutes, to obtain the nitrification; The nitrification liquid will be introduced into the oxidation reaction after the cauldron, adding 7.2 kg catalyst V2O5 and water 315 kg after, raising the temperature to 142 degrees, in the 21 hours the pumping is in the 68% nitric acid 900 kg, at the same time control the reaction temperature is 145 degrees; then in 16 hours the pumping in the 350 - 370 kg of 50% nitric acid, at the same time control the reaction temperature is 143 degrees; after dropping insulation 1.5 hours. The reaction liquid cooling to 100 degrees, then adding 900 kg after lowering the temperature to 49 degrees, then filter to obtain the oxidation product, water 1050 kg circulating rinsing oxidation product; adding NaOH to the oxidation product solution adjusting pH value to 8.5, in order to dissolve the oxidation product, in in the adding process control temperature is 57 C; then is discharging centrifugal, instillment salt acid pH value adjusted to 1.5, at a temperature of 57 C within the range of 40 minutes, cooling to 35 C after centrifugal, rinsing, to obtain the purified 2 - nitro -4 - methylsulfonyl-benzoic acid, and the refined in the 65 C drying; in acyl thionyl chloride is added in the reactor, and then put into the 2 - nitro -4 - methylsulfonyl benzoic acid, DMF in order to heating reflux reaction, reaction 12 hours after separating the distilled thionyl chloride, to obtain 2 - nitro -4 - methylsulfonyl benzoyl chloride. The obtained 2 - nitro -4 - methyl sulfonyl chloride product purity is 97.44%, yield is 90.02%.
90.77%
In the nitration reaction kettle adding 98% concentrated sulfuric acid 1500 kg, P-methylsulfonyl toluene 350 kg and oxidation aqueous mother liquor 625 kg after, 5 hours the pumping is 210 kg of 68% nitric acid for nitration, keeping the heat after dropping 70 minutes, to obtain the nitrification; The nitrification liquid will be introduced into the oxidation reaction after the cauldron, adding 5 kg catalyst V2O5 and 17 kg particle size is in the 1 - 10 micron boron nitride powder, raising the temperature to 142 degrees, in 16 hours the pumping is in the 68% nitric acid 890 kg, at the same time control the reaction temperature is 146 degrees; then in 12 hours the pumping 350 kg of 68% nitric acid, at the same time control the reaction temperature is 144 degrees; after dropping insulation 1 hours. The reaction liquid cooling to 100 degrees, adding water 1000 kg and then lowering the temperature to 50 degrees, then filter to obtain the oxidation product and oxidizing aqueous mother liquor, water 1100 kg circulating rinsing oxidation product; adding NaOH to the oxidation product solution pH value adjusted to 9.0, in order to dissolve the oxidation product, in in the adding process control temperature is 60 C, and filter and isolate the nucleating agent; then is discharging centrifugal, instillment salt acid pH value adjusted to 2, at a temperature of 60 C maintained under 30 minutes, cooling to 35 C after centrifugal, rinsing, to get the purified 2 - nitro -4 - methylsulfonyl benzoic acid; five times will be refined in the 55 C drying; in acyl thionyl chloride is added in the reactor, and then put into the 2 - nitro -4 - methylsulfonyl benzoic acid, DMF in order to heating reflux reaction, reaction 3 - 4 hours after the thionyl chloride is separated by distillation, to obtain 2 - nitro -4 - methylsulfonyl benzoyl chloride. The obtained 2 - nitro -4 - methyl sulfonyl chloride product purity is 91.46%, the yield of 90.77%.
A 2-nitro-p-methylsulfonyl benzoic acid synthesis process,Including 2-nitro-p-methylsulfonyl benzoic acid production materialsMethylsulfonyltoluene,Nitric acid,sulfuric acid,Vanadium pentoxide, and the 2-nitro-p-methylsulfonylbenzoic acid is produced by the following steps:(1) concentrated sulfuric acid and p-methyl sulfone toluene into the reaction kettle, and the full mixing;(2) in the reactor temperature at 0 , droppingMixed acid(3) After the addition of the acid, the mixture was stirred at 10 C for 2 h, then raised to 15 C and stirred for 2 h.(4) Analysis of the amount of methylsulfone toluene in the raw material by means of a high performance liquid chromatograph, and when the content is less than 0.1%Reaction5) adding the catalyst to the reactants, then heating the mixture;(6) When the internal temperature of the reactor is 30 C,Access to oxygen,Simultaneously,A certain concentration was continuously added to the reactionOf the mixed acid,Time is 6.5h;(7) with high performance liquid chromatography analysis of raw materials on the content of methyl sulfone toluene, when the content is less than 0.1%, stopReaction(8) The reaction mixture was cooled to 20-25 C, vacuum filtered, and the filter cake was washed with water to neutral and dried.The content of the p-methyl sulfone toluene, nitric acid and vanadium pentoxide were 98.5%, 65% and 99.5%, respectively.The mixed acid is fused with sulfuric acid and nitric acid, and the ratio is sulfuric acid: nitric acid = 50ml: 20ml.The catalyst is vanadium pentoxide.
With sulfuric acid; nitric acid;
(1) the first nitrification reactor followed by adding methyl sulfone toluene, nitric acid and sulfuric acid, and then stirring reaction to be reactants;(2) then the reaction into the filter device for filtration, filtration will be the mother liquor and the product;(3) finally dehydrating the mother liquor to produce water and sulfuric acid; and the water and sulfuric acid are respectively added to the nitrification reactor by means of a water metering device and a reflux metering device, respectively.Further, the capacity of the nitrification reactor was 2000 L.Further, the stirring reaction time in the nitration step (1) of the 2-nitro-p-methylsulfonylbenzoic acid is 1-1.5 hours.Further, the contents of the methyl sulfone toluene, nitric acid and sulfuric acid were 99%, 68% and 98%, respectively.
In the nitrification reactor by adding 98% concentrated sulfuric acid 500kg,300kg of methyl sulfone toluene and 1100kg of oxidized aqueous mother liquor,5 hours of uniform drop of 180kg of 98% nitric acid nitration reaction,After dropping for 70 minutes,To obtain nitrification solution; nitrification liquid into the oxidation reactor and then add 5kg catalyst V205,After warming to 142 degrees,In 18 hours evenly dropping 68% nitric acid 890kg,While controlling the reaction temperature of 146 degrees; then 14.5 hours evenly drop 350kg of 50% nitric acid,While controlling the reaction temperature of 144 degrees; dripping after the end of 1 hour. The reaction solution was cooled to 50 C,And then filtering to obtain oxidation products and oxidation of water mother liquor,Rinse the oxidation product with 1 l0 kg of water;Add NaOH solution to the oxidation product to adjust the pH to 9.0,To dissolve the oxidation product, during the addition of the control temperature of 60 C; and then hot discharge centrifugation,Add hydrochloric acid to adjust the pH to 2, at 60 C for 30 minutes, cool to 35 C after centrifugation,Rinsed to give the purified 2-nitro-4-methanesulfonylbenzoic acid; it was dried at 55 C to give 2-nitro-4-methanesulfonylbenzoic acid.
In the nitrification reactor by adding 98% concentrated sulfuric acid 1450kg,P-methyl sulfone toluene 355kg, 4.5 hours evenly added205 kg of 68% nitric acid for nitration,Drip finished after holding 65 minutes,To obtain nitrification solution;[025] The nitrification solution was introduced into the oxidation reaction vessel and then 7.2 kg of the catalyst V205 and the water 315 kg, Heated to 142 degrees, within 21 hours evenly dropping 68% nitric acid 900kg, while controlling the reaction temperature of 145 degrees; and then within 16 hours evenly dropping 350 ~ 370kg of 50% nitric acid,While controlling the reaction temperature of 143 degrees; drip after the end of holding 1.5 hours.The reaction solution was addedAfter cooling to 100 degrees,Add water 900kg and then cool to 49 degrees,And then filtered to obtain oxidation products,1050kg of water cycle driftWashing the oxidation product; adding the NaOH solution to the oxidation product to adjust the pH value to 8.5,To dissolve the oxidation product,In the process of joining controlThe system temperature is 57 C; then the hot discharge centrifugation,Dropping hydrochloric acid to adjust the pH to 1.5, at a temperature of 57 C for 40 minutes,After cooling to 35 C after centrifugation,rinsing,Purified 2-nitro-4-methanesulfonylbenzoic acid,Dried at 65 C; thionyl chloride was added to the acid chlorination reactor,2-nitro-4-methanesulfonylbenzoic acid,DMF to carry out the temperature reflux reaction,After 11 to 12 hours of reaction, thionyl chloride was distilled off,To give 2-nitro-4-methanesulfonylbenzoyl chloride.
In the nitrification reactor by adding 98% concentrated sulfuric acid 450kg,300 kg of methyl sulfone toluene and 1100 kg of oxidized aqueous mother liquor were uniformly added dropwise 180 kg of 98% nitric acid for 4.5 hours, and the mixture was incubated for 65 minutes after completion of the dropwise addition,To obtain nitrification solution;The nitrification solution was introduced into the oxidation reaction vessel and then 4.5 kg of catalyst V2O5 was added,After warming to 142 degrees,In 18 hours evenly add 68% nitric acid 900kg,While controlling the reaction temperature of 145 degrees;And then in 50 hours evenly dropping 350 ~ 370kg of 50% nitric acid,While controlling the reaction temperature of 143 degrees;After the dropwise addition, the temperature was maintained for 1.5 hours.The reaction solution was cooled to 49 degrees,And then filtering to obtain oxidation products and oxidation of water mother liquor,Rinse the oxidation product with 1050 kg of water;Adding NaOH solution to the oxidation product to adjust the pH value to 8.5,To dissolve the oxidation product, in the process of adding the control temperature of 57 ;And then hot discharge centrifugal,Dropping hydrochloric acid to adjust the pH to 1.5,Held at a temperature of 57 C for 40 minutes,Cooled to 35 after centrifugation,Rinse, that is refined 2-nitro-4-methanesulfonyl benzoic acid;It was dried at 65 C;Acyl chloride: in the acid chlorination reactor by adding thionyl chloride,2-nitro-4-methanesulfonylbenzoic acid,DMF to carry out the temperature reflux reaction,After 11 to 12 hours of reaction, thionyl chloride was distilled off to give 2-nitro-4-methanesulfonyl-benzoyl chloride.The purity of the obtained 2-nitro-4-methanesulfonylbenzoyl chloride product was 97.45% and the yield was 90.44%.
EXAMPLE 2 68 g of 4-methylsulfonyltoluene (Example 1a) were nitrated in 400 ml of concentrated sulfuric acid as described in Example 1b. 300 ml of water and 1 g of vanadium pentoxide were added to the reaction mixture, and the mixture was heated to 145 C. while air was passed into it at a rate of 100 1/h. Once at that temperature the metered addition was commenced of 65% strength by weight nitric acid and continued for 9 hours, a total of 270 ml being added. The reaction mixture was cooled down to room temperature, and the precipitate was filtered off with suction, washed with water and dried. This yielded 87 g (81% of theory) of 4-methylsulfonyl-2-nitrobenzoic acid (melting point 203-206 C.).
Stage #1: Methyl p-tolyl sulfone With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 5-chloro-2-methylbenzaldehyde With diethyl chlorophosphate In tetrahydrofuran; hexane at -78 - 20℃; for 1.5h;
L.1 Step 1: (E)-2-(5-Chloro-2-methylphenyl)ethenyl 4-methylphenyl sulfone
Step 1: (E)-2-(5-Chloro-2-methylphenyl)ethenyl 4-methylphenyl sulfone To a solution of methyl-(4-methylphenyl)sulphone (6.74 g, 39.6 mmo) in THE (200 mL) n-BuLi (2.5 M in hexane, 34.8 mL, 8712 mmo) was added dropwise at 0 °C under argon atmosphere. After stirring for 30 mm at 0 °C diethy chorophosphate (5.70 mL, 39.6 mmol) in THF (30 mL) was sowy added dropwise. The reaction mixture was stirred at 0 °C for 30 mm, then was cooed to -78 °C, foWowed by addition of a soution of 5-choro-2-methybenzadehyde(6.1 g, 39.6 mmo) in THE (10 mL), After stirring at -78 °C for 1 h, the temperature of the reaction mixture was aWowed to rise to room temperature. Water was added (50 mL) and the reaction mixture was concentrated under reduced pressure to give a precipitated that was fUtered, washed with water and oven-dried under reduced pressure to afford the tWe compound as a beige sohd (824 g, 68%).1H NMR (600 MHz, DMSO-d6) 7.79 - 7.85 (m, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.68 - 7.72 (m, 1H), 7.62 - 7.67 (m,1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.37 - 7.43 (m, 1 H), 7.30 - 7.34 (m, 1 H), 2.41 (s, 3H), 2.39 (s, 3H).
4.10. Procedure for the oxidation of thioanisole to give methyl phenyl sulfone
General procedure: A test tube equipped with a magnetic stirring bar was charged with thioanisole (130.3 mg, 1.0 mmol), aqueous 35% H2O2 (247.7 mg, 2.5 mmol), and Ti-IEZ-MWW (9.9 mg). The mixture was stirred at 50°C for 3 h. The conversion and yield were determined by GC analysis of the toluene solution with biphenyl as an internal standard. The yield of methyl phenyl sulfone was>99%, conversion of thioanisole was >99%, and selectivity (yield/conversion) was >99%.
Stage #1: Methyl p-tolyl sulfone With n-butyllithium In tetrahydrofuran; cyclohexane at 0℃; for 0.5h;
Stage #2: ethyl 4-methyl-4-pentenoate With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; cyclohexane at -78℃; for 17h;
The fresh material added to the primary oxidation reactor was MnO2 dissolved in methyl sulfone toluene and acetic acid And Co(Ac)2*4H2O at a total concentration of 150 ppm and a mass ratio of acetic acid to p-methylsulphenyltoluene of 0.15. When the device was operated at steady state, the flow rate of the fresh p-methylsulphenyl toluene in the oxidation reactor was 9.4 mL / h. The average residence time of the oxidation reactor in liquid phase was 3.5 h, Pure oxygen was continuously introduced into the oxidation reactor, maintaining the reaction temperature at 150 C and the reaction pressure at 1.1MPa. The volume ratio of water added into the hydrolysis reactor to that of the oxidation reaction liquid entering the hydrolysis reactor was 0.42:1, the reaction temperature in the hydrolysis reactor was maintained at 105 C and the reaction pressure was 0.7 MPa. The retention time of liquid phase was 3.5 h. The liquid phase at the outlet of the hydrolysis reactor was continuously fed into a liquid-liquid delaminator at a temperature of 136 C and a pressure of 0.6 MPa. The conversion of p-methylsulphenyl toluene in the system was 97.0%, and the selectivity to p-methylsulfonylbenzyl alcohol, p-methylsulfonylbenzaldehyde and p-methylsulfonylbenzoic acid was 51%.5%, 39.2% and 9.3%, respectively. Other by-products were not detected.
1-[(4-methylphenyl)sulfonyl]-5-phenylpentan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
Stage #1: Methyl p-tolyl sulfone With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1.5h;
Stage #2: ethyl 4-phenylbutyrate In tetrahydrofuran for 0.25h;
With 1,1'-bis-(diphenylphosphino)ferrocene; sodium metabisulfite; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tin; potassium hydrogenphosphate trihydrate; tetrabutylammomium bromide; In dimethyl sulfoxide; at 100℃; for 10h;Inert atmosphere;
Under nitrogen protection, p-methyliodobenzene (0.1 mmol), sodium metabisulfite (0.2 mmol, 2.0 equiv.), Tin powder (0.3 mmol, 3.0 equiv.), 1,1'-bis (diphenylphosphino) Ferrocene palladium dichloride (0.01 mmol, 10 mol%), 1,1'-bis (diphenylphosphine) ferrocene (0.02 mmol, 20 mol%), dipotassium hydrogen phosphate trihydrate (0.2 mmol, 2.0 equiv .), Tetrabutylammonium bromide (0.15 mmol, 1.5 equiv.) Was added to the reaction tube containing the magnet, and after evacuation nitrogen three times, methyl p-toluenesulfonate (0.3 mmol, 3.0 equiv.) Was added, and DMSO was added. (1.0mL), the reaction system was heated to 100 C for 10 hours, and the whole aryl iodide was detected on the spot plate. After the reaction system was cooled to room temperature, diluted with water, ethyl acetate (10mL * 3) was added for extraction, and anhydrous It was dried over sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain purified target product 3u (75%).
With bis-triphenylphosphine-palladium(II) chloride; 1,1,3,3-Tetramethyldisiloxane; tetrabutylammomium bromide In 1,4-dioxane at 120℃; for 18h; Inert atmosphere;
3 Specific Example 3:
109.0 mg (0.5 mmol) 4-iodotoluene, 550.3 mg (5 mmol) dimethyl sulfite, 35.1 mg (0.05 mmol) bistriphenylphosphorus palladium(II) dichloride, 100.7 mg (0.75 mmol) 1,1,3,3- tetramethyl disiloxane, 161.3 mg (0.5 mmol) of tetrabutylammonium bromide to the reaction tubes, 120OC was heated for 18 hours after the reaction was cooled, filtered The filtrate was evaporated to remove the solvent, the residue was chromatographed on silica gel column, washed with petroleum ether, TLC detection, combined the effluent containing the product, the solvent was distilled off by the rotary evaporator, and dried under vacuum to obtain 57.5 mg of 4-methylbenzene as a white solid Methyl sulfone, the yield is 68%.
With triethylamine In dichloromethane; water at 20℃;
1.1.1 1.1 Preparation of ROS-AD 1-1C8
Add 1,8-octanediol (585.2g, 4.0mmol), triethylamine (485.6mg, 4.8mmol) and DCM (8.0mL) in the reaction flask, and slowly dropwise add TsCl (762.2mg, 4.0mmol) DCM (8.0mL) solution,Stir at room temperature until the reaction is complete. After adding water, the liquids were separated, and then the aqueous phase was extracted with DCM,The organic phase was dried and filtered, and the solvent was distilled off under reduced pressure. The residue was separated by silica gel column chromatography to obtain a colorless oily liquid ROS-AD 1-1C8 (895.3 mg, 75%).
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