CN115626880A - Synthetic method of 3-nitro-5-cyano benzotrifluoride - Google Patents
Synthetic method of 3-nitro-5-cyano benzotrifluoride Download PDFInfo
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- CN115626880A CN115626880A CN202211423883.8A CN202211423883A CN115626880A CN 115626880 A CN115626880 A CN 115626880A CN 202211423883 A CN202211423883 A CN 202211423883A CN 115626880 A CN115626880 A CN 115626880A
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- FSQINZQIPFZWKX-UHFFFAOYSA-N 3-nitro-5-(trifluoromethyl)benzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC(C(F)(F)F)=C1 FSQINZQIPFZWKX-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000003756 stirring Methods 0.000 claims abstract description 25
- 239000012074 organic phase Substances 0.000 claims abstract description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012044 organic layer Substances 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 16
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims abstract description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 14
- 239000000706 filtrate Substances 0.000 claims abstract description 14
- 239000005457 ice water Substances 0.000 claims abstract description 13
- WHNAMGUAXHGCHH-UHFFFAOYSA-N 1-nitro-3-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=CC(C(F)(F)F)=C1 WHNAMGUAXHGCHH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 10
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 239000010410 layer Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000006185 dispersion Substances 0.000 claims abstract 2
- 238000004090 dissolution Methods 0.000 claims abstract 2
- 238000000967 suction filtration Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 13
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- 230000031709 bromination Effects 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- FECNOIODIVNEKI-UHFFFAOYSA-N 2-[(2-aminobenzoyl)amino]benzoic acid Chemical class NC1=CC=CC=C1C(=O)NC1=CC=CC=C1C(O)=O FECNOIODIVNEKI-UHFFFAOYSA-N 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of 3-nitro-5-cyano benzotrifluoride, which comprises the following steps: (1) Mixing 3-trifluoromethyl nitrobenzene and sulfuric acid, slowly adding dibromohydantoin and/or bromine at the temperature of 5-10 ℃, reacting for 7-8h, purifying and drying to obtain an intermediate 1; (2) Adding DMSO into a reaction bottle, heating to 12-130 ℃, stirring for dispersion, adding CuCN, stirring for full dissolution, and adding 0.2eq Cu (CN) 2 Heating to 160-180 ℃, dripping the intermediate 1, fully reacting after dripping, pouring the reaction liquid into ice water, stirring, filtering, taking filtrate, extracting by ethyl acetate, taking organic phase by layers, spin-drying the organic layer to obtain a crude product, and recrystallizing by methanol to obtain the 3-nitro-5-organic-saltThe method is simple, the raw material price is low, and the yield is stable.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to synthesis of an aromatic intermediate, in particular to a synthesis method of 3-nitro-5-cyano benzotrifluoride.
Background
In recent years, with the large-scale application of chemistry in the fields of pharmacy and agriculture, aromatic intermediates containing cyano groups show huge growth potential, and the application of the aromatic intermediates containing cyano groups can be used as medicines, dye intermediates, food additives, feed additives, pesticides and the like, but the preparation cost of multi-group cyano compounds is high, and the yield is low.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a novel method for synthesizing an aromatic intermediate 3-nitro-5-cyano trifluoromethyl benzene, which takes 3-trifluoromethyl nitrobenzene as an initial raw material and synthesizes the 3-nitro-5-cyano trifluoromethyl benzene through two steps of reactions of bromination and cyanidation. The method is convenient and high in yield.
The invention takes 3-trifluoromethyl nitrobenzene as an initial raw material, under the condition of sulfuric acid, bromine is added on dibromohydantoin and/or bromine, and then the bromine is cyanided to obtain a target compound of 3-nitro-5-cyano benzotrifluoride.
The reaction formula is as follows:
the synthesis method of the 3-nitro-5-cyano benzotrifluoride is carried out according to the following steps:
(1) Mixing 3-trifluoromethyl nitrobenzene serving as a raw material with sulfuric acid, slowly adding dibromohydantoin and/or bromine at the temperature of 5-10 ℃, reacting for 7-8 hours, pouring the reaction solution into ice water, extracting with ethane, taking an organic phase in layers, taking a sodium sulfite aqueous solution, washing the organic layer in batches until a water layer is colorless, and drying and spin-drying the organic layer to obtain an intermediate 1;
(2) Adding DMSO (5-6 times volume of DMSO in general) into a reaction flask, heating to 12-130 deg.C, stirring for dispersing (10 min in general), adding CuCN, stirring for dissolving completely (5 min in general), adding 0.2eq Cu (CN) 2 Heating to about 160-180 ℃, dropwise adding the intermediate 1, fully reacting after dropwise adding (the reaction time is generally 2 hours), pouring the reaction liquid into ice water, stirring, carrying out suction filtration, taking filtrate, extracting with ethyl acetate, taking an organic phase in a layered manner, spin-drying the organic layer to obtain a crude product, and recrystallizing methanol to obtain the pure 3-nitro-5-cyano trifluoromethyl benzene.
Further, in the step (1), the ratio of 3-trifluoromethyl nitrobenzene: dibromohydantoin: molar ratio of bromine is 1:0.3 to 0.4:0.3 to 0.4, wherein the ratio of dibromohydantoin: the molar ratio of bromine is 1:1, the reaction temperature is 5-10 ℃.
And/or the amount of CuCN in step (2) is generally 1.2 to 1.3eq, and 0.2eq of Cu (CN) is added thereto 2 The reaction temperature is 160-175 ℃, the optimal reaction temperature is about 170 ℃, the reaction of the raw materials at 160 ℃ is incomplete, and DMSO begins to decompose at 180 ℃.
Compared with the prior art, the invention provides a novel synthesis method of 3-nitro-5-cyano trifluoromethyl benzene, which is simple, low in raw material price and stable in yield.
Detailed Description
The invention is described in further detail below with reference to examples:
example 1
Bromination (dibromohydantoin + bromine)
Adding 1L of sulfuric acid into a three-neck flask, adding 430g of 3-trifluoromethyl nitrobenzene (2.25 mol) into the mixture, stirring the mixture at the temperature of between 5 and 10 ℃, adding 250g of dibromohydantoin (0.87 mol) and 140g of bromine (0.87 mol) in batches, reacting the mixture for 6 hours, pouring the reaction solution into 5kg of ice water after the reaction is finished, performing suction filtration after stirring, taking filtrate, extracting the filtrate with 1L of ethane, taking organic phases in layers, extracting an aqueous phase with 0.5L of ethane, and combining the organic phases. 200g of sodium sulfite is taken to prepare an aqueous solution, the organic layer is washed in batches until the water layer is colorless, and then the organic layer is washed by clean water, dried and dried to obtain 575g of crude product. Rectification gave 530g of intermediate 1, purity 99.1%. The molar yield was 87.5%.
Cyanidation (reaction at 170 ℃ C.)
Adding 2.5L DMSO into a reaction bottle, heating to about 120-130 ℃, stirring for 10min, adding 195g CuCN (2.17 mol) and 46g Cu (CN) 2 (0.4 mol), stirring for 5min, heating to 170 ℃, dropwise adding 530g of intermediate 1 (1.97 mol), and reacting for 2h after dropwise adding. Pouring the reaction solution into ice water, stirring and performing suction filtration, adding diatomite during suction filtration, taking filtrate, extracting with 1.5L ethyl acetate, taking an organic phase in a layered mode, extracting a water phase with 0.5L ethyl acetate, combining the organic phase, and spin-drying the organic phase to obtain 430g of a product with the purity of 92%. Recrystallizing with methanol to obtain 380g of pure product with the purity of 99.2 percent and the molar yield of 89.5 percent. The overall molar yield was 78%. The product is light yellow powder.
Example 2
Bromination (bromine)
Adding 1L of sulfuric acid into a three-neck flask, adding 430g of 3-trifluoromethyl nitrobenzene (2.25 mol) into the sulfuric acid, stirring at 5-10 ℃, adding 430g of bromine (2.7 mol) in batches, reacting for 7h, pouring a reaction solution into 5kg of ice water after the reaction is finished, performing suction filtration after stirring, taking a filtrate, extracting with 1.5L of ethane, taking an organic phase by layering, extracting an aqueous phase by using 0.5L of ethane, and combining the organic phases. 200g of sodium sulfite is taken to prepare an aqueous solution, the organic layer is washed in batches until the water layer is colorless, then the organic layer is washed once by clear water, and the crude product 476g is obtained after drying and spin drying. Rectification gave 440g of intermediate 1, with a purity of 98.7% and a molar yield of 72.7%.
Cyanidation (reaction at 170 ℃ C.)
Adding 2.5L DMSO into a reaction bottle, heating to about 120 ℃, stirring for 10min, adding 180g CuCN (2.0 mol), stirring for 5min, heating to 170 ℃, dropwise adding 440g intermediate 1 (1.63 mol), and reacting for 2h after dropwise adding. Pouring the reaction solution into ice water, stirring, performing suction filtration, adding diatomite during suction filtration, taking filtrate, extracting with 1.5L ethyl acetate, taking an organic phase in a layered manner, extracting a water phase with 0.5L ethyl acetate, combining the organic phase, and spin-drying the organic layer to obtain 345g of a product with the purity of 86%. The methanol is recrystallized to obtain 280g of pure product with the purity of 98.5 percent and the molar yield of 79.6 percent. The overall molar yield was 57.8%. The product is light yellow powder.
Example 3
Bromination (dibromohydantoin)
Adding 1L of sulfuric acid into a three-neck flask, adding 430g of 3-trifluoromethyl nitrobenzene (2.25 mol) into the mixture, stirring the mixture at the temperature of between 5 and 10 ℃, adding 500g of dibromohydantoin (1.74 mol) in batches, reacting the mixture for 7 hours, pouring the reaction solution into 5kg of ice water after the reaction is finished, performing suction filtration after stirring, taking filtrate, extracting the filtrate by using 1.5L of ethane, taking an organic phase by layering, extracting an aqueous phase by using 0.5L of ethane, and combining the organic phases. 200g of sodium sulfite is taken to prepare an aqueous solution, the organic layer is washed in batches until the water layer is colorless, then the organic layer is washed once by clean water, and the crude product is dried by spin drying to obtain 530g of crude product. Rectification gave 480g of intermediate 1 with a purity of 98.9% and a molar yield of 79.5%.
Cyanation (reaction at 160 ℃ C.)
2.5L of DMSO is added into a reaction bottle, the temperature is raised to about 120 ℃, the mixture is stirred for 10min, 193g of CuCN (2.14 mol) is added, the mixture is stirred for 5min, the mixture is heated to 160 ℃, 480g of intermediate 1 (1.78 mol) is added dropwise, and the reaction is carried out for 2h after the dropwise addition. Pouring the reaction solution into ice water, stirring, performing suction filtration, adding diatomite during suction filtration, taking filtrate, extracting with 1.5L ethyl acetate, taking an organic phase in a layered manner, extracting a water phase with 0.5L ethyl acetate, combining the organic phase, and spin-drying the organic layer to obtain 340g of a product with the purity of 85%. The methanol is recrystallized to obtain 250g of pure product with the purity of 98.6 percent and the molar yield of 65 percent. The total molar yield was 52%. The product is light yellow powder.
Example 4
Bromination (dibromohydantoin)
Adding 1L of sulfuric acid into a three-neck flask, adding 430g of 3-trifluoromethyl nitrobenzene (2.25 mol) into the mixture, stirring the mixture at the temperature of between 5 and 10 ℃, adding 500g of dibromohydantoin (1.74 mol) in batches, reacting the mixture for 7 hours, pouring the reaction solution into 5kg of ice water after the reaction is finished, performing suction filtration after stirring, taking filtrate, extracting the filtrate by using 1.5L of ethane, taking an organic phase by layering, extracting an aqueous phase by using 0.5L of ethane, and combining the organic phases. 200g of sodium sulfite is taken to prepare an aqueous solution, the organic layer is washed in batches until the water layer is colorless, then the organic layer is washed once by clean water, and the crude product is dried by spin drying to obtain 530g of crude product. Rectification gave 480g of intermediate 1 with a purity of 98.9% and a molar yield of 79.5%.
Cyanidation (reaction at 170 ℃ C.)
2.5L of DMSO is added into a reaction bottle, the temperature is raised to about 120 ℃, the mixture is stirred for 10min, 193g of CuCN (2.14 mol) is added, the mixture is stirred for 5min, the mixture is heated to about 170 ℃, 480g of intermediate 1 (1.78 mol) is dropwise added, and the reaction is carried out for 2h after the dropwise addition. Pouring the reaction liquid into ice water, stirring, performing suction filtration, adding diatomite during suction filtration, taking filtrate, extracting with 1.5L ethyl acetate, taking organic phases in a layered manner, extracting a water phase with 0.5L ethyl acetate, combining the organic phases, and spin-drying the organic phase to obtain 375g of a product with the purity of 84%. The methanol was recrystallized to yield 291g of pure product, 98.6% purity and 75.6% molar yield. The total molar yield was 60%. The product is light yellow powder.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and their concepts should be equivalent or changed within the technical scope of the present invention. It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
Claims (4)
1. A synthetic method of 3-nitro-5-cyano benzotrifluoride is characterized in that: the method comprises the following steps:
(1) Mixing 3-trifluoromethyl nitrobenzene as a raw material with sulfuric acid, slowly adding dibromohydantoin and/or bromine at the temperature of 5-10 ℃, reacting for 7-8 hours, pouring a reaction solution into ice water, extracting with ethane, taking an organic phase in a layered manner, taking a sodium sulfite aqueous solution, washing the organic layer in batches until a water layer is colorless, and drying and spin-drying the organic layer to obtain an intermediate 1;
(2) Adding DMSO into a reaction bottle, heating to 12-130 ℃, stirring for dispersion, adding CuCN, stirring for full dissolution, and adding 0.2eq Cu (CN) 2 Heating to 160-180 ℃, dropwise adding the intermediate 1, fully reacting after dropwise adding, pouring the reaction liquid into ice water, stirring, carrying out suction filtration, taking filtrate, extracting with ethyl acetate, taking an organic phase in a layered manner, spin-drying the organic layer to obtain a crude product, and recrystallizing methanol to obtain a pure product of the 3-nitro-5-cyano trifluoromethyl benzene.
2. The method for synthesizing 3-nitro-5-cyano benzotrifluoride according to claim 1, wherein: 3-trifluoromethyl nitrobenzene in the step (1): dibromohydantoin: molar ratio of bromine is 1:0.3 to 0.4:0.3 to 0.4, wherein the ratio of dibromohydantoin: molar ratio of bromine is 1:1, the reaction temperature is 5-10 ℃.
3. The method for synthesizing 3-nitro-5-cyano trifluorotoluene according to claim 1, wherein the method comprises the following steps: the addition amount of CuCN in the step (2) is 1.2 to 1.3eq, and the reaction temperature is 160 to 175 ℃.
4. The method for synthesizing 3-nitro-5-cyano trifluorotoluene according to claim 1, wherein the method comprises the following steps: the reaction temperature in step (2) was 170 ℃.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1377932A (en) * | 1972-01-07 | 1974-12-18 | Merck & Co Inc | Benzene-sulphonamides |
| CN102174020A (en) * | 2005-06-09 | 2011-09-07 | 诺瓦提斯公司 | Process for the synthesis of organic compounds |
| CN103694176A (en) * | 2014-01-07 | 2014-04-02 | 苏州立新制药有限公司 | Preparation method of nilotinib intermediate |
| CN105051027A (en) * | 2013-03-15 | 2015-11-11 | 葛兰素史密斯克莱知识产权发展有限公司 | Pyridine derivatives as rearranged during transfection (RET) kinase inhibitors |
| CN106431979A (en) * | 2016-07-28 | 2017-02-22 | 山东润博生物科技有限公司 | Method for preparing 2-nitro-4-trifluoromethylbenzonitrile |
| CN113121457A (en) * | 2021-04-23 | 2021-07-16 | 白银康寓信生物科技有限公司 | Synthesis process of Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine |
-
2022
- 2022-11-15 CN CN202211423883.8A patent/CN115626880B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1377932A (en) * | 1972-01-07 | 1974-12-18 | Merck & Co Inc | Benzene-sulphonamides |
| CN102174020A (en) * | 2005-06-09 | 2011-09-07 | 诺瓦提斯公司 | Process for the synthesis of organic compounds |
| CN105051027A (en) * | 2013-03-15 | 2015-11-11 | 葛兰素史密斯克莱知识产权发展有限公司 | Pyridine derivatives as rearranged during transfection (RET) kinase inhibitors |
| CN103694176A (en) * | 2014-01-07 | 2014-04-02 | 苏州立新制药有限公司 | Preparation method of nilotinib intermediate |
| CN106431979A (en) * | 2016-07-28 | 2017-02-22 | 山东润博生物科技有限公司 | Method for preparing 2-nitro-4-trifluoromethylbenzonitrile |
| CN113121457A (en) * | 2021-04-23 | 2021-07-16 | 白银康寓信生物科技有限公司 | Synthesis process of Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine |
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