CN110885298B - Synthesis method of 4-chloro-3- (trifluoromethyl) phenylisocyanate - Google Patents
Synthesis method of 4-chloro-3- (trifluoromethyl) phenylisocyanate Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of 4-chloro-3- (trifluoromethyl) phenylisocyanate. Reacting o-chlorotrifluoromethyl benzene, acetic anhydride and concentrated nitric acid to obtain 4-nitro-2-trifluoromethyl chlorobenzene, activated carbon and FeCl3·6H2Reacting O with hydrazine hydrate to obtain 4-chloro-3-trifluoromethyl aniline, reacting 4-chloro-3-trifluoromethyl aniline, triphosgene and catalyst to obtain 4-chloro-3- (trifluoromethyl) phenyl isocyanate. In the nitration process, the acetic anhydride/concentrated nitric acid system is used for replacing the traditional nitric acid/sulfuric acid mixed acid system, the reaction can be finished at a lower temperature by utilizing the strong nitration effect of the acetyl nitrate, the risk is low, and the amount of multi-nitration impurities is less(ii) a FeCl was used in the reduction step3·6H2The O/active carbon/hydrazine hydrate system replaces the traditional iron powder reduction process, avoids the generation of a large amount of iron mud waste residues, and reduces the environmental protection pressure.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of 4-chloro-3- (trifluoromethyl) phenylisocyanate.
Background
4-chloro-3- (trifluoromethyl) phenylisocyanate is an important medical intermediate and is mainly used for synthesizing the anticancer drug sorafenib. Sorafenib is the first oral multi-kinase inhibitor, targeting serine/threonine kinase and receptor tyrosine kinase on tumor cells and tumor vessels, which influence tumor cell proliferation and angiogenesis, and are vital in the process of tumor growth. These kinases include RAF kinase, VEGFR-2 (vascular endothelial growth factor receptor), VEGFR-3, PDGFR-beta (platelet derived growth factor receptor), KIT and FLT-3 (belonging to the type III family of tyrosine kinase receptors). Sorafenib is a multi-target biological targeting new drug co-developed by Bayer and ONYX companies, and the FDA in the United states has approved sorafenib for treating advanced renal cell carcinoma in 12/20/2005, which is the first new drug approved in the world for treating advanced renal cancer in more than ten years and is a great progress in the treatment of advanced renal cancer.
At present, the main preparation method of 4-chloro-3- (trifluoromethyl) phenylisocyanate takes ortho-chlorotrifluoromethane as a starting material, nitrifies the starting material by concentrated nitric acid/concentrated sulfuric acid mixed acid to obtain a nitride, reduces the nitride into an amide by an iron powder/ethanol system, and reacts with triphosgene to obtain a target product, wherein the nitrifying process needs higher temperature, has high risk and is easy to generate isomer impurities; in the reduction process, iron powder is used as an electron donor, so that iron mud waste residues are difficult to treat, the environment is protected, and hydrogen is generated in the reaction process to bring potential safety hazards. Therefore, the optimization and improvement of the traditional synthesis process are urgently needed at present, so that the process is safer, more environment-friendly and beneficial to industrial production.
Disclosure of Invention
The invention aims to provide a synthetic method of 4-chloro-3- (trifluoromethyl) phenylisocyanate, which has low nitration reaction temperature and small risk, uses a ferric trichloride/hydrazine hydrate system in the reduction reaction, avoids the generation of iron mud waste residue in the traditional reduction process, is safe and environment-friendly, and is easy to industrialize.
The synthesis method of the 4-chloro-3- (trifluoromethyl) phenylisocyanate comprises the step of reacting o-chlorotrifluoromethyl benzene, acetic anhydride and concentrated nitric acid to obtain 4-nitro-2-trifluoromethyl chlorobenzene, activated carbon and FeCl3·6H2Reacting O with hydrazine hydrate to obtain 4-chloro-3-trifluoromethyl aniline, reacting 4-chloro-3-trifluoromethyl aniline, triphosgene and catalyst to obtain 4-chloro-3- (trifluoromethyl) phenyl isocyanate.
The mass ratio of the o-chlorotrifluoromethane to the acetic anhydride to the concentrated nitric acid is 1: 2-2.5: 0.6-0.7.
The mass concentration of the concentrated nitric acid is 68 percent.
The mesh number of the activated carbon is 400-800 meshes, and the mass of the activated carbon is 1-2% of that of the o-chlorotrifluoromethylene.
4-Nitro-2-trifluoromethylchlorobenzene, FeCl3·6H2The weight ratio of O to hydrazine hydrate is 1: 0.06-0.08: 0.7-0.8.
The catalyst is one or more of DMF, pyridine or DMAP, and the mass of the catalyst is 1-2% of that of the o-chlorotrifluoromethylene.
The molar ratio of triphosgene to o-chlorotrifluoromethylene is 0.38-0.42: 1.
the synthesis method of the 4-chloro-3- (trifluoromethyl) phenylisocyanate comprises the following steps:
(1) mixing o-chlorotrifluoromethane and acetic anhydride, dripping concentrated nitric acid, keeping the temperature and stirring after dripping, washing with a sodium hydroxide aqueous solution for layering, and collecting an organic phase;
(2) mixing the organic phase obtained in the step (1), activated carbon and FeCl3·6H2Adding O into ethanol, uniformly mixing, heating to reflux, dropwise adding a hydrazine hydrate solution, filtering while the solution is hot after the dropwise adding is finished, evaporating the ethanol from the filtrate at normal pressure, adding an organic solvent for extraction and layering, and collecting an organic phase;
(3) adding triphosgene and a catalyst into an organic solvent, stirring until the triphosgene and the catalyst are dissolved, dropwise adding the organic phase obtained in the step (2), heating to reflux after the dropwise adding is finished, continuing the reaction, and evaporating the organic solvent under reduced pressure to obtain a crude product;
(4) and (4) rectifying the crude product obtained in the step (3) to obtain a finished product of 4-chloro-3- (trifluoromethyl) phenyl isocyanate.
In the step (1), the dropping temperature is 10-15 ℃.
The heat preservation and stirring time in the step (1) is 3-4 h.
The mass concentration of the sodium hydroxide aqueous solution in the step (1) is 4-6%.
When sodium hydroxide aqueous solution is added in the step (1) for washing, the pH is adjusted to 7.5-8.0.
The mass of the ethanol in the step (2) is 2-2.5 times of that of the o-chlorotrifluoromethylene.
The mass concentration of the hydrazine hydrate solution in the step (2) is 80 percent.
The dripping time in the step (2) is 3-3.5 h.
In the step (2), the organic solvent is one or more of 1, 2-dichloroethane, dioxane or chloroform.
In the step (3), the organic solvent is one or more of 1, 2-dichloroethane, dioxane or chloroform.
In the step (3), the dropping temperature is-5 to 5 ℃.
The reaction time in the step (3) is 3-5 h.
The vacuum degree of the rectification in the step (4) is less than or equal to-0.096 Mpa, and the rectification temperature is 95-100 ℃.
The synthesis method of the 4-chloro-3- (trifluoromethyl) phenylisocyanate comprises the following specific steps:
(1) uniformly mixing o-chlorotrifluoromethane and acetic anhydride, dropwise adding concentrated nitric acid with the mass fraction of 68% at the temperature of 10-15 ℃, keeping the temperature and stirring for 3-4h after dropwise adding, adding 4-6 wt.% of sodium hydroxide aqueous solution to wash and delaminate, and collecting an organic phase;
(2) mixing the organic phase obtained in the step (1), activated carbon and FeCl3·6H2Adding O into ethanol, uniformly mixing, heating to reflux, slowly dropwise adding a hydrazine hydrate solution with the mass fraction of 80%, filtering while hot after dropwise adding, evaporating ethanol from filtrate at normal pressure, adding an organic solvent for extraction and layering, and collecting an organic phase;
(3) adding triphosgene and a catalyst into an organic solvent, stirring until the triphosgene and the catalyst are dissolved clearly, dropwise adding the organic phase obtained in the step (2), controlling the dropwise adding temperature to be-5 ℃, heating to reflux after the dropwise adding is finished, continuing to react for 3-5h, and performing chromatographic detection to obtain a raw material residue of which the content is less than 1%, and then performing reduced pressure distillation to remove the organic solvent to obtain a crude product;
(4) and (4) rectifying the crude product obtained in the step (3), controlling the vacuum degree to be less than or equal to-0.096 Mpa and the tower top temperature to be 95-100 ℃ to obtain a finished product of the 4-chloro-3- (trifluoromethyl) phenyl isocyanate.
Taking acetic anhydride as a solvent, adding o-chlorotrifluoromethane, dropwise adding concentrated nitric acid to carry out nitration reaction, and washing and layering with a sodium hydroxide aqueous solution to obtain a nitride; uniformly mixing the nitride, ferric trichloride hexahydrate, activated carbon and absolute ethyl alcohol, dropwise adding hydrazine hydrate under the reflux state to perform reduction reaction, and rectifying to obtain an amide compound; reacting amine compound with triphosgene under the action of catalyst to obtain isocyanate, spin drying solvent, and rectifying to obtain 4-chloro-3- (trifluoromethyl) phenyl isocyanate with purity over 99.8%.
The synthetic route of the invention is as follows:
the invention has the following beneficial effects:
(1) in the nitration process, an acetic anhydride/concentrated nitric acid system is used for replacing a traditional nitric acid/sulfuric acid mixed acid system, the reaction can be completed at a lower temperature by utilizing the strong nitration action of acetyl nitrate, the risk is low, and more nitrated impurities are less;
(2) FeCl was used in the reduction step3·6H2O/active carbon/hydrazine hydrate system replaces the traditional iron powder reduction process, and FeCl is used as catalytic amount3·6H2O can meet the reaction requirement, thereby avoiding the generation of a large amount of iron mud waste residues and reducing the environmental protection pressure;
(3) the invention has the advantages of total molar yield of more than 80 percent, product purity of more than 99.8 percent, higher cost and quality advantages and higher industrial application value.
Drawings
FIG. 1 is a liquid chromatogram of the final product of example 1.
FIG. 2 is a liquid chromatogram of the finished product of comparative example 1.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
(1) Adding 100g of o-chlorotrifluoromethane and 200g of acetic anhydride into a 500ml three-neck bottle, uniformly mixing, dropwise adding 65g of concentrated nitric acid at the temperature of 10-12 ℃, keeping the temperature and stirring for 3h after dropwise adding, adding 5% of sodium hydroxide aqueous solution to adjust the pH value to 8.0, washing, layering, and collecting 120.7g of an organic phase;
(2) mixing the organic phase obtained in the step (1), 1g of activated carbon and 7.5g of FeCl3·6H2And adding O into 200g of ethanol, uniformly mixing, heating to reflux, dropwise adding 86.5g of hydrazine hydrate solution with the mass fraction of 80%, and finishing dropwise adding within 3 hours. Filtering while hot after dropwise adding, evaporating ethanol from the filtrate at normal pressure, adding 1, 2-dichloroethane for extraction and layering, and collecting an organic phase;
(3) adding 65.7g of triphosgene and 1g of DMAP into 1, 2-dichloroethane, stirring until the mixture is dissolved clearly, dropwise adding the organic phase obtained in the step (2), controlling the dropwise adding temperature to be-5 ℃, heating to reflux after the dropwise adding is finished, continuing to react for 3 hours, and performing chromatographic detection to detect that 0.5 percent of raw material remains, and then starting to evaporate the 1, 2-dichloroethane under reduced pressure to obtain a crude product;
(4) and (3) rectifying the crude product obtained in the step (3), controlling the vacuum degree to be less than or equal to-0.096 Mpa, and extracting 101.2g of 4-chloro-3- (trifluoromethyl) phenyl isocyanate finished product at the tower top temperature of 95-100 ℃, wherein the purity is 99.95 percent, and the molar yield is 82.5 percent.
The results of the finished product testing are shown in FIG. 1 and Table 1.
TABLE 1 example 1 Peak detection results (detector A254 nm) for finished product
| Peak number | When reservedInter (minute) | Area (microvolt seconds) | Height (microvolt) | Area (%) |
| 1 | 2.784 | 16421199 | 2728903 | 99.9473 |
| 2 | 3.435 | 5008 | 1059 | 0.0305 |
| 3 | 4.569 | 3656 | 500 | 0.0223 |
| Total of | 16429863 | 2730461 | 100.0000 |
Example 2
(1) Adding 100g of o-chlorotrifluoromethane and 220g of acetic anhydride into a 500ml three-neck bottle, uniformly mixing, dropwise adding 68g of concentrated nitric acid at the temperature of 10-12 ℃, keeping the temperature and stirring for 3.5h after dropwise adding, adding 5% of sodium hydroxide aqueous solution to adjust the pH value to 7.8, washing, layering, and collecting 123.1g of an organic phase;
(2) will be provided withThe organic phase obtained in the step (1), 1g of activated carbon and 9.6g of FeCl3·6H2And adding O into 200g of ethanol, uniformly mixing, heating to reflux, dropwise adding 88.2g of hydrazine hydrate solution with the mass fraction of 80%, and finishing dropwise adding within 3 hours. Filtering when the solution is hot after the dropwise adding is finished, evaporating ethanol from the filtrate at normal pressure, adding dioxane for extraction and layering, and collecting an organic phase;
(3) adding 65.7g of triphosgene and 1g of pyridine into dioxane, stirring until the mixture is dissolved, dropwise adding the organic phase obtained in the step (2), controlling the dropwise adding temperature to be-5 ℃, heating to reflux after the dropwise adding is finished, continuing to react for 4 hours, and performing chromatographic detection to obtain 0.6% of raw material residue, and then performing reduced pressure distillation to obtain crude product;
(4) and (3) rectifying the crude product obtained in the step (3), controlling the vacuum degree to be less than or equal to-0.096 Mpa, and extracting 98.9g of 4-chloro-3- (trifluoromethyl) phenyl isocyanate finished product at the tower top temperature of 95-100 ℃, wherein the purity is 99.85 percent, and the molar yield is 80.6 percent.
Example 3
(1) Adding 100g of o-chlorotrifluoromethane and 210g of acetic anhydride into a 500ml three-neck bottle, uniformly mixing, dropwise adding 69g of concentrated nitric acid at the temperature of 12-14 ℃, keeping the temperature and stirring for 4h after dropwise adding, adding 5% of sodium hydroxide aqueous solution to adjust the pH to be 7.5, washing, layering, and collecting 119.7g of an organic phase;
(2) mixing the organic phase obtained in the step (1), 1g of activated carbon and 8.4g of FeCl3·6H2And adding O into 200g of ethanol, uniformly mixing, heating to reflux, dropwise adding 83.9g of hydrazine hydrate solution with the mass fraction of 80%, and finishing dropwise adding within 3.5 h. Filtering when the solution is hot after the dropwise addition is finished, evaporating ethanol from the filtrate at normal pressure, adding chloroform for extraction and layering, and collecting an organic phase;
(3) adding 65.7g of triphosgene and 1g of DMF into chloroform, stirring until the mixture is dissolved, dropwise adding the organic phase obtained in the step (2), controlling the dropwise adding temperature to be between 5 ℃ below zero and 5 ℃, heating to reflux after the dropwise adding is finished, continuing to react for 3 hours, and performing chromatographic detection to obtain 0.9% of raw material residue, and then performing reduced pressure distillation to remove chloroform to obtain a crude product;
(4) and (4) rectifying the crude product obtained in the step (3), controlling the vacuum degree to be less than or equal to-0.096 Mpa, and extracting 100.7g of 4-chlorine-3- (trifluoromethyl) phenyl isocyanate finished product at the tower top temperature of 95-100 ℃, wherein the purity is 99.92 percent, and the molar yield is 82.1 percent.
Comparative example 1
(1) Adding 100g of o-chlorotrifluoromethane and 160g of concentrated sulfuric acid (the mass concentration is 98%) into a 500ml three-neck flask, uniformly stirring, controlling the temperature to be 10-15 ℃, dropwise adding 70g of concentrated nitric acid (the mass concentration is 65%) at 40-45 ℃, preserving the temperature and reacting for 5 hours after dropwise adding, adding 80g of water, stirring and layering, and collecting a lower organic phase to obtain 117.8g of nitride;
(2) 400g of ethanol and 300g of water are added into a 1000ml three-necked bottle, 105g of iron powder is added under stirring, and the temperature is raised to 80-85 ℃ for reflux for 2 h. After the reflux is finished, controlling the temperature to be 80-85 ℃, dropwise adding 117.8g of the nitride obtained in the step (1), and continuing to perform heat preservation reaction for 2.5 hours after dropwise adding is finished for 2 hours. Cooling to 30 ℃, and filtering to obtain iron mud; the filtrate was evaporated under reduced pressure to remove ethanol, the pH of the aqueous phase was adjusted to 7.5 with liquid caustic soda, the aqueous phase was extracted three times with 300ml dichloromethane, and the organic phases were combined to spin-dry the solvent to give 104.5g of the amide;
(3) adding 63.5g of triphosgene and 1g of DMAP into 1, 2-dichloroethane, stirring until the mixture is dissolved to be clear, dropwise adding 104.5g of the amide obtained in the step (2), controlling the dropwise adding temperature to be-5 ℃, heating to reflux after the dropwise adding is finished, continuing to react for 3 hours, and performing chromatographic detection to obtain 0.5% of raw material, and then performing reduced pressure distillation to remove 1, 2-dichloroethane to obtain a crude product;
(4) and (3) rectifying the crude product obtained in the step (3), controlling the vacuum degree to be less than or equal to-0.096 Mpa, and extracting 93.5g of 4-chloro-3- (trifluoromethyl) phenyl isocyanate finished product at the tower top temperature of 95-100 ℃, wherein the purity is 99.18%, and the molar yield is 76.2%.
The results of the final product testing are shown in FIG. 2 and Table 2.
TABLE 2 Peak detection results (detector A254 nm) for comparative example 1
| Peak number | Retention time (minutes) | Area (microvolt seconds) | Height (microvolt) | Area (%) |
| 1 | 2.755 | 7268135 | 1296708 | 99.1797 |
| 2 | 3.448 | 2172 | 399 | 0.0296 |
| 3 | 4.345 | 57939 | 7089 | 0.7906 |
| Total of | 7328247 | 1304196 | 100.0000 |
Claims (5)
1. A method for synthesizing 4-chloro-3- (trifluoromethyl) phenylisocyanate is characterized by comprising the following steps:
(1) mixing o-chlorotrifluoromethane and acetic anhydride, dripping concentrated nitric acid, keeping the temperature and stirring after dripping, washing with a sodium hydroxide aqueous solution for layering, and collecting an organic phase;
(2) mixing the organic phase obtained in the step (1), activated carbon and FeCl3·6H2Adding O into ethanol, uniformly mixing, heating to reflux, dropwise adding a hydrazine hydrate solution, filtering while the solution is hot after the dropwise adding is finished, evaporating the ethanol from the filtrate at normal pressure, adding an organic solvent for extraction and layering, and collecting an organic phase;
(3) adding triphosgene and a catalyst into an organic solvent, stirring until the triphosgene and the catalyst are dissolved clearly, dropwise adding the organic phase obtained in the step (2), heating to reflux after the dropwise adding is finished, continuing the reaction, and evaporating the organic solvent under reduced pressure to obtain a crude product;
(4) rectifying the crude product obtained in the step (3) to obtain a finished product of 4-chloro-3- (trifluoromethyl) phenyl isocyanate;
the mass ratio of the o-chlorotrifluoromethylene to the acetic anhydride to the concentrated nitric acid is 1: 2-2.5: 0.6-0.7;
the mesh number of the activated carbon is 400-800 meshes, and the mass of the activated carbon is 1-2% of that of the o-chlorotrifluoromethylene;
4-Nitro-2-trifluoromethylchlorobenzene, FeCl3·6H2The weight ratio of O to hydrazine hydrate is 1: 0.06-0.08: 0.7-0.8;
in the step (1), the dropping temperature is 10-15 ℃.
2. The method for synthesizing 4-chloro-3- (trifluoromethyl) phenylisocyanate according to claim 1, wherein the catalyst is one or more of DMF, pyridine or DMAP, and the mass of the catalyst is 1-2% of the mass of o-chlorotrifluoromethyl benzene.
3. The process for the synthesis of 4-chloro-3- (trifluoromethyl) benzene isocyanate according to claim 1, characterized in that the molar ratio of triphosgene to ortho-chlorotrifluorotoluene is 0.38-0.42: 1.
4. the method for synthesizing 4-chloro-3- (trifluoromethyl) phenylisocyanate according to claim 1, wherein the dropping temperature in the step (3) is-5 to 5 ℃.
5. The method for synthesizing 4-chloro-3- (trifluoromethyl) phenylisocyanate according to claim 1, wherein the reaction time in step (3) is 3-5 h.
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