CN104356003B - The synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline - Google Patents
The synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline Download PDFInfo
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- CN104356003B CN104356003B CN201410502349.5A CN201410502349A CN104356003B CN 104356003 B CN104356003 B CN 104356003B CN 201410502349 A CN201410502349 A CN 201410502349A CN 104356003 B CN104356003 B CN 104356003B
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- boric acid
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Abstract
The invention discloses a kind of new synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline.It comprises the following steps: 1) be medium with dilute phosphoric acid solution, and m-nitraniline carries out doazo reaction with the Sodium Nitrite slowly dripped; The mother liquor of doazo reaction recycles after treatment; 2) passed through to regulate pH value 6 ~ 6.5 by the diazonium salt generated, then in filtrate, drip fluoroboric acid liquid, refining purification, obtains diazonium fluoride boric acid double salt; 3) take dimethylbenzene as solvent, at reflux, diazonium fluoride boric acid double salt carries out pyrolysis, and filter, filtrate fractionation, obtains a fluoronitrobenzene; 4) last, reduce in water with iron powder, to obtain final product.Present invention reduces cost, decrease three waste discharge, improve the thermostability of diazonium fluoride boric acid double salt, the pyrolysis of diazonium fluoride boric acid double salt steadily carries out in a solvent, and process easily controls, and crude product impurity is few, be easy to purify, improve quality product and yield.
Description
Technical field
The present invention relates to the synthetic method of fluoro-containing intermediate, refer to a kind of new synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline particularly.
Background technology
In recent years, obtain large-scale application along with at chemistry, pharmacy and agricultural industry, fluoro-containing intermediate demonstrates huge growth potential just gradually.Particularly at pharmacy field, various pharmaceutical compound all needs to utilize fluoro-containing intermediate in building-up process, and therefore, fluoro-containing intermediate becomes more and more important, and development activities also becomes increasingly active.
Fluoro-containing intermediate is mainly used in the production of raw medicine of pharmaceutical industry.Trend shows, in the production process of pharmaceutical compound, day by day general to the demand of aromatic series fluoro-containing intermediate, in types of drugs, proportion is more and more higher.Organofluorine compound has stronger stability, physiologically active, fat-soluble and sulphur water-based, the parameter such as electronics, lipotropy can be regulated, so, a lot of Drugs Containing Fluorine relatively has the features such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong in performance, produces great impact to the pharmacodynamics of medicine and pharmacokinetics.Because the performance of Drugs Containing Fluorine is superior, therefore, the research and development of Drugs Containing Fluorine have been promoted to the amplification of fluoro-containing intermediate domestic and international market.
For aromatic series fluorochemicals, almost there is no natural goods, can only be synthesized by artificial chemical process.The synthetic method of usual aromatic series fluorochemicals mainly contains: diazotization reaction substituted-amino method, fluorine replace halogen exchange method, direct fluorination, the special fluorizating agent fluorination method of other halogen.
In these methods, diazotization reaction substituted-amino method uses the hydrochloric acid of 25% to make reaction medium, and the mol ratio of acid and reactant is up to 9:1; Directly double salt is separated out with excessive fluoride boric acid after reaction; Need carry out at a lower temperature and produce the high acid waste water of a large amount of saltiness, three-protection design difficulty is large; And the diazonium salt impurity obtained is many, content is low, easily decomposes disproportionation reaction generation impurity occurs during heat drying; Diazonium salt obtains in the process of m-fluoroaniline carrying out pyrolysis, adopts the direct thermolysis of solid dry powder, and reaction is violent, and process is difficult to control, and crude product impurity is many, and purification difficulty is large.Fluorine replaces the halogen exchange method of other halogen and special fluorizating agent fluorination method all needs at high temperature to carry out, and potential safety hazard is large.It is high that direct fluorination has raw material danger, and process is difficult to control, and equipment corrosion is serious, the shortcomings such as by product is many, purification difficult.
Summary of the invention
Object of the present invention is exactly to overcome the deficiency existing for prior art, provides a kind of new synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline.
For achieving the above object, the new synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline provided by the present invention, comprises the following steps:
1) by massfraction be 15 ~ 25% phosphoric acid solution mix with m-nitraniline, heated and stirred, to dissolving, is cooled to less than 8 DEG C, slowly drips Sodium Nitrite, carry out doazo reaction, after dropwising, continues stirring 0.5 ~ 1 hour; In the mother liquor that doazo reaction obtains, add phosphoric acid solution, through stirring, filtering, the filter cake of diazonium salt is used for the next step, reuses after filtrate activated carbon decolorizing;
2) by step 1) filter cake suspended dispersed in water of obtaining, in suspension, add soda ash, regulate pH value to be 6 ~ 6.5, stir 0.5 ~ 1 hour, elimination solid impurity; In filtrate, drip the fluoroboric acid liquid that massfraction is 40 ~ 55%, obtain the diazonium fluoride boric acid double salt of m-nitraniline, leach diazonium fluoride boric acid double salt, heat drying;
3) taking dimethylbenzene as solvent, at reflux, step 2) dried diazonium fluoride boric acid double salt carries out pyrolysis, and react complete and leach solid impurity, filtrate fractionation, obtain a fluoronitrobenzene;
4) fluoronitrobenzene iron powder between obtaining is reduced in water, obtain m-fluoroaniline.
Step 1 of the present invention) in, the phosphoric acid in described phosphoric acid solution and the mol ratio of m-nitraniline are 1.5 ~ 2:1, and the mol ratio of described m-nitraniline and Sodium Nitrite is 1:1 ~ 1.1.
Beneficial effect of the present invention is: the dilute phosphoric acid of employing of the present invention and reactant low mole prop0rtion makes reaction medium, and the mother liquor after doazo reaction can be recycled after treatment, reduces cost, decreases three waste discharge; Regulated by pH value, obtain high-purity fluorine borate after making the refining purification of the diazonium salt of generation, improve the thermostability of diazonium fluoride boric acid double salt, be conducive to the drying of diazonium fluoride boric acid double salt; The pyrolysis of diazonium fluoride boric acid double salt steadily carries out in a solvent, and process easily controls, and crude product impurity is few, is easy to purify, and improves quality product and yield.
Embodiment
In order to explain the present invention better, below in conjunction with specific embodiment, the present invention is described in further detail, but they do not form restriction to the present invention.
Embodiment 1
1) in 500mL there-necked flask, add phosphoric acid solution (0.38mol phosphoric acid), 27.2g (0.20mol) m-nitraniline that 250g massfraction is 15%, stirring is warming up to dissolving, be cooled to 5 DEG C, slowly drip Sodium Nitrite 14.2g (0.206mol), carry out doazo reaction, after dropwising, continue stirring 0.5 hour; In the mother liquor of doazo reaction, add 25mL85% phosphoric acid solution, stir 15 minutes, filter; The filter cake of diazonium salt is used for the next step, and filtrate is heated up and reused with after activated carbon decolorizing;
2) by step 1) filter cake suspended dispersed in water of obtaining, in suspension, add soda ash, regulate pH value to be 6 ~ 6.5, stir 0.5 hour, elimination solid impurity; In filtrate, drip the fluoroboric acid liquid that massfraction is 40%, obtain the diazonium fluoride boric acid double salt solid of m-nitraniline; Leach diazonium fluoride boric acid double salt, heat drying;
3) by step 2) dried diazonium fluoride boric acid double salt slowly joins in the there-necked flask filling 60mL dimethylbenzene, and under reflux state, carry out pyrolysis, react complete and leach solid impurity, filtrate fractionation, obtain a fluoronitrobenzene 21.5g;
4) fluoronitrobenzene 25 grams of iron powders between obtaining are reduced in 100mL water, after separating-purifying, obtain 15.5 grams of weak yellow liquids.
The structure of product is m-fluoroaniline through boiling point, proton nmr spectra and mass spectrum (MS) confirmation, total recovery 71.75%; Wherein, mass spectrum as shown in Figure 1.
Claims (2)
1. a synthetic method for aromatic series fluoro-containing intermediate m-fluoroaniline, comprises the following steps:
1) by massfraction be 15 ~ 25% phosphoric acid solution mix with m-nitraniline, heated and stirred, to dissolving, is cooled to less than 8 DEG C, slowly drips Sodium Nitrite, carry out doazo reaction, after dropwising, continues stirring 0.5 ~ 1 hour; In the mother liquor that doazo reaction obtains, add phosphoric acid solution, through stirring, filtering, the filter cake of diazonium salt is used for the next step, reuses after filtrate activated carbon decolorizing;
2) by step 1) filter cake suspended dispersed in water of obtaining, in suspension, add soda ash, regulate pH value to be 6 ~ 6.5, stir 0.5 ~ 1 hour, elimination solid impurity; In filtrate, drip the fluoroboric acid liquid that massfraction is 40 ~ 55%, obtain the diazonium fluoride boric acid double salt of m-nitraniline, leach diazonium fluoride boric acid double salt, heat drying;
3) taking dimethylbenzene as solvent, at reflux, step 2) dried diazonium fluoride boric acid double salt carries out pyrolysis, and react complete and leach solid impurity, filtrate fractionation, obtain a fluoronitrobenzene;
4) fluoronitrobenzene iron powder between obtaining is reduced in water, obtain m-fluoroaniline.
2. the synthetic method of aromatic series fluoro-containing intermediate m-fluoroaniline according to claim 1, it is characterized in that: step 1) in, phosphoric acid in described phosphoric acid solution and the mol ratio of m-nitraniline are 1.5 ~ 2:1, and the mol ratio of described m-nitraniline and Sodium Nitrite is 1:1 ~ 1.1.
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Effective date of registration: 20170414 Address after: 438000 Hubei Economic Development Zone, HuangZhou Railway Station, Huanggang, Beijing Road, No. 88 Patentee after: Wuhan Ruiyang Chemical Industry Co., Ltd. Address before: 430034 Wuhan City, Hubei Province, No. 28 easy road, Wuhan City, the third high school (Class 4) Patentee before: Wan Kechen |
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