CN106866404A - A kind of synthetic method of the different benzenpropanoic acid of 4 bromomethyl - Google Patents
A kind of synthetic method of the different benzenpropanoic acid of 4 bromomethyl Download PDFInfo
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- CN106866404A CN106866404A CN201710003601.1A CN201710003601A CN106866404A CN 106866404 A CN106866404 A CN 106866404A CN 201710003601 A CN201710003601 A CN 201710003601A CN 106866404 A CN106866404 A CN 106866404A
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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Abstract
A kind of synthesis of the different benzenpropanoic acid of 4 bromomethyl of the present invention, toluene and methylating reagent are in the presence of alkalescence, the different benzenpropanoic acid of GCMS computer under high temperature, reaction solution obtains final product qualified different benzenpropanoic acid of the purity more than 98%, the different benzenpropanoic acid of the bromomethyl of prepare compound 4 through overpickling, distillation：, through the bromomethylation reaction production different benzenpropanoic acid reaction solution of the bromomethyl of compound 4, reaction solution is through dissolving, washing, concentrate, clean, be centrifuged and obtaining qualified finished product for the qualified different benzenpropanoic acid of compound.Compared with prior art, raw material of the present invention is easy to get, with low cost, and raw material is cheap and easy to get, small toxicity, low cost, it is easy to operate, be suitable to industrialization, the three wastes of generation are few, and are the comprehensive utilizations of waste, meet national industrial policies.
Description
Technical field
The present invention relates to a kind of preparation method of organic intermediate, specially a kind of synthesis side of the different benzenpropanoic acid of 4- bromomethyls
Method.
Background technology
Loxoprofen sodium be it is a kind of it is important be 2- phenylpropionic acids non-steroidal anti-inflammatory analgesics, by Japan three altogether companies' exploitation
City.With analgesic activity by force, the characteristics of digestion Small side effects, many countries and regions listing including including China.
And one of them important raw material different benzenpropanoic acid of 4- bromomethyls will be used during synthesis loxoprofen sodium, close on the market at present
Into the high cost of the different benzenpropanoic acid of 4- bromomethyls, with contaminative, therefore the present invention provides a kind of synthesis exploitation different benzene of 4- bromomethyls
A kind of new method of propionic acid, specifically with phenylacetic acid as initiation material, reacts 2 steps and synthesizes by methylation reaction, bromomethylation.
This technique has raw material cheap and easy to get, simple to operate, the features such as environmental pollution is small, is adapted to industrialized production.
The content of the invention
The technical problem to be solved in the present invention is directed to the deficiencies in the prior art, proposes a kind of different benzenpropanoic acid of 4- bromomethyls
Synthetic method.
The technical problem to be solved in the present invention is achieved through the following technical solutions, a kind of different benzenpropanoic acid of 4- bromomethyls
Synthetic method, the synthetic method is comprised the following steps：
Step one：0.5-1.5 moles of phenylacetic acid, 2.0-2.5 moles of potassium carbonate are put into reaction bulb, phenylacetic acid and potassium carbonate are stirred
Mix and be warming up to 50-60 DEG C, 1.0-1.5 moles of dimethyl carbonate is added dropwise when temperature is 50-60 DEG C, time for adding is controlled in 3-5
Hour, after completion of dropping, it is incubated 50-60 DEG C and reacts 5-6 hours, middle control detection：Phenylacetic acid residual≤1% is qualified；
Step 2：To water 250-300g is added in being added in the reaction solution that step one is obtained, it is incubated 30-40 DEG C and stirs 1 hour, it is quiet
Layering is put, point sub-cloud water, then to water 80-100g is added in reaction bulb, stir 30 minutes, stratification, point sub-cloud water has
Machine obtains product, purity >=98%, yield by vacuum distillation：93.3%；
Step 3：To adding 0.5-1.0 moles of different benzenpropanoic acid, 1.0-1.5 moles of paraformaldehyde in the reaction solution that step 2 is obtained,
Hydrobromic acid 150-170g, stirring is warming up to 55-65 DEG C, and insulation is slowly added dropwise concentrated sulfuric acid 250-280g, and time for adding is controlled in 3-4
Hour, completion of dropping is incubated 55-65 DEG C and stirs 4-5 hours, middle control detection：Different benzenpropanoic acid residual≤1% is qualified；
Step 4：The reaction solution that step 3 is obtained is cooled to 20-30 DEG C, insulation is added dropwise water 50-70g, after completion of dropping, once
Property add dichloromethane 300-500g, stir 0.5 hour, stratification, point sub-cloud water, it is organic be added to 5% bisulfite
Sodium water solution 100-150g, stirs 0.5 hour, stratification, and point sub-cloud water, organic phase is concentrated under reduced pressure, and reclaims dichloromethane
About 200-300g, stops concentration, and frozen water is cooled to 0-3 DEG C and is incubated crystallization 5 hours, filters, cake a small amount of water washing, drying
Obtain final product the different benzenpropanoic acid of 4- bromomethyls, purity：>=99%, yield：86.4%.
In a kind of synthetic method of the different benzenpropanoic acid of 4- bromomethyls of the present invention, further preferred technical scheme is characterized in：
1st, the potassium carbonate in the step one can also be inorganic base and the organic bases such as sodium carbonate, NaOH, potassium hydroxide.
2nd, phenylacetic acid can be halomethane, dimethyl suflfate, dimethyl carbonate in the step one.
3rd, hydrobromic acid can be paraformaldehyde or other formalins, and catalyst lewis acid chlorine in the step 3
Change zinc, alchlor, ferric trichloride, titanium tetrachloride, organic acid acetic acid, propionic acid, inorganic acid sulfuric acid, phosphoric acid.
Compared with prior art, raw material of the present invention is easy to get, with low cost, and raw material is cheap and easy to get, small toxicity, low cost, behaviour
Make simplicity, be suitable to industrialization, the three wastes of generation are few, and be the comprehensive utilization of waste, meet national industrial policies.
Brief description of the drawings
Fig. 1 is synthetic schemes of the invention.
Specific embodiment
Concrete technical scheme of the invention described further below, is further understood that in order to those skilled in the art
The present invention, the limitation without constituting its power.
Embodiment 1,
The synthesis of different benzenpropanoic acid
To throwing phenylacetic acid 136g in reaction bulb（1mol）With potassium carbonate 304g（2.2mol）Stirring is warming up to 50-60 DEG C, insulation drop
Plus dimethyl carbonate 99g (1.1mol), time for adding was controlled at 3-5 hours, after completion of dropping, was incubated 50-60 DEG C of reaction 5-6 small
When, middle control detection：Phenylacetic acid residual≤1% is qualified, to water 300g is added in reaction bulb, is incubated 30-40 DEG C and stirs 1 hour, stands
Layering, point sub-cloud water, then to water 100g is added in reaction bulb, stir 30 minutes, stratification, point sub-cloud water.Organic phase
Product 140g, purity >=98%, yield are obtained by vacuum distillation：93.3%
The different benzenpropanoic acid of 4- bromomethyls
To different benzenpropanoic acid 120g (0.8mol) is added in reaction bulb, paraformaldehyde 42g (1.4mol), hydrobromic acid 168g, stirring rise
To 55-65 DEG C, insulation is slowly added dropwise concentrated sulfuric acid 276g to temperature, and at 3-4 hours, completion of dropping was incubated 55-65 DEG C for time for adding control
Stirring 4-5 hours, middle control detection：Different benzenpropanoic acid residual≤1% is qualified, is cooled to 20-30 DEG C, and insulation is added dropwise water 60g, drips
Bi Hou, it is disposable to add dichloromethane 400g, stir 0.5 hour, stratification, point sub-cloud water, it is organic be added to 5% Asia
Sodium bisulphate solution 120g, stirs 0.5 hour, stratification, and point sub-cloud water, organic phase is concentrated under reduced pressure, and reclaims dichloromethane
Alkane about 300g, stops concentration, and frozen water is cooled to 0-3 DEG C and is incubated crystallization 5 hours, filters, and cake is with a small amount of water washing, drying
Obtain the different benzenpropanoic acid 168g of 4- bromomethyls, purity：>=99%, yield：86.4%
Embodiment 2,
（1）The different benzenpropanoic acid of prepare compound：Toluene and methylating reagent in the presence of alkalescence, the different phenylpropyl alcohol of GCMS computer under high temperature
Acid, reaction solution obtains final product qualified different benzenpropanoic acid of the purity more than 98% through overpickling, distillation
（2）The different benzenpropanoic acid of prepare compound 4- bromomethyls：The qualified different benzenpropanoic acid of compound is through bromomethylation reaction production compound
The different benzenpropanoic acid reaction solution of 4- bromomethyls, reaction solution is through dissolving, washing, concentrate, clean, be centrifuged and obtaining qualified finished product.
As a further improvement on the present invention, described（1）Methylating reagent described in step is halomethane, dimethyl sulfate
Ester, dimethyl carbonate etc.；The alkali used is inorganic base and the organic bases such as sodium carbonate, potassium carbonate, NaOH, potassium hydroxide
As a further improvement on the present invention, described（2）Bromomethylation reagent described in step is hydrobromic acid, paraformaldehyde or
Other formalins, and catalyst lewis acid zinc chloride, alchlor, ferric trichloride, titanium tetrachloride, organic acid acetic acid,
Propionic acid, inorganic acid sulfuric acid, phosphoric acid etc..
Claims (4)
1. a kind of synthetic method of the different benzenpropanoic acid of 4- bromomethyls, it is characterised in that the synthetic method is comprised the following steps：
Step one：0.5-1.5 moles of phenylacetic acid, 2.0-2.5 moles of potassium carbonate are put into reaction bulb, phenylacetic acid and potassium carbonate are stirred
Mix and be warming up to 50-60 DEG C, 1.0-1.5 moles of dimethyl carbonate is added dropwise when temperature is 50-60 DEG C, time for adding is controlled in 3-5
Hour, after completion of dropping, it is incubated 50-60 DEG C and reacts 5-6 hours, middle control detection：Phenylacetic acid residual≤1% is qualified；
Step 2：To water 250-300g is added in being added in the reaction solution that step one is obtained, it is incubated 30-40 DEG C and stirs 1 hour, it is quiet
Layering is put, point sub-cloud water, then to water 80-100g is added in reaction bulb, stir 30 minutes, stratification, point sub-cloud water has
Machine obtains product, purity >=98%, yield by vacuum distillation：93.3%；
Step 3：To adding 0.5-1.0 moles of different benzenpropanoic acid, 1.0-1.5 moles of paraformaldehyde in the reaction solution that step 2 is obtained,
Hydrobromic acid 150-170g, stirring is warming up to 55-65 DEG C, and insulation is slowly added dropwise concentrated sulfuric acid 250-280g, and time for adding is controlled in 3-4
Hour, completion of dropping is incubated 55-65 DEG C and stirs 4-5 hours, middle control detection：Different benzenpropanoic acid residual≤1% is qualified；
Step 4：The reaction solution that step 3 is obtained is cooled to 20-30 DEG C, insulation is added dropwise water 50-70g, after completion of dropping, once
Property add dichloromethane 300-500g, stir 0.5 hour, stratification, point sub-cloud water, it is organic be added to 5% bisulfite
Sodium water solution 100-150g, stirs 0.5 hour, stratification, and point sub-cloud water, organic phase is concentrated under reduced pressure, and reclaims dichloromethane
About 200-300g, stops concentration, and frozen water is cooled to 0-3 DEG C and is incubated crystallization 5 hours, filters, cake a small amount of water washing, drying
Obtain final product the different benzenpropanoic acid of 4- bromomethyls, purity：>=99%, yield：86.4%.
2. the synthetic method of a kind of different benzenpropanoic acid of 4- bromomethyls according to claim 1, it is characterised in that：The step one
In potassium carbonate can also be inorganic base and the organic base such as sodium carbonate, NaOH, potassium hydroxide.
3. the synthetic method of a kind of different benzenpropanoic acid of 4- bromomethyls according to claim 1, it is characterised in that：The step one
Middle phenylacetic acid can be halomethane, dimethyl suflfate, dimethyl carbonate.
4. the synthetic method of a kind of 2- hydroxy-3-nitroacetophenones according to claim 1, it is characterised in that：The step
Hydrobromic acid can be paraformaldehyde or other formalins, and catalyst lewis acid zinc chloride, alchlor, three in rapid three
Iron chloride, titanium tetrachloride, organic acid acetic acid, propionic acid, inorganic acid sulfuric acid, phosphoric acid.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180464A (en) * | 2018-09-10 | 2019-01-11 | 浙江大学 | Gas circulation method prepares 2- (4- 2-bromomethylphenyl) propionic acid |
| CN111454145A (en) * | 2020-05-13 | 2020-07-28 | 张明 | Preparation method of p-bromomethyl isophenylpropionic acid |
| CN113527090A (en) * | 2021-07-16 | 2021-10-22 | 江西开元生物医药科技有限公司 | Synthetic method of p-bromomethyl isophenylpropionic acid |
Citations (3)
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| US6013832A (en) * | 1997-07-04 | 2000-01-11 | Kolon Industries, Inc. | Process for the production of benzene derivatives |
| CN104744237A (en) * | 2015-02-16 | 2015-07-01 | 丽水市南明化工有限公司 | Preparation method of 2-(4-bromomethylphenyl) propionic acid |
| CN105753685A (en) * | 2016-03-30 | 2016-07-13 | 浙江丽水有邦新材料有限公司 | Method for preparing loxoprofen intermediate |
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2017
- 2017-01-04 CN CN201710003601.1A patent/CN106866404A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6013832A (en) * | 1997-07-04 | 2000-01-11 | Kolon Industries, Inc. | Process for the production of benzene derivatives |
| CN104744237A (en) * | 2015-02-16 | 2015-07-01 | 丽水市南明化工有限公司 | Preparation method of 2-(4-bromomethylphenyl) propionic acid |
| CN105753685A (en) * | 2016-03-30 | 2016-07-13 | 浙江丽水有邦新材料有限公司 | Method for preparing loxoprofen intermediate |
Non-Patent Citations (2)
| Title |
|---|
| CANICIO,J,A.等: "a new direct a-alkylation of arylacetic acids by solid-liquid phase-transfer catalysis :synthesis of 2-arylalkanoic acids", 《ANALES DE QUIMICA, SERIE C：QUIMICA ORGANICA BIOQUIMICA》 * |
| 刘志雄 等: "2-( 4-溴甲基苯基) 丙酸及其酯的合成", 《化学试剂》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180464A (en) * | 2018-09-10 | 2019-01-11 | 浙江大学 | Gas circulation method prepares 2- (4- 2-bromomethylphenyl) propionic acid |
| CN111454145A (en) * | 2020-05-13 | 2020-07-28 | 张明 | Preparation method of p-bromomethyl isophenylpropionic acid |
| CN113527090A (en) * | 2021-07-16 | 2021-10-22 | 江西开元生物医药科技有限公司 | Synthetic method of p-bromomethyl isophenylpropionic acid |
| CN113527090B (en) * | 2021-07-16 | 2022-02-22 | 江西开元生物医药科技有限公司 | Synthetic method of p-bromomethyl isophenylpropionic acid |
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