CN104292098A - Preparation method of 2-phenylpropionic acid - Google Patents

Preparation method of 2-phenylpropionic acid Download PDF

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Publication number
CN104292098A
CN104292098A CN201410527921.3A CN201410527921A CN104292098A CN 104292098 A CN104292098 A CN 104292098A CN 201410527921 A CN201410527921 A CN 201410527921A CN 104292098 A CN104292098 A CN 104292098A
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phenylpropionic acid
vinylbenzene
toluene
cut
temperature
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CN104292098B (en
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李新法
王瑞涛
王琪
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Dijia Pharmaceutical Group Co ltd
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WEIHAI DIJIA PHARMACEUTICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/08—Preparation of carboxylic acid nitriles by addition of hydrogen cyanide or salts thereof to unsaturated compounds
    • C07C253/10—Preparation of carboxylic acid nitriles by addition of hydrogen cyanide or salts thereof to unsaturated compounds to compounds containing carbon-to-carbon double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a synthetic method of a medical intermediate: 2-phenylpropionic acid and belongs to the field of medicines. The conventional reaction process of 2-phenylpropionic acid is simplified from three steps to two steps. The preparation method comprises the following steps: by using styrene and sodium cyanide as raw materials, carrying out reaction under effects of potassium bicarbonate and a polymerization inhibitor at preferably 130-150 DEG C and 2.1-2.5MPa to prepare 2-phenyl propionitrile; carrying out alkaline hydrolysis and acidification on 2-phenyl propionitrile to obtain 2-phenylpropionic acid; and carrying out 3mmHg reduced pressure distillation on a coarse product to obtain high purity 2-phenylpropionic acid with the HPLC (high performance liquid chromatography) purity which is greater than 99%. In the whole reaction process, noble metal complexes are not used, so that the process is simple and easy to operate.

Description

A kind of preparation method of 2-phenylpropionic acid
Technical field:
The present invention relates to a kind of medicine intermediate---the synthetic method of 2-phenylpropionic acid, belongs to field of medicaments.
Background of invention:
2-arylpropionic acid compounds has obvious anti-inflammatory, analgesia and refrigeration function, the sixties in last century Ibuprofen BP/EP appearance, indicate that the research of non-steroid antiinflammatory drug (NSAID) enters a New Times.At present, more than 30 kind of 2-arylprop acids NSAID has been developed in the world, such as Ibuprofen BP/EP, Ketoprofen BP 93, flurbiprofen, loxoprofen sodium, Naproxen Base etc.These medicines have good curative effect to urgency/chronic arthritis clinically, scapulohumeral periarthritis, soft tissue rheumatism pain, neuritis, respiratory inflammation etc.This kind of medicine is widely used by clinician because having the feature of high-efficiency low-toxicity, instead of the use acetylsalicylic acid that still drug effect is low, dosage is large for a long time gradually.
2-phenylpropionic acid is important, the most basic, structure the simplest 2-arylpropionic acid compounds, is also the basic medicine intermediate of other 2-arylprop acids of synthesis and medicine:
The synthesis of 2-phenylpropionic acid disclosed in Chinese patent 201110288939.9 divides three steps to carry out, first reaction is that the hydrochloric acid soln of 20 ~ 25% is for raw material with vinylbenzene and mass concentration, at 30 ~ 40 DEG C, stirring reaction is after 8 ~ 14 hours, static layering, oil reservoir obtains 2-chloroethyl benzene after washing, and 2-chloroethyl benzene prepares 2-phenylpropionic acid more successively after sodium cyanide cyaniding and hydrolysis:
Organometallics, 2010,29 (20), 4440-4447 and Tetrahedron:Asymmetry, 2010,21 (17), 2153-2157 report under the catalysis of metal complexes, at high temperature under high pressure, vinylbenzene and CO, H 2addition obtains 2-phenylpropionaldehyde, then the oxidation of 2-phenylpropionaldehyde is obtained 2-phenylpropionic acid:
Dalton Transaction, 2008 (15), 1976-1978 report under palladium complex and p-methyl benzenesulfonic acid exist, vinylbenzene and CO, H 2o addition directly obtains 2-phenylpropionic acid; Journal of the American Chemistry, 2008,130 (45), 14936-14937 then use vinylbenzene and CO 2under the catalysis of nickel, addition obtains 2-phenylpropionic acid.
The advantage of these methods is that the productive rate of the raw material availability of addition one step and product is very high, meets the requirement of atom economy, but adopts valuable metal complexes and higher to the requirement of processing condition, also cannot carry out large-scale industrial production.Summary of the invention:
Main purpose of the present invention is to provide a kind of brief, novel preparation method of 2-phenylpropionic acid.
Technical scheme of the present invention is:
Step 1: be dissolved in aprotic polar solvent by vinylbenzene, NaCN, under certain temperature and pressure, reacts under saleratus and stopper effect, preparation 2-phenylpropanenitrile;
Step 2: the 2-phenylpropanenitrile alkaline hydrolysis that step 1 is obtained, acidifying, preparation 2-phenylpropionic acid.
Wherein, temperature described in step 1 controls at 100 ~ 200 DEG C, preferably 130 ~ 150 DEG C; Described pressure-controlling at 1.6 ~ 3.0MPa, preferably 2.1 ~ 2.5MPa; Described aprotic polar solvent is selected from DMF (being called for short DMF) or DMI (being called for short DMI), preferred DMF; Described stopper is adjacent methyl hydroquinone; The quality of vinylbenzene and aprotic polar solvent and volume ratio are 1: 6 ~ 12, preferably 1: 6 ~ 8; The mol ratio of vinylbenzene and NaCN is 1: 1.0 ~ 1.1, and the mol ratio of vinylbenzene and saleratus is 1: 2.0 ~ 2.5, and the mol ratio of vinylbenzene and stopper is 1: 0.005.After reaction terminates, first destroy the remaining sodium cyanide of reaction with thiosulfuric acid potassium solution, use toluene extractive reaction liquid again, extraction liquid is through normal pressure or underpressure distillation desolvation, residual liquid carries out underpressure distillation, the front-end volatiles of 100-120 DEG C under removing 10mmHg, the main cut collecting lower 130 DEG C of 3mmHg, namely obtains 2-phenylpropanenitrile.
The method of the Basic fluxing raction in step 2 and condition are normal condition and method of this type of reaction of this area, and Basic fluxing raction carries out in the basic solution of sodium hydroxide or potassium hydroxide, preferred aqueous sodium hydroxide solution; Basic fluxing raction keeps 4 hours at reflux; After backflow terminates, cooling reaction system, when question response system temperature is chilled to room temperature, with dilute hydrochloric acid or dilute sulphuric acid acidification reaction liquid; Toluene extractive reaction liquid, extraction liquid is through normal pressure or underpressure distillation desolvation, and residual liquid carries out underpressure distillation, and the main cut collecting lower 140 DEG C of 3mmHg, can obtain the 2-phenylpropionic acid of high purity 99%.
The invention has the beneficial effects as follows and traditional reaction process is reduced to two steps by three steps, with vinylbenzene, sodium cyanide for raw material, in certain temperature, preferred 130-150 DEG C and certain pressure, under preferred 2.1-2.5MPa, at saleratus and stopper, such as, react under adjacent methyl hydroquinone effect, preparation 2-phenylpropanenitrile; 2-phenylpropanenitrile, through alkaline hydrolysis, acidifying, obtains 2-phenylpropionic acid.Thick product, in 3mmHg underpressure distillation, can obtain the high purity 2-phenylpropionic acid that HPLC purity is greater than 99%.Avoid in whole reaction process using valuable metal complexes, technique is simple to operation.
Embodiment:
Embodiment 1
10.40g vinylbenzene, 5.0g sodium cyanide, 20g saleratus, the adjacent methyl hydroquinone of 0.06g is added in the airtight high-pressure mini reactor of the 250mL that 60mL DMF is housed, stir lower slowly intensification, control temperature is at 150 DEG C, and pressure reacts 6 hours under 2.1 ~ 2.5MPa.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, adds 20g 15% Potassium Thiosulphate solution stirring half an hour.Add 90mL toluene and the extraction of 60mL water, stratification after stirring 1.5h, stays upper toluene layer, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 10mmHg, collect the front-end volatiles of 100-120 DEG C, after flowing out without cut, continue to heat up, under 3mmHg, collect the cut of 130 DEG C, be prussiate.
Above-mentioned gained prussiate is transferred in the there-necked flask of 250mL, adds the 100mL 8%NaOH aqueous solution, under mechanical stirring, reflux 4h.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, use 8% hcl acidifying, regulates pH ≈ 2, adds 90mL toluene extraction separatory, removes water layer, toluene layer with saturated common salt water washing once, at normal pressure, toluene distillation at temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 3mmHg pressure, collect the cut of 140 DEG C, obtain 12.5g colourless liquid, i.e. 2-phenylpropionic acid, yield 83.2%, through gas chromatographic detection, purity 99.2%.
Embodiment 2
10.40g vinylbenzene, 5.15g sodium cyanide, 25g saleratus, the adjacent methyl hydroquinone of 0.06g is added in the airtight high-pressure mini reactor of the 250mL that 80mL DMF is housed, stir lower slowly intensification, control temperature is at 190 DEG C, and pressure reacts 6 hours under 2.1 ~ 2.5MPa.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, adds 20g 15% Potassium Thiosulphate solution stirring half an hour.Add 90mL toluene and the extraction of 60mL water, stratification after stirring 1.5h, stays upper toluene layer, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 10mmHg, collect the front-end volatiles of 100-120 DEG C, after flowing out without cut, continue to heat up, under 3mmHg, collect the cut of 130 DEG C, be prussiate.
Above-mentioned gained prussiate is transferred in the there-necked flask of 500mL, adds the 100mL 8%NaOH aqueous solution, under mechanical stirring, reflux 4h.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, use 8% hcl acidifying, regulates pH ≈ 2, adds 90mL toluene extraction separatory, removes water layer, toluene layer with saturated common salt water washing once, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 3mmHg pressure, collect the cut of 140 DEG C, obtain 11.8g colourless liquid, i.e. 2-phenylpropionic acid, yield 78.7%, through gas chromatographic detection, purity 98.8%.
Embodiment 3
10.40g vinylbenzene, 6.0g sodium cyanide, 30g saleratus, the adjacent methyl hydroquinone of 0.06g is added in the airtight high-pressure mini reactor of the 250mL that 100mL DMF is housed, stir lower slowly intensification, control temperature is at 110 DEG C, and pressure reacts 6 hours under 1.6 ~ 2.0MPa.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, adds 20g 15% potassium hypochlorite solution stirring half an hour.Add 90mL toluene and the extraction of 60mL water, stratification after stirring 1.5h, stays upper toluene layer, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 10mmHg, collect the front-end volatiles of 100-120 DEG C, after flowing out without cut, continue to heat up, under 3mmHg, collect the cut of 130 DEG C, be prussiate.
Above-mentioned gained prussiate is transferred in the there-necked flask of 250mL, adds the 100mL 10%NaOH aqueous solution, under mechanical stirring, reflux 4h.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, use 8% hcl acidifying, regulates pH ≈ 2, adds 90mL toluene extraction separatory, removes water layer, toluene layer with saturated common salt water washing once, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 3mmHg pressure, collect the cut of 140 DEG C, obtain 11.5g colourless liquid, i.e. 2-phenylpropionic acid, yield 76.7%, through gas chromatographic detection, purity 98.7%.
Embodiment 4
10.40g vinylbenzene, 5.4g sodium cyanide, 25g saleratus, the adjacent methyl hydroquinone of 0.06g is added in the airtight high-pressure mini reactor of the 250mL that 80mL DMI is housed, stir lower slowly intensification, control temperature is at 140 DEG C, and pressure reacts 6 hours under 2.6 ~ 3.0MPa.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, adds 20g 15% Potassium Thiosulphate solution stirring half an hour.Add 90mL toluene and the extraction of 60mL water, stratification after stirring 1.5h, stays upper toluene layer, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 10mmHg, collect the front-end volatiles of 100-120 DEG C, after flowing out without cut, continue to heat up, under 3mmHg, collect the cut of 130 DEG C, be prussiate.
Above-mentioned gained prussiate is transferred in the there-necked flask of 250mL, adds the 100mL 8%NaOH aqueous solution, under mechanical stirring, reflux 4h.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, use 8% hcl acidifying, regulates pH ≈ 2, adds 90mL toluene extraction separatory, removes water layer, toluene layer with saturated common salt water washing once, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 3mmHg pressure, collect the cut of 140 DEG C, obtain 12.3g colourless liquid, i.e. 2-phenylpropionic acid, yield 82.0%, through gas chromatographic detection, purity 99.0%.
Embodiment 5
10.40g vinylbenzene, 5.15g sodium cyanide, 20g saleratus, the adjacent methyl hydroquinone of 0.06g is added in the airtight high-pressure mini reactor of the 250mL that 60mL DMF is housed, stir lower slowly intensification, control temperature is at 130 DEG C, and pressure reacts 6 hours under 2.1 ~ 2.5MPa.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, adds 20g 15% potassium hypochlorite solution stirring half an hour.Add 90mL toluene and the extraction of 60mL water, stratification after stirring 1.5h, stays upper toluene layer, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 10mmHg, collect the front-end volatiles of 100-120 DEG C, after flowing out without cut, continue to heat up, under 3mmHg, collect the cut of 130 DEG C, be prussiate.
Above-mentioned gained prussiate is transferred in the there-necked flask of 250mL, adds the 100mL 8%NaOH aqueous solution, under mechanical stirring, reflux 4h.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, use 8% hcl acidifying, regulates pH ≈ 2, adds 90mL toluene extraction separatory, removes water layer, toluene layer with saturated common salt water washing once, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 3mmHg pressure, collect the cut of 140 DEG C, obtain 12.0g colourless liquid, i.e. 2-phenylpropionic acid, yield 80%, through gas chromatographic detection, purity 99.1%.
Embodiment 6
10.40g vinylbenzene, 5.2g sodium cyanide, 25g saleratus, the adjacent methyl hydroquinone of 0.06g is added in the airtight high-pressure mini reactor of the 250mL that 125mL DMI is housed, stir lower slowly intensification, control temperature is at 190 DEG C, and pressure reacts 6 hours under 2.6 ~ 3.0MPa.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, adds 20g 15% Potassium Thiosulphate solution stirring half an hour.Add 90mL toluene and the extraction of 60mL water, stratification after stirring 1.5h, stays upper toluene layer, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 10mmHg, collect the front-end volatiles of 100-120 DEG C, after flowing out without cut, continue to heat up, under 3mmHg, collect the cut of 130 DEG C, be prussiate.
Above-mentioned gained prussiate is transferred in the there-necked flask of 250mL, adds the 100mL 10%NaOH aqueous solution, under mechanical stirring, reflux 4h.Sampling through vapor detection after completion of the reaction, is cooled to room temperature, use 8% hcl acidifying, regulates pH ≈ 2, adds 90mL toluene extraction separatory, removes water layer, toluene layer with saturated common salt water washing once, toluene distillation at normal pressure, temperature 110 ~ 120 DEG C.After flowing out without cut, stop heating, when system temperature is down to 80 DEG C, start underpressure distillation, under 3mmHg pressure, collect the cut of 140 DEG C, obtain 11.7g colourless liquid, i.e. 2-phenylpropionic acid, yield 78.0%, through gas chromatographic detection, purity 98.8%.

Claims (7)

1. a synthetic method for 2-phenylpropionic acid, is characterized in that:
Step 1: be dissolved in aprotic polar solvent by vinylbenzene, NaCN, under certain temperature and pressure, reacts under saleratus and stopper effect, preparation 2-phenylpropanenitrile;
Step 2: the 2-phenylpropanenitrile alkaline hydrolysis that step 1 is obtained, acidifying, preparation 2-phenylpropionic acid.
2. synthetic method according to claim 1, is characterized in that, aprotic polar solvent described in step 1 is selected from DMF or DMI.
3. synthetic method according to claim 1, is characterized in that, stopper described in step 1 is adjacent methyl hydroquinone.
4. synthetic method according to claim 1, is characterized in that, temperature described in step 1 is 100 ~ 200 DEG C, preferably 130 ~ 150 DEG C; Pressure is 1.6 ~ 3.0MPa.
5. synthetic method according to claim 1, is characterized in that, temperature described in step 1 is 130 ~ 150 DEG C; Pressure is 2.1 ~ 2.5MPa.
6. the synthetic method according to claim arbitrary in claim 1-4, is characterized in that, the mol ratio of vinylbenzene and NaCN is 1: 1.0 ~ 1.1; The quality of vinylbenzene and aprotic polar solvent and volume ratio are 1: 6 ~ 12.
7. synthetic method according to claim 5, is characterized in that, the quality of vinylbenzene and aprotic polar solvent and volume ratio are 1: 6 ~ 8; The mol ratio of vinylbenzene and saleratus is 1: 2 ~ 2.5; The mol ratio of vinylbenzene and stopper is 1: 0.005.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111484472A (en) * 2019-01-28 2020-08-04 中国科学院上海有机化学研究所 Process for producing alkyl nitrile compound
CN113845417A (en) * 2021-09-28 2021-12-28 浙江车头制药股份有限公司 Method for synthesizing (+/-) -naproxen by oxidation through continuous flow microchannel reactor

Citations (1)

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CN102351684A (en) * 2011-09-26 2012-02-15 常州市天华制药有限公司 Preparation method of 2-phenylpropionic acid

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CN102351684A (en) * 2011-09-26 2012-02-15 常州市天华制药有限公司 Preparation method of 2-phenylpropionic acid

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111484472A (en) * 2019-01-28 2020-08-04 中国科学院上海有机化学研究所 Process for producing alkyl nitrile compound
CN111484472B (en) * 2019-01-28 2023-07-07 中国科学院上海有机化学研究所 Process for preparing alkylnitriles
CN113845417A (en) * 2021-09-28 2021-12-28 浙江车头制药股份有限公司 Method for synthesizing (+/-) -naproxen by oxidation through continuous flow microchannel reactor
CN113845417B (en) * 2021-09-28 2023-11-07 浙江车头制药股份有限公司 Method for synthesizing (+/-) -naproxen by using continuous flow micro-channel reactor oxidation

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