CN101759556B - Synthesis method of ketoprofen - Google Patents
Synthesis method of ketoprofen Download PDFInfo
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- CN101759556B CN101759556B CN 200910154414 CN200910154414A CN101759556B CN 101759556 B CN101759556 B CN 101759556B CN 200910154414 CN200910154414 CN 200910154414 CN 200910154414 A CN200910154414 A CN 200910154414A CN 101759556 B CN101759556 B CN 101759556B
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 229960000991 ketoprofen Drugs 0.000 title claims abstract description 53
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 72
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 35
- OJFZCPMENWLPRI-UHFFFAOYSA-N (2-ethylphenyl)-phenylmethanone Chemical compound CCC1=CC=CC=C1C(=O)C1=CC=CC=C1 OJFZCPMENWLPRI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 14
- 150000001298 alcohols Chemical class 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- 238000001953 recrystallisation Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000012065 filter cake Substances 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 238000010189 synthetic method Methods 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 14
- 239000011707 mineral Substances 0.000 claims description 14
- 239000007789 gas Substances 0.000 claims description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000007529 inorganic bases Chemical class 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 9
- 238000000643 oven drying Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of ketoprofen shown as a formula (I), which comprises the following steps: making 3-nitrile ethyl benzophenone shown as a formula (II) to react with a sufficient amount of chlorine hydride gas in an alcohols reaction solvent for producing intermediate compounds shown as a formula (III); adding 0.1 to 10 mol/L inorganic base water solution for hydrolysis reaction after the reaction completion; adding acid for regulating the pH value to 3 to 4 after the hydrolysis completion; and carrying out separation treatment on reaction liquid to obtain the ketoprofen shown as the formula (I). The invention has the advantages of high reaction yield, low cost, mild reaction conditions, no condensation by-product, low energy consumption and simple and convenient operation, and is suitable for industrial production.
Description
(1) technical field
The present invention relates to a kind of synthetic method of Ketoprofen, particularly employing is first with itrile group activation, the again method of hydrolysis Ketoprofen.
(2) background technology
Ketoprofen, chemistry 3-benzoyl by name-Alpha-Methyl toluylic acid is the non-steroidal anti-inflammatory analgesics, has anti-inflammatory, analgesic, analgesic effect.Analgesic activity is better than similar drugs and the length of holding time, and toxic side effect is little, security and better tolerance.At first in France's listing, formally enter China in 1973 the eighties, developed now the multiple formulations such as oral tablet, paster, diaphragm, and at home and abroad obtained using very widely.
Before the present invention makes, the chemical synthesis process of original technology Ketoprofen obtains Ketoprofen by the hydrolysis of key intermediate 3-nitrile ethyl benzophenone mostly, hydrolysis can be carried out under acidic conditions and alkaline condition, such as at the 49% sulphuric acid soln 100mL (vitriol oil: water=1: 1), stir to heat up and remain between 125～130 ℃ backflow 4-5 hour, add the alkali neutralization, last acidifying gets Ketoprofen again.The method solvent corrosion is higher, and processing safety is lower, has brought great inconvenience to industrialization.Or in the presence of mineral alkali in the two-phase system of toluene or dimethylbenzene and water high temperature (130 ℃) reaction obtain Ketoprofen after the acidifying more than 3 hours (ZL99116808.9).Aforesaid method also can produce the impurity that some can't be removed, and affects the purity of Ketoprofen.
(3) summary of the invention
Be to solve 3-nitrile ethyl benzophenone hydrolysis cost height in the prior art, long reaction time, aftertreatment is difficult and the deficiency that easily pollutes, the invention provides that a kind of technique is reasonable, reaction yield is high, the reaction times is short, production cost is low, the Ketoprofen synthetic method of clean environment firendly.
For reaching goal of the invention the technical solution used in the present invention be:
The synthetic method of the Ketoprofen shown in a kind of formula (I): suc as formula the 3-nitrile ethyl benzophenone shown in (II) in the alcohols reaction solvent and the hydrogen chloride gas precursor reactant of capacity, generation is suc as formula intermediate shown in (III), the aqueous solution that adds 0.1～10mol/L mineral alkali after reaction the finishes reaction that is hydrolyzed, be hydrolyzed complete, adjust pH to 3 after the acid adding～4, reaction solution separating treatment obtain suc as formula the Ketoprofen shown in (I); Usually with hydrochloric acid, sulfuric acid, phosphoric acid or aqueous acetic acid adjust pH; Described mineral alkali is potassium hydroxide or sodium hydroxide; The molar ratio of described 3-nitrile ethyl benzophenone and mineral alkali is 1: 1. 0～6.0.
Further, described alcohols reaction solvent is following one or more mixing in any proportion: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol or glycerol.The quality consumption of described alcohols reaction solvent is generally 1～100 times of 3-nitrile ethyl benzophenone quality, is preferably 5～20 times.
Further, described temperature suc as formula intermediate shown in (III) and mineral alkali hydrolysis reaction is 20～100 ℃, is preferably 60～100 ℃.The time of described hydrolysis reaction is 0.1～10 hour, and the time of selective hydrolysis reaction is 0.5～2 hour.
The synthetic method of Ketoprofen of the present invention, the temperature of described 3-nitrile ethyl benzophenone and hydrogen chloride gas precursor reactant is-20～100 ℃, is preferably 20～50 ℃, more preferably room temperature.
Further again, reaction solution method for separating and processing of the present invention is: reacting liquid filtering, and filter cake obtains Ketoprofen through the recrystallization solvent recrystallization; Described recrystallization solvent is following one or more mixing in any proportion: water, acetone, methyl alcohol or ethanol.
Hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid are used in the acid of described adjusting pH value usually.
Concrete, the synthetic method of synthesizing ketoprofen of the present invention, preferably carry out in accordance with the following steps: will be dissolved in alcoholic solvent suc as formula the 3-nitrile ethyl benzophenone shown in (II), pass into capacity HCl gas under the room temperature, TLC follows the tracks of reaction, raw material point disappear namely react complete after, add the aqueous solution of 1～4mol/L mineral alkali, be heated to 60～100 ℃ of hydrolysis reaction, reacted 0.5～2 hour, TLC follows the tracks of reaction, after raw material point disappeared and namely reacts end, reaction solution was cooled to room temperature, with salt acid for adjusting pH value to 3～4, filter, filter cake obtains Ketoprofen through the recrystallization solvent recrystallization; The molar ratio of described 3-nitrile ethyl benzophenone and mineral alkali is 1: 2.0～3.0, and the quality consumption of described reaction solvent is 5～20 times suc as formula the 3-nitrile ethyl benzophenone quality shown in (II); Described mineral alkali is potassium hydroxide or sodium hydroxide; Described alcohols reaction solvent is following one or more mixing in any proportion: methyl alcohol, ethanol, Virahol, propyl carbinol, described recrystallization solvent are following one or more mixing in any proportion: water, acetone, methyl alcohol or ethanol.
The present invention compares with original technology, and beneficial effect is embodied in:
1. reaction yield high (basically all more than 90%)
2. reaction conditions is gentle, and the reaction times is shorter, and the traditional technology reaction times is 8-10 hour, and the time is long, and energy consumption is large.
3. selectivity is good, substantially without condensation by-product.Contain the addition condensation product of active methylene group and carbonyl in the existing conventional process product, need to remove with chlorobenzene, this technique does not need with the unfriendly solvent of the environment such as chlorobenzene.
(4) embodiment
The invention will be further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
With 23.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 200ml methyl alcohol, pour there-necked flask into, pass into HCl gas, normal-temperature reaction 1.5 hours, TLC followed the tracks of reaction, and the i.e. reaction that disappears of raw material point finishes to add 8g (0.2mol) NaOH and 100ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with 1mol/L hydrochloric acid adjust pH to 3.5, separates out solid.Filter paper filtering, filter cake is put into oven drying, crude product methyl alcohol (300mL) recrystallization, filter paper filtering, filter cake is put into oven drying, gets Ketoprofen sterling 22.8g, is white crystal, 95～96 ℃ of fusing points, yield 90%.
Embodiment 2
With 2 3.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 100ml methyl alcohol, pour there-necked flask into, pass into HCl gas, normal-temperature reaction 2 hours, reaction finished to add 12g (0.3mol) NaOH and 100ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with about hydrochloric acid adjust pH to 3.5, separates out solid.Filter paper filtering, drying, filter cake methyl alcohol (300mL) recrystallization, filter paper filtering, filter cake is put into oven drying, gets Ketoprofen sterling 23.6g, is white crystal, 95～96 ℃ of fusing points, yield 93%.
Embodiment 3
With 23.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 100ml methyl alcohol, pour there-necked flask into, pass into HCl gas, normal-temperature reaction 1.5 hours, reaction finished to add 11.2g (0.2mol) KOH and 50ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with about hydrochloric acid adjust pH to 3.5, separates out solid.Filter, drying, filter cake filters with methyl alcohol (300mL) recrystallization, and filter cake is put into oven drying, gets Ketoprofen sterling 24.1g, is white crystal, 95～96 ℃ of fusing points, yield 95%.
Embodiment 4
With 23.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 200ml methyl alcohol, pour there-necked flask into, pass into HCl gas, normal-temperature reaction 2 hours, reaction finished to add 16.8g (0.3mol) KOH and 100ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with about hydrochloric acid adjust pH to 3.5, separates out solid.Filter, drying, filter cake filters with methyl alcohol (300mL) recrystallization, and filter cake is put into oven drying, gets Ketoprofen sterling 24.8g, is white crystal, 95～96 ℃ of fusing points, yield 98%.
Embodiment 5
With 23.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 50ml methyl alcohol, pour there-necked flask into, pass into HCl gas, normal-temperature reaction 2 hours, reaction finished to add 11.2g (0.2mol) KOH and 50ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with about hydrochloric acid adjust pH to 3.5, separates out solid.Filter, drying, filter cake filters with methyl alcohol (300mL) recrystallization, and filter cake is put into oven drying, gets Ketoprofen sterling 24.1g, is white crystal, 95～96 ℃ of fusing points, yield 95%.
Embodiment 6
With 23.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 200ml methyl alcohol, pour there-necked flask into, pass into HCl gas,-10 ℃ of lower reactions 1.5 hours, reaction finished to add 11.2g (0.2mol) KOH and 100ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with about hydrochloric acid adjust pH to 3.5, separates out solid.Filter, drying, filter cake filters with methyl alcohol (300mL) recrystallization, and filter cake is put into oven drying, gets Ketoprofen sterling 23.1g, is white crystal, 95～96 ℃ of fusing points, yield 91%.
Embodiment 7
With 23.5g (0.1mol) 3-nitrile ethyl benzophenone, be dissolved in 100ml methyl alcohol, pour there-necked flask into, pass into HCl gas, 50 ℃ of lower reactions 1.5 hours, reaction finished to add 11.2g (0.2mol) KOH and 100ml water in reaction solution, 70 ℃ of back flow reaction 2 hours.Reaction solution is cooled to room temperature, with about hydrochloric acid adjust pH to 3.5, separates out solid.Filter, drying, filter cake filters with methyl alcohol (300mL) recrystallization, and filter cake is put into oven drying, gets Ketoprofen sterling 24.8g, is white crystal, 95～96 ℃ of fusing points, yield 98%.
Embodiment 8
Reaction solvent changes 200ml ethanol into, and other operations and reaction conditions get Ketoprofen sterling 24.6g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 97%.
Embodiment 9
Reaction solvent changes 200ml n-propyl alcohol and 50ml ethylene glycol into, and other operations and reaction conditions get Ketoprofen sterling 24.8g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 98%.
Embodiment 10
Reaction solvent changes 200ml Virahol and 50ml ethylene glycol into, and other operations and reaction conditions get Ketoprofen sterling 24.6g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 97%.
Embodiment 11
Reaction solvent changes 200ml propyl carbinol and 50ml ethylene glycol into, and other operations and reaction conditions get Ketoprofen sterling 24.1g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 95%.
Embodiment 12
Reaction solvent changes 200ml isopropylcarbinol and 50ml ethylene glycol into, and other operations and reaction conditions get Ketoprofen sterling 24.6g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 97%.
Embodiment 13
Reaction solvent changes 1000ml ethylene glycol into, and other operations and reaction conditions get Ketoprofen sterling 24.1g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 95%.
Embodiment 14
Reaction solvent changes the 1000ml glycerol into, and other operations and reaction conditions get Ketoprofen sterling 23.6g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 93%.
Embodiment 15
Recrystallization solvent is changed to ethanol, and consumption is 500mL, and other operation and reaction conditions get Ketoprofen sterling 23.8g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 94%.
Embodiment 16
Recrystallization solvent is changed to acetone, and consumption is 100mL, and other operates together and reaction conditions embodiment 4, gets Ketoprofen sterling 24.6g, is white crystal, 95～96 ℃ of fusing points, yield 97%.
Embodiment 17
Recrystallization solvent is changed to acetone (100mL) and water (50mL), and other operation and reaction conditions get Ketoprofen sterling 24.6g with embodiment 4, are white crystal, 95～96 ℃ of fusing points, yield 97%.
Comparative Examples 1
In with the 1000mL there-necked flask of thermometer, reflux condensing tube, agitator, add 23.5g (0.1mol) 3-nitrile ethyl benzophenone, 4.0g (0.1mol) sodium hydroxide, 100mL water and 200mL methyl alcohol, heating reflux reaction 2 hours, reaction solution is cooled to room temperature, with hydrochloric acid adjust pH to 3.5, separate out solid.Filter, drying, filter cake filters with methyl alcohol (300mL) recrystallization, and filter cake is put into oven drying, gets Ketoprofen sterling 13.4g, is white crystal, 93～95 ℃ of fusing points, yield 53%.
Comparative Examples 2
Reflux time is 8 hours, and other operates with Comparative Examples 1, gets Ketoprofen sterling 18.0g, is white crystal, 95～96 ℃ of fusing points, yield 71%.
Comparative Examples 3
Reaction solvent is changed to water 200mL, propyl carbinol 200mL and ethylene glycol 100ml, and reflux time is 2 hours, and other operates with Comparative Examples 1, gets Ketoprofen sterling 12.7g, is white crystal, 93～95 ℃ of fusing points, yield 50%.
Comparative Examples 4
Reaction solvent is changed to water 200mL, propyl carbinol 200mL and ethylene glycol 100ml, and reflux time is 8 hours, and other operates with Comparative Examples 1, gets Ketoprofen sterling 19.0g, is white crystal, 93～95 ℃ of fusing points, yield 75%.
Comparative Examples 5
Use acetone 200ml recrystallization instead, other operate with Comparative Examples 1, get Ketoprofen sterling 14.7g, are white crystal, 93～95 ℃ of fusing points, yield 58%.
Claims (9)
1. the synthetic method of the Ketoprofen shown in the formula (I), it is characterized in that described method is: suc as formula the 3-nitrile ethyl benzophenone shown in (II) in the alcohols reaction solvent and the hydrogen chloride gas precursor reactant of capacity, generation is suc as formula intermediate shown in (III), the aqueous solution that adds 0.1～10mol/L mineral alkali after reaction the finishes reaction that is hydrolyzed, the temperature of hydrolysis reaction is 60～100 ℃, be hydrolyzed complete, adjust pH to 3 after the acid adding～4, reaction solution separating treatment obtain suc as formula the Ketoprofen shown in (I); Described mineral alkali is potassium hydroxide or sodium hydroxide; The molar ratio of described 3-nitrile ethyl benzophenone and mineral alkali is 1: 1.0～6.0;
2. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that described alcohols reaction solvent is following one or more mixing in any proportion: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol or glycerol.
3. the synthetic method of Ketoprofen as claimed in claim 1, the quality consumption that it is characterized in that described alcohols reaction solvent is 1～100 times of 3-nitrile ethyl benzophenone quality.
4. the synthetic method of Ketoprofen as claimed in claim 1, the time that it is characterized in that described hydrolysis reaction is 0.1～10 hour.
5. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that the temperature of described 3-nitrile ethyl benzophenone and hcl reaction is-20～100 ℃.
6. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that the temperature of described 3-nitrile ethyl benzophenone and hcl reaction is room temperature.
7. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that described reaction solution method for separating and processing is: reacting liquid filtering, and filter cake obtains Ketoprofen through the recrystallization solvent recrystallization; Described recrystallization solvent is following one or more mixing in any proportion: water, acetone, methyl alcohol or ethanol.
8. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that hydrolysis reaction is complete, transfers pH to 3～4 with hydrochloric acid, sulfuric acid, phosphoric acid or aqueous acetic acid.
9. the synthetic method of synthesizing ketoprofen as claimed in claim 1, it is characterized in that described method carries out in accordance with the following steps: will be dissolved in alcoholic solvent suc as formula the 3-nitrile ethyl benzophenone shown in (II), pass into capacity HCl gas under the room temperature, TLC follows the tracks of reaction, raw material point disappear namely react complete after, the aqueous solution that adds 1～4mol/L mineral alkali, be heated to 60～100 ℃ of hydrolysis reaction, reacted 0.5～2 hour, TLC follows the tracks of reaction, and raw material point disappears after the i.e. reaction end, reaction solution is cooled to room temperature, with salt acid for adjusting pH value to 3～4, filter, filter cake obtains Ketoprofen through the recrystallization solvent recrystallization; The throwing molar ratio of described 3-nitrile ethyl benzophenone and mineral alkali is 1: 2.0～3.0, and the quality consumption of described reaction solvent is 5～20 times suc as formula the 3-nitrile ethyl benzophenone quality shown in (II); Described mineral alkali is potassium hydroxide or sodium hydroxide; Described alcohols reaction solvent is following one or more mixing in any proportion: methyl alcohol, ethanol, Virahol, propyl carbinol, described recrystallization solvent are following one or more mixing in any proportion: water, acetone, methyl alcohol or ethanol.
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| CN 200910154414 CN101759556B (en) | 2009-10-23 | 2009-10-23 | Synthesis method of ketoprofen |
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| CN101759556B true CN101759556B (en) | 2013-03-27 |
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