CN1212254A - Method for preparing naproxen of methyl ester and S-(+) naproxen of methyl ester by using carbonylation - Google Patents
Method for preparing naproxen of methyl ester and S-(+) naproxen of methyl ester by using carbonylation Download PDFInfo
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- CN1212254A CN1212254A CN 97115892 CN97115892A CN1212254A CN 1212254 A CN1212254 A CN 1212254A CN 97115892 CN97115892 CN 97115892 CN 97115892 A CN97115892 A CN 97115892A CN 1212254 A CN1212254 A CN 1212254A
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- methyl ester
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Abstract
The method for synthesizing naproxen methyl ester and S-(+) naproxen methyl ester by homogeneous catalystic carbonylation of 1-(6'-methoxynaphthalene) ethyl alcohol is characterized by that it uses palladium-copper-phosphine-acid to prepare catalyst system in situ, and makes 1-(6'-methoxynaphthalene) ethyl alcohol react with carbon monoxide and methyl alcohol to obtain the naproxen methyl ester whose rate of production is approaching to 100% and selectivity also is approaching to 100%, and substitutes triphenyl phosphine with chiral phosphine ligand, and can obtain the naproxen methyl ester with optical activity, and hydrolyzes the naproxen methyl ester so as to can obtain the naproxen without corrosion to reactor.
Description
The invention discloses the method for a kind of 1-(6 '-methoxynaphthalene) ethanol by homogeneous catalytic reaction and carbon monoxide and methyl alcohol or synthetic Naproxen methyl ester of ethanol synthesis and S-(+) Naproxen methyl ester.
Arylpropionic acid is very important analgesia anti-inflammation medicine, as Naproxen Base, and cloth Lip river phenol and ketone Lip river phenol etc.Usually synthetic this compounds needs long synthetic route, and for example eight steps of synthetic need of Naproxen Base just can finish, and use carbonylation method can shorten synthetic route greatly, the productive rate height.
The Hoechst Celanese Corp of the U.S. in 1988 has applied for the patent CN88102150A of a preparation Ibuprofen BP/EP in China.They utilize Pd (PPh
3)
2Cl
2/ HCl system is 70～175 ℃ and reaction pressure 4.0～20.0MPa in temperature of reaction, and under the existence of acidic medium, the reaction of catalysis 1-(4 '-Isobuytel Benzene) ethyl alcohol carbonylation has obtained 97% transformation efficiency, and the selectivity of Ibuprofen BP/EP is 89.0%.1984, the people such as military Tian Zhen of Japan reported also in day disclosure special permission communique (clear 59-59239) that with this type of catalyst system to 1-(6 '-methoxynaphthalene) ethyl alcohol carbonylation prepared in reaction Naproxen Base, its Naproxen Base yield can reach 90%.But above all these oxonations all need halogen promotor, and in the medium of hydrochloric acid or phosphoric acid, carry out, so must in oxonation, cause equipment corrosion, and the complex compound of catalyst component Pd is reduced into palladium black and causes catalyzer to lose activity.
The object of the present invention is to provide a kind of carbonyl process to prepare the method for Naproxen methyl ester and S-(+) Naproxen methyl ester, avoided corrosion, be unlikely to make catalyst deactivation again carbonylation reaction equipment.
Purpose of the present invention can realize that its reaction formula is as follows by following measure:
The present invention utilizes palladium, copper, and organic phosphine and acid original position synthetic coordination catalyst under carbon monoxide atmosphere make 1-(6 '-methoxynaphthalene) ethanol and carbon monoxide and alcohol that carbonylation reaction take place.This reaction is earlier in the presence of tosic acid, 1-(6 '-methoxynaphthalene) ethanol at first dewaters and generates 6-methoxynaphthalene ethene, 6-methoxynaphthalene ethene carries out carbonylation reaction and generates Naproxen methyl ester in the presence of palladium-copper-organic phosphine catalyst system then.If as part, then generated racemic Naproxen methyl ester with triphenylphosphine; If as part, then generated optically active Naproxen methyl ester with the chirality phosphine.
A kind of by 1-(6 '-methoxynaphthalene) ethanol preparation Naproxen methyl ester and the method that the optical activity Naproxen methyl ester is arranged, be with 1-(6 '-methoxynaphthalene) ethanol, carbon monoxide, methyl alcohol are reaction raw materials, the catalyst system made from bimetal Pd-Cu and organic phosphine and sour original position; The solvent of reaction generally has benzene, toluene, and 1, the 4-dioxane, glycol dimethyl ether, tetrahydrofuran (THF), methyl-phenoxide, methyl ethyl ketone, wherein with 1,4-dioxane, glycol dimethyl ether are solvent the best.Reaction pressure is 2.0～20.0MPa, but is best in the scope of 5.0～8.0MPa.Temperature of reaction is 50～200 ℃, and optimal reaction temperature is 90～110 ℃.Reaction times was generally 24～72 hours.
In above-mentioned catalyst system, used palladium compound generally is a Palladous chloride, also can use palladium, ethanoyl two Bians fork acetone palladium, palladium-carbon (Pd/C), Palladous nitrate etc.; The volumetric molar concentration of used Pd compound is 0.005～0.03mol/l, and best volumetric molar concentration is 0.010～0.016mol/l.
In above-mentioned catalyst system, used copper auxiliary agent generally be cupric chloride, the band crystal water cupric chloride, its consumption in the scope of [Cu]/[Pd]=1.0～5.0 (mol ratio), is the best with [Cu]/[Pd]=1.8～2.8 (mol ratio) wherein generally.
Above-mentioned phosphine part can be a triphenylphosphine, tributylphosphine, and other some biphosphine ligand; The phosphine part also is can be chiral phosphine ligand, three kinds of chiral phosphine ligands described as follows:
In these three kinds of phosphine parts, 1,4:3, the two dehydrations-2 of 6-, ((DDPPI) synthetic method is seen document J.Organomet.Chem., 1983,253:249 to 5-two (diphenylphosphine)-L-idose, with 1,4:3, the two dehydration-2-of 6-see document Chin.Chem.Lett., 1996 to the synthetic method of tosylate-5-diphenylphosphine-L-iditol (DDPSI), 7:2, the third part is the commercially available prod.Wherein with DDPPI during as chiral ligand, enantio-selectivity the best of product.The consumption of phosphine part and chiral phosphine ligand is generally [P]/[Pd]=2.0～10.0 (mol ratio), is the best with [P]/[Pd]=4.0～8.0 (mol ratio) wherein.
In the above-mentioned catalyst system, used acid is the strong oxygen protonic acid that contains, as tosic acid, and trifluoromethyl acetic acid, trifluoromethane sulfonic acids etc. are good with tosic acid wherein.Wherein Suan consumption is in the scope of [p-Ts]/[Pd]=2.0～30.0 (mol ratio), is the best with [p-Ts]/[Pd]=9.9～13.1.
Present method compared with prior art has following characteristics: 1, use tosic acid and without hydrochloric acid, not etching reactor.2, the productive rate height of Naproxen methyl ester is near 100%.3, reaction pressure is low, only needs 5.0～7.0MPa.4, catalyzer can recycle.
The present invention can implement by following examples of implementation:
Example 1～8 is seen in the preparation of racemic Naproxen Base
Example 1, be 1.6cm, high solvent 1 for adding 6.0ml in the high pressure stainless steel reactor (25ml) of 13.5cm at internal diameter, the 4-dioxane, 15.0mg Palladous chloride (0.08mmol), 130.0mg triphenylphosphine (0.50mmol), 25.0mg cupric chloride (0.185mmol), the tosic acid of 113.4mg (0.60mmol), the 1-of 0.8g (6 '-methoxynaphthalene) ethanol, behind the methyl alcohol of 0.5ml, closed reactor.In the Schlenk vacuum line, with CO gas reaction system is replaced three times under the room temperature, charge into CO, pressure rises to 6.0MPa, closed reactor.Reactor is put into the water leak test, reactor is not put on the reaction unit of band stirring after not leaking, under 100 ℃, kept constant temperature 24 hours.After reaction finishes, the record pressure drop, cooling reactor is to room temperature, and the remaining gas of emptying is opened reactor, takes out reaction solution and analyzes with gas chromatograph.Except generating Naproxen methyl ester, also have two by products in this reaction, one is 6-methoxynaphthalene ethene, and another is 1-(6 '-methoxynaphthalene) ethyl-methyl ether.The yield of Naproxen methyl ester is 66.7% in the product, and the yield of 6-methoxynaphthalene ethene is 15.4%, and the yield of 1-(6 '-methoxynaphthalene) ethyl-methyl ether is 17.9%.All reaction product identify that with HP5988A chromatograph-mas spectrometer (hewlette-packard product) it is that molecular weight is 244 that the mass spectrum of Naproxen methyl ester provides its molecular ion peak, and all contains following main fragment peak: 185,141,115,59; The molecular ion peak that contains 6 '-methoxynaphthalene ethane in raw material 1-(6 '-methoxynaphthalene) ethanol is that molecular weight is 216, and main fragment peak has: 201,185,170,141,115,89,63,43; The molecular ion peak of 6-methoxynaphthalene ethene is that molecular weight is 184, and main fragment peak has: 169,152,141,115,102,89,63,51.
Example 2, catalyzer and raw material consumption are with example 1, but the amount of tosic acid is 200.0g (1.05mmol).After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
Example 3, catalyzer and raw material consumption are with example 1, but the used solvent of this catalyzed reaction is a phenmethyl ether.After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
Example 4, catalyzer and raw material consumption are with example 1, but the used solvent of this catalyzed reaction is the 1 dme.After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
Example 5, catalyzer and raw material consumption are with example 1, but the used solvent of this catalyzed reaction is a toluene.After reaction finished, the productive rate of Naproxen methyl ester was 86.8%, and the yield of 1-(6 '-methoxynaphthalene) ethyl-methyl ether is 13.2%.
Example 6, catalyzer and raw material consumption are with example 1, but the used solvent of this catalyzed reaction is a tetrahydrofuran (THF).After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate of Naproxen methyl ester is 65.5%, and the yield of 6-methoxynaphthalene ethene is 23.3%, and the yield of 1-(6 '-methoxynaphthalene) ethyl-methyl ether is 11.2%.
Example 7, promotor and raw material consumption are with example 2, but used palladium compound is Pd/C in this catalyzed reaction.Analytical results shows that the yield of Naproxen methyl ester is 69.1%, and the yield of 6-methoxynaphthalene ethene is 12.6%.
Example 8, promotor and raw material consumption are with example 2, but used palladium compound is a palladium in this catalyzed reaction.Analytical results shows that the yield of Naproxen methyl ester is 85.0%, and the yield of 6-methoxynaphthalene ethene is 7.6%, and the yield of 1-(6 '-methoxynaphthalene) ethyl-methyl ether is 3.1.
Example 9, promotor and raw material consumption are with example 2, but used palladium compound is ethanoyl two a Bians fork acetone palladium in this catalyzed reaction.Analytical results shows that the yield of Naproxen methyl ester is 95.0%, and the yield of 6-methoxynaphthalene ethene is 5.0%.
Example 10, catalyzer and raw material consumption are with example 2, but this catalyzed reaction is to carry out under 110 ℃ temperature of reaction.After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
Example 11, catalyzer and raw material consumption are with example 2, but this catalyzed reaction is to carry out under 90 ℃ temperature of reaction.After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
Example 12, catalyzer and raw material consumption are with example 2, but this catalyzed reaction is to carry out under the carbon monoxide pressure of 5.0MPa.After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
Example 13, catalyzer and raw material consumption are with example 2, but this catalyzed reaction is to carry out under the carbon monoxide pressure of 7.0MPa.After reaction finished, 1-(6 '-methoxynaphthalene) ethanol all changed into the product Naproxen methyl ester, and the productive rate that is to say Naproxen methyl ester is near 100%.
The preparation method of S-(+) Naproxen methyl ester sees example 14～17
Example 14, be 1.6cm, high solvent 1 for adding 6.0ml in the high pressure stainless steel reactor (25ml) of 13.5cm at internal diameter, the 4-dioxane, 15.0mg Palladous chloride (0.08mmol), 120.6mg DDPPI (0.25mmol), 25.0mg cupric chloride (0.185mmol), the tosic acid of 113.4mg (0.60mmol), the 1-of 0.8g (6 '-methoxynaphthalene) ethanol, behind the methyl alcohol of 1.0ml, closed reactor.In the Schlenk vacuum line, with CO gas reaction system is replaced three times under the room temperature, charge into CO, pressure rises to 6.0MPa, closed reactor.Reactor is put into the water leak test, reactor is not put on the reaction unit of band stirring after not leaking, under 100 ℃, kept constant temperature 24 hours.After reaction finishes, the record pressure drop, cooling reactor is to room temperature, and the remaining gas of emptying is opened reactor, takes out reaction solution and analyzes with gas chromatograph.The yield of Naproxen methyl ester is 80.2% in the product, 3-(6 '-methoxynaphthalene) propionic acid 9.2%, and the yield of 6-methoxynaphthalene ethene is 3.3%.Optical yields is the high pressure liquid chromatograph analysis with U.S. Water company, chirality packed column Mierocrystalline cellulose-three (3,5-3,5-dimethylphenyl carbamate) coating-type chiral column, 150 * 4.6I.D.mm, 6 μ m, moving phase normal hexane: Virahol=99: 1 (V/V).The optical yield of Naproxen methyl ester is 7.7%.
Example 15, catalyzer and raw material consumption are with example 9, but the content of used chiral ligand DDPPI is 60.3mg (0.11mmol) in this catalyzed reaction.Analytical results shows that the yield of Naproxen methyl ester is 25.6% in the product, and the yield of 6-methoxynaphthalene ethene is 22.2%, and the yield of 1-(6 '-methoxynaphthalene) ethyl-methyl ether is 49.3%.The optical yield of Naproxen methyl ester is 42.5%.
Example 16, catalyzer and raw material consumption are with example 9, but the content of used chiral ligand DDPPI is 181.0mg (0.36mmol) in this catalyzed reaction.Analytical results shows that the yield of Naproxen methyl ester is 71.2% in the product, 3-(6 '-methoxynaphthalene) propionic acid 11.2%, and the yield of 6-methoxynaphthalene ethene is 13.7%, the yield of 1-(6 '-methoxynaphthalene) ethyl-methyl ether is 1.9%.The optical yield of Naproxen methyl ester is 15.9%.
Example 17, catalyzer and raw material consumption are with example 9, but used solvent is tetrahydrofuran (THF) 6.0ml in this catalyzed reaction.Analytical results shows that the yield of Naproxen methyl ester is 63.5% in the product, 3-(6 '-methoxynaphthalene) propionic acid 16.4%, and the yield of 6-methoxynaphthalene ethene is 20.2%.The optical yield of Naproxen methyl ester is 15.8%.
Claims (5)
1, a kind of by 1-(6 '-methoxynaphthalene) ethanol, carbon monoxide, alcohol prepare Naproxen methyl ester for reaction raw materials and the method for optical activity Naproxen methyl ester are arranged, and it is characterized in that:
1) makes catalyst system with palladium-copper-phosphine-sour original position;
2) Fan Ying solvent is a benzene, toluene, 1,4-dioxane, glycol dimethyl ether, tetrahydrofuran (THF), methyl-phenoxide, methyl ethyl ketone;
3) reaction pressure is 2.0～20.0MPa, and temperature of reaction is 50～200 ℃, and the reaction times is 24～48 hours.
2, method according to claim 1 is characterized in that used palladium compound is a Palladous chloride, palladium, ethanoyl two Bians fork acetone palladium, Pd/C, Palladous nitrate; The volumetric molar concentration of used Pd compound is 0.005～0.03mol/l.
3, method according to claim 1 is characterized in that used copper auxiliary agent is a cupric chloride, or the cupric chloride of band crystal water, and its consumption is in [Cu]/[Pd]=1.0～5.0 (mol ratio).
4, method according to claim 1 is characterized in that above-mentioned phosphine part can be a triphenylphosphine, tributylphosphine, and three kinds of following chiral phosphine ligands:
The consumption of phosphine part and chiral phosphine ligand is [P]/[Pd]=2.0～10.0 (mol ratio).
5, method according to claim 1 is characterized in that used acid is tosic acid, and wherein Suan consumption is in the scope of [p-Ts]/[Pd]=2.0～30.0 (mol ratio).
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1086422C (en) * | 1999-12-18 | 2002-06-19 | 中国科学院兰州化学物理研究所 | Method for preparation of S-(+)-naprosyn by enzyme catalysis of asymmetrical hydrolysis reaction |
| WO2005011863A1 (en) * | 2003-08-05 | 2005-02-10 | Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences | A chiral ligand metalcomplex catalyst system and its preparation and applications |
| CN101486643B (en) * | 2009-02-24 | 2012-08-15 | 湖南大学 | Trans naproxen ester, optical isomer thereof, as well as preparation and use thereof |
| CN110078618A (en) * | 2019-05-10 | 2019-08-02 | 常州大学 | A kind of method that asymmetry catalysis method prepares s- (+) naproxen methylester |
| CN115353448A (en) * | 2022-08-18 | 2022-11-18 | 浙江新和成股份有限公司 | Ibuprofen synthesis method, catalytic system and application thereof |
-
1997
- 1997-09-25 CN CN 97115892 patent/CN1212254A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1086422C (en) * | 1999-12-18 | 2002-06-19 | 中国科学院兰州化学物理研究所 | Method for preparation of S-(+)-naprosyn by enzyme catalysis of asymmetrical hydrolysis reaction |
| WO2005011863A1 (en) * | 2003-08-05 | 2005-02-10 | Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences | A chiral ligand metalcomplex catalyst system and its preparation and applications |
| CN101486643B (en) * | 2009-02-24 | 2012-08-15 | 湖南大学 | Trans naproxen ester, optical isomer thereof, as well as preparation and use thereof |
| CN110078618A (en) * | 2019-05-10 | 2019-08-02 | 常州大学 | A kind of method that asymmetry catalysis method prepares s- (+) naproxen methylester |
| CN115353448A (en) * | 2022-08-18 | 2022-11-18 | 浙江新和成股份有限公司 | Ibuprofen synthesis method, catalytic system and application thereof |
| CN115353448B (en) * | 2022-08-18 | 2023-07-21 | 浙江新和成股份有限公司 | Synthesis method of ibuprofen, catalytic system and application of catalytic system |
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