CN107759466B - Splitting method of (+/-) -2- (3-benzoyl) -phenylpropionic acid - Google Patents
Splitting method of (+/-) -2- (3-benzoyl) -phenylpropionic acid Download PDFInfo
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Abstract
The invention provides a splitting method of (+/-) -2- (3-benzoyl) -phenylpropionic acid, the method uses the (+/-) -2- (3-benzoyl) -phenylpropionic acid alkali salt as a raw material, taking the (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine acid salt as a resolving agent, reacting in the presence of solvent water to obtain diastereoisomer salt of S- (+) -2- (3-benzoyl) -phenyl propionic acid and (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine, namely resolving salt, and then dissociating the obtained resolving salt by acid to obtain S- (+) -2- (3-benzoyl) -phenylpropionic acid. The (+/-) -2- (3-benzoyl) -phenylpropionic acid resolution method provided by the invention does not need to use an organic solvent in the formation process of resolution salt, and uses water as a solvent. In addition, the amount of resolving agent used is reduced by nearly 50%. Therefore, the method is a more advantageous resolution process.
Description
Technical Field
The invention relates to a resolution method of a racemate compound, in particular to a resolution method of (+/-) -2- (3-benzoyl) -phenylpropionic acid.
Background
The (+/-) -2- (3-benzoyl) -phenylpropionic acid is an alpha-aryl propionic acid non-steroidal anti-inflammatory compound, has analgesic and anti-inflammatory effects, and has the common name in the field of medicaments: ketoprofen. Ketoprofen racemate is currently marketed and is clinically used for treating chronic rheumatoid arthritis, osteoarthritis, spondylitis, soft tissue injuries such as tendonitis and bursitis, trauma and postoperative pain. Racemic ketoprofen is potentially toxic to the gastrointestinal tract, liver, kidney, and reduces leukocytes. The structure-activity relationship of the medicine shows that S- (+) -ketoprofen (namely (S) - (+) -2- (3-benzoyl) -phenylpropionic acid, the structure is shown as formula I) has more obvious clinical effect and no toxic or side effect, and the synthesis research thereof, namely the splitting method of (+/-) -2- (3-benzoyl) -phenylpropionic acid, draws wide attention of people.
At present, the literature reporting the preparation of S- (+) -ketoprofen, i.e., (±) -2- (3-benzoyl) -phenylpropionic acid resolution method, is as follows:
s- (+) -ketoprofen was synthesized asymmetrically by Shapless (Charlesis) epoxidation and hydrogenolysis by David P.G Hamom et al (Tetrahedron asymmetry.1993,4,1435; Tetrahedron.1995,51,12645). The asymmetric synthesis method has the disadvantages of more reaction steps, low yield and higher cost, and is difficult to realize industrial production.
2. The patent literature reports enzymatic kinetic resolution of racemic ketoprofen with lipases (WO9304190, WO9325703, WO 9325704). The enzyme preparation is very expensive and has high production cost, so the enzyme preparation cannot be applied to industrial production.
3. In the literature "chemical reagents, 28 (5); 316-; 2006' where diastereomer crystallization resolution is performed using N-octyl-D-glucosamine as a resolving agent, the single-round resolution ratio is low, only 40%.
4. In Chinese patent CN1252035 (patent name: novel chiral amino acid derivative and its synthesis method and application, patentee: Wenzhou institute of academic and vocational study, grant issue date: 2006, 4, 19, months) the chiral amino acid derivative is used as a resolving agent to carry out inclusion resolution, the resolving agent is very complex and expensive, and the chiral purity value of S- (+) -ketoprofen obtained by resolution is not very high, and is 97% at most.
5. The documents "Organic Process Research & Development", 6(3), 291-; 2002 "the resolution reagent used in the chemical resolution method is (S) -3-methyl-2-phenylbutylamine, and although the resolution reagent is simple, the price is also very expensive and the source is not enough, and further cost reduction is needed.
6. European patent EP423467 (patent name: (. + -.) -2- (3-benzoyl) -phenylpropionic acid optical resolution method, patent applicant: NISSAN chemical industry Co., published: 4/24/1991) uses a resolving agent represented by the following formula 1 for resolution:
wherein R is1Hydrogen, chlorine, bromine, methyl or isopropyl, etc.; r2Represents lower alkyl, hydroxymethyl, alpha-hydroxyphenyl, or a group represented by formula 2:
wherein R is3Is hydrogen, chlorine, bromine or methyl.
The patent describes that the method has the following problems: the resolving agent is not easy to obtain, has higher price and uneven resolving effect.
7. Chinese patent 200910152629.7 discloses a very good resolving agent (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine, which can resolve ketoprofen with high yield and purity to obtain a product, but the amount of resolving agent used is large.
Therefore, it is necessary to further study the method for resolving ketoprofen, and find a more suitable resolving process.
Disclosure of Invention
The invention mainly aims to provide a more suitable ketoprofen resolution process which has more advantages. The method has the advantages that a small amount of resolving agent is used, an organic solvent is not needed in the formation process of the resolving salt, the method is green and environment-friendly, and the product can be obtained with high yield and purity after dissociation.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for splitting (+/-) -2- (3-benzoyl) -phenylpropionic acid is characterized in that a splitting reagent is used, and the splitting reagent is shown as a formula II:
the chemical name of the compound is: (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine (English name is (R) -3,4-dimethoxy-N- (1-phenylethyl) -Benzenemethanamine).
Further, the salt form of the resolving agent is used for resolution. The salt form of the resolving agent is acid salt of the resolving agent, and the acid is inorganic acid such as acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like. Preferably, acetic acid.
Further, the resolution substrate is a salt form of ketoprofen. The salt form of ketoprofen is an alkali salt of ketoprofen, and the base is an inorganic base or an organic base. The inorganic alkali is sodium hydroxide, potassium hydroxide, sodium carbonate and the like. The organic base is triethylamine. Preferably, the base is sodium hydroxide.
The method for splitting the (+/-) -2- (3-benzoyl) -phenylpropionic acid comprises the following reaction steps:
step 1
Step 2
The method uses the (+/-) -2- (3-benzoyl) -phenylpropionic acid alkali salt as a raw material, uses (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine acid salt (a compound shown in a formula II) as a resolving agent, and carries out reaction in the presence of solvent water to obtain a diastereomer salt of S- (+) -2- (3-benzoyl) -phenylpropionic acid and (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine, namely a resolving salt (a compound shown in a formula IV), and then uses acid to dissociate the obtained resolving salt to obtain the S- (+) -2- (3-benzoyl) -phenylpropionic acid.
The (+/-) -2- (3-benzoyl) -phenylpropionic acid alkali salt can be an organic alkali salt or an inorganic alkali salt of (+/-) -2- (3-benzoyl) -phenylpropionic acid. The (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine acid salt can be (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine inorganic acid salt such as sodium salt, potassium salt or triethylamine salt. Such as acetate, hydrochloride, sulfate or trifluoroacetate.
Preferably, the (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine acetate is used as a resolving agent to react with (+/-) -2- (3-benzoyl) -phenylpropionic acid sodium salt to prepare resolving salt, and then S- (+) -2- (3-benzoyl) -phenylpropionic acid, namely dextro ketoprofen, is prepared by acid dissociation.
The reaction solvent is water; the reaction temperature is 50-80 ℃, preferably 60-65 ℃.
Further, seeds of the resolving salt (compound of formula IV) may or may not be added to the reaction.
If the raw material (+/-) -2- (3-benzoyl) -phenylpropionic acid is added, the mass ratio of the raw material (+/-) -2- (3-benzoyl) -phenylpropionic acid to the resolution salt seed crystal is 1: 0.01 to 0.03.
Preferably, the starting material (±) -2- (3-benzoyl) -phenylpropionic acid: the feeding molar ratio of the resolving agent (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine is 1: (0.45-0.5).
Preferably, the acid used in the process of freeing the resolved salt is a strong inorganic acid; preferably sulfuric acid, hydrochloric acid or phosphoric acid.
Preferably, in freeing the resolved salt, the resolved salt: the feeding molar ratio of the acid is 1: (5-10).
According to the method for splitting ketoprofen provided by the invention, the resolving agent (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine acid salt is simple and easy to obtain and has a low price; the yield of the resolution route is high, the process is stable and reliable, the resolution purity is high (ee percent is more than or equal to 99.8 percent), the production cost is low, the production environment is basically free of pollution, and the industrial production is easy to realize. Most importantly, in the formation process of the resolution salt, an organic solvent is not needed, and water is used as a solvent. In addition, the amount of resolving agent used is reduced by nearly 50%. Therefore, the method is a more advantageous resolution process.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples.
Preparing a resolving agent: 3, 4-dimethoxybenzaldehyde reacts with alpha-phenylethylamine, and nickel is used as a catalyst to obtain a resolving agent (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine (hereinafter referred to as VEP).
Example 1
In a clean 250ml four-necked flask, 24g of VEP and 300ml of water were charged at room temperature, and 5.3g of glacial acetic acid was added with stirring to obtain a transparent liquid, i.e., a sodium salt of ketoprofen. And then 50g of ketoprofen and 300ml of drinking water are added into another 1000ml reaction bottle, 8g of sodium hydroxide are added in batches, and the temperature is increased to 60-62 ℃. The ketoprofen solution is clear and transparent, the temperature is kept for 10 to 30 minutes, and the internal temperature is controlled to be 60 to 62 ℃. Mixing VEP acetate and ketoprofen sodium salt, adding 1g of resolution salt (compound shown in formula IV) seed crystal, preserving heat for 2-3 hours after finishing dripping, carrying out hot filtration at 60-62 ℃, carrying out rinsing with 100ml/60 ℃ hot water, and carrying out pumping drying to obtain 110-130g of wet product (namely the compound shown in formula IV in the specification). Putting the obtained wet product resolving salt (the compound shown in the formula IV) into a clean 500ml reaction bottle, adding 10g of sodium bicarbonate and 500ml of water, stirring for 2-3h, filtering, pumping to dry to obtain a wet product, drying at 60 ℃ in vacuum to obtain a dry product of about 50.4g, and obtaining the yield of about 47%.
Example 2
In a clean 250ml four-necked flask, 24g of VEP and 300ml of water were charged at room temperature, and 5.3g of glacial acetic acid was added with stirring to obtain a transparent liquid, i.e., a sodium salt of ketoprofen. And then 50g of ketoprofen and 300ml of drinking water are added into another 1000ml reaction bottle, 8g of sodium hydroxide are added in batches, and the temperature is increased to 60-62 ℃. The ketoprofen solution is clear and transparent, the temperature is kept for 10 to 30 minutes, and the internal temperature is controlled to be 60 to 62 ℃. Mixing VEP acetate and ketoprofen sodium salt, dropwise adding 1/5, keeping the temperature for 10-30 minutes until the materials are separated out, keeping the temperature for 2-3 hours after the dropwise adding of the rest materials is finished, carrying out hot filtration at 60-62 ℃, carrying out rinsing with 100ml/60 ℃ hot water, and draining to obtain 110-130g of wet product (namely the compound shown in formula IV in the specification). Putting the obtained wet product resolving salt (the compound shown in the formula IV) into a clean 500ml reaction bottle, adding 10g of sodium bicarbonate and 500ml of water, stirring for 2-3h, filtering, pumping to dry to obtain a wet product, drying at 60 ℃ in vacuum to obtain a dry product of about 48g, and obtaining the yield of about 46.4%.
Example 3
Adding 12g of reagent hydrochloric acid and 400g of purified water into a clean 500ml reaction bottle, controlling the internal temperature to be 10-15 ℃, adding 50g of powder resolving salt (the compound shown in the formula IV) in batches, taking 10-30 minutes, and keeping the temperature for 30-60 minutes after the feeding is finished. Slowly heating to 30-35 ℃, preserving heat for 4-6 hours, measuring the pH value to be 1-3 during heat preservation, starting cooling to 20-25 ℃, preserving heat for 1-2 hours, filtering, pumping out, washing with 200g of purified water, pumping out, and drying a wet product in a vacuum oven at 50-60 ℃ until the wet product is dry. About 23.2g of dry product was obtained, yield: 98 percent. ee% ═ 99.9%.
In summary, the (+/-) -2- (3-benzoyl) -phenylpropionic acid resolution method provided by the invention does not need to use an organic solvent in the formation process of the resolution salt, and uses water as a solvent. In addition, the amount of resolving agent used is reduced by nearly 50%. Therefore, the method is a more advantageous resolution process.
It is noted that all documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that the above-described embodiments of the present invention and the technical principles applied thereto are described, and after reading the above-described contents of the present invention, those skilled in the art can make various changes or modifications to the present invention without departing from the spirit and scope of the present invention, and these equivalents also fall within the scope of the present invention.
Claims (10)
1. A method for splitting (+/-) -2- (3-benzoyl) -phenylpropionic acid is characterized by comprising the following steps:
step 1: reacting the (+/-) -2- (3-benzoyl) -phenylpropionic acid alkali salt with the compound (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine acid salt shown in the formula (II) in the presence of solvent water to prepare a compound shown in the formula (IV), and then dissociating the compound through acid to prepare S- (+) -2- (3-benzoyl) -phenylpropionic acid,
2. a method for splitting (+/-) -2- (3-benzoyl) -phenylpropionic acid is characterized in that (R) -3,4-dimethoxy-N- (1-phenethyl) -benzylamine acetate is used as a splitting agent to react with (+/-) -2- (3-benzoyl) -phenylpropionic acid sodium salt in the presence of solvent water to prepare splitting salt, and then S- (+) -2- (3-benzoyl) -phenylpropionic acid is prepared by acid dissociation,
3. the resolution method according to claim 1, characterized in that the alkali (±) -2- (3-benzoyl) -phenylpropionic acid salt is an organic alkali salt or an inorganic alkali salt of (±) -2- (3-benzoyl) -phenylpropionic acid.
4. The resolution process according to claim 1, characterized in that the (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine acid salt is (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine inorganic acid salt.
5. The resolution process according to claim 3, characterized in that the organic base is triethylamine; the inorganic alkali is sodium hydroxide, potassium hydroxide or sodium carbonate.
6. The resolution process according to claim 4, characterized in that the mineral acid is hydrochloric acid or sulfuric acid.
7. The resolution process according to claim 1, wherein the (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine acid salt is (R) -3,4-dimethoxy-N- (1-phenylethyl) -benzylamine trifluoroacetate salt.
8. The resolution process according to claim 1 or 2, characterized in that the compound of the resolved salt formula (IV) is seeded during the formation of the compound of the resolved salt formula (IV).
9. The resolution process according to claim 8, characterized in that the mass ratio of the starting material (±) -2- (3-benzoyl) -phenylpropionic acid to the resolving salt seed crystals is 1: 0.01 to 0.03.
10. The resolution process according to claim 1 or 2, characterized in that in the step of resolving the salt free, the acid is a strong inorganic acid.
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