CN108440374B - Preparation method of acemetacin - Google Patents
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- CN108440374B CN108440374B CN201810492301.9A CN201810492301A CN108440374B CN 108440374 B CN108440374 B CN 108440374B CN 201810492301 A CN201810492301 A CN 201810492301A CN 108440374 B CN108440374 B CN 108440374B
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- C07—ORGANIC CHEMISTRY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
- C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
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Abstract
The invention discloses a method for synthesizing acemetacin, which comprises the following steps: A. preparation of acemetacin benzyl ester according to patent US 4600783; B. dissolving acemetacin benzyl ester in solvent: the solvent is one of acetonitrile, toluene or dichloromethane, and benzyl positive ion scavenger is added: the scavenger is one of anisole, phenol or N, N-dimethylaniline to obtain a solution A; C. adding aluminum chloride into the solvent, adding the prepared solution A at zero temperature, and stirring at normal temperature; D. after the reaction is finished, pouring the reaction mixture into ice water, stirring and filtering to obtain crude acemetacin; E. the crude acemetacin obtained was purified by mixing with acetone and water: recrystallizing at a volume ratio of 2:1, and drying in vacuum to obtain pure acemetacin. The method is easy to implement, simple and convenient to operate, the price of the aluminum chloride is low, the aluminum chloride is suitable for large-scale preparation, dechlorination byproducts are not generated, and the purity of the product acemetacin reaches and is more than 99.8 percent only by one-step simple recrystallization; no heavy metal residue occurs.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, relates to a preparation method of a non-steroidal anti-inflammatory drug, and more particularly relates to a preparation method of acemetacin.
Background
The product is a nonsteroidal anti-inflammatory analgesic, has the following structure, is a precursor drug of indomethacin, and can be metabolized in vivo after being taken orally to generate the indomethacin to play a role. The acemetacin which was first marketed in 1980 in the original Federal Germany was considered to be the best one in terms of enhancing the anti-inflammatory effect and improving the tolerability, and could significantly reduce the gastrointestinal side effects of indometacin. The preparation is successful in 1992 in China. The medicine has obvious anti-inflammatory effect and strong analgesic effect, and has no obvious influence on hematopoietic system and tissues and organs of the whole body after long-term application. The acemetacin has definite curative effect, less side effect and wide application prospect, and has larger market value along with the deepening of the formulation research and clinical research of the acemetacin.
Most of the methods for preparing acemetacin reported in the literature currently use indometacin as a starting material, prepare acemetacin ester with protecting groups such as tert-butyl, benzyl and pyranyl through esterification, and then remove the ester through hydrogenolysis or acidolysis to obtain the acemetacin. The synthesis of acemetacin benzyl ester by using indometacin as a starting material can generate dechlorination (chlorine on a p-chlorobenzoacetylbenzene ring is removed) in the process of removing benzyl by hydrogenolysis, so that the product is difficult to purify and the yield is reduced, and the specific reactions are shown as follows. The method solves the problem of reductive dechlorination and is the key for determining the quality of the product of the acemetacin prepared by the benzyl ester removing method.
Disclosure of Invention
The invention aims to provide a preparation method of non-steroidal anti-inflammatory drug acemetacin, which is easy to implement and simple and convenient to operate, and improves the existing synthesis method of acemetacin. In the existing method, acemetacin benzyl ester is synthesized by taking indometacin as a starting raw material, and then the benzyl is removed through palladium-carbon hydrogenation to prepare the acemetacin. This approach has two problems to solve: (1) when palladium carbon is subjected to hydrogenation debenzylation, chlorine atoms on benzene rings of p-chlorobenzoylamino are reduced, the chlorine atoms are removed, and a dechlorination byproduct is formed and affects the purity of a product, and meanwhile, the byproduct is difficult to remove through simple recrystallization; (2) the price of palladium carbon is high, which is not beneficial to large-scale industrial production. The invention adopts AlCl3The debenzylation can completely avoid the formation of dechlorination byproducts, the treatment after the reaction is simple, and the purity of the product can reach the requirements of European PHARMACOPOEIA (Eropean Pharmacopoeia 8.0) by one-time recrystallization. In addition, AlCl3The price is low, and the preparation method is suitable for large-scale preparation.
In order to achieve the purpose, the invention adopts the following technical measures:
a method for synthesizing acemetacin comprises the following steps:
the structural formula is as follows:
wherein: me is a methyl group, O is an oxygen atom, N is a nitrogen atom, Cl is a chlorine atom, OBn is a benzyloxy group, and OH is a hydroxyl group.
1. Preparation of acemetacin benzyl ester according to patent US4600783 (filed on 25/04 in 1985): sequentially adding indometacin and potassium carbonate into acetone, stirring for 30 minutes at 56 ℃, cooling to 40 ℃, adding benzyltriethylammonium chloride, dropwise adding benzyl chloroacetate, reacting for 6 hours at 40 ℃, cooling to room temperature, pouring the reaction mixture into ice water, filtering, washing and drying to obtain acemetacin benzyl ester.
2. Dissolving acemetacin benzyl ester in a solvent (the solvent is one of acetonitrile, toluene or dichloromethane), and adding a benzyl positive ion scavenger (the scavenger is one of anisole, phenol or N, N-dimethylaniline) to obtain a solution A;
in the step, the mass ratio of acemetacin benzyl ester to the solvent is 1: 5-10, and the molar mass ratio of acemetacin benzyl ester to the benzyl cation scavenger is 1: 4 to 10. The molar mass ratio of the benzyl cation scavenger to the acemetacin benzyl ester is 1: 4-10, this ratio is more critical. Due to AlCl3After removing benzyl on an ester group, a benzyl group becomes benzyl positive ions firstly, when the lowest equivalent ratio of a benzyl positive ion scavenger is 4, the benzyl positive ions cannot be effectively captured, and the benzyl positive ions are formed to participate in a friedel-crafts alkylation reaction (a reaction substrate can be unreacted raw material acemetacin benzyl ester or product acemetacin), and a specific reaction formula is shown as follows. When the molar mass ratio of the benzyl cation scavenger to the acemetacin benzyl ester is more than 8, the influence of continuously increasing the dosage of the benzyl cation scavenger on the reaction time and the reaction yield is small.
Wherein:me is a methyl group, O is an oxygen atom, N is a nitrogen atom, Cl is a chlorine atom, OBn is a benzyloxy group, OH is a hydroxyl group, Bn+Is formed by removing benzyl on ester group of acemetacin benzyl ester by aluminum chloride, and the benzyl exists in the form of benzyl cation after being removed.
3. Adding aluminum chloride (of the formula AlCl) to a solvent (acetonitrile, toluene or dichloromethane, the same solvent as used in step 2)3) Slowly adding the solution A prepared in the step (2) at zero (0-5 ℃), and stirring for 55-65 minutes at normal temperature (15-25 ℃); in the step, the temperature of the room temperature reaction is 15-25 ℃. In the step, acemetacin benzyl ester and AlCl are added3The feeding molar mass ratio of (A) to (B) is 1: 1.5-3. AlCl capable of completely de-esterifying acemetacin benzyl ester3The minimum molar ratio of (A) is 1.5, below which the reaction does not proceed to completion, see in particular example 10; increase AlCl3The amount of (A) can be reduced to shorten the reaction time, but the corresponding cost is also increased. It should be noted that the order of addition has a large influence on the reaction. The feeding sequence used in the invention is that the mixed solution of acemetacin benzyl ester and benzyl cation is dripped into AlCl3In solution, which helps the reaction proceed rapidly (AlCl)3Excess relative to acemetacin benzyl ester), and simple and safe reaction operation (AlCl)3Poor solubility in acetonitrile, dichloromethane or toluene, AlCl3The above solution of (2) is a suspension, and the transfer dropwise addition operation is difficult).
4. After the reaction was complete, the reaction mixture was poured into ice water, stirred for 28-32 minutes and filtered to give a pale yellow solid (crude acemetacin).
5. And (3) recrystallizing the crude acemetacin obtained in the step (4) by using acetone and water (the volume ratio is 2:1), and drying for 22-26 hours at the temperature of 78-82 ℃ in vacuum to obtain the pure acemetacin. In the step, the refining process is as follows: dissolving the crude product of acemetacin in acetone, adding activated carbon for decolorization after dissolution, filtering, adding water, crystallizing at room temperature (15-25 ℃) until the crystallization is complete, filtering and drying to obtain the finished product of acemetacin.
Compared with the prior patent technology, the invention has the following advantages and effects: by using cheap and easily-obtained reagent AlCl3The conversion of acemetacin benzyl ester to acemetacin is realized. The conversion of acemetacin benzyl ester to acemetacin reported in the literature at present is realized by a palladium-carbon hydrogenation method, and the method has three disadvantages: the existing palladium-carbon has higher price, a considerable amount of dechlorination byproducts are formed, and heavy metal residues easily appear in the product.
Detailed Description
The following examples illustrate the invention in detail: the present embodiment is implemented on the premise of the technical solution of the present invention, and detailed embodiments and processes are given, but the scope of the present invention is not limited to the following embodiments. The preparation method of the intermediate acemetacin benzyl ester used in the invention is reported in many documents, and a commercially available product can also be adopted, and the acemetacin benzyl ester adopted in the invention is prepared according to the method provided by the patent US 4600783.
Example 1:
a method for synthesizing acemetacin comprises the following steps:
A. preparation of acemetacin benzyl ester according to patent US4600783, the specific procedure is: 100g of indomethacin and 40g of potassium carbonate are added into 560mL of acetone, the temperature is raised to 56 ℃ for reaction for 30 minutes, the reaction mixture is cooled to 40 ℃, 2.0 g of benzyltriethylammonium chloride is added into the reaction mixture, 57.2g of benzyl chloroacetate is added dropwise, the reaction mixture is maintained at 40 ℃ for reaction for 6 hours, the reaction mixture is cooled to room temperature, the reaction mixture is poured into 1L of water, filtration is carried out, the filter cake is washed by 1L of water, and drying is carried out, so that 135.7g of acemetacin benzyl ester with the HPLC purity of 98% is obtained.
B. 100g (0.198mol) of acemetacin was dissolved in 400mL of methylene chloride, and 86mL of anisole was added to obtain solution A.
C. To 39.6g (0.297mol) AlCl3100mL of methylene chloride was added and solution A was added slowly at zero degrees (0 or-1 or-2 or-3 or-4 or-5).
D. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
E. And D, recrystallizing the crude acemetacin obtained in the step D by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at 78 or 79 or 80 or 81 or 82 ℃ in vacuum to obtain 76.8g of pure acemetacin with the yield of 93.4%. Melting point: 152-153 ℃.1H-NMR(DMSO-d6,400MHz)δ：13.09(brs,1H),7.66(m,4H),7.07(s,1H),6.94(d,J＝8.8Hz,1H),6.72(d,J＝8.8Hz,1H),4.62(s,2H),3.88(s,2H),3.77(s,3H),2.23(s,3H).13C-NMR(DMSO-d6100MHz) δ: 170.7,169.5,168.3.156.1,138.2,135.9,134.5,131.6,130.9,130.7,129.5,115.0,112.9,112.0,102.0,61.4,55.8,29.4,13.6. purity greater than 99.8% by HPLC, chromatography conditions-column: diamonsil 5 μm C18(2),250 × 4.6 mm; detection wavelength: 235 nm; flow rate: 1.0 mL/min.
Example 2:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of dichloromethane, and 86mL of anisole was added to obtain solution A.
B. To a feed of 79.2g (0.594mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude product acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at the temperature of 80 ℃ in vacuum to obtain 80.2g of pure product acemetacin with the yield of 97.6%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 3:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of acetonitrile, and 86mL of anisole was added to obtain solution A.
B. To 39.6g (0.297mol) AlCl3Adding 100mL of acetonitrile, and addingSolution a was added slowly.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at the temperature of 80 ℃ in vacuum to obtain 76.3g of pure acemetacin with the yield of 92.8%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 4:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of acetonitrile, and 86mL of anisole was added to obtain solution A.
B. To a feed of 79.2g (0.594mol) AlCl3To this was added 100mL of acetonitrile, and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at the temperature of 80 ℃ in vacuum to obtain 78.6g of pure acemetacin with the yield of 95.7%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 5:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 800mL of toluene, and 86mL of anisole was added to obtain solution A.
B. To 39.6g (0.297mol) AlCl3200mL of toluene was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at the temperature of 80 ℃ in vacuum to obtain 77.1g of pure acemetacin with the yield of 93.8%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 6:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 800mL of toluene, and 86mL of anisole was added to obtain solution A.
B. To a feed of 79.2g (0.594mol) AlCl3200mL of toluene was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at the temperature of 80 ℃ in vacuum to obtain 77.5g of pure acemetacin with the yield of 94.3%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 7:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of dichloromethane, and 215mL of anisole was added to obtain solution A.
B. To 39.6g (0.297mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at the temperature of 80 ℃ in vacuum to obtain 78.2g of pure acemetacin with the yield of 95.2%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 8:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of dichloromethane, and 100mL of N, N-dimethylaniline was added to obtain solution A.
B. To 39.6g (0.297mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude product acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), adding activated carbon for decoloring, and drying the obtained crystal at the temperature of 80 ℃ in vacuum for 24 hours to obtain 77.8g of pure acemetacin with the yield of 94.6%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 9:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of dichloromethane, and 100mL of N, N-dimethylaniline was added to obtain solution A.
B. To a feed of 79.2g (0.594mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude product acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), adding activated carbon for decoloring, and drying the obtained crystal at the temperature of 80 ℃ in vacuum for 24 hours to obtain 79.3g of pure acemetacin, wherein the yield is 96.5%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 10:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of dichloromethane, and 250mL of N, N-dimethylaniline was added to obtain solution A.
B. To a feed of 79.2g (0.594mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude product acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), adding activated carbon for decoloring, and drying the obtained crystal at the temperature of 80 ℃ in vacuum for 24 hours to obtain 80.4g of pure acemetacin with the yield of 97.8%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Example 11:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin benzyl ester was dissolved in 400mL of dichloromethane, and 86mL of anisole was added to obtain solution A.
B. 31.7g (0.238mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude product acemetacin obtained in the step C by using acetone and water (the volume ratio is 2:1), adding activated carbon for decoloring, and drying the obtained crystal at the temperature of 80 ℃ in vacuum for 24 hours to obtain 69.1g of pure acemetacin with the yield of 84.1%. Purity by HPLC 95%.
The other steps were the same as in example 1.
Example 12:
a method for synthesizing acemetacin comprises the following steps:
A. 100g (0.198mol) of acemetacin was dissolved in 400mL of methylene chloride, and 70mL of anisole was added to obtain solution A.
B. To 39.6g (0.297mol) AlCl3100mL of dichloromethane was added and solution A was added slowly at zero degrees.
C. After the addition, the temperature is raised to room temperature for reaction for 55 or 58 or 60 or 63 or 65 minutes, after the reaction is finished, the reaction mixture is poured into ice water, stirred for 28 or 29 or 30 or 31 or 32 minutes and then filtered, and crude acemetacin is obtained.
D. And D, recrystallizing the crude acemetacin obtained in the step D by using acetone and water (the volume ratio is 2:1), and drying for 24 hours at 78 or 79 or 80 or 81 or 82 ℃ in vacuum to obtain 74.3g of pure acemetacin with the yield of 90.4%. Purity greater than 99.8% by HPLC.
The other steps were the same as in example 1.
Claims (1)
1. A synthetic method of acemetacin is characterized by comprising the following steps:
A. sequentially adding indometacin and potassium carbonate into acetone, stirring for 30 minutes at 56 ℃, cooling to 40 ℃, adding benzyltriethylammonium chloride, dropwise adding benzyl chloroacetate, reacting for 6 hours at 40 ℃, cooling to room temperature, pouring the reaction mixture into ice water, filtering, washing and drying to obtain acemetacin benzyl ester;
B. dissolving acemetacin benzyl ester in a solvent, wherein the solvent is one of acetonitrile, toluene or dichloromethane, and adding a benzyl positive ion scavenger, and the scavenger is one of anisole or N, N-dimethylaniline, so as to obtain a solution A;
the mass ratio of the acemetacin benzyl ester to the solvent is 1: 5-10, and the molar mass ratio of the acemetacin benzyl ester to the benzyl cation scavenger is 1: 4-10;
C. adding aluminum chloride into the solvent, adding the solution A prepared in the step (B) at zero ℃, and stirring for 55-65 minutes at 15 ℃ -25 ℃;
the solvent is one of acetonitrile, toluene or dichloromethane;
the feeding molar mass ratio of acemetacin benzyl ester to aluminum chloride is 1: 1.5-3;
D. after the reaction is finished, pouring the reaction mixture into ice water, stirring for 28-32 minutes, and filtering to obtain crude acemetacin;
E. dissolving the crude acemetacin obtained in the step (D) in acetone, adding activated carbon for decolorization after dissolution, filtering, adding water, crystallizing at room temperature until the crystallization is complete, filtering, and performing vacuum drying at 78-82 ℃ for 22-26 hours to obtain a finished product of the acemetacin, wherein the volume ratio of acetone to water is 2: 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4600783A (en) * | 1984-05-08 | 1986-07-15 | Bayer Aktiengesellschaft | Process for preparing acemetacin |
| CN102079691A (en) * | 2009-11-28 | 2011-06-01 | 湖北民族学院 | Method for synthesizing trans-resveratrol by combining hydroxyl groups and protective groups |
| CN106316921A (en) * | 2016-08-19 | 2017-01-11 | 河南东泰制药有限公司 | Preparation method for acemetacin |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4600783A (en) * | 1984-05-08 | 1986-07-15 | Bayer Aktiengesellschaft | Process for preparing acemetacin |
| CN102079691A (en) * | 2009-11-28 | 2011-06-01 | 湖北民族学院 | Method for synthesizing trans-resveratrol by combining hydroxyl groups and protective groups |
| CN106316921A (en) * | 2016-08-19 | 2017-01-11 | 河南东泰制药有限公司 | Preparation method for acemetacin |
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