CN108440374A - A kind of preparation method of acemetacin - Google Patents
A kind of preparation method of acemetacin Download PDFInfo
- Publication number
- CN108440374A CN108440374A CN201810492301.9A CN201810492301A CN108440374A CN 108440374 A CN108440374 A CN 108440374A CN 201810492301 A CN201810492301 A CN 201810492301A CN 108440374 A CN108440374 A CN 108440374A
- Authority
- CN
- China
- Prior art keywords
- acemetacin
- benzyl ester
- added
- solvent
- crude product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of acemetacin, step is：A, acemetacin benzyl ester is prepared according to patent US4600783；B, acemetacin benzyl ester is dissolved in solvent：Solvent is that acetonitrile, toluene or dichloromethane are one such, and benzylic cation scavenger is added：The scavenger is methyl phenyl ethers anisole, phenol or N, and N dimethylanilines are one such, obtain solution A；C, aluminium chloride is added into solvent, solution A obtained, stirring at normal temperature are added under zero degree；D, after completion of the reaction, reaction mixture is poured into ice water, is filtered after stirring, obtain crude product acemetacin；E, the crude product acemetacin that will be obtained, with acetone and water：Volume ratio is 2:1 recrystallization, vacuum drying obtain sterling acemetacin.It is easy to implement the method, it is easy to operate, aluminium chloride it is cheap, be suitble to prepare with scale, do not generate dechlorinated side product, only just the purity of product acemetacin need to be reached and be more than 99.8% by a step simply recrystallization；There is not heavy-metal residual.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of preparation method of nonsteroidal anti-inflammatory drug, are more particularly to one
The preparation method of kind acemetacin.
Background technology
This product is a kind of nonsteroidal anti-inflammatory analgetic, and structure is as shown below, is the precursor medicine of Indomethacin, is taken orally
Indomethacin is generated through metabolism in vivo afterwards to play a role.Acemetacin is listed in former federal republic of germany for 1980 for the first time, is considered
Be improve antiphlogistic effects and improve best one in terms of tolerance, and can substantially reduced Indomethacin gastrointestinal side effect.
China was successfully prepared in 1992.It is aobvious to be mainly used for rheumatic arthritis, the postoperative pain and treatment of infection medicine antiphlogistic effects
It writes, analgesic potency is strong, and prolonged application has no significant effect hemopoietic system and body tissue's organ.The effect of acemetacin, is definite,
Few side effects have a extensive future, and with going deep into for acemetacin dosage form research and clinical research, market value also will more
It is huge.
The preparation method of the acemetacin of document report at present, mostly using Indomethacin as starting material, through esterification,
The acemetacin ester with protecting groups such as tertiary butyl, benzyl, pyranoses is made, then takes off ester through hydrogenolysis or acidolysis and obtains A Xi
Mei Xin.Acemetacin benzyl ester is synthesized by starting material of Indomethacin, dechlorination can occur during sloughing benzyl by hydrogenolysis
It reacts (chloro acetyl benzene chlorine in ring is taken off), leading to product, easy purification and yield do not reduce, and specific reaction is as shown in the figure.
It solves the problems, such as reduction dechlorination, is the key that determine that benzyl ester removal method prepares acemetacin product quality.
Invention content
It is easy to implement the method the purpose of the invention is to provide a kind of preparation method of non-steroidal anti-inflammatory drugs acemetacin,
It is easy to operate, the synthetic method of existing acemetacin is improved.Using Indomethacin as starting material in existing method
Acemetacin benzyl ester is synthesized, then benzyl is sloughed by palladium carbon hydrogenation and prepares acemetacin.This method needs to solve there are two problem
Certainly：(1) when palladium carbon hydrogenation debenzylation, the chlorine atom on the phenyl ring of chloro-benzoyl amino can be restored, chlorine atom, shape are sloughed
At dechlorinated side product, this by-product can influence the purity of product, while simple recrystallization is difficult to remove this byproduct；
(2) higher price of palladium carbon, is unfavorable for large-scale industrial production.The present invention uses AlCl3Debenzylation can completely avoid de-
The formation of chlorine byproduct, simultaneous reactions post-processing is simple, the purity of product can be made to reach European Pharmacopoeia by once recrystallizing
(EROPEAN PHARMACOPOEIA 8.0) requirement.In addition, AlCl3It is cheap, be suitble to prepare with scale.
In order to achieve the above purpose, the present invention uses following technical measures：
A kind of synthetic method of acemetacin, step are：
Its structural formula is as follows：
Wherein：Me is methyl, and O is oxygen atom, and N is nitrogen-atoms, and Cl is chlorine atom, and OBn is benzyloxy, and OH is hydroxyl.
1, acemetacin benzyl ester is prepared according to patent US4600783 (applying date is on 04 25th, 1985)：By indoles U.S.
Pungent and potassium carbonate is added sequentially in acetone, and 56 DEG C are stirred 30 minutes, then are cooled to 40 DEG C, and benzyltriethylammoinium chloride is added,
Benzyl chloracetate is added dropwise, is reacted 6 hours at 40 DEG C after adding, is cooled to room temperature, reaction mixture is poured into ice water, crosses diafiltration
It washs and is dried to obtain acemetacin benzyl ester.
2, acemetacin benzyl ester is dissolved in solvent (solvent is that acetonitrile, toluene or dichloromethane are one such), be added
Benzylic cation scavenger (scavenger is methyl phenyl ethers anisole, and phenol or n,N-Dimethylaniline are one such), obtains solution A；
The mass ratio of acemetacin benzyl ester and solvent is 1 in this described step:5~10, with benzylic cation scavenger
Molal weight ratio be 1：4~10.Benzylic cation scavenger and the molal weight ratio of acemetacin benzyl ester are 1：4~10, this
A ratio is more crucial.Due to AlCl3After sloughing the benzyl on ester group, benzyl first become benzylic cation, when benzyl just from
The least equivalent ratio of sub- scavenger is 4, and benzylic cation cannot be effectively trapped, and can form benzylic cation and participate in paying gram alkane
Glycosylation reaction (reaction substrate can be unreacted complete raw material acemetacin benzyl ester or product acemetacin), it is specific to react
Formula is as shown below.After benzylic cation scavenger and the molal weight ratio of acemetacin benzyl ester are more than 8, continue to increase benzyl
Influence of the dosage of cation scavenger to reaction time and reaction yield is smaller.
Wherein：Me is methyl, and O is oxygen atom, and N is nitrogen-atoms, and Cl is chlorine atom, and OBn is benzyloxy, and OH is hydroxyl, Bn+
It is that the benzyl that aluminium chloride is taken off on the ester group of acemetacin benzyl ester is formed, benzyl is deposited after being taken off in the form of benzylic cation
.
3, chlorination is added into solvent (solvent be acetonitrile, toluene or dichloromethane, identical as solvent used in step 2)
Aluminium (aluminium chloride, chemical formula AlCl3), solution A made from step 2 is slow added under zero degree (0--5),
(15-25 DEG C) of room temperature stirs 55-65 minutes；In described step, the temperature of room temperature reaction is 15 DEG C -25 DEG C.Described
Acemetacin benzyl ester and AlCl in this step3Feed intake molal weight ratio be 1: 1.5~3.Acemetacin benzyl ester can be made complete
Slough the AlCl of ester group3Minimum molar ratio be 1.5, cannot then make that the reaction was complete less than this value and carry out, can specifically see reality
Apply example 10；Improve AlCl3Dosage can shorten the reaction time, but corresponding cost can also increase.It should be noted that plus
Material sequence has large effect to reaction.Charging sequence used in the present invention is by the mixed of acemetacin benzyl ester and benzylic cation
It closes solution and is added drop-wise to AlCl3Solution in, contribute in this way reaction quick progress (AlCl3Relative to acemetacin benzyl ester mistake
Amount), simultaneous reactions operation also can simple and safe (AlCl3Dissolubility in acetonitrile, dichloromethane or toluene is poor, AlCl3's
Above-mentioned solution is suspension, carries out transfer dropwise operation and its difficulty).
4, after completion of the reaction, reaction mixture is poured into ice water, stirring is filtered after 28-32 minutes, obtains pale yellow colored solid
Body (crude product acemetacin).
5, the crude product acemetacin for obtaining step 4, with acetone and water (volume ratio 2:1) it recrystallizes, vacuum 78-82
DEG C dry 22-26 hours, obtain sterling acemetacin.In described step, subtractive process is as follows：Acemetacin crude product is molten
In acetone, activated carbon decolorizing is added after dissolving, filters, adds water, room temperature (15-25 DEG C) crystallizes to that crystallization is complete, mistake
Acemetacin finished product is obtained after filter, drying.
The present invention has following advantage and effect compared to pervious patented technology：Utilize reagent A lCl cheap and easy to get3It is real
Now by the conversion of acemetacin benzyl ester to acemetacin.The conversion by acemetacin benzyl ester to acemetacin of document report at present
It is to be realized by palladium carbon method for hydrogenation, there are three drawbacks for this method：There are the higher price of palladium carbon, there is considerable amount of dechlorination pair
Product is formed and product is susceptible to heavy-metal residual.
Specific implementation mode
It elaborates below to the embodiment of the present invention：The present embodiment is carried out lower based on the technical solution of the present invention
Implement, gives embodiment in detail and process, but protection scope of the present invention is not limited to following embodiments.Institute of the present invention
The many documents of preparation method of intermediate acemetacin benzyl ester have been reported that, commercially available product also can be used, what the present invention used
Acemetacin benzyl ester is prepared by the method provided according to patent US4600783.
Embodiment 1：
A kind of synthetic method of acemetacin, step are：
A, acemetacin benzyl ester is prepared according to patent US4600783, concrete operations are：100g Indomethacins and 40g carbonic acid
Potassium is added in 560mL acetone, is warming up to 56 DEG C and is reacted 30 minutes, be cooled to 40 DEG C, 2.0 grams are added into reaction mixture
Benzyltriethylammoinium chloride, then 57.2g benzyl chloracetates are added dropwise, 40 DEG C of reaction 6h are maintained, is cooled to room temperature, reaction is mixed
Liquid pours into 1L water, filtering, dry with 1L water washing filter cakes, obtains 135.7g acemetacin benzyl esters, HPLC purity 98%.
B, 100g (0.198mol) acemetacin is dissolved in 400mL dichloromethane, adds 86mL methyl phenyl ethers anisoles, obtained molten
Liquid A.
C, to 39.6g (0.297mol) AlCl3Middle addition 100mL dichloromethane, (0 or -1 or -2 or -3 or -4 under zero degree
Or -5), solution A is slowly added to.
D, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
E, the crude product acemetacin for obtaining step D, with acetone and water (volume ratio 2:1) it recrystallizes, vacuum 78 or 79
Or 80 or 81 or 82 DEG C of dryings 24 hours, obtain 76.8g sterling acemetacins, yield 93.4%.Fusing point：152~153 DEG C.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-d6,100MHz)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. HPLC measures purity and is more than
99.8%, chromatographic condition is --- chromatographic column：Diamonsil 5μm C18(2),250×4.6mm；Detection wavelength：235nm；Stream
Speed：1.0mL/min.
Embodiment 2：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL dichloromethane, adds 86mL methyl phenyl ethers anisoles, obtains
To solution A.
B, to 79.2g (0.594mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, 80 DEG C of vacuum is dry
Dry 24 hours, obtain 80.2g sterling acemetacins, yield 97.6%.HPLC measures purity and is more than 99.8%.
Other steps are same as Example 1.
Embodiment 3：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL acetonitriles, adds 86mL methyl phenyl ethers anisoles, obtained molten
Liquid A.
B, to 39.6g (0.297mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL acetonitriles.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, 80 DEG C of vacuum is dry
Dry 24 hours, obtain 76.3g sterling acemetacins, yield 92.8%.HPLC measures purity and is more than 99.8%.
Other steps are same as Example 1.
Embodiment 4：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL acetonitriles, adds 86mL methyl phenyl ethers anisoles, obtained molten
Liquid A.
B, to 79.2g (0.594mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL acetonitriles.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, 80 DEG C of vacuum is dry
Dry 24 hours, obtain 78.6g sterling acemetacins, yield 95.7%.HPLC measures purity and is more than 99.8%.
Other steps are same as Example 1.
Embodiment 5：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 800mL toluene, adds 86mL methyl phenyl ethers anisoles, obtained molten
Liquid A.
B, to 39.6g (0.297mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 200mL toluene.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, 80 DEG C of vacuum is dry
Dry 24 hours, obtain 77.1g sterling acemetacins, yield 93.8%.HPLC measures purity and is more than 99.8%.
Other steps are same as Example 1.
Embodiment 6：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 800mL toluene, adds 86mL methyl phenyl ethers anisoles, obtained molten
Liquid A.
B, to 79.2g (0.594mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 200mL toluene.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, 80 DEG C of vacuum is dry
Dry 24 hours, obtain 77.5g sterling acemetacins, yield 94.3%.HPLC measures purity and is more than 99.8%.
Other steps are same as Example 1.
Embodiment 7：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL dichloromethane, adds 215mL methyl phenyl ethers anisoles,
Obtain solution A.
B, to 39.6g (0.297mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, 80 DEG C of vacuum is dry
Dry 24 hours, obtain 78.2g sterling acemetacins, yield 95.2%.HPLC measures purity and is more than 99.8%.
Other steps are same as Example 1.
Embodiment 8：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL dichloromethane, adds 100mL N, N- bis-
Methylaniline obtains solution A.
B, to 39.6g (0.297mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, activated carbon is added
Decoloration, obtains the drying 24 hours of 80 DEG C of crystal vacuum, obtains 77.8g sterling acemetacins, yield 94.6%.HPLC is measured
Purity is more than 99.8%.
Other steps are same as Example 1.
Embodiment 9：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL dichloromethane, adds 100mL N, N- bis-
Methylaniline obtains solution A.
B, to 79.2g (0.594mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, activated carbon is added
Decoloration, obtains the drying 24 hours of 80 DEG C of crystal vacuum, obtains 79.3g sterling acemetacins, yield 96.5%.HPLC is measured
Purity is more than 99.8%.
Other steps are same as Example 1.
Embodiment 10：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL dichloromethane, adds 250mL N, N- bis-
Methylaniline obtains solution A.
B, to 79.2g (0.594mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, activated carbon is added
Decoloration, obtains the drying 24 hours of 80 DEG C of crystal vacuum, obtains 80.4g sterling acemetacins, yield 97.8%.HPLC is measured
Purity is more than 99.8%.
Other steps are same as Example 1.
Embodiment 11：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin benzyl ester is dissolved in 400mL dichloromethane, adds 86mL methyl phenyl ethers anisoles, obtains
To solution A.
B, to 31.7g (0.238mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step C, with acetone and water (volume ratio 2:1) it recrystallizes, activated carbon is added
Decoloration, obtains the drying 24 hours of 80 DEG C of crystal vacuum, obtains 69.1g sterling acemetacins, yield 84.1%.HPLC is measured
Purity 95%.
Other steps are same as Example 1.
Embodiment 12：
A kind of synthetic method of acemetacin, step are：
A, 100g (0.198mol) acemetacin is dissolved in 400mL dichloromethane, adds 70mL methyl phenyl ethers anisoles, obtained molten
Liquid A.
B, to 39.6g (0.297mol) AlCl3Under zero degree, solution A is slowly added to for middle addition 100mL dichloromethane.
C, it is warmed to room temperature reaction 55 or 58 or 60 or 63 or 65 minutes after adding, pours into reaction mixture after having reacted
In ice water, stirring is filtered after 28 or 29 or 30 or 31 or 32 minutes, obtains crude product acemetacin.
D, the crude product acemetacin for obtaining step D, with acetone and water (volume ratio 2:1) it recrystallizes, vacuum 78 or 79
Or 80 or 81 or 82 DEG C of dryings 24 hours, obtain 74.3g sterling acemetacins, yield 90.4%.HPLC measures purity and is more than
99.8%.
Other steps are same as Example 1.
Claims (1)
1. a kind of synthetic method of acemetacin, which is characterized in that include the following steps：
A, acemetacin benzyl ester is prepared according to patent US4600783：Indomethacin and potassium carbonate are added sequentially in acetone, 56
DEG C stirring 30 minutes, then is cooled to 40 DEG C, benzyltriethylammoinium chloride is added, benzyl chloracetate is added dropwise, anti-at 40 DEG C after adding
It answers 6 hours, is cooled to room temperature, reaction mixture is poured into ice water, filtration washing is dried to obtain acemetacin benzyl ester；
B, acemetacin benzyl ester is dissolved in solvent：Solvent is that acetonitrile, toluene or dichloromethane are one such, and benzyl is being added just
Ion scavenger：The scavenger is methyl phenyl ethers anisole, and phenol or n,N-Dimethylaniline are one such, obtain solution A；
The mass ratio of the acemetacin benzyl ester and solvent is 1:5~10, the molal weight ratio with benzylic cation scavenger
It is 1：4~10, the molal weight ratio of benzylic cation scavenger and acemetacin benzyl ester is 1：4~10；
C, aluminium chloride is added into solvent, solution A made from step (B), stirring at normal temperature 55-65 minutes, room are added under zero degree
The temperature of temperature reaction is 15 DEG C -25 DEG C；
The solvent is that acetonitrile, toluene or dichloromethane are one such；
The molal weight ratio that feeds intake of the acemetacin benzyl ester and aluminium chloride is 1: 1.5~3；
D, after completion of the reaction, reaction mixture is poured into ice water, stirring is filtered after 28-32 minutes, obtains crude product A Ximei
It is pungent；
E, the crude product acemetacin for obtaining step (D), with acetone and water：Volume ratio is 2:1 recrystallization, 78-82 DEG C of vacuum are dry
It is 22-26 hours dry, sterling acemetacin is obtained, the process is as follows：Acemetacin crude product is dissolved in acetone, is added after dissolving
Enter activated carbon decolorizing, filtering adds water, and crystallizing at room temperature is complete to crystallizing, and acemetacin finished product is obtained after filtering, drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810492301.9A CN108440374B (en) | 2018-05-22 | 2018-05-22 | Preparation method of acemetacin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810492301.9A CN108440374B (en) | 2018-05-22 | 2018-05-22 | Preparation method of acemetacin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108440374A true CN108440374A (en) | 2018-08-24 |
| CN108440374B CN108440374B (en) | 2022-01-18 |
Family
ID=63205189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810492301.9A Active CN108440374B (en) | 2018-05-22 | 2018-05-22 | Preparation method of acemetacin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108440374B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848487A (en) * | 2020-08-05 | 2020-10-30 | 河南优凯制药有限公司 | Method for purifying indomethacin |
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 |
-
2018
- 2018-05-22 CN CN201810492301.9A patent/CN108440374B/en active Active
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 |
Non-Patent Citations (5)
| Title |
|---|
| MIKKO GYNTHER ET AL.: "Glucose Promoiety Enables Glucose Transporter Mediated Brain Uptake of Ketoprofen and Indomethacin Prodrugs in Rats", 《J.MED.CHEM.》 * |
| TAKAHIKO AKIYAMA ET AL.: "AlCl3-N,N-dimethylaniline: a new benzyl and allyl ether cleavage reagent", 《TETRAHEDRON LETTERS》 * |
| TERUJI TSUJI ET AL.: "Synthetic studies on β-lactam antibiotics.VII.Mild removal of the benzyl ester protecting group with aluminum trichloride", 《TETRAHEDRON LETTERS》 * |
| 姚明等: "阿西美辛的合成新方法", 《合成化学》 * |
| 贺曾佑: "消炎痛醋酸的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848487A (en) * | 2020-08-05 | 2020-10-30 | 河南优凯制药有限公司 | Method for purifying indomethacin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108440374B (en) | 2022-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2972013C (en) | Process-scale synthesis of urolithins | |
| JPS63190857A (en) | 8-substituted 2-aminotetralines | |
| WO2007014524A1 (en) | Erianin salts, their preparation methods and pharmaceutical compositions containing the same | |
| US20210053995A1 (en) | Method for preparing crisaborole | |
| CN109721579B (en) | 7, 8-dehydrograpevine derivatives, preparation method, pharmaceutical composition and use thereof | |
| CN108440374A (en) | A kind of preparation method of acemetacin | |
| CN113582880B (en) | Preparation method of (3-aminobicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester | |
| CN107778189A (en) | A kind of mesalazine industrialized process for preparing | |
| CN113387877B (en) | Preparation method of sodium picosulfate | |
| CN106957237B (en) | A method of synthesis bromfenac sodium | |
| CN102639498A (en) | Processes for the preparation of 2-(1-phenylethyl) isoindolin-1-one compounds | |
| CN106316921B (en) | A kind of preparation method of acemetacin | |
| EP0133423B1 (en) | Use of 4,5'-azo-bis-salicylic acid for the manufacture of a medicament for the treatment of inflammatory disorders in the intestine | |
| US11548906B2 (en) | Processes for the preparation of SGLT-2 inhibitors, intermediates thereof | |
| CN107936045A (en) | A kind of preparation method of high-purity Flurbiprofen known impurities | |
| CN107325133A (en) | A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN106674281A (en) | Rosuvastatin intermediate compound and preparation method and application thereof | |
| CN104926704A (en) | Nitrogen heterocyclic propane compound and preparation method thereof | |
| US5260462A (en) | Purification of tauroursodesoxycholic acid dihydrate | |
| AU2008298402B2 (en) | Method for producing N-methacryloyl-4-cyano-3-trifluoromethylaniline | |
| CN113004355B (en) | Furanone glycoside compound, pharmaceutical composition, preparation method and application thereof | |
| CN111440069B (en) | Synthesis process of disalicylate | |
| CN112341352A (en) | Preparation method of flurbiprofen | |
| CN116554014A (en) | Preparation method of fenofibrate and impurities thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |