CN116836102A - Method for preparing sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) - Google Patents
Method for preparing sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) Download PDFInfo
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- CN116836102A CN116836102A CN202310845626.1A CN202310845626A CN116836102A CN 116836102 A CN116836102 A CN 116836102A CN 202310845626 A CN202310845626 A CN 202310845626A CN 116836102 A CN116836102 A CN 116836102A
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- dichlorophenyl
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- -1 3-chloro-N- (2, 6-dichlorophenyl) indol-2-one Chemical compound 0.000 title claims abstract description 42
- 239000012535 impurity Substances 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000003756 stirring Methods 0.000 claims abstract description 12
- MGEGDVKBXGZTRM-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)indole-2,3-dione Chemical compound ClC1=CC=CC(Cl)=C1N1C2=CC=CC=C2C(=O)C1=O MGEGDVKBXGZTRM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 7
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims 1
- FWDLHTBMGQEUDU-UHFFFAOYSA-M sodium;2-hydroxy-2-phenylacetate Chemical compound [Na+].[O-]C(=O)C(O)C1=CC=CC=C1 FWDLHTBMGQEUDU-UHFFFAOYSA-M 0.000 claims 1
- 229960001193 diclofenac sodium Drugs 0.000 abstract description 10
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract description 6
- 239000013558 reference substance Substances 0.000 abstract description 5
- LSFYCRUFNRBZNC-UHFFFAOYSA-N (2-hydroxyphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1O LSFYCRUFNRBZNC-UHFFFAOYSA-N 0.000 abstract description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 4
- 229910052708 sodium Inorganic materials 0.000 abstract description 4
- 239000011734 sodium Substances 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 239000012670 alkaline solution Substances 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 238000005259 measurement Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 8
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- BPEUHDIEZQWRGC-UHFFFAOYSA-N 2-chloro-n-(2,6-dichlorophenyl)-n-phenylacetamide Chemical compound ClC=1C=CC=C(Cl)C=1N(C(=O)CCl)C1=CC=CC=C1 BPEUHDIEZQWRGC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JCICIFOYVSPMHG-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-3h-indol-2-one Chemical compound ClC1=CC=CC(Cl)=C1N1C2=CC=CC=C2CC1=O JCICIFOYVSPMHG-UHFFFAOYSA-N 0.000 description 1
- HDUUZPLYVVQTKN-UHFFFAOYSA-N 2,6-dichloro-n-phenylaniline Chemical compound ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 HDUUZPLYVVQTKN-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The application discloses a method for synthesizing diclofenac sodium chloro impurity, which comprises the following steps: step one: dissolving N- (2, 6-dichlorophenyl) indole-2, 3-dione in an organic solvent, and then adding a metal reducing agent to generate 3-hydroxy-N- (2, 6-dichlorophenyl) indole-2-ketone; step two: dissolving the 3-hydroxy-N- (2, 6-dichlorophenyl) indol-2-one obtained in the step one in an alkaline solution, and drying to obtain sodium 2- ((2, 6-dichlorophenyl) amino) hydroxyphenylacetate; step three: and (3) adding a catalyst and a chlorinating agent into the product obtained in the step (II) to perform stirring reaction at normal temperature to obtain 3-chloro-N- (2, 6-dichlorophenyl) indol-2-one. The application provides a synthetic method of sodium diclofenac chlorinated impurities, which takes N- (2, 6-dichlorophenyl) indole-2, 3-dione as a raw material, has the advantages of easily available synthetic raw materials, simple operation, mild and controllable reaction, and high purity of the generated product which reaches more than 99 percent, and can be directly used as a reference substance for impurity content measurement and quality research of sodium diclofenac finished products.
Description
Technical Field
The application relates to the technical field of chemical pharmacy, in particular to a synthetic method of chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) in the production of diclofenac sodium.
Background
Sodium diclofenac (diclofenac sodium) sodium N-2, 6-dichlorophenyl phenylacetate. Is a non-steroidal anti-inflammatory drug with obvious analgesic, anti-inflammatory and antipyretic effects. The composition has analgesic, antiinflammatory, and antipyretic effects by inhibiting prostaglandin synthesis. Belongs to one of typical representative medicines of anti-inflammatory analgesic medicines, and is often used for treating various kinds of light, moderate, acute and chronic pains in orthopaedics, such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and the like. Has been recorded in the national basic drug catalog.
With the progress of technology and the improvement of the requirements of people on the safety of medicines, in the quality research at the early stage of medicine registration and the supplement quality research in the whole life cycle of medicines, various potential impurities need to be analyzed and confirmed, especially after the higher requirements on genotoxicity in medicines are put forward in recent years, the nitrosamine impurities need to be researched and evaluated again after the impurities which are not fully researched due to low content are required to be researched, and a reference substance for researching the impurities is provided, because the content of the impurities in the medicines is very small, and the impurities cannot be synthesized or separated by using the original technological method, a new method needs to be developed for preparation. The current industrialized route for synthesizing diclofenac sodium is to take N- (2, 6-dichlorophenyl) aniline as a starting material, react with chloroacetyl chloride to generate N-chloroacetyl-N- (2, 6-dichlorophenyl) aniline, then carry out intramolecular Friedel-crafts reaction under the catalysis of aluminum trichloride to generate N- (2, 6-dichlorophenyl) indol-2-one, and then carry out hydrolysis ring opening by sodium hydroxide to obtain diclofenac sodium (N-2, 6-dichlorophenyl sodium phenylacetate), wherein the reaction process is as follows:
since the raw material chloroacetyl chloride contains a byproduct dichloroacetyl chloride, N- (2-chloroacetyl) -N- (2, 6-dichlorophenyl) aniline can be produced when the compound N- (2, 2-dichloroacetyl) -N- (2, 6-dichlorophenyl) aniline is prepared, wherein the compound A can be changed along with the subsequent synthesis process of diclofenac sodium to produce a compound B, namely the diclofenac sodium chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one).
In order to identify and control the content of sodium diclofenac chlorinated impurities in the finished product, a reference substance of sodium diclofenac chlorinated impurities (compound B) needs to be prepared for research and verification.
Because two electric-absorbing chloride ions exist in the N- (2, 2-dichloroacetyl) -N- (2, 6-dichlorophenyl) aniline structure, the direct ring closing reaction according to the original synthetic route of the diclofenac sodium is difficult, and pure 3-chloro-N- (2, 6-dichlorophenyl) indol-2-one (compound B) cannot be obtained, so that a feasible method for synthesizing pure diclofenac sodium chloride impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) needs to be studied.
Disclosure of Invention
The application aims to provide a synthesis method of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indole-2-ketone), which takes N- (2, 6-dichlorophenyl) indole-2, 3-dione as raw material, has easy obtaining of synthetic raw material, simple operation, mild and controllable reaction, and high purity of the generated product reaching more than 99 percent, and can be directly used as a reference substance for impurity content determination and quality research of sodium diclofenac finished products.
To achieve the aim of the application, the application discloses a method for synthesizing sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one), which comprises the following steps: step one: dissolving N- (2, 6-dichlorophenyl) indole-2, 3-dione in an organic solvent, adding a metal reducing agent, and reducing a ketone group at the 3-position of the N- (2, 6-dichlorophenyl) indole-2, 3-dione into hydroxyl to generate 3-hydroxyl-N- (2, 6-dichlorophenyl) indole-2-ketone; step two: instructions 3 100002 2023.03 dissolving 3-hydroxy-N- (2, 6-dichlorophenyl) indol-2-one obtained in step one in an alkaline solution, carrying out reflux stirring reaction, ensuring that the reaction is complete, standing and cooling to form a solid precipitate, filtering and washing the precipitate, and then drying to obtain sodium 2- ((2, 6-dichlorophenyl) amino) hydroxyphenylacetate; step three: adding a catalyst and a chlorinating agent into the product obtained in the step two, stirring the mixture at normal temperature for reaction to ensure the reaction to be complete, distilling the mixture under reduced pressure to remove excessive chlorinating agent, dissolving the residue in a dichloromethane solvent, washing an organic phase with water, concentrating the organic phase, and purifying the organic phase by using a column chromatography method to obtain the 3-chloro-N- (2, 6-dichlorophenyl) indol-2-one.
In the first step, the organic solvent is methanol, absolute ethyl alcohol or tetrahydrofuran, and the metal reducing agent is one or more of sodium borohydride, potassium borohydride or lithium borohydride.
Further, in the first step, the temperature range of the reaction is-20 ℃ to 40 ℃.
In the first step, the extracting agent is dichloromethane, and the recrystallization solvent is methanol.
Further, in the second step, the reaction temperature of the reflux stirring reaction is 80-110 ℃.
In the second step, the alkali solution is sodium hydroxide or potassium hydroxide, and the concentration of the alkali solution is between 10 and 30 percent.
In the third step, the chlorinating agent is sulfoxide chloride, phosphorus trichloride or phosphorus pentachloride.
Further, in the third step, the catalyst used in the chlorination reaction is pyridine, 4-dimethylaminopyridine or DMF (N, N-dimethylformamide).
The following shows a typical synthetic route for sodium diclofenac chloride impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) provided by the application:
the method comprises the following steps:
in the first step, the compound 3-hydroxy-N- (2, 6-dichlorophenyl) indol-2-one is prepared: reducing 3-keton into hydroxyl by N- (2, 6-dichlorophenyl) indole-2, 3-diketone in tetrahydrofuran or alcohol solvent under the action of metal reducing agents such as sodium borohydride, potassium borohydride or lithium borohydride, preferably using tetrahydrofuran as the solvent, preferably using sodium borohydride as the metal reducing agent, detecting the reaction temperature at about 10 ℃, adding water to stop the reaction, extracting with dichloromethane, evaporating the solvent, and recrystallizing the residue with methanol to obtain the product 3-hydroxy-N- (2, 6-dichlorophenyl) indole-2-ketone.
Second, preparation of sodium 2- ((2, 6-dichlorophenyl) amino) hydroxyphenylacetate: dissolving the 3-hydroxy-N- (2, 6-dichlorophenyl) indol-2-one prepared in the previous step in 10% sodium hydroxide aqueous solution, refluxing and stirring for 5 hours, filtering, adding sodium hydroxide into filtrate, cooling to precipitate solid, filtering and drying to obtain the product.
Thirdly, preparing a compound of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one): dissolving the product of the previous step in thionyl chloride, adding a small amount of pyridine as a catalyst during the reaction, stirring at normal temperature to react completely, evaporating excess thionyl chloride under reduced pressure, adding dichloromethane for dissolving, washing an organic phase, and concentrating the organic phase for column chromatography to obtain the product.
The application has the positive and beneficial technical effects that: according to the application, N- (2, 6-dichlorophenyl) indole 2, 3-dione is used as a raw material, N- (2, 6-dichlorophenyl) -3-hydroxy-indole-2-ketone is generated through reduction, and then sodium diclofenac chloro impurity is generated through hydrolytic chlorination, the reaction conditions of each reaction step are mild and controllable, the conversion rate is high, the purity of the generated sodium diclofenac chloro impurity can reach more than 99%, and the sodium diclofenac can be directly used as a reference substance for impurity content determination and quality research of sodium diclofenac finished products.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the final product in the example of the present application, which shows that the obtained product is diclofenac sodium chloride impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) without errors.
Detailed Description
In order that the application may be more readily understood, the application will be further described with reference to the following examples. These examples are provided only to illustrate the present application and not to limit the scope of the present application, and specific experimental methods not mentioned in the following examples are generally carried out in accordance with conventional experimental methods.
Examples
(1) Preparation of the compound 3-hydroxy-N- (2, 6-dichlorophenyl) indol-2-one:
500ml three-port reaction bottle, add and stir, add 150ml absolute ethyl alcohol, add 10g of N- (2, 6-dichlorophenyl) indole-2, 3-dione, cool to about 0 ℃, under the protection of nitrogen, add 4g of sodium borohydride in several times, after finishing adding, react for 6 hours at room temperature, after detecting no raw material, add 150ml water slowly, stir, decompress and concentrate to three quarters of original volume, add 2 x 100ml dichloromethane and extract, dry anhydrous sodium sulfate, concentrate and get 5g of product through column chromatography after nearly drying.
(2) Preparation of sodium Compound 2- ((2, 6-dichlorophenyl) amino) hydroxyphenylacetate:
adding 5g of the product obtained in the previous step into a 100ml reaction bottle, dissolving in 150ml of 10% sodium hydroxide solution, refluxing and stirring for reaction for 5 hours, filtering to remove impurities, adding 150ml of 10% sodium hydroxide, cooling and standing, separating out solid, filtering and drying to obtain 2.5g of the product.
(3) 2.5g of the product from the above step was placed in 20ml of thionyl chloride, and 0.1ml of pyridine was added thereto, and the reaction was carried out at room temperature for 2 hours until the completion of the reaction. The excess thionyl chloride is distilled off, 50ml of dichloromethane is added, the mixture is distilled off again, 100ml of dichloromethane is added, 100ml of water is added to wash the organic phase, the organic phase is concentrated to near dryness, flash chromatography and air drying are carried out, and 1.5g of product is obtained, and the HPLC purity is 99%.
The above examples are only illustrative of the preferred embodiments of the present application and are not intended to limit the scope of the application, and various modifications to the technical solution of the present application by those skilled in the art should fall within the scope of protection defined by the claims of the present application.
Claims (8)
1. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one), characterized by: the method comprises the following steps:
step one:
dissolving N- (2, 6-dichlorophenyl) indole-2, 3-dione in an organic solvent, adding a metal reducing agent to reduce a ketone group at the 3-position of the N- (2, 6-dichlorophenyl) indole-2, 3-dione into hydroxyl to generate 3-hydroxyl-N- (2, 6-dichlorophenyl) indole-2-ketone, adding water to stop the reaction after the reaction is finished, extracting by an extracting agent, evaporating the solvent, dissolving residues by a recrystallization solvent, and recrystallizing to obtain a product 3-hydroxyl-N- (2, 6-dichlorophenyl) indole-2-ketone;
step two:
dissolving the 3-hydroxy-N- (2, 6-dichlorophenyl) indol-2-one obtained in the step one in an alkali solution, carrying out reflux stirring reaction, ensuring that the reaction is complete, standing and cooling to form a solid precipitate, filtering and washing the precipitate, and then drying to obtain 2- ((2, 6-dichlorophenyl) amino) sodium hydroxyphenylacetate;
step three: adding a catalyst and a chlorinating agent into the product obtained in the step two, stirring the mixture at normal temperature for reaction to ensure the reaction to be complete, distilling the mixture under reduced pressure to remove excessive chlorinating agent, dissolving the residue in a dichloromethane solvent, washing an organic phase with water, concentrating the organic phase, and purifying the organic phase by using a column chromatography method to obtain the 3-chloro-N- (2, 6-dichlorophenyl) indol-2-one.
2. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the first step, the organic solvent is methanol, absolute ethyl alcohol or tetrahydrofuran, and the metal reducing agent is one or more of sodium borohydride, potassium borohydride or lithium borohydride.
3. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the first step, the temperature range of the reduction reaction is-20 ℃ to 40 ℃.
4. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the first step, the extractant is methylene dichloride, and the recrystallization solvent is methanol.
5. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the second step, the reaction temperature of the reflux stirring reaction is 80-110 ℃.
6. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the second step, the alkali solution is sodium hydroxide or potassium hydroxide, and the concentration of the alkali solution is between 10 and 30 percent.
7. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the third step, the chlorinating agent is sulfoxide chloride, phosphorus trichloride or phosphorus pentachloride.
8. A process for the preparation of sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) according to claim 1, characterized in that: in the third step, the catalyst used in the chlorination reaction is pyridine, 4-dimethylaminopyridine or DMF.
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| CN202310845626.1A CN116836102A (en) | 2023-07-11 | 2023-07-11 | Method for preparing sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) |
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| CN202310845626.1A CN116836102A (en) | 2023-07-11 | 2023-07-11 | Method for preparing sodium diclofenac chloro impurity (3-chloro-N- (2, 6-dichlorophenyl) indol-2-one) |
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