CN105037242A - Diclofenac derivative synthesis process - Google Patents
Diclofenac derivative synthesis process Download PDFInfo
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- CN105037242A CN105037242A CN201510342746.5A CN201510342746A CN105037242A CN 105037242 A CN105037242 A CN 105037242A CN 201510342746 A CN201510342746 A CN 201510342746A CN 105037242 A CN105037242 A CN 105037242A
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- dichlorophenyl
- indolone
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- 238000000034 method Methods 0.000 title claims abstract description 28
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical class OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 25
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960001259 diclofenac Drugs 0.000 claims abstract description 25
- 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 claims abstract description 23
- 238000002425 crystallisation Methods 0.000 claims abstract description 19
- 230000008025 crystallization Effects 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000012046 mixed solvent Substances 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000012535 impurity Substances 0.000 claims abstract description 5
- 239000012141 concentrate Substances 0.000 claims abstract description 4
- 239000012043 crude product Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 229960001701 chloroform Drugs 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 abstract description 21
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 238000005138 cryopreservation Methods 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 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 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000007788 liquid Substances 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
- 238000002360 preparation method Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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 invention discloses a synthesis process for 1-(2,6-dichlorophenyl)-2-indolone. The synthesis process comprises the following steps: (1) reaction: by taking diclofenac as a raw material, adding an organic mixed solvent into the diclofenac so as to enable the organic mixed solvent to be completely dissolved, adding N,N'-dicyclohexylcarbodiimide for reacting at a room temperature, and stirring for reacting for 2-3 h so as to obtain reaction liquid containing a 1-(2,6-dichlorophenyl)-2-indolone crude product; (2), crystallization treatment: filtering to remove solid impurities in the reaction liquid obtained the step (1), concentrating filtrate to obtain a concentrate, adding the concentrate into the organic solvent for crystallization, and separating so as to obtain the product 1-(2,6-dichlorophenyl)-2-indolone. According to the method, EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride which is required to be used in the conventional process is replaced with DCC (N,N'-dicyclohexylcarbodiimide), so that the reaction operation is simple and convenient, the cost is reduced and the yield reaches 90% or above.
Description
Technical field
The present invention relates to chemical pharmacy field, be specifically related to the synthesis technique of ramification of diclofenac-1-(2,6-dichlorophenyl)-2-indolone.
Background technology
Diclofenac is novel non-steroid antiinflammatory drug, is also the antiphlogistic drug of non-hormone, non-germ resistance simultaneously.Applying at present both at home and abroad maximum is clinically the sodium salt of diclofenac, but diclofenac sodium has certain pungency to eye, gastric mucosa etc., with after make the sense of eye generation burning pain, not easily by patient is accepted.In order to lower the untoward reaction using diclofenac, some inorganic salt having researchist to be made by diclofenac and organic salt abroad; But because inorganic salt are water-soluble very little, be not suitable for the medicine making liquid form; And organic salt has carcinogenic components, so effect is all undesirable.
ManChinChung etc. on the basis of previous work in order to overcome above-mentioned deficiency, develop a kind of stability strong, water-soluble large and the medicine of different dosage form can be made, therefore the structure of diclofenac is improved, synthesize the derivative 1-(2 of diclofenac, 6-dichlorophenyl)-2-indolone [also can be described as 1-(2,6-dichlorophenyl)-Indolin-2-one], this material has certain anti-inflammatory analgesic effect, and compared with diclofenac, can greatly reduce stomach toxicity.
Meanwhile, 1-(2,6-dichlorophenyl)-2-indolone, is also one of impurity produced in synthesis diclofenac, controls, can improve the quality of diclofenac medicine to the limitation of this impurity.
The synthetic method of 1-(2,6-dichlorophenyl)-2-indolone relates generally to: take diclofenac as raw material, form intramolecular amide and obtain under certain condensation condition.Condensation condition is the key forming intramolecular amide.The condensation condition of bibliographical information has two kinds:
The first reference ManChinChung.Synthesis, exVivoandinVitroHydrolysisStudyofanIndolineDerivativeDes ignedasanAnti-InflammatorywithReducedGastricUlcerationPr operties.Molecules2009, 14, 3187-3197: take diclofenac as raw material, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (being abbreviated as EDC) is coupling reagent, at room temperature react, reaction mixture dchloromethane, dilute with water again, except desolventizing obtains 1-(2, 6-dichlorophenyl)-2-indolone.Its reaction formula is shown in following formula:
The second referenced patent document WO2009016118A1: take diclofenac sodium as raw material, first add concentrated hydrochloric acid, suction filtration, obtains solid after vacuum-drying, then is solvent with tetrahydrofuran (THF), add triethylamine and carbodiimide compound EDC, stirring reaction 3 hours, then through extraction into ethyl acetate, dried over mgso, column chromatography obtains 1-(2,6-dichlorophenyl)-2-indolone.Its reaction formula is shown in following formula:
All need in prior art to use carbodiimide compound-1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (or being EDC), but because the price of EDC is costly on market, and the easy moisture absorption of EDC, need cryopreservation, thus add the synthesis cost of above two kinds of techniques.On the other hand, above two kinds of technological operations are all more complicated, are not suitable for industrialized production, and use the second technique to prepare 1-(2,6-dichlorophenyl)-2-indolone, productive rate is less than 50%.Therefore, the present invention intends the synthesis technique providing a kind of new 1-(2,6-dichlorophenyl)-2-indolone, and simple to operate, reduce costs, productive rate is higher.
Summary of the invention
The object of the invention is to solve above-mentioned existing technique and prepare ramification of diclofenac-1-(2,6-dichlorophenyl)-2-indolone exist defect, provide a kind of newly can adapt to suitability for industrialized production and environmentally friendly, simple to operate, safe synthesis technique.
The present invention take diclofenac as raw material, add N, N'-Dicyclohexylcarbodiimide (being abbreviated as DCC) reacts, obtained 1-(2,6-dichlorophenyl)-2-indolone crude product, then through purification step, obtained product 1-(2,6-dichlorophenyl)-2-indolone, reaction formula is shown in following formula:
A kind of synthesis technique of ramification of diclofenac-1-(2,6-dichlorophenyl)-2-indolone, comprises the steps:
(1) reactions steps: take diclofenac as raw material, add organic mixed solvent, make it to dissolve completely, add N, N'-Dicyclohexylcarbodiimide (being abbreviated as DCC) at room temperature reacts, stirring reaction 2-3 hour, obtains the reaction solution comprising 1-(2,6-dichlorophenyl)-2-indolone crude product;
(2) crystallization treatment step: cross the solid impurity filtered in reaction solution that above-mentioned steps (1) obtains, filtrate concentrates to obtain enriched material, this enriched material adds organic solvent crystallization, is separated and obtains product 1-(2,6-dichlorophenyl)-2-indolone.
In above-mentioned synthesis technique, preferred embodiment: in described reactions steps (1), the mol ratio of diclofenac and N, N'-Dicyclohexylcarbodiimide is 1:(1.2-2.8).
In above-mentioned synthesis technique, preferred embodiment: in described reactions steps (1), organic mixed solvent of reaction is preferably the mixture of ethyl acetate and methylene dichloride or the mixture of ethyl acetate and trichloromethane; More preferably blending ratio is ethyl acetate: methylene chloride volume ratio=1:(0.5-2) or blending ratio be ethyl acetate: mixture trichloromethane volume ratio=1:(0.5-1.5).
In above-mentioned synthesis technique, preferred embodiment: in described crystallization treatment step (2), the organic solvent for crystallization is preferentially selected from the alcohols of the Cl-C4 comprising methyl alcohol, ethanol, propyl alcohol, Virahol or butanols, the ketone comprising acetone or butanone C3-C4, the ester class of Cl-C4, the chlorinated hydrocarbon solvent of Cl-C4 or its mixed solvent; More preferably from ethyl acetate, acetone, methylene dichloride or trichloromethane or its mixed solvent.
In above-mentioned synthesis technique, preferred embodiment: in described crystallization treatment step (2), recrystallization temperature is-10 DEG C ~ 30 DEG C; More preferably, recrystallization temperature is 0 DEG C ~ 25 DEG C.
In above-mentioned synthesis technique, preferred embodiment: in described crystallization treatment step (2), described enriched material is 1:(2.5-3.5 with the volume ratio of the organic solvent added).
Adopt preparation technology of the present invention, the product yield preparing 1-(2,6-dichlorophenyl)-2-indolone from diclofenac reaches more than 90%.Positive progressive effect of the present invention is: adopt N, N'-Dicyclohexylcarbodiimide (being abbreviated as DCC) substitutes 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (being abbreviated as EDC) as reaction condensation reagent, condensation reagent DCC price is only the 1/3-1/6 of EDC, and the easy moisture absorption of EDC need cryopreservation, complex process.Use present invention reduces reaction cost, improves productive rate, operational safety, easy.
Embodiment
Further illustrate the present invention by following examples, following examples, only for further illustrating the preferred embodiment of the invention, being not used in and limiting technical scheme of the present invention.The scheme of the invention described above is the technical scheme that can realize the object of the invention.Temperature that following examples adopt and reagent, all can substitute with above-mentioned relevant temperature and reagent with the object realizing the present invention.
Embodiment 1
Take the diclofenac of 25g (0.08mol), add the methylene dichloride of 320ml ethyl acetate and 160ml, stirring makes solid dissolve completely, add DCC18.6g, system presents muddiness, stirring reaction 2 hours, TLC follows the tracks of, the reaction of raw material point is complete, cross and filter white solid, filtrate is concentrated into 40ml, add 100ml ethyl acetate and be cooled to 0 DEG C of crystallization, isolate product, obtain 1-(2, 6-dichlorophenyl)-2-indolone, productive rate 93%, mp:122-123 DEG C, 1HNMR: δ 3.86 (s, 2H), 6.37 (d, 1H, J=7.61Hz), 7.08 (dt, 1H, J=7.62H, 1.05Hz), 7.18 (dz, 1H, J=7.65Hz, 1.05Hz), 7.37 (d, 1H, J=7.65Hz), 7.74 (d, 2H, J=8.11Hz), 7.61 (dd, 1H, J=8.12Hz).
Embodiment 2
Take the diclofenac of 30g (0.1mol), add the methylene dichloride of 160ml ethyl acetate and 320ml, stir and solid is dissolved completely, add DCC54.4g, system presents muddiness, stirring reaction 2 hours, TLC follows the tracks of, and the reaction of raw material point is complete, crosses and filters white solid, filtrate is concentrated into 40ml, add 100ml ethyl acetate and be positioned over 25 DEG C of crystallizatioies, isolate product, obtain 1-(2,6-dichlorophenyl)-2-indolone, productive rate 92%.
Embodiment 3
Take the diclofenac of 35.5g (0.12mol), add the trichloromethane of 170ml ethyl acetate and 255ml, stir and solid is dissolved completely, add the 65.3g of DCC, system presents muddiness, stirring reaction 3 hours, TLC follows the tracks of, and the reaction of raw material point is complete, crosses and filters white solid, filtrate is concentrated into 50ml, add 175ml ethyl acetate and be cooled to 25 DEG C of crystallizatioies, isolate product, obtain 1-(2,6-dichlorophenyl)-2-indolone, productive rate 92.4%.
Embodiment 4
Take the diclofenac of 25g (0.08mol), add the methylene dichloride of 240ml ethyl acetate and 240ml, stir and solid is dissolved completely, add DCC24g, system presents muddiness, stirring reaction 2 hours, TLC follows the tracks of, and the reaction of raw material point is complete, crosses and filters white solid, filtrate is concentrated into 40ml, add 100ml ethyl acetate and be cooled to 10 DEG C of crystallizatioies, isolate product, obtain 1-(2,6-dichlorophenyl)-2-indolone, productive rate 93.5%.
Embodiment 5
Take the diclofenac of 30g (0.1mol), add the methylene dichloride of 320ml ethyl acetate and 240ml, stir and solid is dissolved completely, add DCC40g, system presents muddiness, stirring reaction 3 hours, TLC follows the tracks of, and the reaction of raw material point is complete, crosses and filters white solid, filtrate is concentrated into 60ml, add 100ml ethyl acetate and be cooled to 20 DEG C of crystallizatioies, isolate product, obtain 1-(2,6-dichlorophenyl)-2-indolone, productive rate 93.2%.
Claims (9)
1. the synthesis technique of 1-(2,6-dichlorophenyl)-2-indolone, comprises the steps:
(1) reactions steps: take diclofenac as raw material, add organic mixed solvent, make it to dissolve completely, add N, N'-Dicyclohexylcarbodiimide (being abbreviated as DCC) at room temperature reacts, stirring reaction 2-3 hour, obtains the reaction solution comprising 1-(2,6-dichlorophenyl)-2-indolone crude product;
(2) crystallization treatment step: cross the solid impurity filtered in reaction solution that above-mentioned steps (1) obtains, filtrate concentrates to obtain enriched material, this enriched material adds organic solvent crystallization, is separated and obtains product 1-(2,6-dichlorophenyl)-2-indolone.
2. synthesis technique according to claim 1, is characterized in that, in described reactions steps (1), the mol ratio of diclofenac and N, N'-Dicyclohexylcarbodiimide is 1:(1.2-2.8).
3. synthesis technique according to claim 1, is characterized in that, in described reactions steps (1), organic mixed solvent of reaction is the mixture of ethyl acetate and methylene dichloride or the mixture of ethyl acetate and trichloromethane.
4. synthesis technique according to claim 3, it is characterized in that, in described reactions steps (1), organic mixed solvent of reaction be blending ratio is ethyl acetate: methylene chloride volume ratio=1:(0.5-2) or blending ratio be ethyl acetate: mixture trichloromethane volume ratio=1:(0.5-1.5).
5. the synthesis technique according to claim 1-3 any one, it is characterized in that, in described crystallization treatment step (2), the organic solvent for crystallization is selected from the alcohols of the Cl-C4 comprising methyl alcohol, ethanol, propyl alcohol, Virahol or butanols, the ketone comprising acetone or butanone C3-C4, the ester class of Cl-C4, the chlorinated hydrocarbon solvent of Cl-C3 or its mixed solvent.
6. synthesis technique according to claim 5, is characterized in that, in described crystallization treatment step (2), the organic solvent for crystallization is selected from ethyl acetate, acetone, methylene dichloride, trichloromethane or its mixed solvent.
7. the synthesis technique according to claim 1-3 any one, is characterized in that, in described crystallization treatment step (2), recrystallization temperature is-10 DEG C ~ 30 DEG C.
8. synthesis technique according to claim 7, is characterized in that, in described crystallization treatment step (2), recrystallization temperature is 0 DEG C ~ 25 DEG C.
9. the synthesis technique according to claim 1-3 any one, is characterized in that, in described crystallization treatment step (2), described enriched material is 1:(2.5-3.5 with the volume ratio of the crystallization organic solvent added).
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| CN201510342746.5A CN105037242A (en) | 2015-06-19 | 2015-06-19 | Diclofenac derivative synthesis process |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220411605A1 (en) * | 2019-01-23 | 2022-12-29 | Lanxess Deutschland Gmbh | Hydrolysis-resistant compositions comprising polyethylene terephthalate (PET) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536758A (en) * | 1966-10-07 | 1970-10-27 | Geigy Chem Corp | Substituted phenylacetamides |
| RU2072309C1 (en) * | 1993-08-18 | 1997-01-27 | Завод магнитных лент и технических пленок Производственного объединения "Тасма" | Method of manufacturing transparent polyethyleneterephthalate insertion for audio cassettes |
| CN1155274A (en) * | 1994-06-29 | 1997-07-23 | 西巴-盖尔基股份公司 | New salts of 2-[(2,6-dichlorophenyl)amine] phenylacetoxyacetic acid with organic basic cations |
-
2015
- 2015-06-19 CN CN201510342746.5A patent/CN105037242A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3536758A (en) * | 1966-10-07 | 1970-10-27 | Geigy Chem Corp | Substituted phenylacetamides |
| RU2072309C1 (en) * | 1993-08-18 | 1997-01-27 | Завод магнитных лент и технических пленок Производственного объединения "Тасма" | Method of manufacturing transparent polyethyleneterephthalate insertion for audio cassettes |
| CN1155274A (en) * | 1994-06-29 | 1997-07-23 | 西巴-盖尔基股份公司 | New salts of 2-[(2,6-dichlorophenyl)amine] phenylacetoxyacetic acid with organic basic cations |
Non-Patent Citations (2)
| Title |
|---|
| MAN CHIN CHUNG，等: "Synthesis, ex Vivo and in Vitro Hydrolysis Study of an Indoline", 《MOLECULES》 * |
| PAULA S. ALMEIDA，等: "Synthetic Applications of N-Aryl-Q-acyl Hydroxamic Acids. A Convenient Route to 3-Substituted N-Benzoyl Oxindoles", 《TETRAHEDRON LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220411605A1 (en) * | 2019-01-23 | 2022-12-29 | Lanxess Deutschland Gmbh | Hydrolysis-resistant compositions comprising polyethylene terephthalate (PET) |
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Application publication date: 20151111 |