CN101812049A - Method for preparing zaltoprofen - Google Patents
Method for preparing zaltoprofen Download PDFInfo
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- CN101812049A CN101812049A CN200910067886A CN200910067886A CN101812049A CN 101812049 A CN101812049 A CN 101812049A CN 200910067886 A CN200910067886 A CN 200910067886A CN 200910067886 A CN200910067886 A CN 200910067886A CN 101812049 A CN101812049 A CN 101812049A
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- Prior art keywords
- zaltoprofen
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- MUXFZBHBYYYLTH-UHFFFAOYSA-N Zaltoprofen Chemical compound O=C1CC2=CC(C(C(O)=O)C)=CC=C2SC2=CC=CC=C21 MUXFZBHBYYYLTH-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229950004227 zaltoprofen Drugs 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 4
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 230000008014 freezing Effects 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 5
- 230000036407 pain Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 230000004054 inflammatory process Effects 0.000 abstract 1
- 150000003431 steroids Chemical class 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 description 11
- 238000006460 hydrolysis reaction Methods 0.000 description 11
- 238000007363 ring formation reaction Methods 0.000 description 9
- 230000008707 rearrangement Effects 0.000 description 8
- NRXDHTYIDMALNV-UHFFFAOYSA-N C(C)(=O)OC.ClC1=CC=CC=C1 Chemical class C(C)(=O)OC.ClC1=CC=CC=C1 NRXDHTYIDMALNV-UHFFFAOYSA-N 0.000 description 6
- 241000534944 Thia Species 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 238000005907 ketalization reaction Methods 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- ZDOYHCIRUPHUHN-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Cl ZDOYHCIRUPHUHN-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 238000007171 acid catalysis Methods 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 230000006103 sulfonylation Effects 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- WORCCYVLMMTGFR-UHFFFAOYSA-M loxoprofen sodium Chemical compound [Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 WORCCYVLMMTGFR-UHFFFAOYSA-M 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 230000000936 membranestabilizing effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 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 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing zaltoprofen. The method, which is simple in operation route, environmentally-friendly and suitable for industrial mass production, can realize industrialization. The zaltoprofen is a non-steroid anti-inflammatory medicament having effects of relieving inflammation, pain and heat.
Description
Technical field
The present invention relates to the medicine synthesising process technical field, relate in particular to the present invention relates to one simple to operate, environmental protection is suitable for the methodology of organic synthesis of industrialized production, relates to a kind of new preparation method of Zaltoprofen specifically.
Background technology
The chemical name 10 of Zaltoprofen, 11-dihydro-Alpha-Methyl-10-oxygen dibenzo [b, f] thiophene pinane-2-acetate, main mechanism is synthetic for suppress prostaglandin(PG) by the obstruction cyclooxygenase in arachidonic acid metabolism, and other are for suppressing leukoplania and suppressing dissociating of lysosomal enzyme and play membrane stabilizing action.Prostaglandin(PG) synthesizes restraining effect, and optionally the prostaglandin(PG) of strongly inhibited cell generates (in vitro), the prostaglandin(PG) Synthesis that suppresses stomach-tissue than INDOMETHACIN a little less than, the slight drainage that suppresses prostaglandin(PG) in the urine.(1) analgesic activity: multiple pain model is had analgesic activity.Particularly, shown stronger analgesic effect, be about INDOMETHACIN, Y-8004, Diclofenac sodium, Ketoprofen, vialidon, loxoprofen sodium 3～28 times for the pain reaction due to the bradykinin.(2) anti-inflammatory action: acute, subacute and chronic various inflammatory models are had anti-inflammatory action.In addition chronic rheumatic arthritis pathological model-adjuvant arthritis model (rat) also there is result of treatment.
The anti-inflammatory analgesic that is used for following disease and symptom
1. chronic rheumatic arthritis, arthritis deformans, pain in the back, scapulohumeral periarthritis, neck shoulder wrist syndromes
2. after the operation, injure anti-inflammatory, analgesia after the exodontia outward.
Usage and dosage: usually, 1 80mg (Zaltoprofen) that is grown up, 3 times on the 1st are oral.During interim the use, 1 80～160mg (Zaltoprofen).
Structural formula is:
Molecular formula: C
17H
14O
3S
Molecular weight: 298.36
Mainly contain following 8 routes according to domestic and foreign literature report Zaltoprofen synthetic:
1, be that starting raw material is through 8 prepared in reaction Zaltoprofens such as condensation, rearrangement, hydrolysis, cyclization, acidylate, esterification, hydrolysis with the o-chloroacetophenone.
2, with synthetic 10 in the route 1; 11-dihydro-dibenzo [b; f]] thia Zhuo-10-ketone and 2-bromo propionyl chloro be raw material; under the Lweis acid catalysis, make 2-(2-martonite)-10 through friedel-crafts reaction; 11-dihydro-dibenzo [b; f]] thia Zhuo-10-ketone, again through ketalization, hydroxylation, sulfonylation, rearrangement, hydrolysis and Zaltoprofen.
3, with synthetic 10 in the route 1,11-dihydro-dibenzo [b, f]] thia Zhuo-10-ketone and 2-bromo propionyl chloro be raw material, under the Lweis acid catalysis, make 2-(2-martonite)-10 through friedel-crafts reaction, 11-dihydro-dibenzo [b, f]] thia Zhuo-10-ketone, through ketal, rearrangement, hydrolysis and Zaltoprofen.
4, be that starting raw material makes Zaltoprofen through reactions such as acidylate, condensation, esterification, reduction, bromo, cyaniding, cyclization, hydrolysis with o-chlorobenzene acetic acid methyl esters and Acetyl Chloride 98Min..
5, be that starting raw material makes Zaltoprofen through reactions such as acidylate, ketalization, esterification, reduction, bromo, cyaniding, hydrolysis, cyclizations with o-chlorobenzene acetic acid methyl esters and Acetyl Chloride 98Min..
6, be that starting raw material makes Zaltoprofen through reactions such as acidylate, iodo, ketalization, rearrangement, hydrolysis, cyclizations with o-chlorobenzene acetic acid methyl esters and propionyl chloride.
7, be that starting raw material makes Zaltoprofen through reactions such as acidylate, esterification, bromo, ketalization, rearrangement, hydrolysis, cyclizations with o-chlorobenzene acetic acid methyl esters and propionyl chloride.
8, be that starting raw material makes Zaltoprofen through reactions such as acidylate, esterification, bromo, ketalization, hydroxylation, sulfonylation, rearrangement, hydrolysis, cyclizations with o-chlorobenzene acetic acid methyl esters and propionyl chloride.
Article the 1st, 2,3, route all is to be that starting raw material becomes female ring 10 through condensation, rearrangement, hydrolysis cyclization with the o-chloroacetophenone, and 11-dihydro-dibenzo [b, f] thia Zhuo-10-ketone is introduced isopropyl acid again; 4,5,6,7,8 routes then are to be that starting raw material is introduced cyclization again behind the side chain earlier with the o-chlorobenzene acetic acid methyl esters, above-mentioned 8 many long reaction times of route, and post-processing operation is numerous and diverse.
Summary of the invention
To the objective of the invention is that of alternative existing route is simple to operate, cost is lower in order seeking, environmental protection, to be suitable for the synthetic route that industrial peanut produces.
The present invention implements by following route:
Having selected with 5-(1-propionyl)-2-thiophenyl toluylic acid is starting raw material, prepares Zaltoprofen through rearrangement, hydrolysis, cyclization.
(a), be starting raw material with 5-(1-propionyl)-2-thiophenyl toluylic acid, intermediate compound I 5-(1-propionyl)-2-thiophenyl toluylic acid, iodine, triethyl orthoformate, Red copper oxide are joined in three mouthfuls of reaction flasks in 55 ℃ of stirring reactions 2 hours.Reduce to room temperature, add 25% sodium thiosulfate solution, stirred 4 hours, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression and solvent recovery adds solvent in the resistates, alkaline solution, back flow reaction 5 hours, with in the hydrochloric acid and after, ethyl acetate extraction, extracting solution washing, drying, concentrating under reduced pressure obtains white solid, i.e. intermediate II.
(b), intermediate II, polyphosphoric acid and methylene dichloride are joined in three mouthfuls of reaction flasks in 33～53 ℃ of reactions 1 hour, pour in the frozen water, tell dichloromethane layer, use NaHCO successively
3The aqueous solution, salt water washing, drying, concentrating under reduced pressure solvent to 1/4 amount adds normal hexane, separates out crystallization, filter faint yellow crystalline solid, obtain the Zaltoprofen crude product.
(d), the Zaltoprofen crude product is added organic solvent, after the reflux dissolving, add the proper amount of active carbon decolouring, filtered while hot, filtrate adds normal hexane to there being crystallization to separate out, and is freezing, filters, and dry off-white color solid obtains Zaltoprofen, i.e. Compound I.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
(a), be starting raw material with 5-(1-propionyl)-2-thiophenyl toluylic acid, intermediate compound I 5-(1-propionyl)-2-thiophenyl toluylic acid 1100g, iodine 1900g, triethyl orthoformate 9000ml, Red copper oxide 41.5g are joined in three mouthfuls of reaction flasks in 55 ℃ of stirring reactions 2 hours.Reduce to room temperature, add 25% sodium thiosulfate solution, stirred 4 hours, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression and solvent recovery adds methyl alcohol 3000ml in the resistates, 5N sodium hydroxide solution 2000ml, back flow reaction 5 hours, with in the hydrochloric acid and after, ethyl acetate extraction, extracting solution washing, drying, concentrating under reduced pressure obtains white solid 921g (yield 77.8%), i.e. intermediate II.
(b), intermediate II 921g, polyphosphoric acid 3500g and methylene dichloride 5900ml are joined in three mouthfuls of reaction flasks in 33～53 ℃ of reactions 1 hour, pour in the frozen water, tell dichloromethane layer, use 1%NaHCO successively
3Aqueous solution 9000ml, salt solution 2000ml washing, drying, concentrating under reduced pressure solvent to 1/4 amount adds normal hexane 2380ml, separates out crystallization, filter faint yellow crystalline solid 742.8g, obtain the Zaltoprofen crude product.
(d), 742.8g Zaltoprofen crude product is added methyl alcohol 15000ml, after the reflux dissolving, add the proper amount of active carbon decolouring, filtered while hot, filtrate adds normal hexane to there being crystallization to separate out, and is freezing, filters, the dry off-white color solid that gets obtains Zaltoprofen 628g, i.e. Compound I.
Embodiment 2
(a), be starting raw material with 5-(1-propionyl)-2-thiophenyl toluylic acid, intermediate compound I 5-(1-propionyl)-2-thiophenyl toluylic acid 1100g, iodine 1900g, triethyl orthoformate 9000ml, Red copper oxide 41.5g are joined in three mouthfuls of reaction flasks in 55 ℃ of stirring reactions 2 hours.Reduce to room temperature, add 25% sodium thiosulfate solution, stirred 4 hours, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression and solvent recovery adds ethanol 3000ml in the resistates, 5N potassium hydroxide solution 2000ml, back flow reaction 5 hours, with in the hydrochloric acid and after, ethyl acetate extraction, extracting solution washing, drying, concentrating under reduced pressure obtains white solid 926g (yield 78.2%), i.e. intermediate II.
(b), intermediate II 926g, polyphosphoric acid 3500g and methylene dichloride 5900ml are joined in three mouthfuls of reaction flasks in 33～53 ℃ of reactions 1 hour, pour in the frozen water, tell dichloromethane layer, use 1%NaHCO successively
3Aqueous solution 9000ml, salt solution 2000ml washing, drying, concentrating under reduced pressure solvent to 1/4 amount adds normal hexane 2380ml, separates out crystallization, filter faint yellow crystalline solid 744.7g, obtain the Zaltoprofen crude product.
(d), 744.7g Zaltoprofen crude product is added ethanol 15000ml, after the reflux dissolving, add the proper amount of active carbon decolouring, filtered while hot, filtrate adds normal hexane to there being crystallization to separate out, and is freezing, filters, the dry off-white color solid that gets obtains Zaltoprofen 631g, i.e. Compound I.
Claims (6)
1. the new preparation method of the following Zaltoprofen of a structural formula may further comprise the steps:
(a), be starting raw material with 5-(1-propionyl)-2-thiophenyl toluylic acid, intermediate compound I 5-(1-propionyl)-2-thiophenyl toluylic acid, iodine, triethyl orthoformate, Red copper oxide are joined in three mouthfuls of reaction flasks in 55 ℃ of stirring reactions 2 hours.Reduce to room temperature, add 25% sodium thiosulfate solution, stirred 4 hours, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression and solvent recovery adds solvent in the resistates, alkaline solution, back flow reaction 5 hours, with in the hydrochloric acid and after, ethyl acetate extraction, extracting solution washing, drying, concentrating under reduced pressure obtains white solid, i.e. intermediate II.
(b), intermediate II, polyphosphoric acid and methylene dichloride are joined in three mouthfuls of reaction flasks in 33～53 ℃ of reactions 1 hour, pour in the frozen water, tell dichloromethane layer, use NaHCO successively
3The aqueous solution, salt water washing, drying, concentrating under reduced pressure solvent to 1/4 amount adds normal hexane, separates out crystallization, filter faint yellow crystalline solid, obtain the Zaltoprofen crude product.
(d), the Zaltoprofen crude product is added organic solvent, after the reflux dissolving, add the proper amount of active carbon decolouring, filtered while hot, filtrate adds normal hexane to there being crystallization to separate out, and is freezing, filters, and dry off-white color solid obtains Zaltoprofen, i.e. Compound I.
2. method according to claim 1 is characterized in that solvent used in the step (a) is methyl alcohol, ethanol, Virahol.
3. method according to claim 1 is characterized in that the used alkali of step (a) is sodium hydroxide, potassium hydroxide.
4. method according to claim 1 is characterized in that temperature of reaction is 35～65 ℃ in the step (a), and the reaction times is 4～24 hours.
5. method according to claim 1 is characterized in that the concentration of sodium-chlor in the step (b) is 5～50%.
6. method according to claim 1 is characterized in that solvent for use is an anhydrous methanol in the step (c), or ethanol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910067886A CN101812049A (en) | 2009-02-19 | 2009-02-19 | Method for preparing zaltoprofen |
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|---|---|---|---|
| CN200910067886A CN101812049A (en) | 2009-02-19 | 2009-02-19 | Method for preparing zaltoprofen |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206150A (en) * | 2011-04-11 | 2011-10-05 | 启东东岳药业有限公司 | Method for purifying 2-phenylpropionic acid |
| CN104016949A (en) * | 2014-06-25 | 2014-09-03 | 天津市炜杰科技有限公司 | Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid |
| CN104098540A (en) * | 2014-06-24 | 2014-10-15 | 浙江亚太药业股份有限公司 | Method for preparing Zaltoprofen |
| CN105198858A (en) * | 2015-10-30 | 2015-12-30 | 天津药物研究院药业有限责任公司 | Purification method of zaltoprofen |
| CN105218514A (en) * | 2015-10-30 | 2016-01-06 | 天津药物研究院药业有限责任公司 | The preparation method of Zaltoprofen |
| CN110407804A (en) * | 2019-07-18 | 2019-11-05 | 河南后羿制药有限公司 | The cyclisation method of application and Zaltoprofen of the micro passage reaction in the cyclization reaction of Zaltoprofen |
| CN110590737A (en) * | 2019-09-25 | 2019-12-20 | 华中农业大学 | Tritium-labeled zaltoprofen with high specific activity and preparation method thereof |
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2009
- 2009-02-19 CN CN200910067886A patent/CN101812049A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206150A (en) * | 2011-04-11 | 2011-10-05 | 启东东岳药业有限公司 | Method for purifying 2-phenylpropionic acid |
| CN104098540A (en) * | 2014-06-24 | 2014-10-15 | 浙江亚太药业股份有限公司 | Method for preparing Zaltoprofen |
| CN104098540B (en) * | 2014-06-24 | 2016-02-17 | 浙江亚太药业股份有限公司 | A kind of method preparing Zaltoprofen |
| CN104016949A (en) * | 2014-06-25 | 2014-09-03 | 天津市炜杰科技有限公司 | Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid |
| CN105198858A (en) * | 2015-10-30 | 2015-12-30 | 天津药物研究院药业有限责任公司 | Purification method of zaltoprofen |
| CN105218514A (en) * | 2015-10-30 | 2016-01-06 | 天津药物研究院药业有限责任公司 | The preparation method of Zaltoprofen |
| CN110407804A (en) * | 2019-07-18 | 2019-11-05 | 河南后羿制药有限公司 | The cyclisation method of application and Zaltoprofen of the micro passage reaction in the cyclization reaction of Zaltoprofen |
| CN110590737A (en) * | 2019-09-25 | 2019-12-20 | 华中农业大学 | Tritium-labeled zaltoprofen with high specific activity and preparation method thereof |
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