CN113698308A - Novel synthesis method of bromfenac sodium - Google Patents
Novel synthesis method of bromfenac sodium Download PDFInfo
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- CN113698308A CN113698308A CN202110978192.3A CN202110978192A CN113698308A CN 113698308 A CN113698308 A CN 113698308A CN 202110978192 A CN202110978192 A CN 202110978192A CN 113698308 A CN113698308 A CN 113698308A
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- bromfenac
- bromfenac sodium
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- 229960002716 bromfenac sodium Drugs 0.000 title claims abstract description 85
- HZFGMQJYAFHESD-UHFFFAOYSA-M bromfenac sodium Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 HZFGMQJYAFHESD-UHFFFAOYSA-M 0.000 title claims abstract description 85
- 238000001308 synthesis method Methods 0.000 title claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 82
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 36
- 229960003655 bromfenac Drugs 0.000 claims abstract description 31
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- KHMNCHDUSFCTGK-UHFFFAOYSA-N 2-aminophenylacetic acid Chemical compound NC1=CC=CC=C1CC(O)=O KHMNCHDUSFCTGK-UHFFFAOYSA-N 0.000 claims abstract description 10
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 6
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 238000006277 sulfonation reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000008213 purified water Substances 0.000 claims description 57
- 238000003756 stirring Methods 0.000 claims description 50
- 239000000047 product Substances 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 35
- 239000002904 solvent Substances 0.000 claims description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- 239000011259 mixed solution Substances 0.000 claims description 25
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 24
- 238000005406 washing Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 16
- 238000000967 suction filtration Methods 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- BOEMFEOUVXWWNZ-UHFFFAOYSA-N 2-(2-acetamidophenyl)acetic acid Chemical compound CC(=O)NC1=CC=CC=C1CC(O)=O BOEMFEOUVXWWNZ-UHFFFAOYSA-N 0.000 claims description 8
- -1 2-acetamido-5-sulfophenylacetic acid Chemical compound 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 24
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 4
- 125000001041 indolyl group Chemical group 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 229960000583 acetic acid Drugs 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000012362 glacial acetic acid Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 24
- 230000001276 controlling effect Effects 0.000 description 22
- 239000012065 filter cake Substances 0.000 description 21
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 18
- 238000007670 refining Methods 0.000 description 12
- 238000007602 hot air drying Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 8
- 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 description 7
- 239000011521 glass Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- YHIWBVHIGCRVLE-UHFFFAOYSA-N 3-bromo-1h-indole Chemical compound C1=CC=C2C(Br)=CNC2=C1 YHIWBVHIGCRVLE-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229960003424 phenylacetic acid Drugs 0.000 description 4
- 239000003279 phenylacetic acid Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 2
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 2
- 235000019838 diammonium phosphate Nutrition 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- NPOSTKZYBVQXNJ-UHFFFAOYSA-N (2-amino-4-bromophenyl)-phenylmethanone Chemical compound NC1=CC(Br)=CC=C1C(=O)C1=CC=CC=C1 NPOSTKZYBVQXNJ-UHFFFAOYSA-N 0.000 description 1
- FUKOTTQGWQVMQB-UHFFFAOYSA-N (2-bromoacetyl) 2-bromoacetate Chemical compound BrCC(=O)OC(=O)CBr FUKOTTQGWQVMQB-UHFFFAOYSA-N 0.000 description 1
- NPVOEMRAKUFYRS-UHFFFAOYSA-N (3-bromo-1H-indol-7-yl)-(4-bromophenyl)methanone Chemical compound Brc1c[nH]c2c(cccc12)C(=O)c1ccc(Br)cc1 NPVOEMRAKUFYRS-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000005550 inflammation mediator Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000013067 intermediate product Substances 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
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/06—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfuric acid or sulfur trioxide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new synthesis method of bromfenac sodium, belonging to the technical field of drug synthesis and comprising the following steps: taking o-aminophenylacetic acid as an initial raw material, and carrying out acylation reaction to obtain an intermediate I; carrying out sulfonation reaction on the intermediate I to obtain an intermediate II; carrying out substitution reaction on the intermediate II and p-bromobenzoyl chloride to obtain an intermediate III; hydrolyzing the intermediate III to obtain bromfenac; reacting bromfenac with sodium hydroxide to obtain a final finished product of bromfenac sodium; the invention has the beneficial effects that: the production of impurities containing indole ring caused by the synthesis method in the prior art is avoided; the problem that the pH of a final finished product exceeds the standard due to the use of acid salt generated by phosphoric acid or glacial acetic acid in the prior art is solved, the quality problem of too low water content due to the proportioning of the materials for preparing the finished bromfenac sodium product is solved, and meanwhile, the synthesis method is simple and easy to control and is suitable for industrial production.
Description
The technical field is as follows:
the invention belongs to the technical field of drug synthesis, and particularly relates to a new synthesis method of bromfenac sodium.
Background art:
bromfenac sodium (Bromfenic sodium) with the chemical name of 2-amino-3- (4-bromobenzoyl) sodium phenylacetate has a structure similar to that of ketoprofen and diclofenac, is one of the most effective cyclooxygenase inhibitors, can inhibit synthesis of cyclooxygenase-mediated prostaglandin inflammation mediators, has strong anti-inflammatory and analgesic effects, and has the action strength 10 times that of other nonsteroidal anti-inflammatory drugs. At present, the eye drop is mainly used as eye drop with anti-inflammatory effect clinically, and is used for symptomatic treatment of inflammatory diseases of outer eyes and anterior eyes.
The existing synthetic routes of bromfenac sodium mainly comprise the following steps:
patent CN106957237A discloses a method for synthesizing bromfenac sodium, wherein a synthetic route of the method is to obtain a target product by using 2-amino-4-bromobenzophenone as an initial raw material and performing acylation reaction, halogen acetylation reaction and friedel-crafts reaction. The synthetic route is as follows:
the bromoacetic anhydride and bromoacetyl bromide used in the method have high use risk coefficient, the volatilized organic gas has great corrosivity to equipment and plants, in addition, solvents such as chloroform and the like are used in the process, the residual limit requirement of the solvents in the raw material medicines is high, and the method is difficult to realize.
Patent CN106397235A, a method for preparing bromfenac sodium of the present invention, which is synthesized by using indole as an initial material, reacting under the condition of dimethyl sulfoxide to generate 3-bromoindole, hydrolyzing, chlorinating, and alkaline hydrolyzing to obtain a target product, wherein the synthetic route is as follows:
the raw material indole used by the method has high price, low yield and unstable pH value of the product. Boron trichloride is used as high-risk fuming gas in the synthesis process, and the safety risk in the synthesis process is very high.
Patent document EP221753 and Chinese materia medica science academy 2003,34(5): 405-406) disclose that bromfenac sodium is obtained by carrying out a friedel-crafts acylation reaction on p-bromobenzonitrile and indoline as raw materials and boron trichloride and aluminum trichloride as catalysts, and then carrying out oxidation, halogenation, phosphohydrolysis and sodium hydroxide alkaline hydrolysis, wherein the synthetic route is as follows:
the method is also a mainstream synthesis route for producing bromfenac sodium in China, but manganese dioxide is used in the synthesis process, so that the heavy metal in a finished product is easy to exceed the standard. Boron trichloride and N-bromosuccinimide (NBS) which belong to high-risk chemicals are also used in the synthesis process, wherein the N-bromosuccinimide (NBS) has high toxicity and is easy to cause explosion or personnel poisoning in the preparation process.
The invention content is as follows:
in order to solve the problems and overcome the defects of the prior art, the invention provides a new synthesis method of bromfenac sodium, which can effectively solve the problem of the generation of indole ring-containing impurities caused by the synthesis method in the prior art.
The specific technical scheme for solving the technical problems comprises the following steps: the new synthesis method of bromfenac sodium is characterized in that the preparation method comprises the following steps:
(1) preparation of intermediate I:
taking o-aminophenylacetic acid as an initial raw material, and carrying out acylation reaction to obtain an intermediate I;
(2) preparing an intermediate II;
carrying out sulfonation reaction on the intermediate I to obtain an intermediate II;
(3) preparing an intermediate III;
carrying out substitution reaction on the intermediate II and p-bromobenzoyl chloride to obtain an intermediate III;
(4) preparing bromfenac;
hydrolyzing the intermediate III to obtain bromfenac;
(5) preparing bromfenac sodium;
the bromfenac reacts with sodium hydroxide to obtain the final finished product of bromfenac sodium.
The intermediate I is o-acetaminophenylacetic acid; the intermediate II is 2-acetamido-5-sulfophenylacetic acid; the intermediate III is 3- (4-bromobenzoyl) -2-acetamido-5-sulfophenylacetic acid.
The preparation of the intermediate I comprises the following steps:
adding o-aminophenylacetic acid into a solvent I, adding acetic anhydride for reaction at room temperature, and slowly adding a reaction auxiliary agent to generate a mixed solution containing an intermediate I; concentrating the mixed solution of the intermediate I under reduced pressure, adding ethanol, stirring uniformly, adding purified water, crystallizing, filtering, and drying with hot air to obtain an intermediate I; the solvent I is dichloromethane or toluene; the reaction auxiliary agent is triethylamine.
Preparation of the intermediate II:
adding the intermediate I into a solvent II, slowly adding sulfuric acid, adding a small amount of purified water after the reaction is finished, and standing for layering; obtaining a mixed solution containing the intermediate II; carrying out vacuum distillation on the organic phase of the mixed solution containing the intermediate II, adding a poor solvent I, cooling, crystallizing, filtering and drying to obtain an intermediate II;
the solvent II is a mixed solution of two solvents of dichloromethane or toluene or methanol or ethanol; the poor solvent I is as follows: methyl tert-butyl ether.
Preparation of the intermediate III:
adding the intermediate II and aluminum trichloride into dichloromethane, slowly dropwise adding p-bromobenzoyl chloride to generate a mixed solution of the intermediate III,
preparing the bromfenac; and (3) concentrating the mixed solution of the intermediate III under reduced pressure to be viscous, adding hydrochloric acid for hydrolysis, crystallizing, filtering, washing with purified water, and drying with hot air to obtain the bromfenac.
Adding bromfenac into a solvent III, controlling the temperature to be 40-50 ℃, adding a sodium hydroxide solution, adjusting the pH value, then adding purified water into the system, fully stirring, standing and layering; extracting the organic layer with water once, and discarding; combining the water phases, dropwise adding a poor solvent II for crystallization, filtering, washing with acetone, and drying in vacuum to obtain a target product, namely a crude product of bromfenac sodium; the solvent III is a mixture of two solvents of toluene or methanol or ethanol, and the poor solvent II is as follows: acetone or ethylene glycol dimethyl ether or isopropyl ether or methyl tert-butyl ether.
Adding the crude bromfenac sodium product and purified water into a reaction bottle, stirring for dissolving, adding activated carbon for decoloring, filtering, adding a poor solvent II for crystallizing, performing suction filtration, and drying by hot air to obtain a finished bromfenac sodium product. The mass ratio of the crude bromfenac sodium product to the purified water is 1: 0.8-1.5.
The invention has the beneficial effects that:
compared with the prior art, the raw and auxiliary materials used in the invention are easily available, safe, low in toxicity and low in cost, and the synthetic route avoids the generation of indole ring-containing impurities caused by a synthetic method in the prior art;
the purity of the bromfenac sodium prepared by the method is high and can reach more than 99.9 percent, and the content is close to 100 percent;
the method avoids the problem that the pH value of the final finished product exceeds the standard due to the use of acid salt generated by phosphoric acid or glacial acetic acid in the prior art, avoids the quality problem of too low water content due to the proportioning of the materials for preparing the finished bromfenac sodium product, is simple and easy to control, and is suitable for industrial production.
Description of the drawings:
FIG. 1 is a chemical equation diagram of the reaction principle of the process of the present invention;
FIG. 2 is a schematic structural diagram of indole impurity I produced in the prior art production;
FIG. 3 is a schematic structural diagram of indole impurity II produced in the prior art production; in the drawings:
the specific implementation mode is as follows:
in the description of the invention, specific details are given only to enable a full understanding of the embodiments of the invention, but it should be understood by those skilled in the art that the invention is not limited to these details for the implementation. In other instances, well-known structures and functions have not been described or shown in detail to avoid obscuring the points of the embodiments of the invention. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
The specific implementation mode of the invention is as follows:
the new synthesis method of bromfenac sodium is characterized in that the preparation method comprises the following steps:
(1) preparation of intermediate I:
taking o-aminophenylacetic acid as an initial raw material, and carrying out acylation reaction to obtain an intermediate I, namely o-acetaminophenylacetic acid;
specifically, the method comprises the following steps:
adding o-aminophenylacetic acid into a solvent I (dichloromethane or toluene), adding acetic anhydride for reaction at room temperature, and slowly adding a reaction auxiliary agent (triethylamine) to generate a mixed solution containing an intermediate I; concentrating the mixed solution of the intermediate I under reduced pressure, adding ethanol, stirring uniformly, adding purified water, crystallizing, filtering, and drying with hot air to obtain an intermediate I, namely o-acetaminophenylacetic acid;
(2) preparing an intermediate II;
the intermediate I is subjected to sulfonation reaction to obtain an intermediate II, namely 2-acetamido-5-sulfophenylacetic acid;
specifically, the method comprises the following steps:
adding the intermediate I, namely o-acetaminophenylacetic acid, into a solvent II (a mixed solution of two solvents of dichloromethane or toluene or methanol or ethanol), slowly adding sulfuric acid, adding a small amount of purified water after the reaction is finished, and standing for layering; obtaining a mixed solution containing the intermediate II; carrying out vacuum distillation on the organic phase of the mixed solution containing the intermediate II, adding a poor solvent I (methyl tert-butyl ether), cooling, crystallizing, filtering, and drying to obtain an intermediate II, namely 2-acetamido-5-sulfophenylacetic acid;
(3) preparing an intermediate III;
carrying out substitution reaction on the intermediate II and p-bromobenzoyl chloride to obtain an intermediate III;
specifically, the method comprises the following steps:
adding an intermediate II (2-acetamido-5-sulfophenylacetic acid) and aluminum trichloride into dichloromethane, slowly dropwise adding p-bromobenzoyl chloride to generate a mixed solution containing an intermediate III, namely the mixed solution containing 3- (4-bromobenzoyl) -2-acetamido-5-sulfophenylacetic acid,
(4) preparing bromfenac;
hydrolyzing the intermediate III to obtain bromfenac;
specifically, the method comprises the following steps:
and (3) concentrating the mixed solution containing the intermediate III under reduced pressure to be viscous, adding hydrochloric acid for hydrolysis, crystallizing, filtering, washing with purified water, and drying with hot air to obtain the bromfenac.
(5) Preparing bromfenac sodium;
the bromfenac reacts with sodium hydroxide to obtain the final finished product of bromfenac sodium,
specifically, the method comprises the following steps:
adding bromfenac into solvent III (mixture of toluene or methanol or ethanol), controlling the temperature at 40-50 ℃, adding sodium hydroxide solution, adjusting the pH value, then adding purified water into the system, fully stirring, standing and layering; extracting the organic layer with water once, and discarding; combining the water phases, dropwise adding a poor solvent II (acetone or ethylene glycol dimethyl ether or isopropyl ether or methyl tert-butyl ether) for crystallization, filtering, washing with acetone, and drying in vacuum to obtain a target product, namely a crude product of bromfenac sodium;
and adding the crude bromfenac sodium product and purified water into a reaction bottle, stirring and dissolving, adding activated carbon for decoloring, filtering, adding a poor solvent II for crystallization, performing suction filtration, and drying by hot air to obtain a finished bromfenac sodium product. The mass ratio of the crude bromfenac sodium product to the purified water is 1: 0.8-1.5.
Example 1
(1) Preparation of intermediate I:
adding 30g (0.20mol) of o-aminophenylacetic acid and 300ml of dichloromethane into a reaction bottle, starting stirring, controlling the temperature to be 20-30 ℃, starting slowly dripping 40.8g (0.4mol) of acetic anhydride, and controlling the dripping time to be 1.5-2 h;
② dripping 40.8g (0.40mol) of triethylamine from the other charging hole of the reaction bottle after dripping acetic anhydride for 30 minutes;
thirdly, after the dripping is finished, the reaction is carried out for 1 hour under the condition of heat preservation;
fourthly, after the reaction is finished, carrying out reduced pressure distillation until the interior is viscous, stopping reducing the pressure, adding 90g of ethanol, and uniformly stirring;
controlling the temperature of the reaction liquid within 20-30 ℃, adding 720g of purified water, and controlling the adding time within 1-1.5 hours;
sixthly, keeping the temperature, stirring and crystallizing for 1 hour, performing suction filtration, washing a filter cake by 100ml of purified water for 1 time, and performing suction filtration. The filter cake was put into a hot air oven and dried at 60 to 70 ℃ for 10 hours to obtain 36.6g of o-acetaminophenylacetic acid (intermediate I).
(2) Preparing an intermediate II;
35g (0.18mol) of intermediate I, methylene chloride (175g) and ethanol (35g) were charged into a 500ml four-necked glass reaction flask, stirred and heated to 30-35 ℃.
Secondly, slowly dripping concentrated sulfuric acid (70g) into the feed liquid, and controlling the temperature of the feed liquid not to exceed 40 ℃.
And maintaining the temperature for reaction for 2 hr.
And fourthly, after the reaction is finished, adding 175g of purified water into the feed liquid, stirring for 5 minutes, standing for 30 minutes, layering, and discarding the water phase.
Fifthly, decompressing and concentrating, decompressing to 50 percent of the original volume, and stopping decompressing.
Sixthly, 280g of methyl tert-butyl ether is dripped into the reaction bottle at the internal temperature of 25-30 ℃, stirred and crystallized, and the dripping time is 0.5-1 hour. Cooling to 5-10 deg.C, stirring, crystallizing for 1 hr, filtering, washing filter cake with 150ml methyl tert-butyl ether, and pumping to dry.
Seventhly, drying the mixture for 8 hours by hot air at the temperature of between 50 and 60 ℃ to obtain an intermediate II, namely 2-acetamido-5 sulfonic phenylacetic acid; 44.7 g.
(3) Intermediate III and preparation of bromfenac
Adding 400ml of dichloromethane, 40g (0.14mol) of intermediate II and 41g of aluminum trichloride into a dry and anhydrous 1000ml reaction bottle, starting stirring, and cooling to below 10 ℃.
② slowly dripping 50.7g (0.23mol) of p-bromobenzoyl chloride into the feed liquid, controlling the internal temperature not to exceed 30 ℃, and finishing the addition within 1.5-2 hours.
Thirdly, after the reaction is finished, decompressing and concentrating, and evaporating dichloromethane until the feed liquid is viscous to generate a mixed solution of an intermediate III;
fourthly, 500ml of 10 percent diluted hydrochloric acid prepared in advance is added into the reaction bottle, the internal temperature is controlled within 20 to 30 ℃, and the addition is finished within 1 to 1.5 hours.
Fifthly, after the purified water is added, continuously stirring and crystallizing for 1 hour, performing suction filtration, washing the filter cake with 500ml of purified water for 3 times, washing with 100ml of isopropanol once, and performing suction drying.
Sixthly, setting the temperature of a hot air drying oven at 70 ℃, and drying the wet product in the drying oven for 12 hours to obtain 44.5g of bromfenac.
(4) Preparation of crude bromfenac sodium
Adding 40g (0.12mol) of bromfenac, 250ml of toluene and 100ml of ethanol into a 1000ml clean glass reaction bottle, stirring and heating to control the temperature to be 30-50 ℃.
② adding 10 percent sodium hydroxide solution into the feed liquid, and adjusting the pH value to 11-14.
③ then adding 100ml of purified water into the feed liquid, fully stirring, standing for 30 minutes and demixing.
And fourthly, adding 40ml of purified water into the organic phase, stirring and extracting for 10 minutes, standing for 30 minutes, and layering.
Fifthly, combining the water phases and discarding the organic phase.
Sixthly, the water phase is transferred to a 2000ml reaction bottle, stirring is started, 1800ml of acetone is dripped at the temperature of 30-40 ℃, and the addition is finished within 2-3 hours.
And slowly cooling to 10-15 ℃, stirring and crystallizing for 10 hours.
Eighthly, filtering, fully washing a filter cake for 3 times by 300ml of acetone, and pumping to dry.
Ninthly, setting the temperature of a hot air drying box at 55 ℃, and drying for 6 hours to obtain 39.3g of crude bromfenac sodium product with the purity of 99.64%.
(5) Preparation of finished bromfenac sodium product
Adding 30g of crude bromfenac sodium product and 24g of purified water into a reaction bottle, heating to 60 ℃, stirring for dissolving, adding 3g of activated carbon for decoloring for 30 minutes, and filtering.
② cooling the filtrate to 15-20 ℃, and then adding 300g of acetone for crystallization within 2 hours.
And thirdly, after the dropwise addition is finished, cooling the feed liquid to 0-5 ℃, and stirring for crystallization for 8 hours.
Fourthly, suction filtration is carried out, the filter cake is fully washed for 2 times by 200ml of acetone, and then the filter cake is drained.
Fifthly, setting the temperature of a hot air drying box to be 55 ℃, and drying for 6 hours to obtain 27.9g of finished bromfenac sodium product with the refining yield of 93 percent; purity: 99.92%, content: 100.1%, pH 8.9.
Example 2
1) Preparation of intermediate I:
adding 15g (0.1mol) of o-aminophenylacetic acid and 150ml of dichloromethane into a reaction bottle, starting stirring, controlling the temperature to be 20-30 ℃, starting slowly dripping 20.4g (0.2mol) of acetic anhydride, and controlling the dripping time to be 1.5-2 h;
② after 30 minutes of adding acetic anhydride dropwise, 20.4g (0.20mol) of triethylamine is added dropwise from the other feeding port of the reaction bottle.
③ after the dropwise addition, the reaction is carried out for 1 hour under the condition of heat preservation.
Fourthly, after the reaction is finished, distilling under reduced pressure until the interior of the reaction is sticky, stopping reducing the pressure, adding 90g of ethanol, and stirring uniformly.
Controlling the temperature of the reaction liquid within 20-30 ℃, adding 360g of purified water, and controlling the adding time within 1-1.5 hours.
Sixthly, keeping the temperature, stirring and crystallizing for 1 hour, performing suction filtration, washing a filter cake for 1 time by using 50ml of purified water, performing suction filtration, putting the filter cake into a hot air oven, and drying for 10 hours at the temperature of 60-70 ℃ to obtain 17.9g of o-acetaminophenylacetic acid (intermediate I);
2) preparation of intermediate II
15g (0.078mol) of the intermediate I, 75g of dichloromethane and 15g of ethanol are added into a 500ml four-necked glass reaction flask, stirred and heated to 30-35 ℃.
Secondly, slowly dripping concentrated sulfuric acid (30g) into the feed liquid, and controlling the temperature of the feed liquid not to exceed 40 ℃.
And maintaining the temperature for reaction for 2 hr.
Fourthly, after the reaction is finished, 75g of purified water is added into the feed liquid, the mixture is stirred for 5 minutes, kept stand for 30 minutes, layered, and the water phase is discarded.
Fifthly, decompressing and concentrating, decompressing to 50 percent of the original volume, and stopping decompressing.
Sixthly, dropping 120g of methyl tert-butyl ether into the reaction bottle at the internal temperature of 25-30 ℃, stirring and crystallizing, dropping the solution for 0.5-1 hour, cooling to 5-10 ℃, stirring and crystallizing for 1 hour, filtering, washing a filter cake by 64ml of methyl tert-butyl ether, and draining.
Seventhly, drying the mixture for 8 hours by hot air at the temperature of between 50 and 60 ℃ to obtain an intermediate II, namely 2-acetamido-5 sulfonic phenylacetic acid; 19.1 g;
3) intermediate III and preparation of bromfenac
Adding 150ml of dichloromethane, 15g (0.052mol) of intermediate 2 and 15.3g of aluminum trichloride into a dry and anhydrous 500ml reaction bottle, starting stirring, and cooling to below 10 ℃.
② slowly dripping 19g (0.086mol) of p-bromobenzoyl chloride into the feed liquid, controlling the internal temperature not to exceed 30 ℃, and finishing the addition within 1.5-2 hours.
Thirdly, after the reaction is finished, decompressing and concentrating, and evaporating dichloromethane until the feed liquid is viscous to generate a mixed solution of an intermediate III;
fourthly, 187ml of 10 percent dilute hydrochloric acid is added into the reaction bottle, the internal temperature is controlled within 20 to 30 ℃, and the addition is finished within 1 to 1.5 hours.
Fifthly, after the purified water is added, continuously stirring and crystallizing for 1 hour. Suction filtration, filter cake with 180ml purified water washing 3 times, 50ml isopropanol fully washed once, suction drying.
Sixthly, setting the temperature of a hot air drying oven at 70 ℃, and drying the wet product in the drying oven for 12 hours to obtain 16.3g of bromfenac;
(4) preparation of crude bromfenac sodium
Adding 15g (0.12mol) of bromfenac, 95ml of toluene and 38ml of ethanol into a 500ml clean glass reaction bottle, stirring and heating to control the temperature to be 30-50 ℃.
Dropping 10% sodium hydroxide solution into the material liquid and regulating pH value to 11-14.
③ then adding 38ml of purified water into the feed liquid, fully stirring, standing for 30 minutes and demixing.
Adding 15ml of purified water into the organic phase, stirring and extracting for 10 minutes, standing for 30 minutes, and layering.
Fifthly, combining the water phases and discarding the organic phase.
Sixthly, transferring the water phase into a 1000ml reaction bottle, starting stirring, controlling the temperature to be 30-40 ℃, and dropwise adding 680ml of acetone for 2-3 hours.
And slowly cooling to 10-15 ℃, stirring and crystallizing for 10 hours.
Eighthly, filtering, fully washing a filter cake for 3 times by using 120ml of acetone, and pumping to dry.
Ninthly, setting the temperature of a hot air drying box at 55 ℃, and drying for 6 hours to obtain 14.5g of crude bromfenac sodium product with the purity of 99.71 percent.
(5) Preparation of finished bromfenac sodium product
Adding 10g of crude bromfenac sodium product and 15g of purified water into a 250ml glass reaction bottle, heating to 60 ℃, stirring for dissolving, adding 1g of activated carbon for decoloring for 30 minutes, and filtering.
② cooling the filtrate to 15-20 ℃, and then adding 100g of acetone for crystallization within 2 hours.
And thirdly, after the dropwise addition is finished, cooling the feed liquid to 0-5 ℃, and stirring for crystallization for 8 hours.
Fourthly, suction filtration is carried out, the filter cake is fully washed for 2 times by 70ml of acetone, and then the filter cake is drained.
Fifthly, setting the temperature of a hot air drying oven to be 55 ℃, drying for 6 hours to obtain 9.0g of finished bromfenac sodium product, wherein the refining yield is 90 percent, and the purity is as follows: 99.95%, content: 100%, pH 9.0;
example 3
(1) Preparation of intermediate I:
adding 30g (0.20mol) of o-aminophenylacetic acid and 300ml of toluene into a reaction bottle, starting stirring, controlling the temperature to be 20-30 ℃, starting slowly dripping 40.8g (0.4mol) of acetic anhydride, and controlling the dripping time to be 1.5-2 h.
② after 30 minutes of dropwise adding acetic anhydride, 40.8g (0.40mol) of triethylamine is dropwise added from the other feeding port of the reaction bottle.
③ after the dropwise addition, the reaction is carried out for 1 hour under the condition of heat preservation.
Fourthly, after the reaction is finished, carrying out reduced pressure distillation until the interior is viscous, stopping reducing the pressure, adding 90g of ethanol, and uniformly stirring;
controlling the temperature of the reaction liquid within 20-30 ℃, adding 720g of purified water, and controlling the adding time within 1-1.5 hours;
sixthly, keeping the temperature, stirring and crystallizing for 1 hour, performing suction filtration, washing a filter cake by 100ml of purified water for 1 time, and performing suction filtration. Putting the filter cake into a hot air oven, and drying for 10 hours at the temperature of 60-70 ℃ to obtain 34.5g of o-acetaminophenylacetic acid (intermediate I);
(2) preparation of intermediate II
30g (0.11mol) of intermediate I, dichloromethane (150g) and ethanol (30g) are introduced into a 500ml four-necked glass reaction vessel, stirred and heated to 30-35 ℃.
Secondly, slowly dripping concentrated sulfuric acid (60g) into the feed liquid, and controlling the temperature of the feed liquid not to exceed 40 ℃.
And maintaining the temperature for reaction for 2 hr.
Fourthly, after the reaction is finished, 150g of purified water is added into the feed liquid, the mixture is stirred for 5 minutes, kept stand for 30 minutes, layered, and the water phase is discarded.
Fifthly, decompressing and concentrating, decompressing to 50 percent of the original volume, and stopping decompressing.
Sixthly, dropping 240g of methyl tert-butyl ether into the reaction bottle at the internal temperature of 25-30 ℃, stirring and crystallizing, dropping the solution for 0.5-1 hour, cooling to 5-10 ℃, stirring and crystallizing for 1 hour, filtering, washing a filter cake by 130ml of methyl tert-butyl ether, and draining.
Seventhly, drying the mixture for 8 hours by hot air at the temperature of between 50 and 60 ℃ to obtain an intermediate II, namely 2-acetamido-5 sulfonic phenylacetic acid; 38.7 g;
(3) intermediate III and preparation of bromfenac
350ml toluene, 35g (0.14mol) intermediate 2 and 35.8g aluminium trichloride are added into a dry 1000ml reaction bottle, stirring is started, and the temperature is reduced to below 10 ℃.
② adding 44.3g (0.20mol) of p-bromobenzoyl chloride slowly dropwise into the feed liquid, controlling the internal temperature not to exceed 30 ℃, and finishing the addition within 1.5-2 hours.
Thirdly, after the reaction is finished, decompressing and concentrating, and evaporating dichloromethane until the feed liquid is viscous to generate a mixed solution of an intermediate III;
fourthly, 440ml of 10 percent diluted hydrochloric acid prepared in advance is added into the reaction bottle, the internal temperature is controlled within 20 to 30 ℃, and the addition is finished within 1 to 1.5 hours.
Fifthly, after the purified water is added, continuously stirring and crystallizing for 1 hour, performing suction filtration, washing the filter cake with 440ml of purified water for 3 times, washing with 100ml of isopropanol once, and performing suction drying.
Sixthly, setting the temperature of a hot air drying oven at 70 ℃, and drying the wet product in the drying oven for 12 hours to obtain 36g of bromfenac;
(4) preparation of crude bromfenac sodium
Adding 35g (0.105mol) of bromfenac, 220ml of toluene and 87ml of ethanol into a 1000ml clean glass reaction bottle, stirring and heating to control the temperature to be 30-50 ℃.
② adding 10 percent sodium hydroxide solution into the feed liquid, and adjusting the pH value to 11-14.
③ then adding 87ml of purified water into the feed liquid, fully stirring, standing for 30 minutes and demixing.
Adding 35ml of purified water into the organic phase, stirring and extracting for 10 minutes, standing for 30 minutes, and layering.
Fifthly, combining the water phases and discarding the organic phase.
Sixthly, transferring the water phase into a 2000ml reaction bottle, starting stirring, controlling the temperature to be 30-40 ℃, and dropwise adding 1580ml of ethylene glycol dimethyl ether for 2-3 hours.
And slowly cooling to 10-15 ℃, stirring and crystallizing for 10 hours.
(viii) filtering, washing the filter cake with 260ml ethylene glycol dimethyl ether for 3 times, and pumping to dry.
Ninthly, setting the temperature of a hot air drying box at 55 ℃, and drying for 6 hours to obtain 34.9g of crude bromfenac sodium product with the purity of 99.58%.
(5) Preparation of finished bromfenac sodium product
Adding 30g of crude bromfenac sodium product and 30g of purified water into a reaction bottle, heating to 60 ℃, stirring for dissolving, adding 3g of activated carbon for decoloring for 30 minutes, and filtering.
② the temperature of the filtrate is reduced to 15-20 ℃, and then 300g of glycol dimethyl ether is added within 2 hours for crystallization.
And thirdly, after the dropwise addition is finished, cooling the feed liquid to 0-5 ℃, and stirring for crystallization for 8 hours.
Fourthly, suction filtration is carried out, the filter cake is fully washed for 2 times by 200ml of glycol dimethyl ether, and the filter cake is drained.
And fifthly, setting the temperature of a hot air drying oven to be 55 ℃, and drying for 6 hours to obtain 28.5g of finished bromfenac sodium product with the refining yield of 95%. Purity: 99.93%, content: 100 percent. pH 8.7.
In order to more intuitively show the process advantages of the invention, the new synthesis method of bromfenac sodium is utilized by the invention and the prior art I (according to the national invention patent CN106397235A, indole is used as the starting material, the target product is obtained by hydrolysis, chlorination and alkaline hydrolysis after 3-bromoindole is generated by reaction under the condition of dimethyl sulfoxide, and the target product is introduced by means of citation),
the prior art II utilizes (according to the invention patent EP0221753, p-bromobenzonitrile and indoline are taken as raw materials, boron trichloride and aluminum trichloride are used for catalyzing and carrying out Friedel-crafts acylation reaction, then sodium bromfenate is obtained after oxidation, halogenation, phosphoric acid hydrolysis and sodium hydroxide alkaline hydrolysis, and the bromfenac sodium is introduced by means of citation),
table 1: comparison of indole impurities produced by different Processes
The test results are as follows:
in the prior art I and the prior art II, due to the defects of the principle of the process, indole impurities are generated in the process of generating the bromfenac sodium, and the indole impurities and the intermediate have similar physicochemical properties and are difficult to separate, so that the purity of the product is influenced;
in order to more intuitively show the process advantages of the invention, the invention compares a new synthesis method of bromfenac sodium with an equivalent replacement method adopted by the same process,
comparative example one:
the preparation method is different from the prior art I in that: in the preparation process of the comparative example, the phosphoric acid obtained by acid hydrolysis is replaced by hydrochloric acid;
comparative example two:
the preparation method is different from the prior art II in that: in the preparation process of the comparative example, the phosphoric acid obtained by acid hydrolysis is replaced by hydrochloric acid;
comparative example three:
the preparation method is the same as the invention, except that: in the preparation process of the comparative example, hydrochloric acid adopted by acid hydrolysis was replaced by phosphoric acid;
the alkalinity detection standard pH of the finished product of the bromfenac sodium is 8.5-9.5;
1.0g of the product was dissolved in 20ml of freshly boiled cold water, and then measured immediately by pH measurement according to the general rule 17 of drug test protocols.
The detection method of the related substances (purity) of the bromfenac sodium comprises the following steps:
chromatographic conditions and system applicability test:
octadecylsilane chemically bonded silica was used as a filler (5 μm, 4.6X 250mm), phosphate buffer (2.5 g of diammonium hydrogen phosphate was taken, dissolved in water and diluted to 1000ml, pH was adjusted to 7-8 with phosphoric acid) -acetonitrile (75: 20) was used as a mobile phase A, phosphate buffer (2.5 g of diammonium hydrogen phosphate was taken, dissolved in water and diluted to 1000ml, pH was adjusted to 7.3 with phosphoric acid) -acetonitrile (20: 70) was used as a mobile phase B, gradient elution was performed according to the following table, the flow rate was adjusted so that the retention time of the bromfenac sodium peak was about 18 minutes, and the detection wavelength was 266 nm.
Table 2: different processes and intermediate acid hydrolysis process alkalinity detection index contrast data
The test results are as follows:
the existing process for producing bromfenac sodium is adopted, and due to the limitation of the process, when the pre-acidified intermediate product 3-bromoindole or 3-bromo-7- (4-bromobenzoyl) indole is acidified; the adopted phosphoric acid generates acid salt, which can cause that the pH value exceeds the standard and does not meet the alkalinity detection standard of finished sodium bromfenate products, namely that the pH value is 8.5-9.5;
the data analysis of the comparative example I and the comparative example II shows that the side reaction is caused by adopting the existing process for producing bromfenac sodium and replacing the acidified phosphoric acid with the hydrochloric acid of the invention, and the target product cannot be obtained;
the data analysis of comparative example III shows that the intermediate 3- (4-bromobenzoyl) -2-acetamido-5-sulfonic phenylacetic acid is adopted for acidification and replaced by phosphoric acid, the pH is not less than 10.1, and the pH does not meet the alkalinity detection standard of finished sodium bromfenate products, namely 8.5-9.5.
In order to more intuitively show the advantages of the refining process, the invention compares a new synthesis method of bromfenac sodium with an equivalent replacement method adopted by the same process,
example four:
the refining method is the same as the third embodiment of the invention, except that: in the preparation process of the comparative example, 30g of crude bromfenac sodium and 30g of purified water were replaced with: 30g of crude bromfenac sodium and 24g of purified water;
example five:
the refining method is the same as the third embodiment of the invention, except that: in the preparation process of the comparative example, 30g of crude bromfenac sodium and 30g of purified water were replaced with: 30g of crude bromfenac sodium and 45g of purified water;
comparative example four:
the refining method is the same as the third embodiment of the invention, except that: in the preparation process of the comparative example, 30g of crude bromfenac and 30g of purified water are replaced in the refining process; 30g of crude bromfenac sodium and 15g of purified water;
comparative example five:
the refining method is the same as the third embodiment of the invention, except that: in the preparation process of the comparative example, 30g of crude bromfenac and 30g of purified water are replaced in the refining process; 30g of crude bromfenac sodium product and 60g of purified water;
table 3: reference data of sodium bromfenac detection indexes of different refining processes
| Crude bromfenac sodium | Purified water | Total yield of refining | Water content | |
| EXAMPLE III | 30 | 30 | 95％ | 7.3％ |
| Example four | 30 | 24 | 96％ | 6.8％ |
| EXAMPLE five | 30 | 45 | 93.3％ | 7.5％ |
| Comparative example No. four | 30 | 15 | 91％ | 6.0％ |
| Comparative example five | 30 | 60 | 72％ | 8.3％ |
The test results are as follows:
from the analysis of the above experimental results, it can be seen that:
from the third embodiment to the fifth embodiment, the following results are obtained: crude bromfenac sodium dosage: the dosage of the purified water is within the range of 1: 0.8-1.5, so that the excellent total yield can be obtained, and the proper water content of the bromfenac sodium can be ensured;
from comparative example four to example five, it can be seen that: the ratio of the crude bromfenac sodium product dosage to the purified water dosage, with the increase of the purified water dosage, the loss of bromfenac sodium can be caused by excessive water, and further the total yield of bromfenac sodium is low;
the proportion of the crude bromfenac sodium product dosage to the purified water dosage can lead to lower water content of a finished bromfenac sodium product along with the reduction of the purified water dosage, and further can not meet the detection index of related substances of the bromfenac sodium.
In summary, the following steps:
the raw and auxiliary materials used in the invention are easily available, safe, low in toxicity and low in cost, and the synthetic route avoids the generation of indole ring-containing impurities caused by the synthetic method in the prior art;
the prepared bromfenac sodium has high purity which can reach more than 99.9 percent, and the content is close to 100 percent;
creatively adopts a brand new process to prepare an intermediate 3- (4-bromobenzoyl) -2-acetamido-5-sulfonic phenylacetic acid, and the intermediate is acidified by hydrochloric acid, so that the problem that the pH value of a final finished product exceeds the standard due to the use of acid salt generated by phosphoric acid or glacial acetic acid in the prior art is avoided;
the quality problem of too low water content caused by the ratio of the sodium bromfenate finished product preparation materials is avoided by adjusting the use amounts of the sodium bromfenate crude product and the purified water, and meanwhile, the synthesis method is simple and easy to control and is suitable for industrial production.
Claims (9)
1. A new synthesis method of bromfenac sodium is characterized in that the preparation method comprises the following steps:
(1) preparation of intermediate I:
taking o-aminophenylacetic acid as an initial raw material, and carrying out acylation reaction to obtain an intermediate I;
(2) preparing an intermediate II;
carrying out sulfonation reaction on the intermediate I to obtain an intermediate II;
(3) preparing an intermediate III;
carrying out substitution reaction on the intermediate II and p-bromobenzoyl chloride to obtain an intermediate III;
(4) preparing bromfenac;
hydrolyzing the intermediate III to obtain bromfenac;
(5) preparing bromfenac sodium;
the bromfenac reacts with sodium hydroxide to obtain the final finished product of bromfenac sodium.
2. The method for synthesizing bromfenac sodium according to claim 1, wherein said intermediate I is o-acetaminophenylacetic acid; the intermediate II is 2-acetamido-5-sulfophenylacetic acid; the intermediate III is 3- (4-bromobenzoyl) -2-acetamido-5-sulfophenylacetic acid.
3. The novel process for the synthesis of bromfenac sodium according to claim 2, characterized in that the preparation of intermediate i:
adding o-aminophenylacetic acid into a solvent I, adding acetic anhydride for reaction at room temperature, and slowly adding a reaction auxiliary agent to generate a mixed solution containing an intermediate I; concentrating the mixed solution of the intermediate I under reduced pressure, adding ethanol, stirring uniformly, adding purified water, crystallizing, filtering, and drying with hot air to obtain an intermediate I; the solvent I is dichloromethane or toluene; the reaction auxiliary agent is triethylamine.
4. The novel synthesis method of bromfenac sodium according to claim 3, characterized in that the preparation of intermediate II:
adding the intermediate I into a solvent II, slowly adding sulfuric acid, adding a small amount of purified water after the reaction is finished, and standing for layering; obtaining a mixed solution containing the intermediate II; carrying out vacuum distillation on the organic phase of the mixed solution containing the intermediate II, adding a poor solvent I, cooling, crystallizing, filtering and drying to obtain an intermediate II;
the solvent II is a mixed solution of two solvents of dichloromethane or toluene or methanol or ethanol; the poor solvent I is as follows: methyl tert-butyl ether.
5. The new synthesis method of bromfenac sodium according to claim 4, characterized in that the preparation of said intermediate III:
and adding the intermediate II and aluminum trichloride into dichloromethane, and slowly dropwise adding p-bromobenzoyl chloride to generate a mixed solution of the intermediate III.
6. The novel method for synthesizing bromfenac sodium according to claim 5, wherein said bromfenac is prepared; and (3) concentrating the mixed solution of the intermediate III under reduced pressure to be viscous, adding hydrochloric acid for hydrolysis, crystallizing, filtering, washing with purified water, and drying with hot air to obtain the bromfenac.
7. The new synthesis method of bromfenac sodium according to claim 6, characterized in that bromfenac is added into a solvent III, the temperature is controlled at 40-50 ℃, a sodium hydroxide solution is added, the pH value is adjusted, then purified water is added into the system, and the mixture is fully stirred, kept stand and layered; extracting the organic layer with water once, and discarding; combining the water phases, dropwise adding a poor solvent II for crystallization, filtering, washing with acetone, and drying in vacuum to obtain a target product, namely a crude product of bromfenac sodium; the solvent III is a mixture of two solvents of toluene or methanol or ethanol, and the poor solvent II is as follows: acetone or ethylene glycol dimethyl ether or isopropyl ether or methyl tert-butyl ether.
8. The new synthesis method of bromfenac sodium according to claim 7, characterized in that the finished product of bromfenac sodium is obtained by adding the crude bromfenac sodium and purified water into a reaction flask, stirring for dissolution, adding activated carbon for decolorization, filtering, adding a poor solvent II for crystallization, performing suction filtration, and drying with hot air.
9. The new synthesis method of bromfenac sodium according to claim 8, wherein the mass ratio of the crude bromfenac sodium to the purified water is 1: 0.8-1.5.
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