CN108658833A - Related substance of a kind of bromfenac sodium and preparation method thereof - Google Patents
Related substance of a kind of bromfenac sodium and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 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 abstract description 21
- 229960002716 bromfenac sodium Drugs 0.000 title abstract description 19
- 239000000126 substance Substances 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 11
- -1 hydrogen indoles Chemical class 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 3
- 239000001257 hydrogen Substances 0.000 claims abstract 3
- 150000002576 ketones Chemical class 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 239000012043 crude product Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 235000019441 ethanol Nutrition 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- HJMPRVFVCNHHCE-UHFFFAOYSA-N BrN(C(NC(CO)=O)=O)Br Chemical compound BrN(C(NC(CO)=O)=O)Br HJMPRVFVCNHHCE-UHFFFAOYSA-N 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 3
- 238000004458 analytical method Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 abstract 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 101100256637 Drosophila melanogaster senju gene Proteins 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- RLYMYJIKUNPYRY-UHFFFAOYSA-N [O-2].O.O.[Mn+2] Chemical class [O-2].O.O.[Mn+2] RLYMYJIKUNPYRY-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 229960003655 bromfenac Drugs 0.000 description 1
- 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 description 1
- 229950011307 bromfenac sodium sesquihydrate Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010015915 eye discharge Diseases 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000006278 hypochromic anemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 206010023683 lagophthalmos Diseases 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N methyl mercaptane Natural products SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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 present invention provides a kind of structure and its preparation, purification process of the bromfenac sodium in relation to substance, structure of the related substance of the bromfenac sodium with compound of formula I, and preparation method step includes：Step (1)：7 (4 benzoyl bromide) 1 hydrogen indoles are reacted with N bromo-acid amides, 2 methyl cellosolves react, and generate intermediate formula III compound：3 bromine 2 (2 methoxy ethoxy) 7 (4 benzoyl bromide) 1 hydrogen indoles；Step (2)：Intermediate formula III compound is reacted with 7 (4 benzoyl bromide) indoline, 2 ketone (formula IV compound) in acid condition generates compound of formula I.The beneficial effects of the invention are as follows：Structural formula, preparation and the purification process of compound of formula I, are of great importance for the quality analysis of bromfenac sodium finished product.The preparation method simple process, agents useful for same is cheap and easy to get, and environmental pollution is small, and product purity is higher.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to related substance of a kind of bromfenac sodium and preparation method thereof.
Background technology
Bromfenac sodium (Bromfenac sodium sesquihydrate, chemical name：2- amino -3- (4- Bromophenacyls
Base) sodium phenylacetate times semihydrate) it is a kind of non-steroidal anti-inflammatory drugs, the prostanoid inflammation that cyclooxygenase mediates can be inhibited to be situated between
The synthesis of matter has strength anti-inflammatory analgesic action.Sodium bromophenolate eye drops are developed by Japanese Senju Pharma Co., Ltd, in 2000
Year lists in Japan, trade name BRONUCK, for 0.1% bromfenac sodium ophthalmic solution of 5ml/ branch.The medicine passed through in 2006
SFDA is examined, in Discussion on Chinese Listed, for outer eye and the symptomatic treatment of the diseases associated with inflammation of preceding eye：It is blepharitis, conjunctivitis, strong
Film scorching (including upper strong film is scorching), post-operation inflammatory etc..It is notable to the therapeutic effect of eyes post-operation inflammatory；Twice a day use prescription
Case compares other administering modes of non-steroidal anti-inflammatory drugs eye drops generally four times a day, and easy to use, patient dependence is strong；It is resistance to
Good by property, on intraocular pressure without influence, ocular side effect incidence is low.
The preparation method of published bromfenac sodium includes mainly following two：(1) 4126635 Hes of United States Patent (USP) US
US4182774 is using 2- amino -4- bromines benzophenone as starting material, with the cyclization under the catalysis of pivaloyl chloride of methylmercaptan ethyl acid esters
Synthesis of indole ketone, then through catalytic hydrogenation, hydrolyze to obtain product.
(2) document J Med Chem 1984,27 (11):1379-1388 and European patent EP 0221753 are with to bromobenzene first
Nitrile and indoline are raw material, carry out Fu Ke acylations as catalyst using alchlor and boron trifluoride, then through activated manganese dioxide oxygen
Change, NCS chloros, acidolysis, basic hydrolysis generate bromfenac sodium.
One severe reaction conditions of method, starting material are not easy；Method second reacts relatively mild and raw material is cheap and easy to get, therefore
And the industrial general preparation that bromfenac sodium bulk pharmaceutical chemicals are carried out using method two, but two complex steps of method.
Our combined methods one and method two are improved the synthesis technology of bromfenac sodium, are found in development, 3-
Chloro- 7- (4- benzoyl bromides) -1 hydrogen-indoles hydrolyzes in acid condition generates 7- (4- benzoyl bromides) Indolin-2-one
During, it is easy to happen dimerization, generates compound of formula I.Although the impurity is in 7- (4- benzoyl bromides) Indolin-2-one
Middle content is relatively low, but is difficult to isolate and purify using the prior art, and the impurity can bring Bromfenac into subsequent reaction process
It is most important for the quality analysis of bromfenac sodium finished product in sodium product.It can be right it has been investigated that there are the impurity in eye drops
Eyes cause different degrees of stimulation, can especially eye discharge be caused to increase.
The impurity is not sold at home and abroad in the market at present, is not also had it has been reported that therefore, the preparation to the impurity
Technique study is of great significance.
Invention content
The object of the present invention is to provide a kind of structure of bromfenac sodium in relation to substance and its preparation, purification process, by this
The related substance of bromfenac sodium of high-purity can be prepared in method.
The related substance of the bromfenac sodium has the structure of compound of formula I.
The present inventor is with bromfenac sodium preparation process, with Formula II compound 7- (4- benzoyl bromides) -1 hydrogen-indoles and formula
IV compounds：7- (4- benzoyl bromides) Indolin-2-one is raw material, controlled syntheses preparation of compounds of formula I, this method operation
The compound of formula I purity of simplicity, preparation is higher, is suitable as the use of contamination levels product.
The structure of compound of formula I is as follows：
Formula I synthetic routes are as follows：
Step (1)：7- (4- benzoyl bromides) -1 hydrogen-indoles is reacted with N- bromo-acid amides, 2-methyl cellosolve reacts, raw
At intermediate-formula III compound；
Step (2)：Intermediate-formula III compound in acid condition with 7- (4- benzoyl bromides) Indolin-2-one
(formula IV compound) reaction generates compound of formula I.
In order to achieve better technical results, described the method for preparing compound of formula I further includes step (3)：It will be described
Compound of formula I crude product is recrystallized using dichloromethane/Organic Alcohol, cooling, and filtering obtains the compound of formula I impurity of high-purity.
Preparation method of the bromfenac sodium in relation to substance of the present invention, includes the following steps：
(1) 7- (4- benzoyl bromides) -1 hydrogen-indoles is added in organic solvent and is dissolved, 2-methyl cellosolve, N- is added
Bromo-acid amide adds rear temperature reaction, obtains intermediate-formula III compound；
(2) above-mentioned formula III compound is added in organic solvent, 7- (4- benzoyl bromides) Indolin-2-one is added
(formula IV compound) is added dropwise acid, first reacts at room temperature, then temperature reaction obtains compound of formula I crude product；
(3) the compound of formula I crude product is recrystallized to give to the compound of formula I of high-purity using dichloromethane/Organic Alcohol
Impurity.
Above-mentioned each reaction step is illustrated below：
The rate of charge of step (1) compound of formula H and the 2-methyl cellosolve, 1 is calculated as by w/v：0.3-0.5.
N- bromo-acid amides described in step (1) are selected from N- bromo-succinimides (NBS) or C5H6Br2N2O2 (DBH), preferably
DBH。
The rate of charge of step (1) compound of formula H and the N- bromo-acid amides, 1 is calculated as by w/v：0.5-0.7.
The reaction temperature of step (1) is 30-40 DEG C.
Organic solvent described in step (1) is dichloromethane or chloroform, and Formula II compound and organic solvent feed intake
Than being 1 based on w/v：20-30.
Organic solvent described in step (2) be dimethylformamide, dimethyl sulfoxide (DMSO), tetrahydrofuran or acetone, preferably two
Methylformamide, formula III compound organic solvent rate of charge, 1 is calculated as by w/v：5-10.
Acid described in step (2) is sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid, perchloric acid, preferably hydrochloric acid.
Step (2) plants the dosage (molar ratio) of 7- (4- benzoyl bromides) Indolin-2-one (formula IV compound)
For 1.0-1.5.
The reaction temperature of step (2) is -60 DEG C of room temperature.
The rate of charge of step (2) compound of formula III and the acid, 1 is calculated as by w/v:0.3-0.5.
The ratio of dichloromethane/Organic Alcohol described in step (3) is 1：5-1:10, preferably 1:8-1:10.
Organic Alcohol described in step (3) is methanol, ethyl alcohol or isopropanol.
Recrystallization temperature described in step (3) is 30-38 DEG C, and cooling temperature is 10-20 DEG C.
The present invention also provides midbody compounds --- and formula III compound, structure are：
The preparation method of formula III compound is：With (1) the step of preparation of compounds of formula I.
We prove compound of formula I concentration to the toxic work of the growth of Human glioma by In vitro cell experiment
With, and as swelling or even solubility phase diagram phenomenon occurs in the increase cell of concentration.Formulas I is also proved by lagophthalmos stimulation test
Closing object single-dose, to be slight or moderate to eyes stimulate, and when multiple dose administration, can eyes be formed with moderate or severe stimulates.
The present invention provides the structural formula of compound of formula I impurity, preparation and purification process, for the matter of bromfenac sodium finished product
Amount analysis is of great importance.The preparation method simple process, agents useful for same is cheap and easy to get, and environmental pollution is small, product purity compared with
It is high.
Description of the drawings
Fig. 1 is the HPLC figures of the compound of formula I prepared in embodiment 2.1.
Fig. 2 is the HPLC figures of the compound of formula I prepared in embodiment 2.2.
Fig. 3 is the HPLC figures of the compound of formula I prepared in embodiment 3.1.
Fig. 4 is the positive ion mode mass spectrogram of the compound of formula I finished product prepared in embodiment 3.1.
Specific implementation mode
Embodiment 1
The preparation of intermediate-formula III compound：
1.1 20g 7- (4- benzoyl bromides) -1 hydrogen-indoles is added in 400ml dichloromethane, after stirring and dissolving, is added
7.8ml2- methyl cellosolves are cooled to 10 DEG C, and 10g DBH are added in three batches, and about 30min is added, 35 DEG C are warming up to after adding and is stirred
Mix reaction 6-8 hours.Water is added, liquid separation after stirring 0.5 hour, twice, organic phase is concentrated to dryness, and obtains 27.1g intermediates for washing
Formula III compound, yield 89.2%.
1.2 20g 7- (4- benzoyl bromides) -1 hydrogen-indoles is added in 500ml chloroforms, after stirring and dissolving, is added
10ml2- methyl cellosolves are cooled to 5 DEG C, and 12g C5H6Br2N2O2s are added in three batches, and about 30min is added, and 40 DEG C are warming up to after adding
It is stirred to react 8 hours.Water is added, liquid separation after stirring 1 hour, twice, organic phase is concentrated to dryness, and obtains 26.7g intermediate formulas for washing
III compounds, yield 87.9%.
1.3 10g 7- (4- benzoyl bromides) -1 hydrogen-indoles is added in 250ml dichloromethane, after stirring and dissolving, is added
3.9ml2- methyl cellosolves are cooled to 25 DEG C, and 5g DBH are added in three batches, and about 30min is added, 30 DEG C are warming up to after adding and is stirred
Mix reaction 5 hours.Water is added, liquid separation after stirring 1 hour, twice, organic phase is concentrated to dryness, and obtains 12.3g intermediate formula IIIs for washing
Compound, yield 81.0%.
1.4 15g 7- (4- benzoyl bromides) -1 hydrogen-indoles is added in 350ml chloroforms, after stirring and dissolving, is added
5.8ml 2-methyl cellosolves are cooled to 18 DEG C, and 10g DBH are added in three batches, and 30min is added, 40 DEG C are warming up to after adding and is stirred
Mix reaction 8 hours.Water is added, stirs liquid separation after 20min, twice, organic phase is concentrated to dryness, and obtains 17.9g intermediate formula IIIs for washing
Compound, yield 78.3%.
1.5 20g 7- (4- benzoyl bromides) -1 hydrogen-indoles is added in 400ml dichloromethane, after stirring and dissolving, is added
6.0ml 2-methyl cellosolves are cooled to 22 DEG C, and 14g C5H6Br2N2O2s are added in three batches, and about 30min is added, is warming up to after adding
38 DEG C are stirred to react 9 hours.Water is added, liquid separation after stirring 0.8 hour, twice, organic phase is concentrated to dryness, and is obtained in 27.0g for washing
Mesosome formula III compound, yield 88.9%.
Embodiment 2
The preparation of 2.1 compound of formula I crude products：
The intermediate formula III compound that the 1.1 of 10g embodiments 1 are prepared is added in 50ml dimethylformamides, and stirring is molten
Xie Hou is cooled to 0 DEG C or so, and 7.74g 7- (4- benzoyl bromides) Indolin-2-one is added, and 3ml hydrochloric acid, control temperature is added dropwise
Degree is less than 10 DEG C, after adding, and is warmed to room temperature reaction 2 hours, is continuously heating to 55 DEG C and reacts 2 hours.It is down to room temperature, is diluted to ice
In water, filtering is washed to neutrality, dry 14.12g compound of formula I crude products, yield 95.5%, purity 85.74%, HPLC
Figure is as shown in Figure 1.
The preparation of 2.2 compound of formula I crude products
The 1.2 of the 10g embodiments 1 intermediate formula III compound prepared is taken to be added in 80ml tetrahydrofurans, stirring and dissolving
Afterwards, 5 DEG C or so are cooled to, 7.98g 7- (4- benzoyl bromides) Indolin-2-one is added, 5ml hydrochloric acid is added dropwise, controls temperature
Less than 10 DEG C, after adding, it is warmed to room temperature reaction 2 hours, 50 DEG C is continuously heating to and reacts 3 hours.It is down to room temperature, is diluted to ice water
In, filtering is washed to neutrality, dry that 13.5g compound of formula I crude products, yield 91.3%, purity 71.97%, HPLC scheme such as
Shown in Fig. 2.
The preparation of 2.3 compound of formula I crude products
The 1.3 of the 10g embodiments 1 intermediate formula III compound prepared is taken to be added in 50ml acetone, after stirring and dissolving, drop
7.74g 7- (4- benzoyl bromides) Indolin-2-one is added to 5 DEG C or so in temperature, and 8ml acetic acid is added dropwise, and control temperature is less than
10 DEG C, after adding, it is warmed to room temperature reaction 3 hours, 40 DEG C is continuously heating to and reacts 2 hours.It is down to room temperature, is diluted in ice water,
Filtering, is washed to neutrality, dry 12.9g compound of formula I crude products, yield 87.22%, purity 73.10%.
The preparation of 2.4 compound of formula I crude products
The 1.4 of the 10g embodiments 1 intermediate formula III compound prepared is taken to be added in 100ml acetone, after stirring and dissolving, drop
8.26g 7- (4- benzoyl bromides) Indolin-2-one is added to 0 DEG C in temperature, and 4ml sulfuric acid is added dropwise, and control temperature is less than 8 DEG C,
After adding, it is warmed to room temperature reaction 2 hours, 55 DEG C is continuously heating to and reacts 2 hours.It is down to room temperature, is diluted in ice water, is filtered,
It is washed to neutrality, dry 13.15g compound of formula I crude products, yield 88.9%, purity 72.31%.
The preparation of 2.5 compound of formula I crude products
The 1.5 of the 10g embodiments 1 intermediate formula III compound prepared is taken to be added in 80ml dimethylformamides, stirring is molten
Xie Hou is cooled to 5 DEG C or so, and 7.74g 7- (4- benzoyl bromides) Indolin-2-one is added, and 5ml hydrochloric acid, control temperature is added dropwise
Degree is less than 10 DEG C, after adding, and is warmed to room temperature reaction 4 hours, is continuously heating to 60 DEG C and reacts 2 hours.It is down to room temperature, is diluted to ice
In water, filtering is washed to neutrality, dry 13.8g compound of formula I crude products, yield 93.3%, purity 71.86%.
Embodiment 3
The preparation of compound of formula I finished product
60ml dichloromethane/ethyl alcohol (1 is added in the 3.1 compound of formula I crude products for taking 10g embodiments 2.1 to obtain：10) it mixes molten
In agent, 38 DEG C of dissolvings are heated to, heat filters out insoluble matter, slowly cools to 10 DEG C under filtrate stirring, filtering, dry 7.8g formulas
Compound I finished product, yield 78%, purity 99.61%, HPLC figures are as shown in figure 3, mass spectrogram (cation point as shown in Figure 4
Daughter ion peak M+1=673.01, molecular weight M=672).
80ml dichloromethane/isopropanol (1 is added in the 3.2 compound of formula I crude products for taking 10g embodiments 2.2 to obtain：5) it mixes
In solvent, 35 DEG C of dissolvings are heated to, heat filters out insoluble matter, slowly cools to 15 DEG C under filtrate stirring, filtering, dry 7.5g
Compound of formula I finished product, yield 75%, purity 99.47%.
80ml dichloromethane/isopropanol (1 is added in the 3.3 compound of formula I crude products for taking 10g embodiments 2.3 to obtain：10) it mixes
In solvent, 37 DEG C of dissolvings are heated to, heat filters out insoluble matter, slowly cools to 15 DEG C under filtrate stirring, filtering, dry 8.1g
Compound of formula I finished product, yield 81%, purity 99.62%.
80ml methylene chloride/methanols (1 are added in the 3.4 compound of formula I crude products for taking 10g embodiments 2.4 to obtain：8) it mixes molten
In agent, 30 DEG C of dissolvings are heated to, heat filters out insoluble matter, slowly cools to 20 DEG C under filtrate stirring, filtering, dry 8.0g formulas
Compound I finished product, yield 80%, purity 99.58%.
80ml dichloromethane/ethyl alcohol (1 is added in the 3.5 compound of formula I crude products for taking 10g embodiments 2.5 to obtain：5) it mixes
In solvent, 32 DEG C of dissolvings are heated to, heat filters out insoluble matter, slowly cools to 18 DEG C under filtrate stirring, filtering, dry 8.3g
Compound of formula I finished product, yield 83%, purity 99.49%.
One embodiment of the present invention has been described in detail above, but the content be only the present invention preferable implementation
Example should not be construed as limiting the practical range of the present invention.It is all according to all the changes and improvements made by the present patent application range
Deng should all still fall within the scope of the patent of the present invention.
Claims (10)
1. a kind of compound, it is characterised in that：The compound has the following structure formula
2. the method for preparing compound of formula I described in claim 1, it is characterised in that：Its preparation route is：
Step (1)：7- (4- benzoyl bromides) -1 hydrogen-indoles is reacted with N- bromo-acid amides, 2-methyl cellosolve reacts, in generation
Mesosome-formula III compound；
Step (2)：Intermediate-formula III compound in acid condition with formula IV compound：7- (4- benzoyl bromides) dihydro Yin
Diindyl -2- reactive ketones generate compound of formula I.
3. the method for preparing compound of formula I according to claim 2, it is characterised in that：N- bromo acyls described in step (1)
Amine is selected from N- bromo-succinimides (NBS) or C5H6Br2N2O2 (DBH)；Described in step (2) acid selected from sulfuric acid, hydrochloric acid, acetic acid,
Phosphoric acid, perchloric acid.
4. the method for preparing compound of formula I according to claim 3, it is characterised in that：The N- bromo-acid amides are dibromo
Glycolylurea (DBH)；The acid is hydrochloric acid.
5. the method for preparing compound of formula I according to claim 2, it is characterised in that：2-methyl cellosolve in step (1)
With the rate of charge of Formula II compound, 1 is calculated as by w/v:0.3-0.5；Step (1) compound of formula H and the N- bromo-acid amides
Rate of charge is calculated as 1 by w/v：0.5-0.7；The rate of charge of step (2) compound of formula III and the acid, 1 is calculated as by w/v:
0.3-0.5。
6. the method for preparing compound of formula I according to claim 2, it is characterised in that：The reaction temperature of step (1) is
30-40 DEG C, the reaction temperature of step (2) is -60 DEG C of room temperature.
7. the method for preparing compound of formula I according to claim 2, it is characterised in that：Step (1) and step (2) will
Reactant is dissolved in organic solvent, the one kind or two of organic solvent in dichloromethane or chloroform described in step (1)
Kind；One kind in dimethylformamide, dimethyl sulfoxide (DMSO), tetrahydrofuran or acetone of organic solvent described in step (2) or
Two kinds.
8. the method for preparing compound of formula I according to claim 2, it is characterised in that：Further include step (3)：It will be described
Compound of formula I crude product is recrystallized using dichloromethane/Organic Alcohol, the Organic Alcohol in methanol, ethyl alcohol or isopropanol one
Kind is several；The ratio of dichloromethane/Organic Alcohol is 1：5-1:10.
9. the method for preparing compound of formula I according to claim 8, it is characterised in that：Dichloromethane in step (3)/have
The ratio of machine alcohol is 1:8-1:10.
10. a kind of compound, it is characterised in that：The compound is the bromo- 2- of 3- (2- methoxy ethoxies) -7- (4- Bromophenacyls
Base) -1 hydrogen indoles, have the following structure formula
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177272A (en) * | 2014-06-16 | 2014-12-03 | 广东众生药业股份有限公司 | Preparation method of bromfenac sodium |
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2017
- 2017-03-31 CN CN201710207071.2A patent/CN108658833A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177272A (en) * | 2014-06-16 | 2014-12-03 | 广东众生药业股份有限公司 | Preparation method of bromfenac sodium |
Non-Patent Citations (1)
| Title |
|---|
| JAYA SHREE ANIREDDY ET AL.: "Development and Validation of a New StabilityIndicating RP-UPLC Method for the Quantitative Determination of Bromfenac Sodium and Its Impurities in an Ophthalmic Dosage Form", 《JOURNAL OF CHROMATOGRAPHIC SCIENCE》 * |
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Address after: 300457 Tianjin Binhai New Area Development Zone West District Xinye nine Street North, Xinhuan West Road East. Applicant after: Tianjin Pharmaceutical Research Institute Co.,Ltd. Address before: 300457 Tianjin Binhai New Area Development Zone West District Xinye nine Street North, Xinhuan West Road East. Applicant before: TIANJIN PHARMACEUTICALS Group Corp. |
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Application publication date: 20181016 |