CN106278917B - A kind of synthetic method of bromfenac sodium degradation impurity standard items - Google Patents
A kind of synthetic method of bromfenac sodium degradation impurity standard items Download PDFInfo
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- CN106278917B CN106278917B CN201610662554.7A CN201610662554A CN106278917B CN 106278917 B CN106278917 B CN 106278917B CN 201610662554 A CN201610662554 A CN 201610662554A CN 106278917 B CN106278917 B CN 106278917B
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- amino
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- bromophenacyls
- bromfenac sodium
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- 0 OC(C(c1ccc2)=*c1c2C(C1C=CC(Br)=CC1)=O)=O Chemical compound OC(C(c1ccc2)=*c1c2C(C1C=CC(Br)=CC1)=O)=O 0.000 description 1
Classifications
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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
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
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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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Abstract
The invention discloses a kind of synthetic method of bromfenac sodium degradation impurity standard items; it is with 7 (4 benzoyl bromide) indoline 2; 3 diketone are raw material; through hydrolyzing, obtained 2 (2 amino 3 (4 Bromophenacyl) phenyl) 2 Oxoacetic Acid sterlings are refined, sterling is using conventional analysis means calibration content.Impurity preparation method technique provided by the invention is simple and direct, short preparation period, is more than 97.0% through demarcating product content.Bromfenac sodium impurity provided by the invention can be used as contamination levels product, qualitative and quantitative study and detection applied to bromfenac sodium raw material and its preparation impurity.
Description
First, technical field
The present invention relates to a kind of preparation method of impurity of the drug standard items, specifically a kind of bromfenac sodium degradation impurity
The synthetic method of standard items 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acids, belongs to pharmaceutical technology field.
2nd, background technology
Bromine phenolic acid sodium (Bromfenac sodium sesquihydrate), entitled 2- amino -3- (the 4- Bromophenacyls of chemistry
Base) phenylacetic acid sodium salt sesquialter hydrate, it is a kind of non-steroid anti-inflammatory drug, is developed by Japanese Senju Pharma Co., Ltd, 2000
Obtaining Japanese PMDA listings approval March in year, trade name " BRONUCK ", specification is 0.1% sodium bromophenolate eye drops of 5ml/ branch,
For outer eye and the diseases associated with inflammation symptomatic treatment of preceding eye, including scorching (including the upper strong film of blepharitis, conjunctivitis, strong film
It is scorching), post-operation inflammatory etc..
Bromfenac sodium raw material and its preparation can produce degradation impurity in storage, transportational process：2- (2- amino -3- (4- bromines
Benzoyl) phenyl) -2- Oxoacetic Acids, shown in its structure such as formula (I).JapanIF files report the impurity in bromine
Exist in fragrant acid sodium eye drops and can further increase during stability keeps sample, but do not report synthesis and the content of the impurity
Scaling method.In view of the Control of Impurities is most important to bromfenac sodium product quality, and it can make as those skilled in the art
The preparation method and quality determining method of standard items not yet it has been reported that therefore the acquisition of the contamination levels product to effectively control
Bromfenac sodium raw material processed and its quality of the pharmaceutical preparations have great significance.
3rd, the content of the invention
A kind of the present invention is intended to provide bromfenac sodium degradation impurity standard items --- 2- (2- amino -3- (4- Bromophenacyls)
Phenyl) -2- Oxoacetic Acids synthetic method, this method has the advantages that technique is simple and direct, short preparation period, through demarcating product content
It is high.
The synthetic method of bromfenac sodium degradation impurity standard items of the present invention, includes the following steps：
1st, hydrolyze
7- (4- benzoyl bromides) indoline -2,3- diketone is added in 1N potassium hydroxide solutions, it is warming up to 50~
60 DEG C of stirring reaction 6h, are cooled to 20~30 DEG C after the completion of reaction, filtering, and filtrate stirs 0.5h with salt acid for adjusting pH to 3~4,
Filtering, washing, solid are dried under reduced pressure 4~6h in 50~60 DEG C, obtain 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- oxos
Acetic acid crude product.
The molar ratio of (4- benzoyl bromides) indoline -2,3- diketone of 7- described in step 1 and potassium hydroxide is 1:2~
5。
2nd, refine
Organic solvent, agitating and heating are added into 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid crude products
Dissolving, is filtered while hot, and filtrate is cooled to 0~10 DEG C, 3~4h of stirring and crystallizing, filtering, and solid is dried under reduced pressure 4 in 50~60 DEG C~
6h, obtains 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid sterlings, is pale yellow crystals.
(2- amino -3- (4- Bromophenacyls) the phenyl) -2- Oxoacetic Acids of 2- described in step 2 and organic solvent quality volume
Than for 1g:10~30ml.
Organic solvent described in step 2 is selected from one or both of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile.
Synthetic route of the present invention is as follows：
The content calculation method of 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acids produced by the present invention is such as
Under：
Content (%)=(100.0%-loss on drying %-residue on ignition %) × chromatographic purity
Loss on drying is used to measure in sample volatile impurity (such as：Residual solvent) or low boiling impurity is (such as：Moisture)
Content, analysis method are as follows：
Take this product 1g, totally 2 parts, put in the constant temperature vacuum drying apparatus added with phosphorus pentoxide, according to dry weightless mensuration (in
Four general rules of state's pharmacopeia 2015 edition<0831>) 60 DEG C be dried under reduced pressure to constant weight, calculate less loss weight respectively and account for the hundred of sample total amount
Divide ratio, take the average value of 2 results.
Residue on ignition is used to measure in sample inorganic impurity (such as：Inorganic salts) or can not carbide (such as：Metal) content,
Analysis method is as follows：
This product 1g is taken, totally 2 parts, according to residue on ignition determination method (four general rules of Chinese Pharmacopoeia 2015 edition<0841>) measure, point
Not Ji Suan level of residue account for the percentage of sample total amount, take the average value of 2 results.
Chromatographic purity is used to analyze the ratio that main composition in sample accounts for detection total organic matter, and analysis method is as follows：
HPLC methods：
Chromatographic column：Hypersil ODS2 (4.6mm × 150mm, 5.0 μm)
Mobile phase：0.05mol/L ammonium acetates-methanol-tetrahydrofuran (60：55：15)
Detection wavelength：266nm
Sample concentration：0.3mg/ml (solvent is mobile phase)
Flow velocity：1ml/min
Sample size：10μl
In HPLC chromatogram, after deducting solvent peak, calculating main peak content by areas of peak normalization method, (main peak area accounts for Zong Feng
The percentage of area).Chromatographic purity is calculated as follows：
Chromatographic purity=main peak content %/100%
As stated above, 2- produced by the present invention (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acids are demarcated to contain
Amount, calibration content are all higher than 97.0%.
2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid preparation processes of the invention are simple and direct, synthesis cycle
Short, synthesis cost is low, is both adapted to laboratory to synthesize in a small amount, it can also be used to mass produce.2- (2- amino -3- (the 4- of the present invention
Bromophenacyl) phenyl) -2- Oxoacetic Acid contents scaling method is conventional method of analysis, appointed condition is not high, easily realizes.Adopt
The calibration content of 2- (2- amino -3- (4- Bromophenacyls) the phenyl) -2- Oxoacetic Acids prepared with the method for the present invention is all higher than
97.0%, contamination levels product can be used as, applied to the qualitative and quantitative study and detection of bromfenac sodium raw material and its preparation impurity,
There is positive progress meaning to effectively control bromfenac sodium raw material and its quality of the pharmaceutical preparations.
4th, illustrate
Fig. 1 is 2- in embodiment 2 (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid purity detecting chromatograms.
It will be seen from figure 1 that chromatographic purity is 0.9803.
Fig. 2 is 2- in embodiment 3 (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid purity detecting chromatograms.
Figure it is seen that chromatographic purity is 0.9773.
5th, embodiment
Preferable examples of the present invention will be described below, it will be appreciated that preferred embodiment described herein is only used for
The bright and explanation present invention, is not intended to limit the present invention.
Raw material 7- (4- benzoyl bromides) indoline -2,3- diketone of the present invention can be general commercially available commercial synthesis
Product, can be also made by 1 method of embodiment.
Embodiment 1：The preparation of 7- (4- benzoyl bromides) indoline -2,3- diketone
Using 7- made from general industrial method (4- benzoyl bromides) Indolin-2-one, (No. CAS is 91713-
91-6) it is raw material.
7- (4- benzoyl bromides) Indolin-2-one 25g (79mmol) stirrings are dissolved in 750ml ethyl acetate, are thrown
Enter copper bromide 88.2g (395mmol), reaction 4h be refluxed in 78~85 DEG C, is cooled to 20~30 DEG C, reaction solution successively with
The isometric water of ethyl acetate, saturated sodium-chloride water solution washing, organic phase be concentrated under reduced pressure into 50~60 DEG C it is dry, add methanol/
Water (volume ratio 4:1) mixed solution 700ml, reaction 3h is refluxed in 70~80 DEG C, is cooled to 20~30 DEG C, is filtered, filter cake
Washed successively with suitable quantity of water, methanol, solid adds methanol 500ml, and flow back 30min in 65~70 DEG C, filters while hot, filtrate cooling
To -5~0 DEG C of stirring and crystallizing 2h, filtering, solid is dried under reduced pressure 8h in 60~70 DEG C, obtain 7- (4- benzoyl bromides) indoline -
2,3- diketone 13.5g, yield 51.7%.
Elemental analysis is C15H8BrNO3
| Analysis project | C (%) | H (%) | N (%) | Br (%) |
| Theoretical value | 54.57 | 2.44 | 4.24 | 24.20 |
| Measured value | 54.28 | 2.47 | 4.67 | 24.07 |
TOF-MS[M-H]-：327.9(Exact Mass：328.97)
IR(KBr)ν(cm-1)：3243,3080,1760,1745,1653,1599,1481,1461,1268,1195,1007
1HNMR(DMSO-d6)δ(ppm)：11.03 (s, 1H, NH), 7.69~7.81 (m, 6H, Ar-H), 7.17 (t, 1H,
Ar-H)
13CNMR(DMSO-d6)δ(ppm)：193.2,183.7,160.2,150.4,138.7,135.9,132.4,132.1,
128.4 (2C), 128.0 (2C), 122.6,121.4,119.7
Embodiment 2：The preparation of 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acids
1st, 7- (4- benzoyl bromides) indoline -2,3- diketone 8.25g (25mmol) are added to 75ml (75mmol)
In 1N potassium hydroxide solutions, stirring is warming up to 50~60 DEG C, and stirring reaction 6h, stirring is cooled to 20~30 DEG C, and filtering, filtrate is used
Dilute hydrochloric acid adjusts pH to 3~4, stirs 0.5h, filtering is appropriate to wash, and solid is dried under reduced pressure 4~6h in 50~60 DEG C, obtains 2- (2-
Amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid crude product 7g, yield 80.5%；
2nd, 7g 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid crude products are added in 100ml ethanol,
Stirring is warming up to 75~80 DEG C of dissolvings, filters while hot, and filtrate is cooled to 0~10 DEG C, 3~4h of stirring and crystallizing, and filtering, solid is in 50
~60 DEG C are dried under reduced pressure 4~6h, obtain 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid sterling 5.5g, yield
78.6%.
Elemental analysis is C15H10BrNO4
| Analysis project | C (%) | H (%) | N (%) |
| Theoretical value | 51.75 | 2.90 | 4.02 |
| Measured value | 51.62 | 3.05 | 4.12 |
TOF-MS[M-H]-：345.9(Exact Mass：346.98)
IR(KBr)ν(cm-1)：3409,3292,1632,1602,1585,1556,1232,1006,767
1HNMR(DMSO-d6)δ(ppm)：12.71 (brs, 1H, COOH), 8.16 (s, 2H, NH), 7.98 (m, 1H, Ar-
H), 7.62 (d, 2H, Ar-H), 7.43 (m, 3H, Ar-H), 6.47 (t, 1H, Ar-H)
13CNMR(DMSO-d6)δ(ppm)：197.0,196.2,172.8,150.2,138.7,138.4,135.3,132.8
(2C), 131.5 (2C), 124.3,120.8,113.7,112.7
Content calibration result：
Purity detecting chromatogram is shown in Fig. 1.
Embodiment 3：The preparation of 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acids
1st, 7- (4- benzoyl bromides) indoline -2,3- diketone 10g (30.2mmol) are added to 120ml
In (120mmol) 1N potassium hydroxide solutions, stirring is warming up to 50~60 DEG C, and stirring reaction 6h, stirring is cooled to 20~30 DEG C, mistake
Filter, filtrate adjust pH to 3~4 with dilute hydrochloric acid, stir 0.5h, filtering, appropriate washing, and solid is dried under reduced pressure 4 in 50~60 DEG C~
6h, obtains 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid crude product 8.3g, yield 78.9%；
2nd, 8.3g 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid crude products are added to 160ml acetonitriles
In, stirring is warming up to 75~80 DEG C of dissolvings, filters while hot, and filtrate is cooled to 0~10 DEG C, 3~4h of stirring and crystallizing, filters, solid
4~6h is dried under reduced pressure in 50~60 DEG C, obtains 2- (2- amino -3- (4- Bromophenacyls) phenyl) -2- Oxoacetic Acid sterling 6.2g, is received
Rate 74.7%.
Content calibration result：
Purity detecting chromatogram is shown in Fig. 2.
Unless otherwise defined, all professional terms and term used in the present invention are familiar with one skilled in the art
Meaning it is consistent.In addition, any method similar or impartial to described content and material all can be applied in the method for the present invention.
Claims (2)
1. a kind of synthetic method of bromfenac sodium degradation impurity standard items, it is characterised in that include the following steps：
（1）Hydrolysis
By 7-（4- benzoyl bromides）Indoline -2,3- diketone is added in 1N potassium hydroxide solutions, is warming up to 50 ~ 60 DEG C and is stirred
Reaction 6h is mixed, is cooled to 20 ~ 30 DEG C after the completion of reaction, filtering, filtrate stirs 0.5h, filtering, water with salt acid for adjusting pH to 3 ~ 4
Wash, solid is dried under reduced pressure 4 ~ 6h in 50 ~ 60 DEG C, obtains 2-（2- amino -3-（4- Bromophenacyls）Phenyl）- 2- Oxoacetic Acid crude products；
Step（1）Described in 7-（4- benzoyl bromides）The molar ratio of indoline -2,3- diketone and potassium hydroxide is 1:2~5；
（2）It is refined
To 2-（2- amino -3-（4- Bromophenacyls）Phenyl）Organic solvent is added in -2- Oxoacetic Acid crude products, agitating and heating is molten
Solution, is filtered while hot, and filtrate is cooled to 0 ~ 10 DEG C, 3 ~ 4h of stirring and crystallizing, and filtering, solid is dried under reduced pressure 4 ~ 6h in 50 ~ 60 DEG C, obtains 2-
（2- amino -3-（4- Bromophenacyls）Phenyl）- 2- Oxoacetic Acid sterlings, are pale yellow crystals；
Step（2）Described in organic solvent be selected from methanol, ethanol, isopropanol, ethyl acetate, one or both of acetonitrile.
2. synthetic method according to claim 1, it is characterised in that：
Step（2）Described in 2-（2- amino -3-（4- Bromophenacyls）Phenyl）- 2- Oxoacetic Acids and organic solvent mass volume ratio
For 1g:10~30ml.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4126635A (en) * | 1975-08-13 | 1978-11-21 | A. H. Robins Company, Incorporated | 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
| 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 |
| WO2016126570A1 (en) * | 2015-02-06 | 2016-08-11 | Merck Sharp & Dohme Corp. | Aminoquinazoline compounds as a2a antagonist |
-
2016
- 2016-08-12 CN CN201610662554.7A patent/CN106278917B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4126635A (en) * | 1975-08-13 | 1978-11-21 | A. H. Robins Company, Incorporated | 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
| 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 |
| WO2016126570A1 (en) * | 2015-02-06 | 2016-08-11 | Merck Sharp & Dohme Corp. | Aminoquinazoline compounds as a2a antagonist |
Non-Patent Citations (5)
| Title |
|---|
| A simple one-pot synthesis of quinoline-4-carboxylic acids by the Pfitzinger reaction of isatin with enaminones in water;Elghamry,Ibrahim 等;《Tetrahedron Letters》;20151125;第57卷(第1期);第111页图解2 * |
| Ocular tissue distribution in rabbit after instillation of bromfenac sodium ophthalmic solution;Isaka, Mitsuyoshi 等;《Yakubutsu Dotai》;19991231;第14卷(第1期);第40页图解1 * |
| The cleavage of heterocyclic compounds in organic synthesis II [1] Use of 5-nitroisatin for synthesis of various nitrogenous heterocycles;Hlavac,Jan 等;《Journal of Heterocyclic Chemistry》;20041116;第41卷(第4期);第633页右栏图解1和第634页右栏第2段 * |
| Utility of the Pfitzinger reaction in the Synthesis of Novel Quinoline Derivatives and Related Heterocycles;Goek, Dervis 等;《Journal of Heterocyclic Chemistry》;20131031;第51卷(第1期);第225页图解1和第228页实验部分第2段 * |
| 溴芬酸钠的合成;夏泽宽 等;《中国药科大学学报》;20031025;第34卷(第5期);第405-406页 * |
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