CN106278918A - A kind of bromfenac sodium contamination levels product 2 amino 3 (4 benzoyl bromide) benzoic synthetic method - Google Patents
A kind of bromfenac sodium contamination levels product 2 amino 3 (4 benzoyl bromide) benzoic synthetic method Download PDFInfo
- Publication number
- CN106278918A CN106278918A CN201610662569.3A CN201610662569A CN106278918A CN 106278918 A CN106278918 A CN 106278918A CN 201610662569 A CN201610662569 A CN 201610662569A CN 106278918 A CN106278918 A CN 106278918A
- Authority
- CN
- China
- Prior art keywords
- benzoyl bromide
- amino
- synthetic method
- benzoic acid
- indoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of bromfenac sodium contamination levels product 2 amino 3 (4 benzoyl bromide) benzoic synthetic method; it is with 7 (4 benzoyl bromide) indoline 2; 3 diketone are raw material; through decarboxylation, refined 2 amino 3 (4 benzoyl bromide) the benzoic acid sterlings that prepare, the analysis means demarcation content that sterling employing is conventional.The impurity preparation method technique that the present invention provides is simple and direct, manufacturing cycle is short, through demarcating product content more than 99.0%.The bromfenac sodium impurity that the present invention provides can be applied to bromfenac sodium raw material and the qualitative and quantitative study of preparation impurity thereof and detection as contamination levels product.
Description
One, technical field
The present invention relates to the preparation method of a kind of impurity of the drug standard substance, specifically a kind of bromfenac sodium contamination levels
Product 2-amino-3-(4-benzoyl bromide) benzoic synthetic method, belongs to pharmaceutical technology field.
Two, background technology
Bromine phenolic acid sodium (Bromfenac sodium sesquihydrate), chemical entitled 2-amino-3-(4-Bromophenacyl
Base) phenylacetic acid sodium salt sesquialter hydrate, it is a kind of nonsteroidal antiinflammatory drug, Senju Pharma Co., Ltd of Japan develops, 2000
Obtaining Japan PMDA listing approval, trade name " BRONUCK " March in year, specification is 0.1% sodium bromophenolate eye drops that 5ml/ props up,
For the diseases associated with inflammation symptomatic treatment of outer eye and front eye, (include upper strong film including blepharitis, conjunctivitis, strong film inflammation
Scorching), post-operation inflammatory etc..
Bromfenac sodium raw material and preparation thereof can produce degradation impurity in storage, transportation: 2-amino-3-(4-bromobenzene
Formoxyl) benzoic acid, shown in its structure such as formula (I).JapanIF file reports that this impurity is at bromfenac sodium eye drip
Liquid exist and can increase further during stability keeps sample, but not reporting synthesis and the content scaling method of this impurity.
In view of this Control of Impurities is most important to bromfenac sodium product quality, and its standard substance that can use as those skilled in the art
Preparation method and quality determining method not yet have document to report, therefore the acquisition of these contamination levels product is to effectively controlling bromfenac sodium
Raw material and the quality of the pharmaceutical preparations thereof have great significance.
Three, summary of the invention
It is desirable to provide a kind of bromfenac sodium contamination levels product 2-amino-3-(4-benzoyl bromide) benzoic acid
Synthetic method, this method has the advantage that technique is simple and direct, manufacturing cycle is short, high through demarcating product content.
The synthetic method of bromfenac sodium contamination levels product of the present invention, comprises the steps:
1, decarboxylation
By 7-(4-benzoyl bromide) indoline-2,3-diketone puts in the sodium hydrate aqueous solution of 5wt%, 50~60
DEG C stirring and dissolving, drips the hydrogen peroxide of 30wt% subsequently, in 50~60 DEG C of stirring reaction 1h after dripping off, is cooled to after having reacted
20~30 DEG C, filtering, filtrate, with 10% salt acid for adjusting pH value to 3~4, is filtered, and filter cake washes with water, and solid subtracts in 50~60 DEG C
Press dry dry 4~6h, obtain 2-amino-3-(4-benzoyl bromide) benzoic acid crude product;
The mol ratio of 7-described in step 1 (4-benzoyl bromide) indoline-2,3-diketone and sodium hydroxide be 1:5~
8;7-(4-benzoyl bromide) indoline-2,3-diketone and H2O2Mol ratio be 1:40~60.
2, refined
Adding organic solvent in 2-amino-3-(4-benzoyl bromide) benzoic acid crude product, 75~85 DEG C of heated and stirred are molten
Solving, filtered while hot, filtrate stirring is cooled to 0~5 DEG C, and stirring and crystallizing 2~3h filters, solid in 50~60 DEG C of drying under reduced pressure 4~
6h, obtains 2-amino-3-(4-benzoyl bromide) benzoic acid sterling, for pale yellow crystals.
-the 3-of 2-amino described in step 2 (4-benzoyl bromide) benzoic acid crude product with the mass volume ratio of organic solvent is
1g:20~150ml;
One or both in ethanol, the ethyl acetate of organic solvent in described in step 2.
Synthetic route of the present invention is as follows:
2-amino-3-(4-benzoyl bromide) the benzoic cubage method that the present invention prepares is as follows:
Content (%)=(100.0% loss on drying % residue on ignition %) × chromatographic purity
Loss on drying is used for measuring volatile impurity in sample (such as residual solvent) or low boiling impurity (such as: moisture)
Content, analyzes method 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
2015 editions four general rules<0831>of state's pharmacopeia) 60 DEG C of drying under reduced pressure to constant weight, calculate less loss weight respectively and account for the hundred of sample total amount
Proportion by subtraction, takes the meansigma methods of 2 results.
Residue on ignition be used for measuring inorganic impurity in sample (such as: inorganic salt) or can not the content of carbide (such as: metal),
Analysis method is as follows:
Take this product 1g, totally 2 parts, measure according to residue on ignition algoscopy (2015 editions four general rules<0841>of Chinese Pharmacopoeia), point
Ji Suan not account for the percentage ratio of sample total amount by level of residue, take the meansigma methods of 2 results.
Chromatographic purity accounts for the ratio of detection total organic matter for analyzing main composition in sample, analyzes method as follows:
HPLC method:
Chromatographic column: Hypersil ODS2 (4.6mm × 150mm, 5.0 μm)
Flowing phase: 0.05mol/L ammonium acetate-methanol-oxolane (60:55:15)
Detection wavelength: 266nm
Sample concentration: 0.3mg/ml (solvent is flowing phase)
Flow velocity: 1ml/min
Sample size: 10 μ l
In HPLC chromatogram, after deduction solvent peak, (main peak area accounts for Zong Feng to calculate main peak content by areas of peak normalization method
The percentage ratio of area).It is calculated as follows chromatographic purity:
Chromatographic purity=main peak content %/100%
As stated above, demarcate 2-amino-3-(4-benzoyl bromide) benzoic acid content that the present invention prepares, demarcate content
It is all higher than 99.0%.
Benzoic acid preparation technology is simple and direct, synthesis cycle is short for the 2-amino-3-(4-benzoyl bromide) of the present invention, synthesizes cost
Low, both it was suitable for laboratory in a small amount synthesis it can also be used to large-scale production.2-amino-3-(4-benzoyl bromide) benzene of the present invention
Formic acid content scaling method is conventional method of analysis, and appointed condition is the highest, easily realizes.Use 2-ammonia prepared by the inventive method
Base-3-(4-benzoyl bromide) benzoic demarcation content is all higher than 99.0%, can be applied to bromfenac as contamination levels product
Sodium raw materials and the qualitative and quantitative study of preparation impurity thereof and detection, to effectively controlling bromfenac sodium raw material and quality of the pharmaceutical preparations tool thereof
There is positive progressive meaning.
Four, accompanying drawing explanation
Fig. 1 is 2-amino-3-(4-benzoyl bromide) benzoic acid purity detecting chromatogram in embodiment 2.Can from Fig. 1
Going out, chromatographic purity is 0.9977.
Fig. 2 is 2-amino-3-(4-benzoyl bromide) benzoic acid purity detecting chromatogram in embodiment 3.Can from Fig. 2
Going out, chromatographic purity is 0.9983.
Five, detailed description of the invention
Following preferable examples of the present invention will be described, it will be appreciated that preferred embodiment described herein is only used for
Bright and explain the present invention, be not intended to limit the present invention.
Raw material 7-of the present invention (4-benzoyl bromide) indoline-2,3-diketone can be general commercially available commercial synthesis
Product, it is possible to prepared by embodiment 1 method.
The preparation of embodiment 1:7-(4-benzoyl bromide) indoline-2,3-diketone
Use general industrial method prepare 7-(4-benzoyl bromide) Indolin-2-one (No. CAS is 91713-
91-6) it is raw material.
7-(4-benzoyl bromide) Indolin-2-one 25g (79mmol) stirring is dissolved in 750ml ethyl acetate, throws
Enter copper bromide 88.2g (395mmol), react 4h in 78~85 DEG C of return stirrings, be cooled to 20~30 DEG C, reactant liquor successively with
The isopyknic water of ethyl acetate, saturated sodium-chloride water solution wash, organic facies is evaporated to do in 50~60 DEG C, add methanol/
Water (volume ratio 4:1) mixed solution 700ml, reacts 3h in 70~80 DEG C of return stirrings, is cooled to 20~30 DEG C, filters, filter cake
Successively with suitable quantity of water, methanol washing, solid adds methanol 500ml, and in 65~70 DEG C of 30min that reflux, filtered while hot, filtrate is lowered the temperature
To-5~0 DEG C of stirring and crystallizing 2h, filter, solid in 60~70 DEG C of drying under reduced pressure 8h, obtain 7-(4-benzoyl bromide) indoline-
2,3-diketone 13.5g, yield 51.7%.
Elementary 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 2:2-amino-3-(4-benzoyl bromide) benzoic preparation
1,7-(4-benzoyl bromide) indoline-2,3-diketone 12g (36.3mmol) is put into 180g (225mmol)
In 5% sodium hydrate aqueous solution, 50~60 DEG C of stirring and dissolving, drip 30% hydrogen peroxide 180ml (1.8mol), drip complete, in
50~60 DEG C of stirring reaction 1h, stirring is cooled to 20~30 DEG C, filters, and filtrate, with 10% salt acid for adjusting pH to 3~4, is filtered, filter
Cake water washs in right amount, and solid, in 50~60 DEG C of drying under reduced pressure 4h, obtains 2-amino-3-(4-benzoyl bromide) benzoic acid crude product
8.85g, yield 76.1%.
2, in 8.85g 2-amino-3-(4-benzoyl bromide) benzoic acid crude product, ethyl acetate 450ml, 75~85 are added
DEG C heated and stirred is dissolved, filtered while hot, and filtrate stirring is cooled to 0~5 DEG C, and stirring and crystallizing 2h filters, and solid subtracts in 50~60 DEG C
Press dry dry 4h, obtain 2-amino-3-(4-benzoyl bromide) benzoic acid sterling 7.2g, yield 81.3%.
Elementary analysis is C14H10BrNO3
Analysis project | C (%) | H (%) | N (%) | Br (%) |
Theoretical value | 52.52 | 3.15 | 4.38 | 24.96 |
Measured value | 52.43 | 3.20 | 4.42 | 24.79 |
TOF-MS[M-H]-: 317.9 (Exact Mass:318.98)
IR(KBr)ν(cm-1): 3434,3300,3058,1663,1600,1572,1550,1289,1254,1164,1070,
768
1HNMR (DMSO-d6) δ (ppm): 13.07 (brs, 1H, COOH), 8.36 (s, 2H, NH), 8.09 (m, 1H, Ar-
H), 7.74 (d, 2H, Ar-H), 7.55 (m, 3H, Ar-H), 6.60 (t, 1H, Ar-H)
13CNMR (DMSO-d6) δ (ppm): 197.2,169.6,153.1,140.3,139.0,138.3,131.9 (2C),
131.3 (2C), 125.7,118.7,113.7,112.7
Content calibration result:
Purity detecting chromatogram is shown in Fig. 1.
Embodiment 3:2-amino-3-(4-benzoyl bromide) benzoic preparation
1,7-(4-benzoyl bromide) indoline-2,3-diketone 10.0g (30.3mmol) is put into 160g (200mmol)
In 5% sodium hydrate aqueous solution, 50~60 DEG C of stirring and dissolving, drip 30% hydrogen peroxide 170ml (1.7mol), drip complete, in
50~60 DEG C of stirring reaction 1h, stirring is cooled to 20~30 DEG C, filters, and filtrate, with 10% salt acid for adjusting pH to 3~4, is filtered, filter
Cake water washs in right amount, and solid, in 50~60 DEG C of drying under reduced pressure 6h, obtains 2-amino-3-(4-benzoyl bromide) benzoic acid crude product
7.5g, yield 77.3%.
2, adding ethanol 200ml in 7.5g 2-amino-3-(4-benzoyl bromide) benzoic acid crude product, 75~85 DEG C add
Thermal agitation is dissolved, filtered while hot, and filtrate stirring is cooled to 0~5 DEG C, and stirring and crystallizing 3h filters, and solid is dry in 50~60 DEG C of decompressions
Dry 6h, obtains 2-amino-3-(4-benzoyl bromide) benzoic acid sterling 5.7g, yield 76.0%.
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 consistent.Additionally, any method similar or impartial to described content and material all can be applicable in the inventive method.
Claims (5)
1. bromfenac sodium contamination levels product 2-amino-3-(4-benzoyl bromide) benzoic synthetic method, its feature exists
In comprising the steps:
(1) decarboxylation
By 7-(4-benzoyl bromide) indoline-2,3-diketone puts in the sodium hydrate aqueous solution of 5wt%, and 50~60 DEG C are stirred
Mix dissolving, drip the hydrogen peroxide of 30wt% subsequently, after dripping off in 50~60 DEG C stirring reaction 1h, be cooled to after having reacted 20~
30 DEG C, filtering, filtrate, with salt acid for adjusting pH value to 3~4, is filtered, and filter cake washes with water, and solid is in 50~60 DEG C of drying under reduced pressure 4
~6h, obtain 2-amino-3-(4-benzoyl bromide) benzoic acid crude product;
(2) refined
Adding organic solvent in 2-amino-3-(4-benzoyl bromide) benzoic acid crude product, 75~85 DEG C of heated and stirred are dissolved, and take advantage of
Heat filtering, filtrate stirring is cooled to 0~5 DEG C, and stirring and crystallizing 2~3h filters, and solid, in 50~60 DEG C of drying under reduced pressure 4~6h, obtains
2-amino-3-(4-benzoyl bromide) benzoic acid sterling, for pale yellow crystals.
Synthetic method the most according to claim 1, it is characterised in that:
Indoline-2,3-the diketone of 7-(4-benzoyl bromide) described in step (1) is 1:5~8 with the mol ratio of sodium hydroxide.
Synthetic method the most according to claim 1, it is characterised in that:
Indoline-2,3-the diketone of 7-(4-benzoyl bromide) described in step (1) and H2O2Mol ratio be 1:40~60.
Synthetic method the most according to claim 1, it is characterised in that:
The benzoic acid crude product of 2-amino-3-(4-benzoyl bromide) described in step (2) is 1g with the mass volume ratio of organic solvent:
20~150ml.
Synthetic method the most according to claim 1, it is characterised in that:
One or both in ethanol, the ethyl acetate of organic solvent in described in step (2).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610662569.3A CN106278918B (en) | 2016-08-12 | 2016-08-12 | A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610662569.3A CN106278918B (en) | 2016-08-12 | 2016-08-12 | A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106278918A true CN106278918A (en) | 2017-01-04 |
CN106278918B CN106278918B (en) | 2018-05-11 |
Family
ID=57669137
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610662569.3A Active CN106278918B (en) | 2016-08-12 | 2016-08-12 | A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106278918B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114736131A (en) * | 2022-04-28 | 2022-07-12 | 郑州灏瑞医药科技有限公司 | Synthetic method of bromfenac sodium |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4182774A (en) * | 1975-08-13 | 1980-01-08 | A. H. Robins Company, Incorporated | Method of inhibiting blood platelet aggregation with 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
CN103435594A (en) * | 2013-08-22 | 2013-12-11 | 中国药科大学 | 2-amino-quinazolines PLK1 (Polo-like kinase1) inhibitor and application 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 |
WO2015009930A2 (en) * | 2013-07-17 | 2015-01-22 | The Trustees Of Columbia University In The City Of New York | Novel phosphodiesterase inhibitors and uses thereof |
US20150239900A1 (en) * | 2013-10-10 | 2015-08-27 | Araxes Pharma Llc | Inhibitors of kras g12c |
WO2016025669A1 (en) * | 2014-08-13 | 2016-02-18 | Eolas Therapeutics, Inc. | Difluoropyrrolidines as orexin receptor modulators |
-
2016
- 2016-08-12 CN CN201610662569.3A patent/CN106278918B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4182774A (en) * | 1975-08-13 | 1980-01-08 | A. H. Robins Company, Incorporated | Method of inhibiting blood platelet aggregation with 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
WO2015009930A2 (en) * | 2013-07-17 | 2015-01-22 | The Trustees Of Columbia University In The City Of New York | Novel phosphodiesterase inhibitors and uses thereof |
CN103435594A (en) * | 2013-08-22 | 2013-12-11 | 中国药科大学 | 2-amino-quinazolines PLK1 (Polo-like kinase1) inhibitor and application thereof |
US20150239900A1 (en) * | 2013-10-10 | 2015-08-27 | Araxes Pharma Llc | Inhibitors of kras g12c |
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 |
WO2016025669A1 (en) * | 2014-08-13 | 2016-02-18 | Eolas Therapeutics, Inc. | Difluoropyrrolidines as orexin receptor modulators |
Non-Patent Citations (5)
Title |
---|
FENG ZHAI 等: "Hydrogen Bonding Behavior of Amide-Functionalized α-Diimine Palladium Complexes", 《AMERICAN CHEMICAL SOCIETY》 * |
ISAKA, MITSUYOSHI等: "Ocular tissue distribution in rabbit after instillation of bromfenac sodium ophthalmic solution", 《YAKUBUTSU DOTAI》 * |
夏泽宽 等: "秀芬酸钠的合成", 《中国药科大学学报》 * |
康从民 等: "2,5-二甲基-3,4-二氢-4-氧代喹唑啉的合成研究", 《化学与生物工程》 * |
曹敏 等: "含嘧啶氧基和一氟甲氧基的吡唑邻甲酰氨基苯甲酰胺的合成及杀虫活性", 《农药学学报》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114736131A (en) * | 2022-04-28 | 2022-07-12 | 郑州灏瑞医药科技有限公司 | Synthetic method of bromfenac sodium |
Also Published As
Publication number | Publication date |
---|---|
CN106278918B (en) | 2018-05-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102558056B (en) | Celecoxib and preparing method thereof | |
KR101333620B1 (en) | Crystals of morphinan derivative and process for producing the same | |
Wei et al. | A two-step responsive colorimetric probe for fast detection of formaldehyde in weakly acidic environment | |
Qin et al. | A sensor for selective detection of Al3+ based on quinoline Schiff-base in aqueous media | |
CN107721922B (en) | Quinoline biological thiol fluorescent probe and preparation and application thereof | |
CN110746321B (en) | Malononitrile Schiff base hypochlorous acid fluorescent probe and preparation method thereof | |
CN105510459A (en) | Method for detecting febuxostat raw material | |
Hou et al. | The first ratiometric probe for lysine in water | |
Qin et al. | Ratiometric fluorescent probe for Al 3+ based on coumarin derivative in aqueous media | |
Qi et al. | Cyanide detection using azo-acylhydrazone in aqueous media with high sensitivity and selectivity | |
CN104277061A (en) | Boric acid fluorescence molecular probe as well as preparation method and application thereof | |
Xu et al. | A novel fluorescent probe for hydrazine based on acetyl-deprotection and iminocoumarin formation | |
CN101914126B (en) | Preparation method of diammonium glycyrrhizinate salt capable of accurately controlling ammonium radical content | |
CN106278918A (en) | A kind of bromfenac sodium contamination levels product 2 amino 3 (4 benzoyl bromide) benzoic synthetic method | |
CN109575003A (en) | A kind of cumarin Cu of pyridine triazole modification2+The preparation method of fluorescence probe | |
CN106554770B (en) | A kind of triazole derivative metal-ion fluorescent probe and its preparation method and application | |
CN106278988A (en) | A kind of synthetic method of bromfenac sodium contamination levels product | |
CN102775424A (en) | Preparation method for levofloxacin impurity | |
CN106278917A (en) | A kind of synthetic method of bromfenac sodium degradation impurity standard substance | |
CN106478524A (en) | A kind of preparation method of ambroxol hydrochloride impurity standard substance | |
JP5936511B2 (en) | Method for purifying 3,3'-dinitro-4,4'-dihydroxydiphenyl ether and method for producing 3,3'-dinitro-4,4'-dihydroxydiphenyl ether | |
Zbačnik et al. | Supramolecular influence on keto-enol tautomerism and thermochromic properties of o-hydroxy Schiff bases | |
CN110590680B (en) | Preparation method of anagrelide Lei Kaihuan methyl esterification impurity | |
CN109776543A (en) | Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application are replaced according to Shandong | |
Jin et al. | A novel near-infrared colorimetric probe for fluoride anions based on a heptamethine dye |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |