CN106278918B - A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid - Google Patents
A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid Download PDFInfo
- Publication number
- CN106278918B CN106278918B CN201610662569.3A CN201610662569A CN106278918B CN 106278918 B CN106278918 B CN 106278918B CN 201610662569 A CN201610662569 A CN 201610662569A CN 106278918 B CN106278918 B CN 106278918B
- Authority
- CN
- China
- Prior art keywords
- benzoic acid
- amino
- benzoyl bromides
- benzoyl
- bromides
- 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.)
- Active
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 synthetic method of 2 amino 3 (4 benzoyl bromide) benzoic acid of bromfenac sodium contamination levels product; it is with 7 (4 benzoyl bromide) indoline 2; 3 diketone are raw material; through decarboxylation, refined obtained 2 amino 3 (4 benzoyl bromide) benzoic acid sterlings, 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 99.0% 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 contamination levels
The synthetic method of product 2- amino -3- (4- benzoyl bromides) benzoic acid, 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- amino -3- (4- bromobenzenes
Formoxyl) benzoic acid, shown in its structure such as formula (I).JapanIF files report the impurity in bromfenac sodium eye drip
Exist in liquid and can further increase during stability keeps sample, but do not report synthesis and the content scaling method of the impurity.
In view of the Control of Impurities is most important to bromfenac sodium product quality, and it can be as the standard items that those skilled in the art use
Preparation method and quality determining method not yet it has been reported that therefore the acquisition of the contamination levels product to effectively control bromfenac sodium
Raw material 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 contamination levels product --- 2- amino -3- (4- benzoyl bromides) benzoic acid
Synthetic method, this method has the advantages that technique is simple and direct, short preparation period, high through demarcating product content.
The synthetic method of bromfenac sodium contamination levels product of the present invention, includes the following steps：
1st, decarboxylation
7- (4- benzoyl bromides) indoline -2,3- diketone is put into the sodium hydrate aqueous solution of 5wt%, 50~60
DEG C stirring and dissolving, is then added dropwise the hydrogen peroxide of 30wt%, drips off after 50~60 DEG C of stirring reaction 1h, is cooled to after the completion of reaction
20~30 DEG C, filtering, filtrate is washed with water with 10% salt acid for adjusting pH value to 3~4, filtering, filter cake, and solid subtracts in 50~60 DEG C
Dry 4~6h is pressed dry, obtains 2- amino -3- (4- benzoyl bromides) benzoic acid crude product；
The molar ratio of (4- benzoyl bromides) indoline -2,3- diketone of 7- described in step 1 and sodium hydroxide is 1:5~
8；7- (4- benzoyl bromides) indoline -2,3- diketone and H2O2Molar ratio be 1:40~60.
2nd, refine
Organic solvent is added into 2- amino -3- (4- benzoyl bromides) benzoic acid crude product, 75~85 DEG C of heating stirrings are molten
Solution, is filtered while hot, and filtrate stirring is cooled to 0~5 DEG C, 2~3h of stirring and crystallizing, filtering, and solid is dried under reduced pressure 4 in 50~60 DEG C~
6h, obtains 2- amino -3- (4- benzoyl bromides) benzoic acid sterling, is pale yellow crystals.
The mass volume ratio of-the 3- of 2- amino described in step 2 (4- benzoyl bromides) benzoic acid crude products and organic solvent is
1g:20~150ml；
Middle organic solvent described in step 2 is selected from one or both of ethanol, ethyl acetate.
Synthetic route of the present invention is as follows：
The content calculation method of 2- amino -3- (4- benzoyl bromides) benzoic acid produced by the present invention is as follows：
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- amino -3- (4- benzoyl bromides) benzoic acid content produced by the present invention is demarcated, demarcates content
It is all higher than 99.0%.
2- amino -3- (4- benzoyl bromides) benzoic acid preparation process of the invention is simple and direct, synthesis cycle is short, synthesizes cost
It is low, both it was adapted to laboratory to synthesize in a small amount, it can also be used to mass produce.2- amino -3- (4- benzoyl bromides) benzene of the present invention
Formic acid content scaling method is conventional method of analysis, and appointed condition is not high, easily realizes.The 2- ammonia prepared using the method for the present invention
The calibration content of base -3- (4- benzoyl bromides) benzoic acid is all higher than 99.0%, contamination levels product can be used as, applied to Bromfenac
The qualitative and quantitative study and detection of sodium raw materials and its preparation impurity, have effectively control bromfenac sodium raw material and its quality of the pharmaceutical preparations
There is positive progress meaning.
4th, illustrate
Fig. 1 is 2- amino -3- (4- benzoyl bromides) benzoic acid purity detecting chromatogram in embodiment 2.Can from Fig. 1
Go out, chromatographic purity 0.9977.
Fig. 2 is 2- amino -3- (4- benzoyl bromides) benzoic acid purity detecting chromatogram in embodiment 3.Can from Fig. 2
Go out, chromatographic purity 0.9983.
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- amino -3- (4- benzoyl bromides) benzoic acid
1st, by 7- (4- benzoyl bromides) indoline -2,3- diketone 12g (36.3mmol) input 180g (225mmol)
In 5% sodium hydrate aqueous solution, 50~60 DEG C of stirring and dissolvings, are added dropwise 30% hydrogen peroxide 180ml (1.8mol), are added dropwise, in
50~60 DEG C of stirring reaction 1h, stirring are cooled to 20~30 DEG C, and filtering, filtrate uses 10% salt acid for adjusting pH to 3~4, and filtering, is filtered
Cake is washed with appropriate amount of water, and solid is dried under reduced pressure 4h in 50~60 DEG C, obtains 2- amino -3- (4- benzoyl bromides) benzoic acid crude product
8.85g, yield 76.1%.
2nd, the addition ethyl acetate 450ml into 8.85g 2- amino -3- (4- benzoyl bromides) benzoic acid crude product, 75~85
The dissolving of DEG C heating stirring, is filtered while hot, and filtrate stirring is cooled to 0~5 DEG C, stirring and crystallizing 2h, and filtering, solid subtracts in 50~60 DEG C
Dry 4h is pressed dry, obtains 2- amino -3- (4- benzoyl bromides) benzoic acid sterling 7.2g, yield 81.3%.
Elemental 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：The preparation of 2- amino -3- (4- benzoyl bromides) benzoic acid
1st, by 7- (4- benzoyl bromides) indoline -2,3- diketone 10.0g (30.3mmol) input 160g (200mmol)
In 5% sodium hydrate aqueous solution, 50~60 DEG C of stirring and dissolvings, are added dropwise 30% hydrogen peroxide 170ml (1.7mol), are added dropwise, in
50~60 DEG C of stirring reaction 1h, stirring are cooled to 20~30 DEG C, and filtering, filtrate uses 10% salt acid for adjusting pH to 3~4, and filtering, is filtered
Cake is washed with appropriate amount of water, and solid is dried under reduced pressure 6h in 50~60 DEG C, obtains 2- amino -3- (4- benzoyl bromides) benzoic acid crude product
7.5g, yield 77.3%.
2nd, ethanol 200ml is added into 7.5g 2- amino -3- (4- benzoyl bromides) benzoic acid crude product, 75~85 DEG C add
Thermal agitation is dissolved, and is filtered while hot, and filtrate stirring is cooled to 0~5 DEG C, stirring and crystallizing 3h, and filtering, solid is done in 50~60 DEG C of decompressions
Dry 6h, obtains 2- amino -3- (4- benzoyl bromides) 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 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)
- A kind of 1. bromfenac sodium contamination levels product 2- amino -3-（4- benzoyl bromides）The synthetic method of benzoic acid, its feature exist In including the following steps：（1）DecarboxylationBy 7-（4- benzoyl bromides）In the sodium hydrate aqueous solution of indoline -2,3- diketone input 5wt%, 50 ~ 60 DEG C of stirrings Dissolving, is then added dropwise the hydrogen peroxide of 30wt%, drips off after 50 ~ 60 DEG C of stirring reaction 1h, 20 ~ 30 DEG C are cooled to after the completion of reaction, Filtering, filtrate are washed with water with salt acid for adjusting pH value to 3 ~ 4, filtering, filter cake, and solid is dried under reduced pressure 4 ~ 6h in 50 ~ 60 DEG C, obtains 2- Amino -3-（4- benzoyl bromides）Benzoic acid crude product；Step（1）Described in 7-（4- benzoyl bromides）The molar ratio of indoline -2,3- diketone and sodium hydroxide is 1:5~8；Step（1）Described in 7-（4- benzoyl bromides）Indoline -2,3- diketone and H2O2Molar ratio be 1:40~60；（2）It is refinedTo 2- amino -3-（4- benzoyl bromides）Organic solvent is added in benzoic acid crude product, 75 ~ 85 DEG C of heating stirring dissolvings, take advantage of Heat filtering, filtrate stirring are cooled to 0 ~ 5 DEG C, 2 ~ 3h of stirring and crystallizing, and filtering, solid is dried under reduced pressure 4 ~ 6h in 50 ~ 60 DEG C, obtains 2- ammonia Base -3-（4- benzoyl bromides）Benzoic acid sterling, is pale yellow crystals；Step（2）Described in middle organic solvent be selected from ethanol, one or both of ethyl acetate.
- 2. synthetic method according to claim 1, it is characterised in that：Step（2）Described in 2- amino -3-（4- benzoyl bromides）The mass volume ratio of benzoic acid crude product and organic solvent is 1g: 20~150ml。
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 CN106278918A (en) | 2017-01-04 |
| CN106278918B true 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) |
Families Citing this family (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 (5)
| 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 |
| WO2016025669A1 (en) * | 2014-08-13 | 2016-02-18 | Eolas Therapeutics, Inc. | Difluoropyrrolidines as orexin receptor modulators |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO3805B1 (en) * | 2013-10-10 | 2021-01-31 | Araxes Pharma Llc | Inhibitors of kras g12c |
-
2016
- 2016-08-12 CN CN201610662569.3A patent/CN106278918B/en active Active
Patent Citations (5)
| 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 |
| 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 |
|---|
| 2,5-二甲基-3,4-二氢-4-氧代喹唑啉的合成研究;康从民 等;《化学与生物工程》;20120625;第29卷(第6期);第24页1.4 * |
| Hydrogen Bonding Behavior of Amide-Functionalized α-Diimine Palladium Complexes;Feng Zhai 等;《American Chemical Society》;20141126;第33卷(第24期);Supporting Information第S2和S3页 * |
| 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 * |
| 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;曹敏 等;《农药学学报》;20120215;第14卷(第1期);第100页图解1 * |
| 秀芬酸钠的合成;夏泽宽 等;《中国药科大学学报》;20031025;第34卷(第5期);第405-406页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106278918A (en) | 2017-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Robinson et al. | 7-Azaindole. I. Synthesis and conversion to 7-azatryptophan and other derivatives | |
| Snyder et al. | The Synthesis of Derivatives of β-Carboline. II. Syntheses from dl-Tryptophan and Aldehydes1 | |
| CN102558056B (en) | Celecoxib and preparing method thereof | |
| CN106278918B (en) | A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid | |
| JP7274000B2 (en) | A novel method for producing peramivir trihydrate and its aqueous drying | |
| Leuck et al. | The mercuration of naphthalic acids | |
| CN104945383B (en) | Hold in the palm his preparation method of pyrrole department | |
| CN106831793A (en) | A kind of synthesis technique for treating ovarian cancer Rucaparib intermediates | |
| CN106188040B (en) | A kind of Fevipiprant and its intermediate preparation method | |
| CN107235957A (en) | A kind of synthetic method for preparing Niraparib | |
| CN102267994A (en) | Preparation method of moxifloxacin hydrochloride known impurity | |
| CN106278917B (en) | A kind of synthetic method of bromfenac sodium degradation impurity standard items | |
| CN106478524B (en) | A kind of preparation method of ambroxol hydrochloride impurity standard items | |
| WO2023174449A1 (en) | Method for preparing n-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide | |
| CN105777573B (en) | The preparation method of N coumaric acyl dopamines | |
| Albert et al. | 972. Analogues of 8-hydroxyquinoline having additional cyclic nitrogen atoms. Part I. Preparative | |
| CN105693632B (en) | A kind of preparation method of polysubstituted quinoxaline derivant | |
| JP5936511B2 (en) | Method for purifying 3,3'-dinitro-4,4'-dihydroxydiphenyl ether and method for producing 3,3'-dinitro-4,4'-dihydroxydiphenyl ether | |
| WO2008028959A1 (en) | Crystalline form of moxifloxacin hydrochloride | |
| CN107011322B (en) | Preparation and purification method of dehydrophenylahistine compound | |
| CN105153126B (en) | A kind of preparation method of bisindole maleimide class compound | |
| CN111875594A (en) | Indazole heterocycles having phosphodiesterase 4B inhibitory activity | |
| Snyder et al. | A Synthesis of 6-Methylindole and dl-6-Methyltryptophan | |
| JP2019509293A (en) | 4-Pentafluorothiophenol compounds and preparation method, and preparation method of pentafluorosulfur-substituted benzopyran compounds | |
| JP6126102B2 (en) | Pure S-(−)-9-fluoro-6,7-dihydro-8- (4-hydroxypiperidin-1-yl) -5-methyl-1-oxo-1H, 5H-benzo [i, j] quinolidine -2-carboxylic acid L-arginine salt tetrahydrate and process for producing the same |
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 |