CN106748884A - A kind of preparation method of Bicalutamide intermediate - Google Patents
A kind of preparation method of Bicalutamide intermediate Download PDFInfo
- Publication number
- CN106748884A CN106748884A CN201611148101.9A CN201611148101A CN106748884A CN 106748884 A CN106748884 A CN 106748884A CN 201611148101 A CN201611148101 A CN 201611148101A CN 106748884 A CN106748884 A CN 106748884A
- Authority
- CN
- China
- Prior art keywords
- preparation
- cyano group
- methacrylamide
- acid
- trifluoromethyls
- 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
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of preparation method of Bicalutamide intermediate, specifically a kind of method that 3 chlorine N (trifluoromethyl of 4 cyano group 3) methyl propanamide of 2 hydroxyl 2 is prepared with N (trifluoromethyl of 4 cyano group 3) Methacrylamide：In a solvent, with N (trifluoromethyl of 4 cyano group 3) Methacrylamide as raw material, add acid, it is cooled to 0 ~ 15 DEG C, stirring, it is added dropwise to liquor natrii hypochloritis's oxidation, drop finishes holding temperature of reaction system at 0 ~ 15 DEG C, reaction is carried out 0.5 ~ 1 hour, separated 3 chlorine N (trifluoromethyl of the 4 cyano group 3) methyl propanamide of 2 hydroxyl 2 that can obtain high-purity after purification of resulting solution, the preparation method safety, it is economical, large-scale production is applicable to prepare than card sulfide intermediate, and raw material is cheap and easy to get, production cycle shortens, not generation environment pollution.
Description
Technical field
The invention belongs to the chemicals synthesis of biomedicine field, and in particular to a kind of antiandrogens are than card Shandong
The preparation method of amine intermediate.
Background technology
Bicalutamide（Bicalutamide）, chemical entitled N- [4- cyano group -3- (trifluoromethyl) phenyl] -3- (4- fluorobenzene
Sulfonyl) -2- methyl -2- hydroxypropanamides, English entitled N- [4-cyano-3- (trifluoromethyl) phenyl] -3-
[(4-flurophenyl) sulfonyl] -2-hydroxy-2-methyl-propanamide, chemical formula is as follows：
Nineteen ninety-five takes the lead in listing in Britain, trade name Casodex, and China was in approval of import Bicalutamide tablet in 1999.Than
Card Shandong amine is 32 editions determined curative effects for recording of American Pharmacopeia, and action specificity is strong, oral effective, convenient drug administration, better tolerance, and
There is a kind of nonsteroidal antiandrogen medicine of half-life period more long, be currently the only oral once (50mg/ pieces) treatment prostatitis
The medicine of gland cancer, the treatment that can be applied to advanced prostate cancer is shared with LHRH, with first generation antiandrogen medicine Flutamide phase
Than that can reduce various toxic and side effects 70%, and effect is higher than Flutamide, is the fastest-rising antineoplastic of current sales volume
Thing, with good potential applicability in clinical practice, domestic independent development Bicalutamide can reduce drug price, reduce foreign exchange, meet
People's medication needs.
The synthetic method of the Bicalutamide of document report is a lot, and route with practical value is by 4- amino -3- fluoroforms
Base aniline and 2- methacrylic chlorides are condensed into acid amides, then oxidized epoxides, and open loop is obtained than card with 4- fluoro thiophenols
The important thiophenol intermediate of Shandong amine, so aoxidize Bicalutamide (Howard Tucker J.Med.Chem., 1988,31,
954-959；Howard Tucker, USP4636505), synthetic route is as follows：
The physiologically active of RBIC is stronger than the isomers of dextrorotation 60 times, therefore asymmetric syntheses laevoisomer is outstanding
For important.RBIC synthetic route (Leonid Kirkovsky.et al. J.Med.Chem., 2000,43,
It is 581-590) that acid amides, NBS brominations, with 4- amino -3- after acidifying open loop are condensed into by D-PROLINE and 2- methacrylic chlorides
5-trifluoromethylaniline obtains acid amides, then generates (R)-thiophenol intermediate with 4- fluoro thiophenols, finally oxidized to obtain left-handed than card Shandong
Amine, synthetic route is as follows：
Also having many patents (WO0128990, WO134563, WO9519770 and US5985868) in addition also has similar preparation left
Revolve the report of Bicalutamide.
See to find out from above-mentioned main two lines, it is epoxide to prepare than two important intermediates of card thioether
（Ⅰ）And halohydrin compound（Ⅱ）, chemical formula is as follows：
（Ⅰ）
（Ⅱ）
Wherein epoxide（Ⅰ）The report of preparation is a lot, there is O. Payen et al.；J. Organomet. Chem.,
2011,696,1049-1056; K.M. Schragl et al., Tetrahedron Letters , 2013,54,2239–
2242; Q. Shi et al., Bioorg. Med. Chem., 2012,20,4020–4031; Howard Tucker
J.Med.Chem., 1988,31,954-959 etc.；
Halohydrin compound（Ⅱ）Mainly synthesized by following two lines（WO2010116342, US2005085449,
WO2009036206, WO2007027582, WO2009155481, WO2013067170 etc.）：
In this two lines, first route is more long, and the cycle is long, and yield is medium, and has used mesyl chloride control reagent and alkene
Hydrocarbon bishydroxy reagent (is mostly Heavy Metal Reagent, such as osmium tetroxide, potassium permanganate etc.), causes great environmental pollution, no
Beneficial to industrialized production；The raw material of Article 2 is a more difficult acquisition of grease, and synthetic route is more long, and purification is difficult.
In order to overcome problem present in above route as far as possible, the present inventor designs synthesizing halogen alcoholic compound（Ⅱ）
Novel process route, and be experimentally confirmed the feasibility of this route.There is this route starting material to be easy to get, reaction yield
The advantages of height, reaction easy to operate, with extensive prospects for commercial application.
The content of the invention
Technical scheme and content are related to a kind of preparation method of Bicalutamide intermediate, in the middle of the Bicalutamide
Body such as following formula（Ⅲ）It is shown：
（Ⅲ）
Its object is to：A new method of the preparation than card sulfide intermediate for being applicable to large-scale production is provided, so as to solve
Certainly security present in the existing synthetic technology of Bicalutamide is poor, environment is polluted, the problems such as high cost.
A kind of preparation method of Bicalutamide intermediate, it is specifically a kind of to use N- (4- cyano group -3- trifluoromethylbenzenes
Base) the Methacrylamide method for preparing the chloro- N- of 3- (4- cyano group -3- trifluoromethyls) -2- hydroxy-2-methyl propionamides,
Its synthetic route chart is as follows：
Comprise the following steps that：
In a solvent, with N- (4- cyano group -3- trifluoromethyls) Methacrylamide as raw material, acid is added, is cooled to 0 ~ 15
DEG C, stirring is added dropwise to liquor natrii hypochloritis's oxidation, and drop finishes holding temperature of reaction system at 0 ~ 15 DEG C, and it is small that reaction carries out 0.5 ~ 1
When, the solution containing crude product is obtained, separated purifying obtains the compound of high-purity（Ⅲ）；
Wherein described solvent can select the mixture of any one or more solvents miscible with water, such as water, acetone, methyl alcohol, second
Alcohol, DMSO, DMF, DMA, dioxane, acetonitrile etc., preferably acetone；The solvent and N- (4- cyano group -3- trifluoromethylbenzenes
Base) Methacrylamide envelope-bulk to weight ratio be 10 ~ 20:1, preferably 15:1；
Wherein described acid may optionally be hydrochloric acid, sulfuric acid, the preferably one kind in glacial acetic acid or phosphoric acid, sulfuric acid；The acid and N- (4-
Cyano group -3- trifluoromethyls) Methacrylamide mole dosage ratio be 1 ~ 3:1, preferably 1.5:1；
Oxidant wherein used is liquor natrii hypochloritis conventional on the market（Bleaching agent）, its mass percent concentration be 10 ~
13%, preferred mass percentage concentration is 10%；Sodium hypochlorite rubs with N- (4- cyano group -3- trifluoromethyls) Methacrylamides
Your amount ratio is 1 ~ 5:1, preferably 2:1；
Wherein described chilling temperature and temperature of reaction system are 0 ~ 15 DEG C, preferably 0 ~ 5 DEG C；
Wherein described isolating and purifying is will to obtain the solution containing crude product, through extraction, point liquid, washing, anhydrous sodium sulfate drying, mistake
Filter, re crystallization from toluene；The extract of the extraction includes ethyl acetate, dichloromethane, isopropyl acetate or butyl acetate, excellent
Elect ethyl acetate as.
The present invention has easily operated, the mild condition of reaction, and post processing is easy, non-environmental-pollution, low cost and other advantages, and receives
Rate can reach 75-90% substantially, and purity can reach more than 97%.Most prominent advantage：One is to greatly shorten in the reaction time, uses N-
When (4- cyano group -3- trifluoromethyls) Methacrylamide needed for mCPBA epoxidation reactions prepare compound (I) by reacting
Between be 10 hours or so, and use N- (4- cyano group -3- trifluoromethyls) Methacrylamides by hypochlorite oxidation reaction
Prepare compound（Ⅱ）[X=Cl, i.e. compound（Ⅲ）], required time is 0.5 ~ 1 hour, significantly reduces power consumption, is improve
Kettle is imitated and production efficiency；Two is that Material Cost is significantly reduced, originally epoxidation reagent metachloroperbenzoic acid generally
（mCPBA）300 yuan or so of per kilogram, 1100 yuan per ton or so of the liquor natrii hypochloritis for currently using, is prepared by mCPBA epoxidations
Compound（Ⅰ）Cost be 2200 yuan/kilogram, using this patent, prepare compound is aoxidized by liquor natrii hypochloritis（Ⅱ）Into
This is 1500 yuan/kilogram, and liquor natrii hypochloritis is widely used in multiple industries, and raw material is easy to get very much.The present invention provides one can
Suitable for new method of the preparation than card sulfide intermediate for mass producing, so as to solve to be deposited in the existing synthetic technology of Bicalutamide
Security it is poor, environment is polluted, the problems such as high cost.
Pass through1H-NMR (Fig. 1),13C-NMR (Fig. 2),19F-NMR (Fig. 3) and LCMS (Fig. 4) are to compound（Ⅲ）Carry out
Structure and purity are characterized, and refer to accompanying drawing.
Brief description of the drawings
Fig. 1 compounds（Ⅲ）'s1H-NMR collection of illustrative plates, in figure1HNMR(d6-DMSO,400MHz)：δ 1.46 (s, 3H), 3.71
(d, 1H, J=11.2), 3.94 (d, 1H, J=11.2), 6.42 (s, 1H), 8.12 (d, 1H, J=8.8), 8.34 (dd, 1H, J=
8.8,1.6), 8.57 (d, 1H, J=1.6), 10.57 (s, 1H).
Fig. 2 compounds（Ⅲ）'s13C-NMR collection of illustrative plates, in figure13CNMR(d6-DMSO,100MHz)：24.71,51.98,
75.56,102.57 (d, 1C, J=2), 116.22,117.91,122.94 (q, 1C, J=272), 123.23,132.01 (q, 1C, J=
32), 136.74 (q, 1C, J=5), 143.50,174.27.
Fig. 3 compounds（Ⅲ）'s19F-NMR collection of illustrative plates, in figure19FNMR(d6-DMSO,376MHz)：-61.21.
Fig. 4 compounds（Ⅲ）LCMS collection of illustrative plates, ESIMS in figure：m/z305 [M-H]-。
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but not as limitation of the present invention.
Embodiment 1
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (1g) is dissolved in 15 milliliters of acetone, is cooled to 0 ~ 5 DEG C, is delayed
It is slow to add the 0.58g concentrated sulfuric acids, under stirring, 10% liquor natrii hypochloritis 5.86g is added dropwise, drop finishes stirring 0.5h, second is added in reaction solution
20 milliliters and 20 milliliters water of acetoacetic ester, point liquid, organic phase uses saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous
Sodium sulphate is dried, and filtering, precipitation obtains yellow crude 1.2g, 1g off-white color crystal, yield are obtained with 10 milliliters of re crystallization from toluene
83%, HPLC purity 98.02%.
Embodiment 2
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (1g) is dissolved in 15 milliliters of methyl alcohol, is cooled to 0 ~ 5 DEG C, is delayed
It is slow to add 1.17g concentrated hydrochloric acids, under stirring, 10% liquor natrii hypochloritis 5.86g is added dropwise, drop finishes stirring 0.5h, two is added in reaction solution
20 milliliters and 20 milliliters water of chloromethanes, point liquid, organic phase uses saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous
Sodium sulphate is dried, and filtering, precipitation obtains yellow crude 1.1g, 0.95g off-white color crystal is obtained with 10 milliliters of re crystallization from toluene, is received
Rate 79%, HPLC purity 97.27%.
Embodiment 3
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (1g) is dissolved in 25 milliliters of ethanol, is cooled to 0 ~ 5 DEG C, is delayed
It is slow to add the 0.58g concentrated sulfuric acids, under stirring, 10% liquor natrii hypochloritis 5.86g is added dropwise, drop finishes stirring 0.5h, second is added in reaction solution
20 milliliters and 20 milliliters water of acetoacetic ester, point liquid, organic phase uses saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous
Sodium sulphate is dried, and filtering, precipitation obtains yellow crude 1.2g, 0.91g off-white color crystal is obtained with 10 milliliters of re crystallization from toluene, is received
Rate 76%, HPLC purity 97.95%.
Embodiment 4
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (1g) is dissolved in DMF15 milliliters, is cooled to 0 ~ 5 DEG C, slowly
1.16g phosphoric acid is added, under stirring, 10% liquor natrii hypochloritis 5.86g is added dropwise, drop finishes stirring 0.5h, acetic acid second is added in reaction solution
20 milliliters and 20 milliliters water of ester, point liquid, organic phase uses saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous slufuric acid successively
Sodium is dried, and filtering, precipitation obtains yellow crude 1.2g, 0.95g off-white color crystal, yield are obtained with 10 milliliters of re crystallization from toluene
79%, HPLC purity 97.98%.
Embodiment 5
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (1g) is dissolved in DMSO15 milliliters, is cooled to 0 ~ 5 DEG C, is delayed
It is slow to add the 0.58g concentrated sulfuric acids, under stirring, 10% liquor natrii hypochloritis 10.7g is added dropwise, drop finishes stirring 0.5h, second is added in reaction solution
20 milliliters and 20 milliliters water of acetoacetic ester, point liquid, organic phase uses saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous
Sodium sulphate is dried, and filtering, precipitation obtains yellow crude 1.1g, 0.90g off-white color crystal is obtained with 10 milliliters of re crystallization from toluene, is received
Rate 75%, HPLC purity 97.12%.
Embodiment 6
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (1g) is dissolved in 15 milliliters of acetonitrile, is cooled to 10 ~ 15 DEG C,
0.58g glacial acetic acid is slowly added to, under stirring, 10% liquor natrii hypochloritis 5.86g is added dropwise, drop finishes stirring 0.5h, added in reaction solution
20 milliliters and 20 milliliters water of ethyl acetate, point liquid, organic phase uses saturated sodium bicarbonate solution and saturated common salt water washing, nothing successively
Aqueous sodium persulfate is dried, and filtering, precipitation obtains yellow crude 0.9g, 0.7g off-white color crystal is obtained with 10 milliliters of re crystallization from toluene,
Yield 58%, the % of HPLC purity 96.68.
Embodiment 7
N- (4- cyano group -3- trifluoromethyls) Methacrylamide (100g) is dissolved in 1.5 liters of acetone, is cooled to 0 ~ 5 DEG C, is delayed
Slow to add the 58g concentrated sulfuric acids, stirring is lower to be added dropwise 10% liquor natrii hypochloritis 586g, and drop finishes stirring 1h, ethyl acetate is added in reaction solution
2 liters and 2 liters of water, point liquid, organic phase use saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous sodium sulfate drying,
Filtering, precipitation obtains yellow crude 120g, 106g off-white color crystal, yield 88%, HPLC purity is obtained with 1 liter of re crystallization from toluene
97.38%, its fusing point is determined for 145.2 ~ 147 DEG C.
Claims (10)
1. a kind of preparation method of Bicalutamide intermediate, specifically a kind of with N- (4- cyano group -3- trifluoromethyls)
The method that Methacrylamide prepares the chloro- N- of 3- (4- cyano group -3- trifluoromethyls) -2- hydroxy-2-methyl propionamides, it is special
Levy and be：
In a solvent, with N- (4- cyano group -3- trifluoromethyls) Methacrylamide as raw material, acid is added, is cooled to 0 ~ 15
DEG C, stirring is added dropwise to liquor natrii hypochloritis's oxidation, and drop finishes holding temperature of reaction system at 0 ~ 15 DEG C, and it is small that reaction carries out 0.5 ~ 1
When, obtain the solution containing crude product, separated purifying, obtain the chloro- N- of 3- (4- cyano group -3- trifluoromethyls) of high-purity -
2- hydroxy-2-methyl propionamides（Ⅲ）.
2. preparation method according to claim 1, it is characterised in that：The solvent can select any one kind miscible with water
Or the mixture of several solvents, such as water, acetone, methyl alcohol, ethanol, DMSO, DMF, DMA, dioxane, acetonitrile, preferably third
Ketone.
3. preparation method according to claim 1, it is characterised in that：The acid may optionally be hydrochloric acid, sulfuric acid, glacial acetic acid or
One kind in phosphoric acid, preferably sulfuric acid.
4. preparation method according to claim 1, it is characterised in that：The oxidant of the oxidation is conventional on the market
Liquor natrii hypochloritis, its mass percent concentration is 10 ~ 13%, and preferred mass percentage concentration is 10%.
5. preparation method according to claim 1, it is characterised in that：The chilling temperature and temperature of reaction system are 0 ~ 15
DEG C, preferably 0 ~ 5 DEG C.
6. preparation method according to claim 1, it is characterised in that：Described isolating and purifying is will to obtain containing the molten of crude product
Liquid, through extraction, point liquid, washing, anhydrous sodium sulfate drying, filtering, re crystallization from toluene.
7. preparation method according to claim 6, it is characterised in that：The extract of the extraction include ethyl acetate,
Dichloromethane, isopropyl acetate or butyl acetate, preferably ethyl acetate.
8. preparation method according to claim 1 and 2, it is characterised in that：The solvent and N- (4- cyano group -3- fluoroforms
Base phenyl) Methacrylamide envelope-bulk to weight ratio be 10 ~ 20:1, preferably 15:1.
9. the preparation method according to claim 1 or 3, it is characterised in that：The acid and N- (4- cyano group -3- trifluoromethyls
Phenyl) Methacrylamide mole dosage ratio be 1 ~ 3:1, preferably 1.5:1.
10. the preparation method according to claim 1 or 4, it is characterised in that：Liquor natrii hypochloritis and N- (4- cyano group -3- three
Trifluoromethylphenyl) Methacrylamide mole dosage ratio be 1 ~ 5:1, preferably 2:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611148101.9A CN106748884B (en) | 2016-12-13 | 2016-12-13 | Preparation method of bicalutamide intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611148101.9A CN106748884B (en) | 2016-12-13 | 2016-12-13 | Preparation method of bicalutamide intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106748884A true CN106748884A (en) | 2017-05-31 |
| CN106748884B CN106748884B (en) | 2021-08-20 |
Family
ID=58880954
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611148101.9A Active CN106748884B (en) | 2016-12-13 | 2016-12-13 | Preparation method of bicalutamide intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106748884B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456227A (en) * | 2018-11-19 | 2019-03-12 | 启东华拓药业有限公司 | A kind of preparation method of Bicalutamide epoxy intermediate |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100172A1 (en) * | 1982-07-23 | 1984-02-08 | Imperial Chemical Industries Plc | Amide derivatives |
| CN1036564A (en) * | 1988-01-28 | 1989-10-25 | 三菱化成株式会社 | Sulfanilamide (SN) and contain the weedkiller of sulfanilamide (SN) as activeconstituents |
| WO2003053920A1 (en) * | 2001-12-13 | 2003-07-03 | Sumika Fine Chemicals Co., Ltd. | Crystals of bicalutamide and process for their production |
| US20040068135A1 (en) * | 2002-10-02 | 2004-04-08 | Lambertus Thijs | Process for making bicalutamide and intermediates thereof |
| WO2004039791A1 (en) * | 2002-10-30 | 2004-05-13 | Instytut Farmaceutyczny | A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide |
| WO2005014531A1 (en) * | 2003-08-12 | 2005-02-17 | Sumitomo Chemical Company, Limited | Process for production of n-methacryloyl-4-cyano-3- trifluoromethylaniline, method for stabilization of the same, and process for production of bicalutamide |
| EP1679306A1 (en) * | 2003-10-16 | 2006-07-12 | Sumitomo Chemical Company, Limited | Process for producing bicalutamide and method of purifying intermediate therefor |
| CN101103003A (en) * | 2004-11-16 | 2008-01-09 | 詹森药业有限公司 | Novel heterocycle derivatives useful as selective androgen receptor modulators (SARMS) |
| EP1506170B1 (en) * | 2002-05-17 | 2008-02-27 | Helm AG | Method for producing bicalutamide |
| CN101516840A (en) * | 2006-07-12 | 2009-08-26 | 田纳西大学研究基金会 | Substituted acylanilides and methods of use thereof |
| CN101528214A (en) * | 2006-08-24 | 2009-09-09 | 田纳西大学研究基金会 | Substituted acylanilides and methods of use thereof |
| CN101830869A (en) * | 2010-04-28 | 2010-09-15 | 宁波人健医药化工有限公司 | New process for preparing epoxide intermediate of Bicalutamide by utilizing air oxidation |
| CN1700923B (en) * | 2002-02-28 | 2011-06-15 | 田纳西大学研究基金会 | Multi-substituted selective androgen receptor modulators and methods of use thereof |
-
2016
- 2016-12-13 CN CN201611148101.9A patent/CN106748884B/en active Active
Patent Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636505A (en) * | 1982-07-23 | 1987-01-13 | Imperial Chemical Industries Plc | Amide derivatives |
| EP0100172A1 (en) * | 1982-07-23 | 1984-02-08 | Imperial Chemical Industries Plc | Amide derivatives |
| CN1036564A (en) * | 1988-01-28 | 1989-10-25 | 三菱化成株式会社 | Sulfanilamide (SN) and contain the weedkiller of sulfanilamide (SN) as activeconstituents |
| WO2003053920A1 (en) * | 2001-12-13 | 2003-07-03 | Sumika Fine Chemicals Co., Ltd. | Crystals of bicalutamide and process for their production |
| CN1700923B (en) * | 2002-02-28 | 2011-06-15 | 田纳西大学研究基金会 | Multi-substituted selective androgen receptor modulators and methods of use thereof |
| EP1506170B1 (en) * | 2002-05-17 | 2008-02-27 | Helm AG | Method for producing bicalutamide |
| US20040068135A1 (en) * | 2002-10-02 | 2004-04-08 | Lambertus Thijs | Process for making bicalutamide and intermediates thereof |
| WO2004031136A1 (en) * | 2002-10-02 | 2004-04-15 | Synthon B.V. | Process for making bicalutamide and intermediates thereof |
| WO2004039791A1 (en) * | 2002-10-30 | 2004-05-13 | Instytut Farmaceutyczny | A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide |
| WO2005014531A1 (en) * | 2003-08-12 | 2005-02-17 | Sumitomo Chemical Company, Limited | Process for production of n-methacryloyl-4-cyano-3- trifluoromethylaniline, method for stabilization of the same, and process for production of bicalutamide |
| EP1679306A1 (en) * | 2003-10-16 | 2006-07-12 | Sumitomo Chemical Company, Limited | Process for producing bicalutamide and method of purifying intermediate therefor |
| CN101103003A (en) * | 2004-11-16 | 2008-01-09 | 詹森药业有限公司 | Novel heterocycle derivatives useful as selective androgen receptor modulators (SARMS) |
| CN101516840A (en) * | 2006-07-12 | 2009-08-26 | 田纳西大学研究基金会 | Substituted acylanilides and methods of use thereof |
| CN101528214A (en) * | 2006-08-24 | 2009-09-09 | 田纳西大学研究基金会 | Substituted acylanilides and methods of use thereof |
| CN103251579A (en) * | 2006-08-24 | 2013-08-21 | 田纳西大学研究基金会 | Substituted acylanilides and methods of use thereof |
| CN101830869A (en) * | 2010-04-28 | 2010-09-15 | 宁波人健医药化工有限公司 | New process for preparing epoxide intermediate of Bicalutamide by utilizing air oxidation |
Non-Patent Citations (7)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456227A (en) * | 2018-11-19 | 2019-03-12 | 启东华拓药业有限公司 | A kind of preparation method of Bicalutamide epoxy intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106748884B (en) | 2021-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2020147861A1 (en) | Electrochemical preparation method for β-trifluoromethylamide compound | |
| CN102516122B (en) | Environment friendly method for preparing DMF (Dimethyl Formamide) solution of 2-hydroxy-benzonitril | |
| CN105085322A (en) | Preparation method and intermediate of AHU-377 intermediate and preparation method of intermediate | |
| CN107365275A (en) | The Sai Lexipa of high-purity | |
| CN105732444B (en) | A kind of his synthetic method of Baily department | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN106565531A (en) | Synthesis method for pharmaceutically acceptable salt of alkylhydrazine | |
| CN106748884A (en) | A kind of preparation method of Bicalutamide intermediate | |
| CN112645833A (en) | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid | |
| CN108467353B (en) | Preparation method of enantiopure tert-butyl sulfinamide | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN111635358B (en) | Preparation method of hydroxychloroquine | |
| CN107501171B (en) | Synthetic method of 2-chloro-3-pyridylaldehyde | |
| CN111978218A (en) | Synthetic method of florfenicol | |
| CN106883192B (en) | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification | |
| CN106045995B (en) | A kind of synthetic method of 5 bromine 1H pyrrolo-es [2,3 b] pyridines | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN108409615B (en) | Method for synthesizing enantiopure tert-butyl sulfenamide | |
| CN103450066B (en) | The preparation method of Telaprevir intermediate | |
| CN111574384A (en) | Preparation method of chiral 1-amino-2-propanol | |
| CN105218519A (en) | A kind of preparation method of dabigatran etexilate intermediate | |
| CN105037193A (en) | Preparation method of otilonium bromide | |
| CN107602477A (en) | A kind of process for purification of cyazofamid active compound | |
| CN111303120A (en) | Preparation method of fasudil hydrochloride | |
| CN111333529A (en) | Preparation method of pregabalin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210806 Address after: 047100 Zhendong science and Technology Park, Guangming South Road, Shangdang District, Changzhi City, Shanxi Province Applicant after: SHANXI ZHENDONG PHARMACEUTICAL Co.,Ltd. Applicant after: BEIJING ZHENDONG GUANGMING PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd. Address before: 047100 Shanxi city of Changzhi province Changzhi County Guangming Road Zhendong Science Park Applicant before: SHANXI ZHENDONG PHARMACEUTICAL Co.,Ltd. Applicant before: BEIJING ZHENDONG BIOTECHNOLOGY Co.,Ltd. |