CN102617457A - New method for preparing roflumilast - Google Patents
New method for preparing roflumilast Download PDFInfo
- Publication number
- CN102617457A CN102617457A CN2011100316053A CN201110031605A CN102617457A CN 102617457 A CN102617457 A CN 102617457A CN 2011100316053 A CN2011100316053 A CN 2011100316053A CN 201110031605 A CN201110031605 A CN 201110031605A CN 102617457 A CN102617457 A CN 102617457A
- Authority
- CN
- China
- Prior art keywords
- compound
- roflumilast
- methoxy
- difluoro
- methoxyl group
- 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.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a simple method for preparing roflumilast. According to the invention, 3-bromine-4-hydroxy-benzaldehyde (I) is etherified to obtain 4-difluoromethoxy-3-hydroxybenzaldehyde (II), the compound II is subjected to an Ullmann condensation reaction to obtain 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde (III), the compound III is oxidized by sodium hypochlorite to obtain 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid (IV), the compound IV is chloridized to obtain 3-cyclopropylmethoxy-4-difluoromethoxy-benzoyl chloride (V), and the compound V and 3,5-dichloro-4-aminopyridine are acylated to obtain the roflumilast. The method of the invention has the advantages of no need of selective etherification and column chromatography purification in the preparation process, simple reaction operation, simple post-treatment, low cost, high yield, and high purity.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to the synthetic roflumilast preparing method's of industry improvement.
Background technology
Daxas (R) (roflumilast) is a kind of oral selectivity phosphodiesterase 4 (PDE4) suppressor factor, and this medicine is verified can be suppressed and the relevant inflammation of chronic obstructive pulmonary disease (COPD) with a kind of brand-new mode of action.Roflumilast has several compound methods, but existing method exists separation and purification difficulty, the not high shortcoming of yield.With 3, the ring third monobromomethane etherificate is used in 4-Dihydroxy benzaldehyde and chlorodifluoromethane reaction then like world patent WO9501338A1, hypochlorite oxidation, and chloro, acidylate obtains roflumilast.This method the first step selectivity is low, need column chromatography for separation, and yield is low, and it is expensive to encircle the third monobromomethane price, is not suitable for suitability for industrialized production.Described with 3 among the world patent WO2005026095A1; 4-dihydroxyl-oil of Niobe is a raw material, and synthetic roflumilast midbody 3-encircles third methoxyl group-4-difluoro-methoxy-phenylformic acid through the reaction of 3 steps, needs column chromatography purification equally; Yield is lower, and reaction formula is following:
Consider the pharmaceutical use of this compound, effective industrial preparative method can be easy to be converted into plant-scale and obtains the compound method of roflumilast with good yield and high purity, and it is very important obtaining this compound.
Summary of the invention
The purpose of this invention is to provide a kind of easy practicable roflumilast new synthetic method.
The compound of the present invention's design is expressed from the next:
The applicant has developed a kind of new industriallization compound method at present, has obtained to overcome the problem of the poor selectivity that runs in patent specification WO2005026095A1 and the said method of WO9501338A1.This method does not need column chromatography for separation in addition, and operation is easy, and aftertreatment is simple, and cost is low, and yield is high, and purity is high, and suitable industry changes into the needs of product.The present invention implements through following key step, and reaction formula is following:
1. starting raw material 3-bromo-4-hydroxy benzaldehyde (I) and chlorine difluoroacetic acid sodium or chlorodifluoromethane obtain compound 4-difluoro-methoxy-3-hydroxy benzaldehyde (II) in 25-130 ℃ of following etherificate in basic soln.Reaction solvent is anhydrous polar aprotic solvent, like DMF, and DMA, DMSO 99.8MIN. etc.; Basic soln is sodium hydroxide, Pottasium Hydroxide etc.
2. compound I I encircles third methoxyl group-4-difluoro-methoxy-phenyl aldehyde (III) through obtaining 3-through the Liv Ullmann condensation reaction, and part is oxine, 8-methoxy quinoline, 1,10-phenanthroline, N; N '-dimethyl-ethylenediamine, 2-carboxyl pyridine, 3-dimethylamino propionic acid, 2; Bidentate ligand, catalyzer such as 2 '-Lian, two pyridines, 2-ethanoyl-pimelinketone, 8-ethanoyl quinoline are copper compound, and alkalescence is alkaline carbonate or phosphoric acid salt, and reaction solvent is anhydrous polar aprotic solvent; Like DMF; DMA, DMSO 99.8MIN. etc., temperature is chosen between 20-150 ℃..
3. compound III further obtains 3-with hypochlorite oxidation and encircles third methoxyl group-4-difluoro-methoxy-phenylformic acid (IV).
4. compound IV obtains 3-through chloro and encircles third methoxyl group-4-difluoro-methoxy-Benzoyl chloride 99min. (V).
5. compound V and 3,5-two chloro-4-aminopyridine acidylates obtain roflumilast (VI).
This method is particularly advantageous, this be because:
This method can be encircled third methoxyl group-4-difluoro-methoxy-phenyl aldehyde with the exclusive acquisition 3-of technical scale.Consider that synthetic route can avoid 3,4-dihydroxyl selective etherification, and only carry out the drawback that column chromatography for separation could purifying, can high yield obtain target compound.
Do not need selective etherification in the whole piece reaction scheme, do not need column chromatography purification, operation is easy, and aftertreatment is simple, and cost is low, and yield is high, and purity is high.
Embodiment
Following embodiment can make those skilled in the art more comprehensively understand the present invention, but does not limit the present invention in any way.
Synthesizing of embodiment 14-difluoro-methoxy-3-hydroxy benzaldehyde (II)
In 100mL single port bottle, add successively 3-bromo-4-hydroxy benzaldehyde (1.66g, 8.3mmol), chlorine difluoroacetic acid sodium (1.27g; 8.3mmol), (0.48g 12mmol), DMF (15mL) and water (0.3mL), heats 120 ℃ to sodium hydroxide; Reacted 2 hours, steaming desolventizes.Add the 10mL hydrochloric acid soln, ethyl acetate extraction, evaporate to dryness adds water, the sodium hydroxide adjust pH is about 13-14, ethyl acetate extraction, dried over mgso is filtered solvent evaporated, brown oil, low temperature place white needle-like crystals 1.90g, yield 91.6%.mp?68-70℃；1H?NMR(400MHZ?DMSO)：δ7.239(s，0.2H，CHF2)，7.420(s，0.5H，CHF2)，7.474-7.495(d，1H，J＝8.4，ArH)，7.601(s，0.3H，CHF2)，?7.933-7.959(q，1H，J＝2，J＝8.4，ArH)，8.164-8.169(d，1H，J＝2，ArH)，9.920(s，1H，CHO)，ESI-MS：m/z?251[M+H]+。
With reference to the method for embodiment 1, change the synthetic 4-difluoro-methoxy of experiment condition-3-hydroxy benzaldehyde (II):
| Batch | Solvent | Temperature | Alkali | Fluorochemical | Yield (%) |
| 1 | DMF | 25 | Sodium hydroxide | Chlorine difluoroacetic acid sodium | 10 |
| 2 | DMA | 50 | Pottasium Hydroxide | Chlorine difluoroacetic acid sodium | 25 |
| 3 | DMF | 80 | Sodium hydroxide | Chlorodifluoromethane | 60 |
| 4 | DMA | 110 | Sodium hydroxide | Chlorodifluoromethane | 84 |
| 5 | DMF | 120 | Pottasium Hydroxide | Chlorodifluoromethane | 90 |
| 6 | DMA | 130 | Pottasium Hydroxide | Chlorine difluoroacetic acid sodium | 89 |
Embodiment 23-encircles the synthetic of third methoxyl group-4-difluoro-methoxy-phenyl aldehyde (III)
In 100mL single port bottle, add successively 4-difluoro-methoxy-3-hydroxy benzaldehyde (0.25g, 1.0mmol), cyclopropyl-carbinol (0.30g; 4.2mmol), oxine (0.04g, 0.28mmol), cuprous iodide (0.04g, 0.22mmol), salt of wormwood (0.69g; 5.0mmol), DMF (10mL); Heat 140 ℃, reacted 20 hours, steaming desolventizes.Ethyl acetate extraction, dried over mgso is filtered solvent evaporated, gets yellow oil 0.15g, yield 62.0%.1H?NMR(400MHZ DMSO)：δ0.563-0.609(m，2H，CH2)，0.912-0.929(m，2H，CH2)，1.224-1.286(m，1H，CH)，3.991-4.008(d，2H，J＝6.8，CH2)，7.239(s，0.2H，CHF2)，7.420(s，0.5H，CHF2)，7.474-7.495(d，1H，J＝8.4，ArH)，7.601(s，0.3H，CHF2)，7.933-7.959(q，1H，J＝2，J＝8.4，ArH)，8.164-8.169(d，1H，J＝2，ArH)，9.920(s，1H，CHO)，ESI-MS：m/z243[M+H]+。
With reference to the method for embodiment 2, change the synthetic 3-of experiment condition and encircle third methoxyl group-4-difluoro-methoxy-phenyl aldehyde (III):
| Batch | Temperature | Part | Catalyzer | Alkali | Solvent | Yield (%) |
| 1 | 20 | Oxine | Cuprous iodide | Yellow soda ash | DMA | 5 |
| 2 | 50 | N, N '-dimethyl-ethylenediamine | Cuprous chloride | Potassiumphosphate | DMF | 9 |
| 3 | 100 | 1, the 10-phenanthroline | Red copper oxide | Sodium phosphate | DMA | 20 |
| 4 | 130 | Oxine | Cuprous bromide | Salt of wormwood | DMF | 54 |
| 5 | 150 | 1, the 10-phenanthroline | Cuprous iodide | Salt of wormwood | DMA | 38 |
| 6 | 150 | Oxine | Cuprous iodide | Potassiumphosphate | DMF | 42 |
Following examples are carried out with reference to patent WO2005026095A1, WO9501338A1 and CN1701062A.
Embodiment 33-encircles the synthetic of third methoxyl group-4-difluoro-methoxy-phenylformic acid (IV)
In 100mL single port bottle, add successively 3-encircle third methoxyl group-4-difluoro-methoxy-phenyl aldehyde (1.54g, 6.4mmo1), thionamic acid (0.90g; 9.3mmo1), Youxiaolin (1.00g, 11.0mmol), Glacial acetic acid min. 99.5 (6mL), water (2mL), room temperature reaction 1 hour; Separate out solid, add 30mL water, filter; Oven dry obtains white crystal 1.40g, yield 87.5%.mp?129-130℃；1H?NMR(400MHZ?DMSO)：δ0.563-0.609(m，2H，CH2)，0.912-0.929(m，2H，CH2)，1.224-1.286(m，1H，CH)，3.991-4.008(d，2H，J＝6.8，CH2)，7.239(s，0.2H，CHF2)，7.420(s，0.5H，CHF2)，7.474-7.495(d，1H，J＝8.4，ArH)，7.601(s，0.3H，CHF2)，7.933-7.959(q，1H，J＝2，J＝8.4，ArH)，8.164-8.169(d，1H，J＝2，ArH)，12.969(s，1H，COOH)，ESI-MS：m/z?259[M+H]+。
Embodiment 43-encircles the synthetic of third methoxyl group-4-difluoro-methoxy-Benzoyl chloride 99min. (V)
In 100mL single port bottle, add successively 3-encircle third methoxyl group-4-difluoro-methoxy-phenylformic acid (1.40g, 5.4mmol), thionyl chloride (3mL), the DMF of catalytic amount, toluene (10mL); Reflux; Reacted 2 hours, solvent evaporated is directly carried out next step reaction.
Synthesizing of embodiment 53-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM (VI)
In 100mL single port bottle, add 3,5-two chloro-4-aminopyridines (1.70g, 10.5mmol) and DMF (10mL), stirring and dissolving, add under the room temperature in batches potassium tert.-butoxide (1.20g, 21.0mmol).Drip 3-again and encircle third methoxyl group-4-difluoro-methoxy-Benzoyl chloride 99min. (1.40g, DMF 5.1mmol) (10mL) solution, room temperature reaction 2 hours; The Hydrogen chloride adjust pH is 2-3, filters, and is suspended in the pH value in the sodium hydroxide solution of 9-10; Filter, 95: 5 recrystallizations of Virahol and water obtain white solid 1.74g; Yield 85.2%, mp 160-161 ℃; 1H NMR (400MHZ DMSO): δ 0.563-0.609 (m, 2H, CH2), 0.912-0.929 (m, 2H, CH2), 1.224-1.286 (m, 1H, CH); 3.991-4.008 (d, 2H, J=6.8, CH2), 7.239 (s, 0.2H, CHF2), 7.420 (s, 0.5H; CHF2), 7.474-7.495 (d, 1H, J=8.4, ArH), 7.601 (s, 0.3H, CHF2); 7.933-7.959 (q, 1H, J=2, J=8.4, ArH), 8.164-8.169 (d, 1H, J=2; ArH), 8.733 (s, 2H, ArH), 10.805 (s, 1H, NH), ESI-MS:m/z 403 [M+H]+.
Claims (8)
1. one kind is encircled third methoxyl group-4-difluoro-methoxy-phenyl aldehyde by 3-and prepares improving one's methods of roflumilast, it is characterized in that the following compound III of structural formula is a key intermediate:
2. according to claim 1ly a kind ofly encircle third methoxyl group-4-difluoro-methoxy-phenyl aldehyde by 3-and prepare improving one's methods of roflumilast, it is characterized in that the key intermediate compound III obtains through two-step reaction, obtain roflumilast through three-step reaction again:
1) starting raw material 3-bromo-4-hydroxy benzaldehyde etherificate gets compound 4-difluoro-methoxy-3-hydroxy benzaldehyde (II);
2) compound I I encircles third methoxyl group-4-difluoro-methoxy-phenyl aldehyde (III) through obtaining 3-through the Liv Ullmann condensation reaction;
3) compound III further obtains 3-with hypochlorite oxidation and encircles third methoxyl group-4-difluoro-methoxy-phenylformic acid (IV);
4) compound IV obtains 3-through chloro and encircles third methoxyl group-4-difluoro-methoxy-Benzoyl chloride 99min. (V);
5) compound V and 3,5-two chloro-4-aminopyridine acidylates obtain roflumilast (VI).
3. improving one's methods of preparation roflumilast according to claim 1 is characterized in that step 1) compound 3-bromo-4-hydroxy benzaldehyde (I) and chlorine difluoroacetic acid sodium or chlorodifluoromethane in basic soln, obtain compound I I in 80-130 ℃ of following etherificate.
4. improving one's methods of preparation roflumilast according to claim 1; It is characterized in that step 2) compound I I is through the Liv Ullmann condensation reaction; Part is oxine, 8-methoxy quinoline, 1; 10-phenanthroline, N, N '-dimethyl-ethylenediamine, 2-carboxyl pyridine, 3-dimethylamino propionic acid, 2, bidentate ligand, catalyzer such as 2 '-Lian, two pyridines, 2-ethanoyl-pimelinketone, 8-ethanoyl quinoline are copper compound; Alkalescence is alkaline carbonate or phosphoric acid salt, and reaction obtains compound III under 80-150 ℃ of condition in non-protonic solvent.
5. improving one's methods of preparation roflumilast according to claim 1 is characterized in that the step 3) compound III obtains 3-with hypochlorite oxidation and encircles third methoxyl group-4-difluoro-methoxy-phenylformic acid (IV).
6. improving one's methods of preparation roflumilast according to claim 1 is characterized in that the step 4) compound IV obtains 3-through chloro and encircles third methoxyl group-4-difluoro-methoxy-Benzoyl chloride 99min. (V).
7. improving one's methods of preparation roflumilast according to claim 1 is characterized in that step 5) compound V and 3, and 5-two chloro-4-aminopyridine acidylates obtain roflumilast (VI).
8. improving one's methods of preparation roflumilast according to claim 1 is characterized in that not needing selective etherification in the process of the synthetic roflumilast of step 1 to step 5, do not need column chromatography purification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100316053A CN102617457A (en) | 2011-01-28 | 2011-01-28 | New method for preparing roflumilast |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100316053A CN102617457A (en) | 2011-01-28 | 2011-01-28 | New method for preparing roflumilast |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102617457A true CN102617457A (en) | 2012-08-01 |
Family
ID=46557721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100316053A Pending CN102617457A (en) | 2011-01-28 | 2011-01-28 | New method for preparing roflumilast |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102617457A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102928546A (en) * | 2012-11-13 | 2013-02-13 | 南京艾德凯腾生物医药有限责任公司 | Reversed high-efficiency liquid chromatography used for detecting roflumilast raw materials and impurity content thereof |
| CN103304408A (en) * | 2013-06-05 | 2013-09-18 | 威海迪素制药有限公司 | Preparation method of roflumilast intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid |
| CN103319333A (en) * | 2013-07-15 | 2013-09-25 | 天津南开允公医药科技有限公司 | Preparation method for 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride compound |
| CN103992220A (en) * | 2014-06-05 | 2014-08-20 | 山东省医学科学院药物研究所 | Method for preparing roflumilast intermediate |
| CN104130116A (en) * | 2014-08-18 | 2014-11-05 | 王深涧 | Preparation method of roflumilast intermediate |
| CN105254559A (en) * | 2015-11-30 | 2016-01-20 | 山东罗欣药业集团股份有限公司 | Preparation method for high-purity roflumilast |
| CN106290597A (en) * | 2015-06-05 | 2017-01-04 | 天津药物研究院有限公司 | A kind of detection method of roflumilast mineral oil in fluid residual |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126468A (en) * | 1993-07-02 | 1996-07-10 | 比克·古尔顿·劳姆贝尔格化学公司 | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| WO2004033430A2 (en) * | 2002-10-08 | 2004-04-22 | Albemarle Corporation | Process for production of fluoroalkoxy-substituted benzamides and their intermediates |
| WO2005026095A1 (en) * | 2003-09-12 | 2005-03-24 | Ranbaxy Laboratories Limited | Process for the preparation of roflumilast |
| CN100471840C (en) * | 2003-03-10 | 2009-03-25 | 尼科梅德有限责任公司 | Novel process for the preparation of roflumilast |
| WO2009067600A2 (en) * | 2007-11-21 | 2009-05-28 | Decode Genetics Ehf | Biaryl pde4 inhibitors for treating inflammation |
| CN101490004A (en) * | 2006-07-14 | 2009-07-22 | 奇斯药制品公司 | Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors |
| WO2011006903A1 (en) * | 2009-07-15 | 2011-01-20 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Substituted triazole and imidazole derivatives as gamma secretase modulators |
-
2011
- 2011-01-28 CN CN2011100316053A patent/CN102617457A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126468A (en) * | 1993-07-02 | 1996-07-10 | 比克·古尔顿·劳姆贝尔格化学公司 | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| US5712298A (en) * | 1993-07-02 | 1998-01-27 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| WO2004033430A2 (en) * | 2002-10-08 | 2004-04-22 | Albemarle Corporation | Process for production of fluoroalkoxy-substituted benzamides and their intermediates |
| CN100471840C (en) * | 2003-03-10 | 2009-03-25 | 尼科梅德有限责任公司 | Novel process for the preparation of roflumilast |
| WO2005026095A1 (en) * | 2003-09-12 | 2005-03-24 | Ranbaxy Laboratories Limited | Process for the preparation of roflumilast |
| CN101490004A (en) * | 2006-07-14 | 2009-07-22 | 奇斯药制品公司 | Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors |
| WO2009067600A2 (en) * | 2007-11-21 | 2009-05-28 | Decode Genetics Ehf | Biaryl pde4 inhibitors for treating inflammation |
| WO2011006903A1 (en) * | 2009-07-15 | 2011-01-20 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Substituted triazole and imidazole derivatives as gamma secretase modulators |
Non-Patent Citations (1)
| Title |
|---|
| IN 478/MUM/2004 A * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102928546A (en) * | 2012-11-13 | 2013-02-13 | 南京艾德凯腾生物医药有限责任公司 | Reversed high-efficiency liquid chromatography used for detecting roflumilast raw materials and impurity content thereof |
| CN103304408A (en) * | 2013-06-05 | 2013-09-18 | 威海迪素制药有限公司 | Preparation method of roflumilast intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid |
| CN103319333A (en) * | 2013-07-15 | 2013-09-25 | 天津南开允公医药科技有限公司 | Preparation method for 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride compound |
| CN103992220A (en) * | 2014-06-05 | 2014-08-20 | 山东省医学科学院药物研究所 | Method for preparing roflumilast intermediate |
| CN103992220B (en) * | 2014-06-05 | 2015-11-18 | 山东省医学科学院药物研究所 | A kind of preparation method of roflumilast intermediate |
| CN104130116A (en) * | 2014-08-18 | 2014-11-05 | 王深涧 | Preparation method of roflumilast intermediate |
| CN104130116B (en) * | 2014-08-18 | 2015-11-11 | 朱丽平 | A kind of method preparing roflumilast intermediate |
| CN106290597A (en) * | 2015-06-05 | 2017-01-04 | 天津药物研究院有限公司 | A kind of detection method of roflumilast mineral oil in fluid residual |
| CN105254559A (en) * | 2015-11-30 | 2016-01-20 | 山东罗欣药业集团股份有限公司 | Preparation method for high-purity roflumilast |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617457A (en) | New method for preparing roflumilast | |
| CN108299423B (en) | A kind of synthetic method of dihydropyrrolo 2-aminoquinoline compounds | |
| JP7368636B2 (en) | Method for synthesizing roxadustat and its intermediates and intermediates thereof | |
| JP2019521165A5 (en) | ||
| CN108864164B (en) | A kind of synthetic method of primary amine-directed 2-alkynyl indole compounds | |
| CN103588765B (en) | The synthetic method of the synthetic method of Azilsartan or its salt and intermediate and intermediate | |
| JP3911008B2 (en) | Improved production of rebamipide | |
| CN110606839B (en) | A kind of green synthesis method of polysubstituted quinazoline derivatives | |
| CN104080770A (en) | An improved process for the preparation of roflumilast | |
| JP5936511B2 (en) | Method for purifying 3,3'-dinitro-4,4'-dihydroxydiphenyl ether and method for producing 3,3'-dinitro-4,4'-dihydroxydiphenyl ether | |
| CN105566260A (en) | Furosemide preparation method | |
| CN102127014B (en) | Azaphenanthrone compound and preparation method thereof | |
| CN101805265B (en) | Synthesis method of 2-nitro-4-substituted phenylacetic acid | |
| CN101486676B (en) | The preparation method of cyanomethylpyridine compound | |
| CN106928040A (en) | The preparation method of SGLT2 inhibitor intermediate | |
| CN107628964B (en) | A kind of synthetic method of N-aryl secondary aromatic amide | |
| CN102241629B (en) | Chemical preparation method of norfloxacin | |
| CN109867633B (en) | Method for synthesizing 1,2, 3-triazole from beta-bromostyrene | |
| CN109400507A (en) | The synthesis of Ailamode intermediate impurities | |
| CN111320622A (en) | Method for synthesizing moxifloxacin hydrochloride | |
| CN108129409B (en) | Improved method for synthesizing lamotrigine | |
| CN105250228B (en) | A kind of tablet of Gefitinib and its preparation method of raw material | |
| CN102030705A (en) | Synthesis method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline | |
| CN108558878B (en) | A kind of synthesis technology of quindoline and derivatives thereof | |
| CN108148005B (en) | A kind of o-aminophenol derivatives and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120801 |