CN104072409B - A kind of synthetic method of pyridine amides - Google Patents

A kind of synthetic method of pyridine amides Download PDF

Info

Publication number
CN104072409B
CN104072409B CN201410302244.5A CN201410302244A CN104072409B CN 104072409 B CN104072409 B CN 104072409B CN 201410302244 A CN201410302244 A CN 201410302244A CN 104072409 B CN104072409 B CN 104072409B
Authority
CN
China
Prior art keywords
pyridine
formula
reaction
ets
catalyst
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.)
Expired - Fee Related
Application number
CN201410302244.5A
Other languages
Chinese (zh)
Other versions
CN104072409A (en
Inventor
熊静
胡蓉蓉
刘武强
陶央央
冯晓刚
周政
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wenzhou University
Original Assignee
Wenzhou University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wenzhou University filed Critical Wenzhou University
Priority to CN201410302244.5A priority Critical patent/CN104072409B/en
Publication of CN104072409A publication Critical patent/CN104072409A/en
Application granted granted Critical
Publication of CN104072409B publication Critical patent/CN104072409B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Abstract

The invention discloses the synthetic method of a kind of pyridine amides, described method is: the pyridine cyanides shown in Formula II is raw material, with water as solvent, under the effect of catalyst ETS 10 molecular sieve, it is heated to 100 150 DEG C react, to reaction completely, reactant liquor post processing prepares pyridine amides shown in formula I to TLC tracing detection.The present invention, with ETS 10 molecular sieve as catalyst, carries out the hydrolysis of pyridine cyanogen, obtains single picolinamide class product, conversion ratio 100%, yield more than 95%, and catalyst can reuse more than 5 times.

Description

A kind of synthetic method of pyridine amides
(1) technical field
The present invention relates to the new synthetic method of a series of pyridine amides.
(2) background technology
Pyridine amides has and much has biological activity.Such as Niacinamide (nicotinoyl Amine), i.e. vitamin B3, it is the stable small molecular weight material of a kind of water solublity, can wear rapidly Cross horny layer.When human body lacks, pellagra can be obtained.Therefore nicotiamide is mainly used in preventing and treating rough Skin disease, stomatitis, glossitis etc. and sick sinus syndrome and atrioventricular block.Additionally, Nicotiamide plays a role in the metabolism of protein and sugar, can improve the mankind and move The nutrition of thing, as food additive and feed additive etc..Isonicotinamide (different nicotinoyl Amine) can be used as medicine intermediate, it is used for synthesizing cefalonium (Cefalonium) etc..Additionally Some patent was also reported some compound containing picolinamide group and is also had and preferably remove Grass effect and insecticidal action, for agricultural and plant protection etc..
The method of industrial pyridine synthesis amide is more, and one of them is using pyridine cyanogen as former Material, hydrolyzes in acid or alkaline medium and obtains.But the method is because using strong acid, highly basic to setting Standby seriously corroded, unfriendly to environment, and the product obtained mostly is the mixture of carboxylic acid and amide. Also patent and document report is had to use nickel oxide, magnesium oxide, nickel dioxide to carry out as catalyst Hydrolysis, but catalysis activity is relatively low.
(3) summary of the invention
It is an object of the invention to use strong acid or highly basic to environment not for the hydrolysis of present pyridine cyanogen Close friend, and easily etching apparatus, and the catalytic efficiency of the catalyst such as magnesium oxide, nickel oxide is relatively low Shortcoming, it is provided that a kind of zeolite ETS-10 catalyzing hydrolysis pyridine cyanogen generates picolinamide class chemical combination The preparation method of thing, the method has no that document is reported.
The technical solution used in the present invention is:
A kind of synthetic method of pyridine amides shown in formula I, described method is: Pyridine cyanides shown in Formula II is raw material, with water as solvent, at catalyst ETS-10 Under the effect of molecular sieve, being heated to 100-150 DEG C and react, TLC tracing detection is to reaction Completely, reactant liquor post processing prepares pyridine amides shown in formula I；
In Formulas I or Formula II, R is H, methyl, ethyl, methoxyl group or chlorine；R is that H is Represent that on pyridine ring, only cyano group replaces, and does not has other substituent groups；
In Formula II ,-CN can be 2-CN, 3-CN or 4-CN, and the corresponding Formulas I prepared is produced -CONH in thing2For 2-CONH2、3-CONH2Or 4-CONH2。
In described Formula II, kind and the position of R keep constant, with product Formulas I in course of reaction The kind of middle R is identical with position.
The quality consumption of described catalyst ETS-10 is the pyridine cyanides shown in Formula II The 1～20% of quality, preferably 1～10%.
The volumetric usage of described aqueous solvent is in terms of the quality of the pyridine cyanides shown in Formula II It is 20～100mL/g, preferably 25～50mL/g.
Preferred 100-135 DEG C of the temperature of described reaction, more preferably 110-120 DEG C.
The described response time is usually 15～40 hours.
Described reactant liquor post-processing approach is: reaction terminates the cooling of rear reactant liquor, centrifugal or filtration Separating, the aqueous solution obtained is evaporated, and prepares pyridine amides shown in formula I.
Described centrifugal or filtration isolated residual solids catalyst is reusable.
Described catalyst ETS-10 molecular sieve is a kind of titanium silicon molecule with unique microcellular structure Sieve.Molecular sieve is the crystal that a class has regular microcellular structure, being catalyzed, adsorb, separate, The fields such as photocatalysis are widely used already.The synthesis of ETS-10 also early has been reported that, this patent The ETS-10 used synthesizes according to document.Concrete grammar is as follows:
By 20g sodium silicate (Na2SiO3) join in 60mL distilled water, stir about 10min, then Add 3.90g potassium chloride (KCl), 3.50g sodium chloride (NaCl) and 1.33g titanium dioxide (TiO2), Stirring 1-2h, is loaded in reactor, crystallization three days at 230 DEG C.By sample after three days Taken out by reactor, cleaning, sucking filtration, and put into drying in 100 DEG C of baking ovens.After drying Sample mortar is smashed to pieces.
List of references: Wang Lingling, Ding Jielu, Zhu Luping, thanks to the brave .ETS-10 molecular sieve of flood Synthesis and application, Shanghai second Industry Univ's journal, 2011,28 (3): 34-38.
The method that the present invention hydrolyzes with existing pyridine cyanogen compares, and has the advantage that
(1) catalytic efficiency is high, feed stock conversion 100%, yield more than 95%, and purity is high.
(2) convenient post-treatment, it is only necessary to aqueous solvent is evaporated off.
(3) catalyst can be reused, cost-effective.
The inventive method, with ETS-10 molecular sieve as catalyst, carries out the hydrolysis of pyridine cyanogen, To single picolinamide class product, conversion ratio 100%, yield more than 95%, catalyst can To reuse more than 5 times.
(4) detailed description of the invention
With specific embodiment, the present invention will be further described below, but the protection model of the present invention Enclose and be not limited to this.
Embodiment 1
Weigh 3-pyridine cyanogen 1.04g and 0.10g ETS-10 in reaction tube, add 30mL Water, is warmed up at 100 DEG C reaction, TLC tracing detection, and reaction in 24 hours is complete, after cooling, Centrifugation, solution is evaporated off water and obtains product Niacinamide 1.18g, and yield 97% is pure Degree 99.99% (gas chromatographic detection).The centrifugal solid obtained is anti-for repeating as catalyst Should, reaction condition, material quantity ibid, when being repeated 5 times, yield equal more than 93%, repeat the When 6 times, yield is 90%, purity equal more than 98%.
Embodiment 2
Weigh 3-pyridine cyanogen 1.04g and 0.10g ETS-10 in reaction tube, add 30mL Water, is warmed up at 120 DEG C reaction, TLC tracing detection, and reaction in 15 hours is complete, after cooling, Centrifugation, is evaporated off the solution of isolated water and obtains product Niacinamide 1.20g, Yield 98%, purity 99.99% (gas chromatographic detection).The centrifugal solid obtained is for repeating Reaction, reaction condition, material quantity are constant, when being repeated 5 times, product Niacinamide yield All more than 95%, during 6 secondary response, yield is 92%, purity equal more than 98%.
Embodiment 3
Weigh 3-pyridine cyanogen 1.04g and 0.04g ETS-10 in reaction tube, add 30mL Water, is warmed up at 130 DEG C reaction, TLC tracing detection, and reaction in 28 hours is complete, after cooling, Centrifugation, gained solution is evaporated off water and obtains product Niacinamide 1.16g, yield 95%, Purity 99.94% (gas chromatographic detection).Centrifugal gained solid is used for repeating reaction, reacts bar Ibid, when being repeated 5 times, yield is more than 91% for part, material quantity, during 6 secondary response, Yield is 88%, purity equal more than 98%.
Embodiment 4
Weigh 4-pyridine cyanogen 1.04g and 0.05g ETS-10 in reaction tube, add 30mL Water, is warmed up at 120 DEG C reaction, TLC tracing detection, and reaction in 24 hours is complete, after cooling, Centrifugation, gained solution is evaporated off water and obtains product Isonicotinamide 1.21g, yield 99%, Purity 99.97% (gas chromatographic detection).Centrifugal gained solid is used for repeating reaction, reacts bar Part, material quantity ibid, when being repeated 6 times, yield equal more than 95%, during 7 secondary response, receive Rate is 91%, purity equal more than 98%.
Embodiment 5
Weigh 4-pyridine cyanogen 1.04g and 0.02g ETS-10 in reaction tube, add 30mL Water, is warmed up at 135 DEG C reaction, TLC tracing detection, and reaction in 40 hours is complete, after cooling, Centrifugation, gained solution is evaporated off water and obtains product Isonicotinamide 1.17g, yield 96%, Purity 99.63% (gas chromatographic detection).Centrifugal gained solid is used for repeating reaction, reacts bar Part, material quantity ibid, when being repeated 5 times, yield equal more than 92%, during 6 secondary response, receive Rate is 87%, purity equal more than 98%.
Embodiment 6
Weigh 2-pyridine cyanogen 1.04g and 0.05g ETS-10 in reaction tube, add 30mL Water, is warmed up at 120 DEG C reaction, TLC tracing detection, and reaction in 24 hours is complete, after cooling, Centrifugation, gained solution is evaporated off water and obtains product 2-ascorbyl palmitate 1.18g, yield 97%, Purity 99.54% (gas chromatographic detection).Centrifugal gained solid is used for repeating reaction, reacts bar Part, material quantity ibid, when being repeated 5 times, yield equal more than 93%, during 6 secondary response, receive Rate is 89%, purity equal more than 99%.
Embodiment 7
Weigh 4-methyl-nicotinonitrile 1.18g and 0.08g ETS-10 in reaction tube, add Enter 50mL water, be warmed up at 120 DEG C reaction, TLC tracing detection, within 22 hours, reacted Entirely, after cooling, centrifugation, gained solution is evaporated off water and obtains product 4-methyl-3-pyridine first Amide 1.28g, yield 94%, purity 98.75% (gas chromatographic detection).Centrifugal gained is solid Body is used for repeating reaction, reaction condition, material quantity ibid, when being repeated 5 times, yield equal 91% Above, during 6 secondary response, yield is 85%, purity equal more than 99%.
Embodiment 8
Weigh 2-chloro-4-cyanopyridine 1.38g and 0.07g ETS-10 in reaction tube, add 50mL water, is warmed up at 110 DEG C reaction, TLC tracing detection, and reaction in 20 hours is complete, After cooling, centrifugation, gained solution is evaporated off water and obtains the chloro-Isonicotinamide of product 2- 1.48g, yield 95%, purity 99.78% (gas chromatographic detection).Centrifugal gained solid is used In repeat reaction, reaction condition, material quantity ibid, when being repeated 5 times, yield equal more than 90%, During 6 secondary response, yield is 83%, purity equal more than 98%.
Embodiment 9
Weigh 2-chloro-6-cyanopyridine 1.38g and 0.05g ETS-10 in reaction tube, add 50mL water, is warmed up at 110 DEG C reaction, TLC tracing detection, and reaction in 22 hours is complete, After cooling, centrifugation, gained solution is evaporated off water and obtains product 2-chloro-6-ascorbyl palmitate 1.46g, yield 94%, purity 99.75% (gas chromatographic detection).Centrifugal gained solid is used In repeat reaction, reaction condition, material quantity ibid, when being repeated 4 times, yield equal more than 90%, During the 5th reaction, yield is 84%, purity equal more than 97%.
Embodiment 10
Weigh 2-chloro-3-cyano group-4-picoline 1.52g and 0.06g ETS-10 in reaction tube, Add 60mL water, be warmed up at 120 DEG C reaction, TLC tracing detection, reaction in 22 hours Completely, after cooling, centrifugation, gained solution is evaporated off water and obtains product 2-chloro-4-methyl-3- Ascorbyl palmitate 1.62g, yield 95%, purity 99.25% (gas chromatographic detection).Centrifugal Gained solid is used for repeating reaction, reaction condition, material quantity ibid, when being repeated 4 times, yield Equal more than 90%, during the 5th reaction, yield is 85%, purity equal more than 97%.
Embodiment 11
Weigh 2-ethyl-4-cyanopyridine 1.32g and 0.06g ETS-10 in reaction tube, add Enter 50mL water, be warmed up at 110 DEG C reaction, TLC tracing detection, within 24 hours, reacted Entirely, after cooling, centrifugation, gained solution is evaporated off water and obtains product 2-ethyl-4-pyridine first Amide 1.45g, yield 97%, purity 99.72% (gas chromatographic detection).Centrifugal gained is solid Body is used for repeating reaction, reaction condition, material quantity ibid, when being repeated 5 times, yield equal 92% Above, during the 5th reaction, yield is 90%, purity equal more than 98%.
Embodiment 12
Weigh 2-methoxyl group-nicotinonitrile 1.34g and 0.07g ETS-10 in reaction tube, Add 50mL water, be warmed up at 120 DEG C reaction, TLC tracing detection, reaction in 24 hours Completely, after cooling, centrifugation, gained solution is evaporated off water and obtains product 2-methoxyl group-3-pyrrole Pyridine Methanamide 1.48g, yield 97%, purity 99.26% (gas chromatographic detection).Centrifugal institute Obtaining solid to be used for repeating reaction, ibid, when being repeated 5 times, yield is equal for reaction condition, material quantity More than 93%, during 6 secondary response, yield is 90%, purity equal more than 98%.

Claims (6)

1. a synthetic method for pyridine amides shown in formula I, its feature exists In described method it is: the pyridine cyanides shown in Formula II is raw material, with water as solvent, Under the effect of catalyst ETS-10 molecular sieve, it is heated to 100-150 DEG C and reacts, TLC To reaction completely, reactant liquor post processing prepares picolinamide class shown in formula I to tracing detection Compound；The quality consumption of described catalyst ETS-10 is the pyridine cyanides shown in Formula II Quality 1～20%；The volumetric usage of described aqueous solvent is with the pyridine cyanogen class shown in Formula II The quality of compound is calculated as 20～100mL/g；
In Formulas I or Formula II, R is H, methyl, ethyl, methoxyl group or chlorine.
2. the method for claim 1, it is characterised in that described reactant liquor post processing side Method is: reaction terminates the cooling of rear reactant liquor, centrifugal or filtration separation, and the aqueous solution obtained is evaporated, Prepare pyridine amides shown in formula I.
3. method as claimed in claim 2, it is characterised in that described centrifugal or filtration separates The residual solids obtained is reused as catalyst.
4. the method for claim 1, it is characterised in that described catalyst ETS-10 The quality that quality consumption is the pyridine cyanides shown in Formula II 1～10%.
5. the method for claim 1, it is characterised in that the temperature of described reaction is 100-135℃。
6. the method for claim 1, it is characterised in that the temperature of described reaction is 110-120℃。
CN201410302244.5A 2014-06-27 2014-06-27 A kind of synthetic method of pyridine amides Expired - Fee Related CN104072409B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410302244.5A CN104072409B (en) 2014-06-27 2014-06-27 A kind of synthetic method of pyridine amides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410302244.5A CN104072409B (en) 2014-06-27 2014-06-27 A kind of synthetic method of pyridine amides

Publications (2)

Publication Number Publication Date
CN104072409A CN104072409A (en) 2014-10-01
CN104072409B true CN104072409B (en) 2016-08-24

Family

ID=51594058

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410302244.5A Expired - Fee Related CN104072409B (en) 2014-06-27 2014-06-27 A kind of synthetic method of pyridine amides

Country Status (1)

Country Link
CN (1) CN104072409B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104592106A (en) * 2014-10-23 2015-05-06 华中药业股份有限公司 Improvement preparation method of nicotinamide
CN105693602A (en) * 2016-03-24 2016-06-22 广西新天德能源有限公司 Method for producing nicotinamide by virtue of catalysis of modified molecular sieve

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101239311A (en) * 2002-12-23 2008-08-13 科学与工业研究委员会 Method for converting cyanopyridine compounds into niacinamide compounds, its catalyst and the catalyst preparation
CN102627602A (en) * 2012-03-23 2012-08-08 天津中瑞药业有限公司 Efficient production technology of nicotinamide

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56169672A (en) * 1980-06-02 1981-12-26 Koei Chem Co Ltd Preparation of 2-chloro-3-cyanopyridine and 2- chloronicotinic acid
JPS59144759A (en) * 1983-02-07 1984-08-18 Yuki Gosei Yakuhin Kogyo Kk Preparation of 2-chloronicotinic acid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101239311A (en) * 2002-12-23 2008-08-13 科学与工业研究委员会 Method for converting cyanopyridine compounds into niacinamide compounds, its catalyst and the catalyst preparation
CN102627602A (en) * 2012-03-23 2012-08-08 天津中瑞药业有限公司 Efficient production technology of nicotinamide

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
从3-氰基吡啶合成烟酰胺-N-氧化物的研究;王谦等;《化学工程师》;20050630;第117卷(第6期);57-58 *
吡啶酰胺类化合物的合成及其抗植物真菌活性;吴志兵等;《贵州农业科学》;20131231;第41卷(第1期);93-94 *
酶法水解3-氰基吡啶制备烟酸;张淑蓉等;《西南大学学报（自然科学版）》;20101130;第32卷(第11期);30-34 *

Also Published As

Publication number Publication date
CN104072409A (en) 2014-10-01

Similar Documents

Publication Publication Date Title
CN104945299B (en) A kind of high-efficiency synthesis method of vildagliptin
CN109320498A (en) The bromo- 1-(3- chloro-2-pyridyl of 3-) -1H- pyrazoles -5- formic acid alkyl ester preparation method
CN104072409B (en) A kind of synthetic method of pyridine amides
CN102336703B (en) Method for preparing roflumilast
CN1188475A (en) Process for producing guanidine derivatives, intermediates therefor and their production
CN104311535A (en) Method for preparing DPP-IV inhibitor
CN109575017A (en) A kind of preparation method of Olprinone HCl compound
CN101362729B (en) Valsartan postprocessing method
CN105399667A (en) Preparation method of edoxaban intermediate
CN105541705B (en) A kind of synthetic method of flupirtine maleate compound
CN105315256A (en) Industrialization-suitable preparation method of high-purity trelagliptin succinate
CN104163787A (en) Preparation methods of Atazanavir and sulfate of Atazanavir
CN108997209B (en) Preparation method of regorafenib
CN104910068B (en) A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5
CN108864041A (en) A kind of preparation method of medicine intermediate tetrazole compound
CN106478515B (en) A kind of preparation method of Azilsartan intermediate
CN104447697B (en) A kind of preparation method of dabigatran etexilate intermediate
CN105949133B (en) A kind of synthetic method of the chloro- 5- formamido group pyrimidine of 2- amino -4,6- two
JPH09508379A (en) Method for preparing nicotinic acid
CN103880708A (en) Improved catalytic synthesis method of malononitrile
CN101121692A (en) Synthesis method for alpha-carbonylamide compound
CN109251170B (en) Method for preparing pyridine-2-formamide by using 2-OP rectification residue
CN103936825B (en) The environment-friendly preparation method thereof of phthaloyl-L-alanyl-L-glutamine
CN106866628A (en) A kind of RTIs of aryl heteroaryl miazines HIV 1 and preparation method thereof
CN102942521B (en) The preparation method of roflumilast

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160824

Termination date: 20170627

CF01 Termination of patent right due to non-payment of annual fee