CN107879986A - A kind of synthetic method of avanaphil impurity - Google Patents
A kind of synthetic method of avanaphil impurity Download PDFInfo
- Publication number
- CN107879986A CN107879986A CN201711381418.1A CN201711381418A CN107879986A CN 107879986 A CN107879986 A CN 107879986A CN 201711381418 A CN201711381418 A CN 201711381418A CN 107879986 A CN107879986 A CN 107879986A
- Authority
- CN
- China
- Prior art keywords
- synthetic method
- impurity
- avanaphil
- potassium
- methoxies
- 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
- 239000012535 impurity Substances 0.000 title claims abstract description 53
- 238000010189 synthetic method Methods 0.000 title claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000007530 organic bases Chemical class 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- DOJUQNDTUGUKLL-UHFFFAOYSA-N ethyl 2-methylsulfanylpyrimidine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC(SC)=N1 DOJUQNDTUGUKLL-UHFFFAOYSA-N 0.000 claims 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 7
- -1 methoxYbenzylamino Chemical group 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- LWMNQZSYAOWVPE-UHFFFAOYSA-N 2-methylsulfinylpyrimidine Chemical compound CS(=O)C1=NC=CC=N1 LWMNQZSYAOWVPE-UHFFFAOYSA-N 0.000 abstract 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
- 229910052801 chlorine Inorganic materials 0.000 abstract 2
- 239000000460 chlorine Substances 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000006482 condensation reaction Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical class CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000307 avanafil Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940046921 stendra Drugs 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of synthetic method of avanaphil impurity, comprise the following steps：A) in organic solvent and water, using the methylsulfinyl pyrimidine of 4 (methoxYbenzylamino of 3 chlorine 4) 5 carbethoxyl group 2 as raw material, hydrolyzed under the conditions of alkali is existing and obtain the first intermediate；B) first intermediate and the methylsulfinyl pyrimidine of 4 (methoxYbenzylamino of 3 chlorine 4) 5 carbethoxyl group 2 are condensed under conditions of organic base, obtain the second intermediate；C) second intermediate is reacted under basic conditions with 2 methylaminopyrimidins, obtains avanaphil impurity.The route can not only obtain the preferable target impurity of purity, also can provide purity preferable intermediate for the impurity, and provide a kind of synthetic method of the new impurity of avanaphil, perfect in order to be composed to the impurity of the drug.
Description
Technical field
The invention belongs to medical synthesis technical field, more particularly to a kind of synthetic method of avanaphil impurity.
Background technology
Avanaphil is a kind of (PDE-5) inhibitor of high selectivity second generation phosphodiesterase -5, is by day Honda side system
Medicine Co., Ltd (being now renamed as drugmaker of Tian Bian Mitsubishis) exploitation.2001, Vivus companies of the U.S. were permitted through Tian Bian companies
Can, obtain the right that avanaphil is developed and sold outside specific Asian market.On April 27th, 2012, FDA approval new drugs
Avanaphil (trade name:Stendra the treatment for male ED (Erectile Dysfunc-tion)) is listed.
Studies have shown that avanaphil has higher selectivity to PDE-5, and this will substantially reduce the generation of adverse effect
Rate.In addition, compared with his PDE-5 inhibitor, avanaphil has the important intermediate A key Avanafil of avanaphil
The prior synthesizing method Traditional synthetic method of the title of intermediate title compounds
Compound is rapid-action, action time is short and the features such as less drug interaction, it has also become the first choice of ED patient.
Patent document US6797709 discloses A Fanafei two kinds of synthetic methods, and the synthetic route of one of which is as follows：
When using route synthesis avanaphil instead, a kind of impurity for being difficult to remove be present in obtained avanaphil product,
Have great importance to the miscellaneous Quality Research for the quality control level for improving the medicine.
The content of the invention
In view of this, it is an object of the invention to provide a kind of synthetic method of avanaphil impurity, the side in the present invention
Method can be prepared the preferable target impurity of purity, the perfect impurity spectrum of avanaphil.
The present invention provides a kind of synthetic method of avanaphil impurity, comprises the following steps：
A) in organic solvent and water, with 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyls Asia sulphur
Acyl pyrimidine is raw material, is hydrolyzed under the conditions of alkali is existing and obtains the first intermediate；
B) by first intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyls
Pyrimidine is condensed under conditions of organic base, obtains the second intermediate；
C) second intermediate is reacted under basic conditions with 2- methylaminopyrimidins, obtains the miscellaneous of avanaphil
Matter.
Preferably, 4- (3- chloro-4-methoxies the benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines and alkali
Mol ratio be 1：(1.2~10).
Preferably, the step A) in alkali be sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium acid carbonate in
One or more；
The mass concentration of the alkali is 5~40%.
Preferably, the step A) in hydrolysis temperature be -30~100 DEG C；
The step A) in hydrolysis time be 2~10 hours.
Preferably, the mol ratio of first intermediate and organic base is 1：(1.02~10)；
First intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines
Mol ratio be 1：(1.02~10).
Preferably, the organic base is triethylamine, diethylamine, diisopropylethylamine, tri-n-butylamine, pyridine and N- methylpyrroles
One or more in alkanone.
Preferably, the step B) in condensation temperature be 20~150 DEG C；
The step B) in condensation time be 3~8 hours.
Preferably, the mol ratio of second intermediate and 2- methylaminopyrimidins is 1：(2.1~5)；
The mol ratio of second intermediate and highly basic is 1：(2.1~5).
Preferably, the highly basic is sodium methoxide, potassium methoxide, caustic alcohol, potassium ethoxide, sodium hydroxide, potassium hydroxide and tertiary fourth
One or more in potassium alcoholate.
Preferably, the step C) in reaction temperature be 40~150 DEG C；
The step C) in reaction time be 3~8 hours.
Avanaphil synthetic route in the patent document US6797709 mentioned with reference to background section, applicant's research
It is that sulfoxide radicals prepare production with oxidizing sulfide group in organic solvent with product 1 it was found that in the synthetic route
During thing 2, a kind of impurity of extremely difficult removing is produced, the impurity prepares Ah cutting down follow-up with the reaction of 2- methylaminopyrimidins
During that is non-, fail to remove, and a new impurity is generated with the reaction of 2- methylaminopyrimidins, and in the final product,
Equally it is difficult to remove the new impurity.The report to both impurity is yet there are no, to preparing impurity caused by product 2 and most
Control of the new miscellaneous Quality Research for avanaphil drug quality in whole avanaphil has great importance.
The invention provides a kind of synthetic method of avanaphil impurity, comprise the following steps：A) in organic solvent and water
In, using 4- (3- chloro-4-methoxies benzylamino), -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines is raw materials, condition existing for alkali
Lower hydrolysis obtains the first intermediate；B) by first intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxy carbonyls
Base -2- methylsulfinyl pyrimidines are condensed under conditions of organic base, obtain the second intermediate；C) by second intermediate
Reacted with 2- methylaminopyrimidins under basic conditions, obtain avanaphil impurity.The present invention is with 4- (3- chloro-4-methoxies
Benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyls pyrimidine be raw material be sequentially prepared out the first intermediate, the second intermediate and
Impurity, the route can not only obtain the preferable target impurity of purity, also can provide purity preferable intermediate for the impurity,
And a kind of synthetic method of A Fanafeixin impurity is provided, perfect in order to be composed to the impurity of the drug, the present invention can also lead to
The restriction to impurity intermediates content when preparing intermediate is crossed, to improve the quality control to the medicine, for the poison of the impurity
Pharmacological research provides the experimental method for synthesizing the impurity.
Brief description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
There is the required accompanying drawing used in technology description to be briefly described, it should be apparent that, drawings in the following description are only this
The embodiment of invention, for those of ordinary skill in the art, on the premise of not paying creative work, can also basis
The accompanying drawing of offer obtains other accompanying drawings.
Fig. 1 is the liquid phase analysis collection of illustrative plates of the product that product 1 prepares product 2 in avanaphil synthetic route；
Fig. 2 is the liquid phase analysis collection of illustrative plates of the second intermediate in the embodiment of the present invention 1；
Fig. 3 is the mass spectrogram of the second intermediate in the embodiment of the present invention 1.
Embodiment
The invention provides a kind of synthetic method of avanaphil impurity, comprise the following steps：
A) in organic solvent and water, with 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyls Asia sulphur
Acyl pyrimidine is raw material, is hydrolyzed under the conditions of alkali is existing and obtains the first intermediate；
B) by first intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyls
Pyrimidine is condensed under conditions of organic base, obtains the second intermediate；
C) second intermediate is reacted under basic conditions with 2- methylaminopyrimidins, obtains the miscellaneous of avanaphil
Matter.
The present invention is first in organic solvent and water, with 4- (3- chloro-4-methoxies benzylamino) -5- carbethoxyl groups -2-
Methylsulfinyl pyrimidine is raw material, controls low temperature, is slowly added dropwise alkali, hydrolyzed under basic conditions, through adjusting pH value as after neutral, You Jirong
Agent extracts, and dries, the first intermediate is obtained after distillation；Reaction is shown in formula I：
The alkali is preferably the one or more in sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium acid carbonate；
The mass concentration of the alkali is preferably 5~40%, more preferably 10~30%, most preferably 20%；
The mol ratio of 4- (3- chloro-4-methoxies the benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines and alkali
Preferably 1：(1.2~10), more preferably 1：(1.2~5), most preferably 1：(1.2~3)；
The organic solvent is preferably C1~C5Chlorohydrocarbon, C2~C10Ester, C5~C15Aromatic hydrocarbon and C4~C10Ether
In one or several kinds, more preferably dichloromethane, chloroform, 1,2- dichloroethanes, ethyl acetate, methyl acetate, acetic acid fourth
One or several kinds in ester, isopropyl acetate, benzene,toluene,xylene, chlorobenzene, ether, isopropyl ether and tetrahydrofuran；
The temperature of the hydrolysis is preferably -30~100 DEG C, more preferably -20~50 DEG C, is most preferably -10~20 DEG C, tool
Body, can be -5~5 DEG C；The time of the hydrolysis is preferably 2~10 hours, more preferably 3~8 hours, most preferably 5~
6 hours.
After hydrolysis, the present invention preferably separates organic layer, wherein, water layer is extracted twice with dichloromethane, will be had
Machine is laminated simultaneously, is then dried again with anhydrous magnesium sulfate, obtains the first intermediate.
After obtaining the first intermediate, then by the first intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxy carbonyls
Base -2- methylsulfinyls pyrimidine is raw material, in organic solvent, adds organic base and is used as acid binding agent, the condensation reaction that heats up into ether,
After adjusting pH value, organic solvent extraction, dry, the second intermediate is obtained after distillation；Condensation reaction is as shown in Formula II：
The organic base is preferably triethylamine, diethylamine, diisopropylethylamine, tri-n-butylamine, pyridine and N- crassitudes
One or more in ketone；
The mol ratio of first intermediate and organic base is preferably 1：(1.02~10), more preferably 1：(1.02~5),
Most preferably 1:(1.02~3)；
First intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines
Mol ratio be preferably 1：(1.02~10), more preferably 1：(1.02~5), most preferably 1:(1.02~3)；
The organic solvent is preferably C1~C5Chlorohydrocarbon, C2~C10Ester, C5~C15Aromatic hydrocarbon, C4~C10Ether
One or several kinds of mixing, more preferably dichloromethane, chloroform, 1,2- dichloroethanes, ethyl acetate, methyl acetate, acetic acid
One or several kinds in butyl ester, isopropyl acetate, benzene,toluene,xylene, chlorobenzene, ether, isopropyl ether, tetrahydrofuran；
The temperature of the condensation reaction is preferably 20~150 DEG C, more preferably 30~120 DEG C, most preferably 50~100
℃；The time of the condensation reaction is preferably 3~8 hours, more preferably 5~7 hours.
After condensation reaction, system pH is adjusted to neutrality present invention preferably employs hydrochloric acid, then adds bicarbonate
Sodium solution is washed, and organic layer is dried using anhydrous magnesium sulfate, is filtered, and is evaporated under reduced pressure and is obtained the second intermediate to after stopping.
In the present invention, second intermediate is product in the avanaphil synthetic route that background section is mentioned
1 prepares caused impurity during product 2.
Using the second intermediate as raw material, highly basic and 2- methylamine yl pyrimidines are added in anhydrous organic solvent, ester occurs for heating
Aminolysis reaction, after adjusting pH value, organic solvent extraction, dry, the new impurity of avanaphil is obtained after distillation.The reaction is such as formula
Shown in III：
The anhydrous organic solvent is preferably C1~C5Chlorohydrocarbon, C5~C15Aromatic hydrocarbon, C4~C10Ether one kind or
It is several, more preferably dichloromethane, chloroform, 1,2- dichloroethanes, benzene,toluene,xylene, chlorobenzene, ether, isopropyl ether, tetrahydrochysene
One or several kinds in furans；
The highly basic is preferably sodium methoxide, potassium methoxide, caustic alcohol, potassium ethoxide, sodium hydroxide, potassium hydroxide and potassium tert-butoxide
In one or more；
The mol ratio of second intermediate and 2- methylaminopyrimidins is preferably 1：(2.1~5), more preferably 1：(2.1~
3)；
The mol ratio of second intermediate and highly basic is preferably 1：(2.1~5), more preferably 1：(2.1~3)；
The temperature of the reaction is preferably 40~150 DEG C, more preferably 60~130 DEG C, most preferably 80~110 DEG C；Institute
The time for stating reaction is preferably 3~8 hours, more preferably 5~7 hours.
The pH value of system is adjusted to neutrality present invention preferably uses hydrochloric acid, extracted using dichloromethane, merges organic layer,
Using saturated common salt water washing organic layer, then it is dried with anhydrous magnesium sulfate, is filtrated to get avanaphil impurity.
In the avanaphil synthetic route that background section is mentioned, the second intermediate is remained in product 2, can not be passed through
Purification scheme removes completely, is carrying out subsequent reactions 3., and 3. the second intermediate cannot participate in reaction, and can not refine removing, after
Continuous to remain in product 3, product 3 carries out subsequent reactions generation product 4, and the second intermediate generates corresponding carboxylic in this step
Acid, then react with 2- methylamines yl pyrimidines in acyl chlorides and generate A Fanafei impurity.
The invention provides a kind of synthetic method of avanaphil impurity, comprise the following steps：A) in organic solvent and water
In, using 4- (3- chloro-4-methoxies benzylamino), -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines is raw materials, condition existing for alkali
Lower hydrolysis obtains the first intermediate；B) by first intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxy carbonyls
Base -2- methylsulfinyl pyrimidines are condensed under conditions of organic base, obtain the second intermediate；C) by second intermediate
Reacted with 2- methylaminopyrimidins under basic conditions, obtain avanaphil impurity.The present invention is with 4- (3- chloro-4-methoxies
Benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyls pyrimidine be raw material be sequentially prepared out the first intermediate, the second intermediate and
Impurity, the route can not only obtain the preferable target impurity of purity, also can provide purity preferable intermediate for the impurity,
And a kind of synthetic method of A Fanafeixin impurity is provided, perfect in order to be composed to the impurity of the drug, the present invention can also lead to
The restriction to impurity intermediates content when preparing intermediate is crossed, to improve the quality control to the medicine, for the poison of the impurity
Pharmacological research provides the experimental method for synthesizing the impurity.
In order to further illustrate the present invention, with reference to embodiments to a kind of conjunction of avanaphil impurity provided by the invention
It is described in detail into method, but limiting the scope of the present invention can not be understood as.
Embodiment 1
The synthesis of first intermediate
Compound 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyls pyrimidine (38.38g,
0.1mol) put into 150mL water and 100mL dichloromethane, open stirring, after being dissolved completely after stirring 10min, reaction bulb is put
- 5 DEG C are cooled in ice bath, 0 ± 5 DEG C of temperature control, (30g, 0.15mol) 20% sodium hydrate aqueous solution is slowly added dropwise, drips
Bi Hou, it is incubated -5~5 DEG C and reacts 1 hour, sample organic layer TLC (ethyl acetate：Ethanol：Ammoniacal liquor=4:1:0.1), until without change
Compound 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines, after question response, control is anti-
Temperature in system≤5 DEG C of 10% hydrochloric acid of dropwise addition are answered, adjust system pH to separate organic layer for neutrality, water layer extracts two with dichloromethane
It is secondary, merge organic layer, anhydrous magnesium sulfate is dried, and filtering, 21.95g faint yellow solids, purity 99.9% is obtained after distillation；Yield：
65.06%.mp：117~122 DEG C.
The synthesis of second intermediate
Impurity (3) (21.95g, 64.98mmol) and Compound Compound 4- (3- chloro-4-methoxies benzylamino) -5- second
In oxygen carbonyl -2- methylsulfinyls pyrimidine (27.43g, 71.48mmol) input 250mL chloroforms, triethylamine is then added
(15.23g, 149.45mmol), system temperature rising reflux reacts 4 hours after feeding intake, TLC (solvents：Ethyl acetate) control eventually
To without untill the first intermediate spot, after completion of the reaction, room temperature is cooled to, system pH is adjusted to neutrality with 3% aqueous hydrochloric acid solution,
Then the washing of the saturated sodium bicarbonate solution of 100mL × 2 is added, after organic layer anhydrous magnesium sulfate is dried, is filtered, is evaporated under reduced pressure to disconnected
Faint yellow solid 29.9g, purity 99.5%, yield are obtained after stream：70.11%.
Mass Spectrometer Method is carried out to the second intermediate, spectrogram is as shown in figure 3, from the figure 3, it may be seen that the molecular weight of the second intermediate is
657.50；
Chromatography is carried out to the second intermediate, spectrogram is as shown in Figure 2；Simultaneously Ah the cutting down that is mentioned to background section that
In non-synthetic route, product 1 prepares product during product 2 and carries out liquid phase analysis, as a result as shown in figure 1, comparison diagram 1 and Fig. 2,
Under identical liquid-phase condition, preparing impurity caused by product 2 and the second intermediate has identical big relative retention time, and has
Maximum absorption wavelength is identical, thus proves, prepares in second prepared in caused impurity and the present embodiment during product 2
Mesosome is same material, and liquid-phase condition is as follows：
Chromatographic column：Inertsil ODS-SP(250mm×4.6mm×5μm)
Detection wavelength：254nm
Column temperature：30℃
Flow velocity：1.0ml/min
Mobile phase：A phases：0.02mol/L potassium dihydrogen phosphates (weigh potassium dihydrogen phosphate 2.72g, adding water to 1000mL makes
Dissolving, pH4.5 is adjusted with phosphoric acid, is produced.)：Acetonitrile=75:25, B phases：0.02mol/L potassium dihydrogen phosphates (weigh di(2-ethylhexyl)phosphate
Hydrogen potassium 2.72g, adding water to 1000mL makes dissolving, adjusts pH4.5 with phosphoric acid, produces.)：Acetonitrile=20:80
Gradient elution program：
| Time | A phases (%) | B phases (%) |
| 0 | 90 | 10 |
| 10 | 30 | 70 |
| 35 | 30 | 70 |
| 37 | 90 | 10 |
| 45 | 90 | 10 |
Detection can prove above, and the second intermediate synthesized by the application is with preparing caused impurity during product 2
It is same material with identical structure.
The synthesis of avanaphil impurity
Second intermediate (29.9g, 45.47mmol) and compound 2- methylaminos phonetic (11.41g, 104.58mmol) input
In 200ml dry DMFs, after unlatching stirs, potassium tert-butoxide (13.27g, 118.22mmol) is slowly added in batches, has been fed intake
Bi Hou, system are warming up to 110 DEG C, insulation reaction 5 hours, TLC (solvents：Ethyl acetate：Petroleum ether=2:1) in monitoring second
Untill mesosome spot, after question response, it is by near 0 DEG C of reaction system, 0~5 DEG C of 5% hydrochloric acid of dropwise addition of temperature control, tune system pH
Neutrality, extracted with the dichloromethane of 100mL × 3, merge organic layer, with saturated common salt water washing organic layer, the anhydrous sulphur of organic layer
Sour magnesium is dried, and is then filtered, and yellow solid powder 21.37g, purity 99.% are obtained after distillation；Yield：60.01%.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of avanaphil impurity, comprises the following steps：
A it is phonetic with 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyls) in organic solvent and water
Pyridine is raw material, is hydrolyzed under the conditions of alkali is existing and obtains the first intermediate；
B) by first intermediate and 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines
It is condensed under conditions of organic base, obtains the second intermediate；
C) second intermediate is reacted under basic conditions with 2- methylaminopyrimidins, obtains the impurity of avanaphil.
2. synthetic method according to claim 1, it is characterised in that 4- (3- chloro-4-methoxies the benzylamino) -5-
The mol ratio of ethoxycarbonyl-2-methyl sulfenyl pyrimidine and alkali is 1：(1.2~10).
3. synthetic method according to claim 1, it is characterised in that the step A) in alkali for sodium hydroxide, hydrogen-oxygen
Change the one or more in potassium, potassium carbonate, sodium carbonate and sodium acid carbonate；
The mass concentration of the alkali is 5~40%.
4. synthetic method according to claim 1, it is characterised in that the step A) in hydrolysis temperature be -30~100
℃；
The step A) in hydrolysis time be 2~10 hours.
5. synthetic method according to claim 1, it is characterised in that the mol ratio of first intermediate and organic base is
1：(1.02~10)；
First intermediate rubs with 4- (3- chloro-4-methoxies benzylamino) -5- ethoxycarbonyl-2-methyl sulfenyl pyrimidines
You are than being 1：(1.02~10).
6. synthetic method according to claim 1, it is characterised in that the organic base is triethylamine, diethylamine, diisopropyl
One or more in base ethamine, tri-n-butylamine, pyridine and 1-METHYLPYRROLIDONE.
7. synthetic method according to claim 1, it is characterised in that the step B) in condensation temperature be 20~150
℃；
The step B) in condensation time be 3~8 hours.
8. synthetic method according to claim 1, it is characterised in that second intermediate rubs with 2- methylaminopyrimidins
You are than being 1：(2.1~5)；
The mol ratio of second intermediate and highly basic is 1：(2.1~5).
9. synthetic method according to claim 1, it is characterised in that the highly basic be sodium methoxide, potassium methoxide, caustic alcohol,
One or more in potassium ethoxide, sodium hydroxide, potassium hydroxide and potassium tert-butoxide.
10. synthetic method according to claim 1, it is characterised in that the step C) in reaction temperature be 40~150
℃；
The step C) in reaction time be 3~8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711381418.1A CN107879986A (en) | 2017-12-20 | 2017-12-20 | A kind of synthetic method of avanaphil impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711381418.1A CN107879986A (en) | 2017-12-20 | 2017-12-20 | A kind of synthetic method of avanaphil impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107879986A true CN107879986A (en) | 2018-04-06 |
Family
ID=61771175
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711381418.1A Pending CN107879986A (en) | 2017-12-20 | 2017-12-20 | A kind of synthetic method of avanaphil impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107879986A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111208232A (en) * | 2020-01-20 | 2020-05-29 | 山东省药学科学院 | Analysis method of related substances in avanafil and preparation thereof |
| CN112812101A (en) * | 2021-01-19 | 2021-05-18 | 山东省药学科学院 | Preparation method of avanafil impurity |
| CN114280174A (en) * | 2021-12-07 | 2022-04-05 | 嘉实（湖南）医药科技有限公司 | Detection method of avanafil and related impurities thereof |
| CN118777452A (en) * | 2024-06-21 | 2024-10-15 | 北京沃邦医药科技有限公司 | A method for detecting impurity G of avanafil |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440393A (en) * | 2000-04-28 | 2003-09-03 | 田边制药株式会社 | Cyclic compound |
| CN1505625A (en) * | 2001-04-30 | 2004-06-16 | Triazole compounds useful in treating diseases associated with unwanted cytokine activity | |
| CN102584799A (en) * | 1999-09-16 | 2012-07-18 | 田边三菱制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
-
2017
- 2017-12-20 CN CN201711381418.1A patent/CN107879986A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584799A (en) * | 1999-09-16 | 2012-07-18 | 田边三菱制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| CN1440393A (en) * | 2000-04-28 | 2003-09-03 | 田边制药株式会社 | Cyclic compound |
| CN1505625A (en) * | 2001-04-30 | 2004-06-16 | Triazole compounds useful in treating diseases associated with unwanted cytokine activity |
Non-Patent Citations (4)
| Title |
|---|
| 冯务群 主编: "《分析化学》", 31 July 2007, 河南科学技术出版社 * |
| 容蓉、邓赟 主编: "《仪器分析》", 31 August 2009, 河南科学技术出版社 * |
| 王积涛 等编著: "《有机化学（第三版·下册）》", 31 December 2009, 南开大学出版社 * |
| 郭书好 主编: "《有机化学》", 31 July 2004, 广东科技出版社 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111208232A (en) * | 2020-01-20 | 2020-05-29 | 山东省药学科学院 | Analysis method of related substances in avanafil and preparation thereof |
| CN112812101A (en) * | 2021-01-19 | 2021-05-18 | 山东省药学科学院 | Preparation method of avanafil impurity |
| CN114280174A (en) * | 2021-12-07 | 2022-04-05 | 嘉实（湖南）医药科技有限公司 | Detection method of avanafil and related impurities thereof |
| CN114280174B (en) * | 2021-12-07 | 2023-12-29 | 嘉实（湖南）医药科技有限公司 | Detection method of avanafil and related impurities thereof |
| CN118777452A (en) * | 2024-06-21 | 2024-10-15 | 北京沃邦医药科技有限公司 | A method for detecting impurity G of avanafil |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107879986A (en) | A kind of synthetic method of avanaphil impurity | |
| CN110627736B (en) | Method for recycling 1-phenyl-5-hydroxy tetrazole | |
| CN108467360B (en) | Preparation method and intermediate of apatinib | |
| CN114436929B (en) | Synthesis method of N-protected 3, 4-dehydro-L-proline ester | |
| CN112679420A (en) | Preparation method of 2,5-dibromopyridine | |
| CN103896855B (en) | The synthetic method of the fluoro-6-chlorine of a kind of 4-(1-bromoethyl)-5-pyrimidine | |
| CN105541819A (en) | Preparation method and intermediate of brexpiprazole and preparation method of intermediate | |
| CN114349690A (en) | Synthesis method of dorawirin intermediate | |
| CN114805164A (en) | Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole | |
| CN116829554A (en) | A kind of thiohydantoin pharmaceutical intermediate and its preparation method and use | |
| CN102887856B (en) | Method for synthesizing Blonanserin | |
| EP3422855B1 (en) | Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids | |
| CN105461640B (en) | A kind of preparation method of tyrosine kinase inhibitor | |
| JP4028021B2 (en) | Method for producing asymmetric 4,6-bis (aryloxy) pyrimidine compound | |
| CN105566209A (en) | Purifying method of beta-trifluoromethylpyridine chloride | |
| CN108997324A (en) | The preparation method of rosuvastain calcium intermediate | |
| CN104262441B (en) | The method of dichloro fluorine compound ethyl ester one-step synthesis halometasone | |
| CN109293587B (en) | Preparation method of clofazimine and intermediate thereof | |
| KR101471047B1 (en) | Improved process for preparation of highly pure bosentan | |
| CN109836425B (en) | Preparation process of synthetic pemetrexed | |
| CN108017573A (en) | The preparation method of 4- methylenepiperidines or its acid-addition salts | |
| CN104529924A (en) | Method for preparing 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl] isoxazole | |
| CN109320511A (en) | A kind of high-purity Pa Boxini intermediate product and preparation method thereof | |
| CN115477635B (en) | A preparation method of lasmiditan | |
| EP2540717B1 (en) | Lamivudine oxalate and preparation method thereof |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180406 |
|
| WD01 | Invention patent application deemed withdrawn after publication |