CN104557877A - Avanafil intermediate as well as preparation method and application thereof - Google Patents
Avanafil intermediate as well as preparation method and application thereof Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
The invention discloses an avanafil intermediate as well as a preparation method and application thereof. The avanafil intermediate is a compound having a general formula as shown in the description, wherein R in the general formula is selected from C1-C4 alkyl. The preparation method of the intermediate comprises the steps a-d in the synthesis route as shown in the description. The invention also discloses an application of the intermediate. Each reaction step for preparing avanafil from the intermediate has the advantages of simple operation, mild reaction conditions, easily available reaction raw materials, high reaction yield and the like, the products are easy to separate and purify; the total yield of prepared avanafil is increased to 40% and the HPLC purity reaches up to 99.8%; the preparation cost of avanafil is greatly reduced, the quality of avanafil is ensured, and thus the intermediate is very much in line with industrial production requirements and has practical value.
Description
Technical field
The present invention relates to a kind of avanaphil intermediate and its preparation method and application, belong to field of pharmaceutical chemistry technology.
Background technology
Avanaphil, is Ai Wanafei again, and its chemical structural formula is as follows:
Avanaphil (STENDRA) is used for the treatment of erectile dysfunction new drug for day Honda limit pharmaceutical Co. Ltd researchs and develops.It belongs to 5 type phosphodiesterase inhibitors (PDE5-I), and it can increase the volume of blood flow of penis.Identical with other PDE5-I, this medicine can not be used for the male patient simultaneously taking Nitrates treatment pectoralgia, because its conbined usage can cause the sharply reduction of blood pressure.U.S. FDA is approval new drug avanaphil treatment erective dysfunction on April 27th, 2012 (ED).
Patent documentation WO2001019802 discloses two kinds of synthetic methods of this compound, and wherein the route of method one is as follows:
The method uses 2,4-dichloro pyrimidine to be Material synthesis Z3, uses carbonic acid gas to introduce the severe reaction conditions of carboxyl in the first step reaction; In 3rd step substitution reaction, the selectivity of 2,4 two chlorine is strong, and the content of isomer can be caused comparatively large, affects quality and route total recovery that finished product wants, is not suitable for industrialization.
Wherein the route of method two is as follows:
Use in the method in m-CPBA (metachloroperbenzoic acid) oxidizing sulfur ether to the process of sulfoxide and the nitrogen in intermediate structure can be caused to be oxidized the oxynitride producing and have genotoxicity; And do not use reduction reaction in later reaction step and cause the oxynitride in this step can remain in bulk drug, be the serious challenge to bulk drug final product quality, so that be also not suitable for industrialization.
Summary of the invention
In order to solve the above-mentioned problems in the prior art, the invention provides the method for this Intermediate Preparation avanaphil of preparation method and application of a kind of intermediate for the preparation of avanaphil and this intermediate.
Avanaphil intermediate of the present invention, has following chemical structure of general formula:
r in general formula is selected from C
1~ C
4alkyl.
Preferably, the R in general formula is methyl, ethyl or sec.-propyl.
The preparation method of avanaphil intermediate of the present invention, comprises the step a ~ d in following synthetic route:
There is ammonolysis reaction with oxygen methyl-isourea salt by the proline ester hydrochloride shown in formula I in described step a, compound shown in obtained formula II in alcoholic solvent;
Described step b is reacted with ethoxymethylidene in alcoholic solvent and under base catalysis by compound shown in formula II, compound shown in obtained formula III;
Described step c is reacted with chlorinating agent in organic solvent by compound shown in formula III, compound shown in obtained formula IV;
Described steps d is reacted with 3-chloro-4-methoxy benzylamine under base catalysis by compound shown in formula IV, obtained described intermediate.
Oxygen methyl-isourea salt described in step a can be the salt that oxygen methyl-isourea and organic acid or mineral acid are formed, and is recommended as the vitriol of oxygen methyl-isourea, mesylate or hydrochloride; Described alcoholic solvent is recommended as methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of the proline ester hydrochloride shown in formula I and oxygen methyl-isourea salt is recommended as (1.0 ~ 1.2): 1; The proportioning of the proline ester hydrochloride shown in formula I and alcoholic solvent is recommended as 1 gram: (6 ~ 10) milliliter; Ammonolysis reaction temperature is recommended as 30 ~ 100 DEG C.
Alcoholic solvent described in step b is recommended as methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol; Described alkali is recommended as sodium hydroxide, sodium hydride, potassium hydroxide, sodium ethylate, sodium methylate or potassium tert.-butoxide; The proportioning of compound shown in formula II and alcoholic solvent is recommended as 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula II and alkali is recommended as 1:(2.5 ~ 3.5); Temperature of reaction is recommended as 20 ~ 100 DEG C.
Organic solvent described in step c is recommended as methylene dichloride, chloroform, ethylene dichloride, toluene or benzene; Described chlorinating agent is recommended as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or chlorsulfonic acid; The proportioning of compound shown in formula III and organic solvent is recommended as 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula III and chlorinating agent is recommended as 1:(1.0 ~ 3.0); Temperature of reaction is recommended as 30 ~ 120 DEG C.
Alkali described in steps d is recommended as sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine; Solvent for use is recommended as methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF or dimethyl sulfoxide (DMSO); The proportioning of compound shown in formula IV and solvent is recommended as 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula IV and alkali is recommended as 1:(2.5 ~ 3.5); Temperature of reaction is recommended as 30 ~ 100 DEG C.
Apply the method for Intermediate Preparation avanaphil of the present invention, comprise step in following synthetic route 1. ~ 3.:
1. described step is reduce described intermediate by reductive agent, compound shown in obtained formula V;
2. described step is by compound shown in basic hydrolysis formula V, compound shown in obtained formula VI;
3. described step is make compound shown in formula VI carry out condensation reaction with 2-amine methylpyrimidine under condensing agent effect, obtained avanaphil.
The 1. described reductive agent of step is recommended as sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, zinc borohydride, borine, lithium aluminum hydride or hydrogenation sec.-propyl aluminium; Solvent used is recommended as methyl alcohol, ethanol, Virahol or tetrahydrofuran (THF); The mol ratio of described intermediate and reductive agent is recommended as (1.0 ~ 1.2): 1; The proportioning of described intermediate and solvent is recommended as 1 gram: (5 ~ 10) milliliter; Reduction reaction temperature is recommended as-10 ~ 30 DEG C.
The 2. described alkali of step is recommended as sodium hydroxide, lithium hydroxide or potassium hydroxide; Solvent used is recommended as methyl alcohol, ethanol, Virahol, water or dimethyl sulfoxide (DMSO); The proportioning of compound shown in formula V and solvent is recommended as 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula V and alkali is recommended as 1:(1.0 ~ 2.0); Hydrolysising reacting temperature is recommended as 0 ~ 50 DEG C.
The 3. described condensing agent of step is recommended as N, the compound of the compound of the compound of N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), diethyl azodiformate (DEAD) and triphenylphosphine (Ph3P), N, N'-dicyclohexylcarbodiimide (DCC) and I-hydroxybenzotriazole (HOBT) or carbodiimide hydrochloride (EDCI) and I-hydroxybenzotriazole (HOBT); Solvent used is recommended as tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF or acetonitrile; The mol ratio of compound shown in formula VI and condensing agent is recommended as 1:(1.0 ~ 1.2); The mol ratio of compound shown in formula VI and 2-amine methylpyrimidine is recommended as 1:(1.0 ~ 2.5); The proportioning of compound shown in formula VI and solvent is recommended as 1 gram: (5 ~ 10) milliliter; Setting-up point is recommended as 0 ~ 50 DEG C.
Compared with prior art, the present invention has following beneficial effect:
1, because intermediate of the present invention adopts proline ester to be that pyrrolidine carbinol structure introduced by raw material, the chirality dried meat ammonia raw polyol that use cost therefore can be avoided higher synthesis avanaphil;
2, because intermediate of the present invention adopts proline ester to be raw material, ring-closure reaction is carried out with ethoxymethylidene after proline biosynthesis ester guanidine, the side chain of avanaphil is comparatively early introduced in precursor structure, therefore can avoid adopting 2, the method synthesis avanaphil of five-ring side chain introduced by the selectivity substitution reaction of 4 and use superoxide;
3, intermediate of the present invention and each step reaction of applying Intermediate Preparation avanaphil of the present invention all have simple to operate, reaction conditions is gentle, product is easily separated and purifying, reaction raw materials are easy to get, reaction yield advantages of higher, the total recovery of prepared avanaphil can be made to bring up to 40% and HPLC high purity 99.8%; Not only greatly reduce the preparation cost of avanaphil, and ensure that the quality of avanaphil, very meet industrialization production requirements, there is practical value.
Embodiment
Below in conjunction with embodiment, technical solution of the present invention is described in further detail and completely.Raw material used in embodiment and reagent are all commercially available to be obtained.
Embodiment 1: prepare intermediate of the present invention
Step a: compound shown in preparation formula II
12.9g proline methyl ester hydrochloride (shown in formula I compound), 17.2g oxygen Methyl Isourea Sulfate and 65mL methyl alcohol is added to being equipped with in the 250mL there-necked flask of reflux condensing tube, thermometer; Be heated to backflow; Back flow reaction, after 16 hours, terminates reaction, is cooled to 0 DEG C, the obtained methanol solution containing compound shown in formula II, for subsequent use.
Step b: prepare compound shown in formula III
18.9g sodium methylate and 30mL methyl alcohol is added in the methanol solution containing compound shown in formula II obtained by step a;
Control temperature of reaction below 10 DEG C, drip 21.6g ethoxymethylidene; Dropwise rear recovery room temperature reaction 16 hours; After completion of the reaction, adding 3g acetic acid regulates reaction system pH between 6 ~ 7; Reaction system poured in 100mL water, have solid to separate out, suction filtration, dry, obtaining the 22g of compound shown in formula III, is white solid, and molar yield is 73%, HPLC purity 97%.
The test condition of HPLC purity is:
Chromatographic column: C18, flow velocity: 1.0mL/min, wavelength: 254nm;
Mobile phase A: 0.02mol/L potassium primary phosphate (phosphoric acid regulates pH=5.0);
Mobile phase B: acetonitrile;
| Time (min) | Mobile phase A | Mobile phase B |
| 0 | 75 | 25 |
| 15 | 40 | 60 |
| 20 | 20 | 80 |
| 35 | 20 | 80 |
| 40 | 75 | 25 |
| 50 | 75 | 25 |
Step c: compound shown in preparation formula IV
Compound shown in 22g formula III and 9.6g sulfur oxychloride is added in the 250mL there-necked flask being equipped with reflux condensing tube and thermometer; Reinforced complete, be heated to back flow reaction 20 hours; React complete, cool to 0 DEG C, in reaction system, add 100mL water, and regulate pH to neutral with anhydrous sodium carbonate; Separatory, aqueous phase dichloromethane extraction; Merge organic phase, use anhydrous sodium sulfate drying with after saturated common salt water washing, be spin-dried for solvent, obtain compound shown in 19.8g formula IV, faint yellow solid, molar yield is 85%, HPLC purity 96.5%.
The test condition of HPLC purity is:
Chromatographic column: C18, flow velocity: 1.0mL/min, wavelength: 254nm;
Mobile phase A: 0.02mol/L potassium primary phosphate (phosphoric acid regulates pH=5.0);
Mobile phase B: acetonitrile;
| Time (min) | Mobile phase A | Mobile phase B |
| 0 | 75 | 25 |
| 15 | 40 | 60 |
| 20 | 20 | 80 |
| 35 | 20 | 80 |
| 40 | 75 | 25 |
| 50 | 75 | 25 |
Steps d: prepare described intermediate
Compound shown in 19.8g formula IV and 10.8g3-chloro-4-methoxy benzylamine, 8g anhydrous sodium carbonate and 120mL DMF is added in the 250mL there-necked flask being equipped with reflux condensing tube and thermometer; Reinforced complete, reaction system is heated to 60 DEG C, reacts 4 hours; React complete, be cooled to room temperature, reaction system poured in 120g frozen water, have solid to separate out, suction filtration, dry, obtain intermediate described in 26.9g (R is methyl), white solid, molar yield is 95%, HPLC purity 98%.
The test condition of HPLC purity is:
Chromatographic column: C18, flow velocity: 1.0mL/min, wavelength: 254nm;
Mobile phase A: 0.02mol/L potassium primary phosphate (phosphoric acid regulates pH=5.0);
Mobile phase B: acetonitrile;
| Time (min) | Mobile phase A | Mobile phase B |
| 0 | 75 | 25 |
| 15 | 40 | 60 |
| 20 | 20 | 80 |
| 35 | 20 | 80 |
| 40 | 75 | 25 |
| 50 | 75 | 25 |
1HNMR(CDCl
3)δ：1.096～1.149(t，3H)，1.706～1.902（m，4H），3.159～3.504（m，3H），3.685（s，3H），3.713（s，3H），4.215～4.511（m，4H），6.944～7.3019(m，3H)，8.318（s，1H），8.414（s，1H）。
Embodiment 2: apply Intermediate Preparation avanaphil of the present invention
Step is 1.: compound shown in preparation formula V
The of the present invention intermediate of 26.9g prepared by embodiment 1 and 150mL methyl alcohol is added in the 250mL there-necked flask being equipped with reflux condensing tube and thermometer; Reinforced complete, be cooled to 0 DEG C with icy salt solution; In reaction system, add 2.3g sodium borohydride in batches; Reinforced complete, be slowly warming up to room temperature reaction 3 hours; React complete, with concentrated hydrochloric acid regulation system pH to neutral; Reaction system poured in 150g frozen water, have solid to separate out, filter, dry, obtain compound shown in 25g formula V, white solid, molar yield is 90%, HPLC purity 98%.
Step is 2.: compound shown in preparation formula VI
To be equipped with reflux condensing tube and thermometer 250mL there-necked flask in add compound shown in 25g formula V and 100mL methyl-sulphoxide, be stirred to dissolving; The aqueous sodium hydroxide solution of 12g20% is added in ice-water bath condition downhill reaction system; Dropwise rear room temperature reaction 3 hours; After completion of the reaction, reaction system poured in 200g frozen water, adjust pH to 5 ~ 6 with concentrated hydrochloric acid, have a large amount of solid to separate out, suction filtration, filter cake washes with water, and dry, obtain compound shown in 20g formula VI, faint yellow solid, molar yield is 86%, HPLC purity 99%.
Step is 3.: prepare avanaphil
Compound shown in 20g formula VI, 6.9gHOBT, 6g2-amine methylpyrimidine and 100mL methyl-sulphoxide is added in the 250mL there-necked flask being equipped with thermometer and constant pressure funnel; 11g DCC is dripped at ambient temperature in reaction system, after dropwising, stirring at room temperature 4 hours; React complete, reaction system poured in 200g frozen water, have a large amount of solid to separate out, suction filtration, filter cake re-crystallizing in ethyl acetate, obtain avanaphil 22g, white solid, molar yield is 90%, HPLC purity 99.8%.
The present invention can with reference to the preparation method described in embodiment 1, by selecting the proline methyl ester hydrochloride (shown in formula I compound) in other alkyl ester salt hydrochlorate (such as: proline ethyl ester hydrochloride, proline(Pro) isopropyl ester hydrochloride etc.) replacement embodiment 1 of proline(Pro), just can obtain R is C
1~ C
4the intermediate of the present invention of alkyl; Content described in embodiment 2 is all can refer to by the method for Intermediate Preparation avanaphil of the present invention.
In a word, because intermediate of the present invention adopts proline ester to be that pyrrolidine carbinol structure introduced by raw material, and ring-closure reaction is carried out with ethoxymethylidene after proline biosynthesis ester guanidine, the side chain of avanaphil is comparatively early introduced in precursor structure, therefore, intermediate of the present invention is adopted to synthesize avanaphil, the chirality dried meat ammonia raw polyol that use cost can be avoided higher adopts 2 with avoiding, and selectivity substitution reaction and the use superoxide of 4 introduce the method for five-ring side chain to synthesize avanaphil; And, intermediate of the present invention and each step reaction of applying Intermediate Preparation avanaphil of the present invention all have simple to operate, reaction conditions is gentle, product is easily separated and purifying, reaction raw materials are easy to get, reaction yield advantages of higher, the total recovery of prepared avanaphil can be made to bring up to 40% and HPLC high purity 99.8%; Not only greatly reduce the preparation cost of avanaphil, and ensure that the quality of avanaphil, very meet industrialization production requirements, there is practical value.
Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. an avanaphil intermediate, is characterized in that, is the compound with following chemical structure of general formula:
r in general formula is selected from C
1~ C
4alkyl.
2. avanaphil intermediate as claimed in claim 1, is characterized in that: the R in general formula is methyl, ethyl or sec.-propyl.
3. a preparation method for avanaphil intermediate according to claim 1, is characterized in that, comprises the step a ~ d in following synthetic route:
There is ammonolysis reaction with oxygen methyl-isourea salt by the proline ester hydrochloride shown in formula I in described step a, compound shown in obtained formula II in alcoholic solvent;
Described step b is reacted with ethoxymethylidene in alcoholic solvent and under base catalysis by compound shown in formula II, compound shown in obtained formula III;
Described step c is reacted with chlorinating agent in organic solvent by compound shown in formula III, compound shown in obtained formula IV;
Described steps d is reacted with 3-chloro-4-methoxy benzylamine under base catalysis by compound shown in formula IV, obtained described intermediate.
4. preparation method as claimed in claim 3, is characterized in that: the oxygen methyl-isourea salt described in step a is the salt that oxygen methyl-isourea and organic acid or mineral acid are formed; Described alcoholic solvent is methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of the proline ester hydrochloride shown in formula I and oxygen methyl-isourea salt is (1.0 ~ 1.2): 1; The proportioning of the proline ester hydrochloride shown in formula I and alcoholic solvent is 1 gram: (6 ~ 10) milliliter; Ammonolysis reaction temperature is 30 ~ 100 DEG C.
5. preparation method as claimed in claim 3, is characterized in that: the alcoholic solvent described in step b is methyl alcohol, ethanol, Virahol, propyl carbinol or the trimethyl carbinol; Described alkali is sodium hydroxide, sodium hydride, potassium hydroxide, sodium ethylate, sodium methylate or potassium tert.-butoxide; The proportioning of compound shown in formula II and alcoholic solvent is 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula II and alkali is 1:(2.5 ~ 3.5); Temperature of reaction is 20 ~ 100 DEG C.
6. preparation method as claimed in claim 3, is characterized in that: the organic solvent described in step c is methylene dichloride, chloroform, ethylene dichloride, toluene or benzene; Described chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or chlorsulfonic acid; The proportioning of compound shown in formula III and organic solvent is 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula III and chlorinating agent is 1:(1.0 ~ 3.0); Temperature of reaction is 30 ~ 120 DEG C.
7. preparation method as claimed in claim 3, is characterized in that: the alkali described in steps d is sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine; Solvent for use is methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF or dimethyl sulfoxide (DMSO); The proportioning of compound shown in formula IV and solvent is 1 gram: (5 ~ 10) milliliter; The mol ratio of compound shown in formula IV and alkali is 1:(2.5 ~ 3.5); Temperature of reaction is 30 ~ 100 DEG C.
8. application rights requires a method for avanaphil Intermediate Preparation avanaphil described in 1, it is characterized in that, comprise step in following synthetic route 1. ~ 3.:
1. described step is reduce described intermediate by reductive agent, compound shown in obtained formula V;
2. described step is by compound shown in basic hydrolysis formula V, compound shown in obtained formula VI;
3. described step is make compound shown in formula VI carry out condensation reaction with 2-amine methylpyrimidine under condensing agent effect, obtained avanaphil.
9. method as claimed in claim 8, is characterized in that: the 1. described reductive agent of step is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, zinc borohydride, borine, lithium aluminum hydride or hydrogenation sec.-propyl aluminium; Solvent used is methyl alcohol, ethanol, Virahol or tetrahydrofuran (THF); The mol ratio of described intermediate and reductive agent is (1.0 ~ 1.2): 1; The proportioning of described intermediate and solvent is 1 gram: (5 ~ 10) milliliter; Reduction reaction temperature is-10 ~ 30 DEG C.
10. method as claimed in claim 8, it is characterized in that: the 3. described condensing agent of step is N, the compound of N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, diethyl azodiformate and triphenylphosphine, N, N'-dicyclohexylcarbodiimide and the compound of I-hydroxybenzotriazole or the compound of carbodiimide hydrochloride and I-hydroxybenzotriazole; Solvent used is tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF or acetonitrile; The mol ratio of compound shown in formula VI and condensing agent is 1:(1.0 ~ 1.2); The mol ratio of compound shown in formula VI and 2-amine methylpyrimidine is 1:(1.0 ~ 2.5); The proportioning of compound shown in formula VI and solvent is 1 gram: (5 ~ 10) milliliter; Setting-up point is 0 ~ 50 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106198766A (en) * | 2015-05-04 | 2016-12-07 | 南京从医药科技有限公司 | A kind of avanaphil and the HPLC (high performance liquid chromatography) of preparation thereof |
| CN108593805A (en) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | The separation method and detection method of 3- chloro-4-methoxy benzylamine hydrochloride isomers |
| CN111253288A (en) * | 2020-03-27 | 2020-06-09 | 上海阿拉丁生化科技股份有限公司 | Synthesis method of N, N' -diisopropyl-O- (4-nitrobenzyl) isourea |
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|---|---|---|---|---|
| WO2001019802A1 (en) * | 1999-09-16 | 2001-03-22 | Tanabe Seiyaku Co., Ltd. | Aromatic nitrogenous six-membered ring compounds |
| CN103254179A (en) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | Preparation method of Avanafil |
| CN103254180A (en) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | Preparation method of Avanafil |
| CN103265534A (en) * | 2013-05-23 | 2013-08-28 | 苏州明锐医药科技有限公司 | Method for preparing avanafil |
-
2013
- 2013-10-28 CN CN201310516008.9A patent/CN104557877B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001019802A1 (en) * | 1999-09-16 | 2001-03-22 | Tanabe Seiyaku Co., Ltd. | Aromatic nitrogenous six-membered ring compounds |
| CN103254179A (en) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | Preparation method of Avanafil |
| CN103254180A (en) * | 2013-05-23 | 2013-08-21 | 苏州明锐医药科技有限公司 | Preparation method of Avanafil |
| CN103265534A (en) * | 2013-05-23 | 2013-08-28 | 苏州明锐医药科技有限公司 | Method for preparing avanafil |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106198766A (en) * | 2015-05-04 | 2016-12-07 | 南京从医药科技有限公司 | A kind of avanaphil and the HPLC (high performance liquid chromatography) of preparation thereof |
| CN108593805A (en) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | The separation method and detection method of 3- chloro-4-methoxy benzylamine hydrochloride isomers |
| CN111253288A (en) * | 2020-03-27 | 2020-06-09 | 上海阿拉丁生化科技股份有限公司 | Synthesis method of N, N' -diisopropyl-O- (4-nitrobenzyl) isourea |
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| CN104557877B (en) | 2016-08-17 |
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