CN109776505A - A kind of preparation method of avanaphil - Google Patents
A kind of preparation method of avanaphil Download PDFInfo
- Publication number
- CN109776505A CN109776505A CN201910193398.8A CN201910193398A CN109776505A CN 109776505 A CN109776505 A CN 109776505A CN 201910193398 A CN201910193398 A CN 201910193398A CN 109776505 A CN109776505 A CN 109776505A
- Authority
- CN
- China
- Prior art keywords
- preparation
- avanaphil
- added
- boric acid
- 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.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The present invention provides a kind of preparation methods of avanaphil, the following steps are included: starting material 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid and 2- amino methylpyrimidine are dissolved in reaction dissolvent toluene, boric acid porphyrin catalyst is added, heating stirring is catalyzed to obtain avanaphil to reflux state.The present invention directly catalyzes and synthesizes avanaphil using boric acid porphyrin as catalyst.Catalyst amount is smaller, reactivity is high, it operates relatively easy, target product is easily isolated with catalyst after reaction, greatly reduces the difficulty of late-stage products separating-purifying, and the catalyst of recycling can recycle, preparation cost can be reduced significantly, entirely catalysis reaction has the characteristics that reduce the input costs such as manpower, raw material simple, green, environmentally friendlyly and significant, is conducive to large-scale industrialized production.
Description
Technical field
The present invention relates to medical production technical field more particularly to a kind of preparation methods of avanaphil.
Background technique
Avanaphil CAS registration number: 330784-47-9, structural formula of compound are shown in Fig. 1.It is by the pharmacy of day Honda side Mitsubishi
The drug for being used to treat male erectile dysfunction of authorization U.S. Wei Fusi (Vivus) drugmaker, Co., Ltd. exploitation.In
April 27 in 2012 is ratified to list in the U.S. through U.S. FDA, trade name Stendra.
As shown in Figure 2, the committed step of avanaphil synthesis is the chemical reaction of the 4th step: i.e. by intermediate 3,4- [(3-
Chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid and starting material 3,2- ammonia
Ylmethyl pyrimidine carries out amidation splicing.Specifically, passing through carbodiimide class condensing agent and assisting that acylated activation is added
Reagent condensation prepares amide.Common carbodiimide class condensing agent has dicyclohexylcarbodiimide (DCC) and 1- (3- dimethylamino
Propyl) -3- ethyl carbodiimide (EDCI), needing to assist being added acylated activating reagent is mainly 1- hydroxy benzo triazole
(HOBt).Due to the first stage acid in reaction to the addition intermediate radical of carbodiimide itself and it is unstable, if not having to acylated activation
Agent transforms are corresponding active ester, its own can be by being rearranged into the by-product of urea stable accordingly.Domestic and international patent
WO2015001567A1, EP1366760A1, CN201310516008.9 are to this existing sufficiently full and accurate report.
Above-mentioned amide synthetic method the problem is that: the use of activating reagent in the reaction will stoichiometry, sometimes
It is even greatly excessive；And after the completion of acylation reaction, and it is changed into useless by-product, belong to expendable reagent, with " atom warp
Ji property " principle is disagreed；The separation of by-product and amide that activating reagent generates, it is sometimes difficult and cumbersome；In addition, activation
The most expensive price of reagent, in large scale preparation amide product, cost problem will become especially prominent.
In view of this, it is necessary to the preparation method of avanaphil in the prior art be improved, to solve above-mentioned ask
Topic.
Summary of the invention
It is an object of the invention to disclose a kind of preparation method of avanaphil, in the presence of overcoming the prior art
Deficiency, to improve the rate of recovery of catalyst and reduce preparation cost.
To achieve the above object, the present invention provides the preparation methods of one kind avanaphil as shown in formula (II), including
Following steps:
S1, by compound (I) 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base]
Pyrimidine -5-carboxylic acid and 2- amino methylpyrimidine are dissolved in reaction dissolvent toluene, and boric acid porphyrin catalyst, heating stirring to reflux is added
State, be catalyzed compound (II), the chemical equation are as follows:
After S2, fully reacting, by reaction solution slow cooling, dilute hydrochloric acid is added dropwise, boric acid porphin is recovered by filtration in stirring and dissolving product
Quinoline catalyst, liquid separation take lower layer's water phase (upper toluene can mutually retain, and recycle remaining boric acid porphyrin catalyst), methylene chloride are added
Extract wash water phase, is slowly added to solid NaOH and adjusts water phase to pH7.0, be stirred at room temperature and avanaphil crude product, filtering is precipitated, filter cake is used
Purify water washing；
Avanaphil crude product after washing in S3, step S2, which is added in anhydrous methanol, is heated to reflux state, is added and lives
Property charcoal stirring and adsorbing decoloration, filter while hot, filtrate stir cooling, crystallization, filtering, after filter cake is washed with ice methanol, be dried to obtain
Avanaphil finished product.
As a further improvement of the present invention, the molar ratio of compound (I) and 2- amino methylpyrimidine is 1:1.0~1.2.
As a further improvement of the present invention, the molar ratio of compound (I) and boric acid porphyrin catalyst be 1:0.01~
0.1。
As a further improvement of the present invention, the ratio of reaction dissolvent toluene and compound (I) is 3~5:1L/mol.
It as a further improvement of the present invention, is 8~16h between the inverse time for being heated to reflux state.
As a further improvement of the present invention, the concentration of dilute hydrochloric acid is 2~8wt%.
As a further improvement of the present invention, the volume ratio of dilute hydrochloric acid and reaction dissolvent toluene is 1:0.5~2.
As a further improvement of the present invention, the volume ratio of methylene chloride and reaction dissolvent toluene is 1:0.5~2.
As a further improvement of the present invention, the ratio of anhydrous methanol and compound (I) is 8~10:1L/mol.
As a further improvement of the present invention, the ratio of active carbon and compound (I) is 20~30:1g/mol.
Compared with prior art, the beneficial effects of the present invention are: preparation method disclosed herein, is made with boric acid porphyrin
For catalyst, avanaphil is directly catalyzed and synthesized.Catalyst amount is smaller, and reactivity is high, operates relatively easy.Reaction terminates
Target product is easily isolated with catalyst afterwards, greatly reduces the difficulty of late-stage products separating-purifying.The catalyst of recycling can be with
It recycles, preparation cost can be reduced significantly.Entire catalysis, which is reacted, has the characteristics that simple, green, environmental protection, and significant
The input costs such as manpower, raw material are reduced, large-scale industrialized production is conducive to.
In addition, preparing the yield of avanaphil with the directly catalysis of boric acid porphyrin compared with activating reagent condensation prepares amide
Considerably higher, purity is also relatively more preferable.
Detailed description of the invention
Fig. 1 is the chemical structural formula of avanaphil；
Fig. 2 is the synthetic route chart for synthesizing avanaphil in the prior art；
Fig. 3 is the mechanism schematic diagram that aryl boric acid according to the present invention catalyzes and synthesizes amide；
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of avanaphil of the invention；
Fig. 5 is the mass spectrogram of avanaphil of the invention；
Fig. 6 is the liquid phase spectrogram of avanaphil of the invention.
Specific embodiment
The present invention is described in detail for each embodiment shown in reference to the accompanying drawing, but it should be stated that, these
Embodiment is not limitation of the present invention, those of ordinary skill in the art according to these embodiments made by function, method,
Or equivalent transformation or substitution in structure, all belong to the scope of protection of the present invention within.
Before each embodiment of the application is described in detail, organic synthesis mechanism involved in the present invention work is briefly explained
It states.
It is anti-directly to catalyze and synthesize amide that a kind of preparation process of avanaphil involved in the application is related to chemical reaction
It answers.Mono-acyloxy boric acid activity can be generated using aryl boric acid (wherein containing a certain amount of aryl boric acid acid anhydride) and carboxylic acid reaction
Intermediate (mixed acid anhydride that may be regarded as carboxylic acid and aryl boric acid).The boron of intramolecular hydrogen bond and electron deficient in reactive intermediate can
With activated carboxyl carbon, be conducive to the characteristic of the nucleophilic attack of amine, innovation and application is in the preparation synthesis of avanaphil.Catalysis course
As shown in Figure 3.
Embodiment 1:
By 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid
(39.3g, 100mmol, 1.0eq), 2- amino methylpyrimidine (10.9g, 100mmol, 1.0eq) and boric acid porphyrin (0.79g,
1mmol, 0.01eq) it is added in 300mL toluene solution, heating stirring to reflux state, it reacts 8 hours.
After reaction, reaction solution is slow cooling to 10~20 DEG C, 300mL 5wt% aqueous hydrochloric acid solution is added dropwise.Control
System temperature is no more than 20 DEG C, stirs 30min, boric acid porphyrin catalyst is recovered by filtration.Liquid separation takes lower layer's water phase, and 300mL is added
Methylene chloride extracts wash water phase, is slowly added to solid NaOH and adjusts water phase pH to 7.0, crystallization 2h is stirred at room temperature, Ah cutting down is obtained by filtration
That non-crude product, filter cake purifying water washing 2 times.
Avanaphil crude product is added in 800mL anhydrous methanol and is heated to reflux state, 2.0g active carbon is added later
Stirring and adsorbing decoloration 30min, is filtered while hot, and filtrate stirring is cooled to 30 DEG C, and crystallization about 3 hours, filtering, ice methanol washed 2 times
White needles 40.4g (yield 83.5%, purity 99.74%) is obtained in 50 DEG C of forced air dryings afterwards.
Embodiment 2:
By 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid
(39.3g, 100mmol, 1.0eq), 2- amino methylpyrimidine (10.9g, 100mmol, 1.0eq) and boric acid porphyrin (3.95g,
5mmol, 0.05eq) it is added in 400mL toluene solution, heating stirring to reflux state, it reacts 12 hours.
After reaction, reaction solution is slow cooling to 10~20 DEG C, 200mL 8wt% aqueous hydrochloric acid solution is added dropwise.Control
System temperature is no more than 20 DEG C, stirs 30min, boric acid porphyrin catalyst is recovered by filtration.Liquid separation takes lower layer's water phase, and 200mL is added
Methylene chloride extracts wash water phase, is slowly added to solid NaOH and adjusts water phase pH to 7.0, crystallization 2h is stirred at room temperature, Ah cutting down is obtained by filtration
That non-crude product, filter cake purifying water washing 2 times.
Avanaphil crude product is added in 900mL anhydrous methanol and is heated to reflux state, 2.5g active carbon is added later
Stirring and adsorbing decoloration 30min, is filtered while hot, and filtrate stirring is cooled to 30 DEG C, and crystallization about 3 hours, filtering, ice methanol washed 2 times
White needles 42.6g (yield 88.1%, purity 99.8%) is obtained in 50 DEG C of forced air dryings afterwards.
Embodiment 3:
By 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid
(39.3g, 100mmol, 1.0eq), 2- amino methylpyrimidine (12.0g, 110mmol, 1.1eq) and boric acid porphyrin (3.95g,
5mmol, 0.05eq) it is added in 400mL toluene solution, heating stirring to reflux state, it reacts 12 hours.
After reaction, reaction solution is slow cooling to 10~20 DEG C, 400mL 5wt% aqueous hydrochloric acid solution is added dropwise.Control
System temperature is no more than 20 DEG C, stirs 30min, boric acid porphyrin catalyst is recovered by filtration.Liquid separation takes lower layer's water phase, and 400mL is added
Methylene chloride extracts wash water phase, is slowly added to solid NaOH and adjusts water phase pH to 7.0, crystallization 2h is stirred at room temperature, Ah cutting down is obtained by filtration
That non-crude product, filter cake purifying water washing 2 times.
Avanaphil crude product is added in 900mL anhydrous methanol and is heated to reflux state, 2.5g active carbon is added later
Stirring and adsorbing decoloration 30min, is filtered while hot, and filtrate stirring is cooled to 30 DEG C, and crystallization about 3 hours, filtering, ice methanol washed 2 times
White needles 43.6g (yield 90.0%, purity 99.92%) is obtained in 50 DEG C of forced air dryings afterwards.
Embodiment 4:
By 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid
(39.3g, 100mmol, 1.0eq), 2- amino methylpyrimidine (12.0g, 110mmol, 1.1eq) and boric acid porphyrin (7.9g,
10mmol, 0.1eq) it is added in 500mL toluene solution, heating stirring to reflux state, it reacts 16 hours.
After reaction, reaction solution is slow cooling to 10~20 DEG C, 1000mL 2wt% aqueous hydrochloric acid solution is added dropwise.Control
System temperature is no more than 20 DEG C, stirs 30min, boric acid porphyrin catalyst is recovered by filtration.Liquid separation takes lower layer's water phase, and 500mL is added
Methylene chloride extracts wash water phase, is slowly added to solid NaOH and adjusts water phase pH to 7.0, crystallization 2h is stirred at room temperature, Ah cutting down is obtained by filtration
That non-crude product, filter cake purifying water washing 2 times.
Avanaphil crude product is added in 1000mL anhydrous methanol and is heated to reflux state, 3.0g active carbon is added later
Stirring and adsorbing decoloration 30min, is filtered while hot, and filtrate stirring is cooled to 30 DEG C, and crystallization about 3 hours, filtering, ice methanol washed 2 times
White needles 44.1g (yield 91.2%, purity 99.63%) is obtained in 50 DEG C of forced air dryings afterwards.
Embodiment 5:
By 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid
(39.3g, 100mmol, 1.0eq), 2- amino methylpyrimidine (13.1g, 120mmol, 1.2eq) and boric acid porphyrin (0.79g,
1mmol, 0.01eq) it is added in 300mL toluene solution, heating stirring to reflux state, it reacts 8 hours.
After reaction, reaction solution is slow cooling to 10~20 DEG C, 300mL 8wt% aqueous hydrochloric acid solution is added dropwise.Control
System temperature is no more than 20 DEG C, stirs 30min, boric acid porphyrin catalyst is recovered by filtration.Liquid separation takes lower layer's water phase, and 600mL is added
Methylene chloride extracts wash water phase, is slowly added to solid NaOH and adjusts water phase pH to 7.0, crystallization 2h is stirred at room temperature, Ah cutting down is obtained by filtration
That non-crude product, filter cake purifying water washing 2 times.
Avanaphil crude product is added in 800mL anhydrous methanol and is heated to reflux state, 2.0g active carbon is added later
Stirring and adsorbing decoloration 30min, is filtered while hot, and filtrate stirring is cooled to 30 DEG C, and crystallization about 3 hours, filtering, ice methanol washed 2 times
White needles 43.6g (yield 84.2%, purity 99.68%) is obtained in 50 DEG C of forced air dryings afterwards.
Embodiment 6:
By 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] pyrimidine -5-carboxylic acid
(39.3g, 100mmol, 1.0eq), 2- amino methylpyrimidine (13.1g, 120mmol, 1.2eq) and boric acid porphyrin (7.9g,
10mmol, 0.1eq) it is added in 500mL toluene solution, heating stirring to reflux state, it reacts 16 hours.
After reaction, reaction solution is slow cooling to 10~20 DEG C, 1000mL 5wt% aqueous hydrochloric acid solution is added dropwise.Control
System temperature is no more than 20 DEG C, stirs 30min, boric acid porphyrin catalyst is recovered by filtration.Liquid separation takes lower layer's water phase, and 1000mL is added
Methylene chloride extracts wash water phase, is slowly added to solid NaOH and adjusts water phase pH to 7.0, crystallization 2h is stirred at room temperature, Ah cutting down is obtained by filtration
That non-crude product, filter cake purifying water washing 2 times.
Avanaphil crude product is added in 1000mL anhydrous methanol and is heated to reflux state, 3.0g active carbon is added later
Stirring and adsorbing decoloration 30min, is filtered while hot, and filtrate stirring is cooled to 30 DEG C, and crystallization about 3 hours, filtering, ice methanol washed 2 times
White needles 43.7g (yield 90.3%, purity 99.59%) is obtained in 50 DEG C of forced air dryings afterwards.
Obtained avanaphil finished product is detected using HPLC, and purity is greater than 99.5%, and list is miscellaneous less than 0.1%.
The testing conditions of HPLC are as follows: with octadecylsilane chemically bonded silica be filler (250 × 4.6mm, 5 μm)；With
0.02mol/L sodium dihydrogen phosphate is mobile phase A, and acetonitrile is Mobile phase B；Detection wavelength is 240nm；Flow velocity is 1.0ml/
min；Column temperature is 30 DEG C.According to the form below carries out gradient elution:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 62 | 38 |
| 10 | 62 | 38 |
| 17 | 25 | 75 |
| 40 | 25 | 75 |
| 45 | 62 | 38 |
| 55 | 62 | 38 |
Through detecting, the hydrogen nuclear magnetic resonance spectrogram of avanaphil finished product of the invention as shown in figure 4, mass spectrogram as shown in figure 5,
Liquid phase spectrogram is as shown in Figure 6.
Compared with activating reagent condensation prepares amide, the application prepares the yield of avanaphil with the directly catalysis of boric acid porphyrin
Considerably higher, purity is also relatively more preferable.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.Any reference signs in the claims should not be construed as limiting the involved claims.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (10)
1. a kind of preparation method of the avanaphil as shown in formula (II), which comprises the following steps:
It is S1, compound (I) 4- [(3- chloro-4-methoxy phenyl) methylamino] -2- [(S) -2- hydroxymethylpyrrol -1- base] is phonetic
Pyridine -5- carboxylic acid and 2- amino methylpyrimidine are dissolved in reaction dissolvent toluene, and boric acid porphyrin catalyst, heating stirring to the shape that flows back is added
State, be catalyzed compound (II), the chemical equation are as follows:
Boric acid porphyrin:
After S2, fully reacting, by reaction solution slow cooling, dilute hydrochloric acid is added dropwise, stirring and dissolving product is recovered by filtration boric acid porphyrin and urges
Agent, liquid separation take lower layer's water phase (upper toluene can mutually retain, and recycle remaining boric acid porphyrin catalyst), methylene chloride extraction are added and washes
Water phase is slowly added to solid NaOH and adjusts water phase to pH7.0, is stirred at room temperature and avanaphil crude product, filtering is precipitated, filter cake purifies
Water washing；
Avanaphil crude product after washing in S3, step S2, which is added in anhydrous methanol, is heated to reflux state, and active carbon is added
Stirring and adsorbing decoloration, is filtered while hot, and filtrate stirring cooling, crystallization, filtering are dried to obtain Ah cutting down after filter cake is washed with ice methanol
That non-finished product.
2. preparation method according to claim 1, which is characterized in that the compound (I) and 2- amino methylpyrimidine
Molar ratio is 1:1.0~1.2.
3. preparation method according to claim 1, which is characterized in that the compound (I) and boric acid porphyrin catalyst
Molar ratio is 1:0.01~0.1.
4. preparation method according to claim 1, which is characterized in that the ratio of the reaction dissolvent toluene and compound (I)
Example is 3~5:1L/mol.
5. preparation method according to claim 1, which is characterized in that between the inverse time for being heated to reflux state for 8~
16h。
6. preparation method according to claim 1, which is characterized in that the concentration of the dilute hydrochloric acid is 2~8wt%.
7. preparation method according to claim 1, which is characterized in that the volume ratio of the dilute hydrochloric acid and reaction dissolvent toluene
For 1:0.5~2.
8. preparation method according to claim 1, which is characterized in that the volume of the methylene chloride and reaction dissolvent toluene
Than for 1:0.5~2.
9. preparation method according to claim 1, which is characterized in that the ratio of the anhydrous methanol and compound (I) is 8
~10:1L/mol.
10. preparation method according to claim 1, which is characterized in that the ratio of the active carbon and compound (I) is 20
~30:1g/mol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910193398.8A CN109776505B (en) | 2019-03-14 | 2019-03-14 | Preparation method of avanafil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910193398.8A CN109776505B (en) | 2019-03-14 | 2019-03-14 | Preparation method of avanafil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109776505A true CN109776505A (en) | 2019-05-21 |
| CN109776505B CN109776505B (en) | 2021-07-27 |
Family
ID=66489568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910193398.8A Active CN109776505B (en) | 2019-03-14 | 2019-03-14 | Preparation method of avanafil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109776505B (en) |
Cited By (1)
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374953A (en) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| WO2015001567A1 (en) * | 2013-07-01 | 2015-01-08 | Msn Laboratories Private Limited | Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide |
| CN104650045A (en) * | 2013-11-19 | 2015-05-27 | 苏州旺山旺水生物医药有限公司 | Preparation method of avanafil |
| CN108658872A (en) * | 2018-05-03 | 2018-10-16 | 无锡富泽药业有限公司 | A kind of preparation method of avanaphil intermediate |
-
2019
- 2019-03-14 CN CN201910193398.8A patent/CN109776505B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374953A (en) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| WO2015001567A1 (en) * | 2013-07-01 | 2015-01-08 | Msn Laboratories Private Limited | Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide |
| CN104650045A (en) * | 2013-11-19 | 2015-05-27 | 苏州旺山旺水生物医药有限公司 | Preparation method of avanafil |
| CN108658872A (en) * | 2018-05-03 | 2018-10-16 | 无锡富泽药业有限公司 | A kind of preparation method of avanaphil intermediate |
Non-Patent Citations (1)
| Title |
|---|
| HIROO TOI等: "Preparation of Porphyrins Having Phenylboronic Acid Groups", 《CHEMISTRY LETTERS》 * |
Cited By (1)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109776505B (en) | 2021-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103524383B (en) | Method for preparing peramivir | |
| CN109867673B (en) | Method for synthesizing palbociclib | |
| JP5465724B2 (en) | Labeling reagent having pyridine nucleus having diazomethyl functional group, method for synthesizing the reagent, and method for detecting biomolecule | |
| CN109776505A (en) | A kind of preparation method of avanaphil | |
| CN108129397B (en) | Synthetic method of olaparib | |
| CN105712919B (en) | The amide condensed dose of application in vildagliptin synthetic method | |
| CN111100128A (en) | Synthetic method of Ribocini intermediate product and intermediate compound thereof | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| CN106111190B (en) | A kind of chirality biaryl skeleton pyridoxamine class catalyst and its synthetic method and application | |
| CN106636241B (en) | Method for preparing esmollin intermediate by enzyme method | |
| CN102786543B (en) | The preparation method of imidazo [1,2-a] pyridine-6-pinacol borate and derivative thereof | |
| CN109678686A (en) | A kind of preparation method of anti-hepatitis drug Lei Dipawei key intermediate | |
| CN104592122A (en) | Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline | |
| CN104447534A (en) | 6-[(7-chloroquinoline-4-oxyl) phenolic ether]-2-naphthamide derivative as well as preparation method and application thereof | |
| CN1865259B (en) | Process for preparing piperidine derivative | |
| CN113372341A (en) | Synthesis method and device of dihydroisoquinoline trifluoroacetate derivative | |
| CN104761599B (en) | A kind of preparation method of the O D glucuronic acids of 5,4 ' dihydroxyflavone 7 | |
| CN111848546A (en) | 2- (aminomethyl) thiazole-5-nitrile and synthesis method thereof | |
| CN109796409A (en) | A kind of method of tetrahydrobiopterin synthesis indazole compound | |
| CN112574106B (en) | Synthesis method of 7-amino-5-bromoquinoline | |
| US8309695B2 (en) | Marking reagents bearing diazo and nitro functions, methods for the synthesis of such reagents and methods for detecting biological molecules | |
| CN103242244B (en) | Canertinib preparation method | |
| CN112500341B (en) | Synthesis method of 7-hydroxyquinoline-4-carboxylic acid | |
| CN106432182B (en) | Specially the synthetic method of azoles amine intermediate | |
| CN106632057B (en) | A kind of ionic liquid and the method for being synthesized by Thiazovivin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |