CN104151299B - Compound, crystal-form compound and preparation method thereof - Google Patents
Compound, crystal-form compound and preparation method thereof Download PDFInfo
- Publication number
- CN104151299B CN104151299B CN201410418849.0A CN201410418849A CN104151299B CN 104151299 B CN104151299 B CN 104151299B CN 201410418849 A CN201410418849 A CN 201410418849A CN 104151299 B CN104151299 B CN 104151299B
- Authority
- CN
- China
- Prior art keywords
- avanaphil
- fumarate
- preparation
- present
- crude product
- 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.)
- Active
Links
- 0 C*c(c(C)n1)cnc1S Chemical compound C*c(c(C)n1)cnc1S 0.000 description 2
- YFEYCJPGFGFDBV-UHFFFAOYSA-N CCC(CCC1)N1c1ncc(C(O)=O)c(N)n1 Chemical compound CCC(CCC1)N1c1ncc(C(O)=O)c(N)n1 YFEYCJPGFGFDBV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Abstract
The invention provides a kind of avanaphil fumarate and the crystallization of avanaphil fumarate, not only purity is high for the avanaphil salt that the present invention is provided, and single miscellaneous content is low, and good stability.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, more particularly to a kind of compound, crystal-form compound and preparation method thereof.
Background technology
Avanaphil, chemical name are 4- [(3- chloro-4-methoxy benzyl) amino] -2- [2- (methylol) -1- pyrrolidines
Base]-N- (2- Pyrimidylmethyl) -5- pyrimidine carboxamide, shown in its structure such as formula (I)：
Avanaphil is a kind of PDE5 type (PDE5) inhibitor, is Vivus company and the pharmacy of day Honda side Mitsubishi
The project of company's joint research, avanaphil are ratified new drug on April 27th, 2012 by FDA (FDA)
Avanaphil treatment male erectile dysfunction (Erectile Dysfunction, ED), the medicine can increase the CBF of penis,
Compare with other anti-ED medicines, the sharpest edges of avanaphil are rapid-action, and taking food does not affect the medicine of avanaphil to move
Mechanics.
Method currently, with respect to synthesis avanaphil is mainly synthetic method disclosed in United States Patent (USP) US2003195220,
Its preparation technology is as follows：
The major defect of the technique is to use metachloroperbenzoic acid oxidant in building-up process, accessory substance more and
The avanaphil bulk drug obtained after column chromatography still has individual impurities overrun, is extremely difficult to the standard being used as medicine, and needs repeatedly
Recrystallization can be only achieved standard of being used as medicine, and stability is poor.
Content of the invention
In view of this, the technical problem to be solved is to provide a kind of avanaphil salt and preparation method thereof,
The purity of the avanaphil salt prepared by the present invention is higher, and good stability.
The invention provides a kind of avanaphil fumarate.
Present invention also offers a kind of preparation method of avanaphil fumarate, including：By avanaphil and fumaric acid
Reaction, obtains avanaphil fumarate.
Present invention also offers a kind of crystallization of avanaphil fumarate, its X-ray diffraction figure show 2 θ values 10.94,
14.76th, there is characteristic diffraction peak at 16.50,21.46,22.86,24.94 and 25.44.
Present invention also offers a kind of preparation method of avanaphil fumarate crystallization, including：By avanaphil, rich horse
Acid and solvent hybrid reaction, obtain the crystallization of avanaphil fumarate；
The solvent is one or more in methyl alcohol, ethanol, methanol aqueous solution and ethanol water.
Preferably, the avanaphil is 1 with the amount ratio of the material of the fumaric acid:(1～2).
Preferably, the solvent is one or two in methyl alcohol and ethanol.
Preferably, the temperature of the reaction is 20～70 DEG C.
Preferably, the time of the reaction is 2～6 hours.
Present invention also offers a kind of preparation method of avanaphil, including：Avanaphil fumarate is reacted with alkali,
Obtain avanaphil.
Preferably, it is characterised in that the alkali is sodium carbonate or potassium carbonate.
Compared with prior art, the invention provides a kind of avanaphil fumarate and avanaphil fumarate knot
Crystalline substance, not only purity is high for the avanaphil salt that the present invention is provided, and single miscellaneous content is low, and good stability.Test result indicate that, the present invention
The high purity 99.84% of the avanaphil fumarate crystallization of offer, maximum single miscellaneous be down to 0.045%, and at 60 DEG C and
All more stable under illumination condition.
The present invention also provides a kind of preparation method of avanaphil, by the avanaphil fumarate provided with the present invention
For raw material, the purity of the avanaphil for preparing is higher, test result indicate that, the purity of the avanaphil that the present invention is provided is high
99.86% is reached, maximum list is miscellaneous to be down to 0.043%.
Description of the drawings
Fig. 1 is the x-ray diffraction pattern of avanaphil fumarate crystallization prepared by the embodiment of the present invention 2.
Specific embodiment
The invention provides a kind of avanaphil fumarate.
According to the present invention, shown in the structure such as formula (II) of the avanaphil fumarate,
The present invention also provides a kind of preparation method of avanaphil fumarate, including：Will be anti-to avanaphil and fumaric acid
Should, obtain avanaphil fumarate.
According to the present invention, avanaphil and fumaric acid are reacted, wherein, the present invention does not have to the source of the avanaphil
Specifically limited, can make by oneself and can also buy, also without particular/special requirement, react the crude product for preparing is the purity to avanaphil
Can, such as purity is 99.0% crude product；The amount ratio preferably 1 of the avanaphil and the material of the fumaric acid:(1～2), more
Preferably 1:1；The solvent of the reaction is preferably one or more in methyl alcohol, ethanol, methanol aqueous solution and ethanol water,
One or more more preferably in methyl alcohol and ethanol；The temperature of the reaction is preferably 20～70 DEG C, and more preferably 50～68
℃.
Present invention also offers the crystallization of avanaphil fumarate, is characterized by X-ray diffraction figure, its 2 θ value exists
10.94th, show characteristic diffraction peak at 14.76,16.50,21.46,22.86,24.94 and 25.44.
Present invention also offers a kind of avanaphil fumarate crystallization preparation method, including：By avanaphil, fumaric acid
With solvent hybrid reaction, the crystallization of avanaphil fumarate is obtained；
The solvent is one or more in methyl alcohol, ethanol, methanol aqueous solution and ethanol water.
According to the present invention, by avanaphil, fumaric acid and solvent hybrid reaction, wherein, the present invention is to the avanaphil
Source be not particularly limited, can make by oneself and can also buy, to the purity of avanaphil also without particular/special requirement, prepared by reaction
Crude product, such as purity is 99.0% crude product；The amount ratio preferably 1 of the avanaphil and the material of the fumaric acid:
(1～2), more preferably 1:1；The solvent of the reaction is preferably one or more in methyl alcohol and ethanol, and the reaction is preferably
React under agitation；The temperature of the reaction is preferably 20～70 DEG C, more preferably 50～68 DEG C；The time of the reaction
Preferably 2～6 hours.
In order that the compound crystal form for arriving is more preferably, the hybrid reaction is preferably first heated to backflow, to hybrid reaction
Reactant liquor clarification after, stop heating, continue stirring to solid separate out, will separate out solid drying under reduced pressure, obtain avanaphil
Fumarate is crystallized；The temperature of the drying under reduced pressure is preferably 50 DEG C.
The invention provides a kind of avanaphil fumarate and the crystallization of avanaphil fumarate, present invention offer
Not only purity is high for avanaphil salt, and single miscellaneous content is low, and good stability.
Present invention also offers a kind of preparation method of avanaphil, including：The present invention is provided avanaphil fumaric acid
Salt is reacted with alkali, obtains avanaphil.
Specifically, avanaphil fumarate and alkali hybrid reaction are obtained avanaphil by the present invention, and wherein described alkali is excellent
Elect sodium carbonate or potassium carbonate as, more preferably mass concentration is 4～8 aqueous sodium carbonate or carbonic acid that mass concentration is 4～8
Aqueous solutions of potassium, the temperature of the reaction are preferably room temperature, and the solvent of the reaction is dichloromethane, chloroform or acetone, more preferably
For dichloromethane.
In order that the compound purity for arriving is higher, the compound for obtaining preferably is beaten by the present invention, the beating molten
Agent is preferably ethanol water, and more preferably ethanol is 1 with the volume ratio of water:2 solution.
The preparation method of the avanaphil that the present invention is provided, the avanaphil salt with present invention offer are prepared into as raw material
The purity of the avanaphil for arriving is higher.
For a further understanding of the present invention, the hardening coat material present invention provided with reference to embodiment and its preparation
Methods and applications are specifically described.
Embodiment 1
In 1L there-necked flask, (39.28g, 0.10mol) (S) -4- (3- chloro-4-methoxy benzylamino) -5- carboxylic is added
Acid -2- (2- methylol -1- pyrrolidinyl) pyrimidine (AFZJT-3), (21.84g, 0.15mol) 2- amino methylpyrimidine hydrochloride,
(28.76g, 0.15mmol) 1- (3- dimethylaminopropyl) -3- ethyl phosphinylidyne diimmonium salt hydrochlorate, (20.26g, 0.15mol)
I-hydroxybenzotriazole, 0.8L DMF, (30.36g, 0.30mol) triethylamine, 30 DEG C of reactions 24h, HPLC
Show reaction completely, add 1.2L water, extracted using dichloromethane, washed with 5% or so aqueous sodium carbonate 2 times, go from
Sub- water washing 1 time, anhydrous sodium sulfate drying, suction filtration, remove drier, reduced pressure concentration dichloromethane solvent, addition ethyl acetate
Beating, suction filtration, 50 DEG C of drying under reduced pressure 5h, 40.72g avanaphil richness crude product is obtained, yield is 84.13%.
Crude product 10g prepared by embodiment, carries out column chromatography, and is recrystallized twice with solvent methanol, obtains 5.48g purifying
Avanaphil, purify yield 54.80%；
The avanaphil for purifying is detected by HPLC, as a result show, its purity is 99.72%, maximum list is miscellaneous to be
0.064%.
Embodiment 2
Under room temperature, in 500ml there-necked flask, add methyl alcohol 200.0mL, embodiment 1 prepare avanaphil crude product (9.68g,
20.0mmol), fumaric acid (2.32g, 20.0mmol), under stirring, is warming up to backflow, molten clear after, stop heating, continue stirring 4
Hour, precipitation solid, 50 DEG C of drying under reduced pressure 5h, obtain avanaphil fumarate crystallization 10.94g, yield 91.17%.
Avanaphil fumarate is prepared by HPLC to detect to embodiment, as a result show, its purity is
99.84%, maximum single miscellaneous 0.045%, other larger impurity 0.039%.
By the avanaphil fumarate for preparing embodiment under 60 DEG C with illumination condition, place 10 days, lead to
Cross HPLC and its stability is detected, as a result referring to table 1, table 1 is avanaphil fumarate provided in an embodiment of the present invention and Ah cutting down
That non-stability result under 60 DEG C with illumination condition.
By being detected to avanaphil fumarate prepared by embodiment with melting point apparatus, as a result show, its fusing point is
176.4～178.5 DEG C.
Avanaphil fumarate (AFNF-FMS) is tested using Switzerland Mettler DSC1 thermal analyzer, arrange
30 DEG C of initial temperature, 200 DEG C of final temperature, heating rate 10K/min.There is an endothermic peak at 177.86 DEG C, should be that sample melts
Melting absorption heat causes, and this data is coincide with fusing point test result.
By the avanaphil for arriving for Japanese Rigaku D/max-2550 Powder X-ray Diffractometer being prepared by embodiment
Fumarate is detected that test condition is：Cu-K α is radiated, pipe stream 150mA, and pipe presses 40kV, 8 °/point of sweep speed, step-length
0.02 °, as a result referring to the x-ray diffraction pattern that Fig. 1, Fig. 1 are avanaphil fumarate crystallization prepared by the embodiment of the present invention 2,
As seen from Figure 1,2 θ values have characteristic diffraction peak at 10.94,14.76,16.50,21.46,22.86,24.94 and 25.44.
The avanaphil fumarate of the purifying that the embodiment is provided is detected by nuclear magnetic resonance chemical analyser, its
Spectral data is：1HNMR(DMSO-d6):δ 11.55 (2H, br, s), δ 9.16 (1H, br, s), δ 8.72～8.76 (3H, m), δ
8.51 (1H, s), δ 7.34～7.37 (2H, m), δ 7.26 (1H, dd), δ 7.06 (1H, d), δ 6.62 (2H, s), δ 4.56 (2H,
D), δ 4.49 (2H, d), δ 4.09 (1H, d), δ 3.80 (3H, s), δ 3.60～3.64 (1H, m), δ 3.44～3.51 (2H, m), δ
3.31～3.33 (1H, m), δ 1.82～1.94 (1H, m).
Embodiment 3
Under room temperature, in 500ml there-necked flask, embodiment 1 prepares avanaphil crude product (9.68g, 20.0mmol), fumaric acid
(2.32g, 20.0mmol), adds ethanol 180.0mL, under stirring, is warming up to 65 DEG C or so, molten clear after, stop heating, continue to stir
Mix 4 hours, precipitation solid, 50 DEG C of drying under reduced pressure 5h, obtain avanaphil fumarate crystallization 11.08g, yield 92.33%.
Avanaphil fumarate is prepared by HPLC to detect to embodiment, as a result show, its purity is
99.81%, maximum single miscellaneous 0.047%, other larger impurity 0.038%.
Embodiment 4
Under room temperature, in 500ml there-necked flask, embodiment 1 prepares avanaphil crude product (9.68g, 20.0mmol), fumaric acid
(2.32g, 20.0mmol), adds 80% methyl alcohol 250.0mL, under stirring, is warming up to 65 DEG C or so, molten clear after, stop heating, continue
Continuous stirring 4 hours, precipitation solid, 50 DEG C of drying under reduced pressure 5h, obtain avanaphil fumarate crystallization 11.12g, yield
92.67%.
Avanaphil fumarate is prepared by HPLC to detect to embodiment, as a result show, its purity is
99.80%, maximum single miscellaneous 0.048%, other larger impurity 0.036%.
Embodiment 5
The avanaphil fumarate 8.00g of the preparation of embodiment 2 in 250ml beaker, is added, under room temperature, adds 5% carbon
Acid sodium aqueous solution, stirs 30min, adds dichloromethane to be extracted, reactant liquor is transferred in separatory funnel, is separated organic
Layer, continues to be extracted twice, and merges organic phase, continues to be washed with 5% sodium carbonate liquor, and deionized water is washed, and organic layer is using no
Aqueous sodium persulfate dries 2h, suction filtration, filtrate reduced in volume, addition ethanol solution (volume ratio in residue：Ethanol/water=1/2) beat
Slurry, suction filtration, obtain white powdery solids avanaphil 5.56g, yield 86.20%, purifying total recovery 78.59%.
Avanaphil is prepared by HPLC to embodiment to detect, as a result show, its high purity 99.86%,
Maximum list is miscellaneous to be down to 0.043%.
By the compound for preparing embodiment under 60 DEG C with illumination condition, place 10 days, detected by HPLC
Its stability, as a result referring to table 1, table 1 is for avanaphil fumarate provided in an embodiment of the present invention and avanaphil at 60 DEG C
With the stability result under illumination condition.
The avanaphil fumarate of the purifying that the embodiment is provided is detected by nuclear magnetic resonance chemical analyser, its
Spectral data is：1HNMR(DMSO-d6):δ 9.16 (1H, br, s), δ 8.73～8.74 (3H, m), δ 8.51 (1H, s), δ 7.35～
7.37(2H,m),δ7.26(1H,dd),δ7.06(1H,d),δ4.95(1H,br,s),δ4.56(2H,d),δ4.49(2H,d),δ
4.09 (1H, d), δ 3.78 (3H, s), δ 3.62～3.65 (1H, m), δ 3.42～3.51 (2H, m), δ 3.28～3.30 (1H, m),
δ 1.83～1.95 (1H, m).
The avanaphil fumarate provided in an embodiment of the present invention of table 1 and avanaphil are under 60 DEG C with illumination condition
Stability result
As can be seen from the above table, avanaphil fumarate is all stable than avanaphil under high temperature or illumination.
And embodiment 1 can be seen that by column chromatography by crude product avanaphil purifying by embodiment, its yield only has
58.48%, and pass through the method for the present invention, first crude product avanaphil is become salt, then dissociate avanaphil is obtained, its purifying is total to be received
Rate is 78.59%.
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.It should be pointed out that right
For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out
Some improvement and modification, these improve and modification is also fallen in the protection domain of the claims in the present invention.
Claims (8)
1. a kind of avanaphil fumarate crystallization, its X-ray diffraction figure show 2 θ values 10.94,14.76,16.50,
21.46th, there is characteristic diffraction peak at 22.86,24.94 and 25.44.
2. the preparation method that the avanaphil fumarate described in a kind of claim 1 is crystallized, including：By avanaphil crude product,
Fumaric acid and solvent hybrid reaction, obtain the crystallization of avanaphil fumarate；The avanaphil crude product is 99.0% for purity
Crude product；
The solvent is one or more in methyl alcohol, ethanol, methanol aqueous solution and ethanol water.
3. preparation method according to claim 2, it is characterised in that the thing of the avanaphil crude product and the fumaric acid
The amount ratio of matter is 1：(1～2).
4. preparation method according to claim 2, it is characterised in that the solvent is the one kind or two in methyl alcohol and ethanol
Kind.
5. preparation method according to claim 2, it is characterised in that the temperature of the reaction is 20～70 DEG C.
6. preparation method according to claim 2, it is characterised in that the time of the reaction is 2～6 hours.
7. a kind of preparation method of avanaphil, including：Will be anti-with alkali for the avanaphil fumarate crystallization described in claim 1
Should, obtain avanaphil.
8. the preparation method described in claim 7, it is characterised in that the alkali is sodium carbonate or potassium carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410418849.0A CN104151299B (en) | 2014-08-22 | 2014-08-22 | Compound, crystal-form compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410418849.0A CN104151299B (en) | 2014-08-22 | 2014-08-22 | Compound, crystal-form compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104151299A CN104151299A (en) | 2014-11-19 |
| CN104151299B true CN104151299B (en) | 2017-03-08 |
Family
ID=51876957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410418849.0A Active CN104151299B (en) | 2014-08-22 | 2014-08-22 | Compound, crystal-form compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104151299B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866638A (en) * | 2017-03-23 | 2017-06-20 | 中山大学 | A kind of avanaphil citric acid eutectic and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1219609A1 (en) * | 1999-09-16 | 2002-07-03 | Tanabe Seiyaku Co., Ltd. | Aromatic nitrogenous six-membered ring compounds |
| CN101798301A (en) * | 2010-04-13 | 2010-08-11 | 漆又毛 | Pyrrolidyl pyrimidine methanesulfonamide derivatives and preparation method thereof |
| CN103845333A (en) * | 2012-12-07 | 2014-06-11 | 天津市汉康医药生物技术有限公司 | Novel use of avanafil |
-
2014
- 2014-08-22 CN CN201410418849.0A patent/CN104151299B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1219609A1 (en) * | 1999-09-16 | 2002-07-03 | Tanabe Seiyaku Co., Ltd. | Aromatic nitrogenous six-membered ring compounds |
| CN101798301A (en) * | 2010-04-13 | 2010-08-11 | 漆又毛 | Pyrrolidyl pyrimidine methanesulfonamide derivatives and preparation method thereof |
| CN103845333A (en) * | 2012-12-07 | 2014-06-11 | 天津市汉康医药生物技术有限公司 | Novel use of avanafil |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104151299A (en) | 2014-11-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN107365275B (en) | High purity celecoxib | |
| CN104945299B (en) | A kind of high-efficiency synthesis method of vildagliptin | |
| CN113292535B (en) | Method for preparing apaluamide intermediate and apaluamide | |
| WO2011160594A1 (en) | New preparation method of lapatinib | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN110256425A (en) | A kind of synthesis technology of palmitinic acid 9-hydroxy-risperidone | |
| CN104151299B (en) | Compound, crystal-form compound and preparation method thereof | |
| CN105358529B (en) | A kind of new method of synthesis Eliquis important intermediate | |
| CN101531654A (en) | Preparation method for Rupatadine | |
| CN108558759A (en) | The method that one kettle way prepares celecoxib | |
| CN114727977A (en) | Process for the preparation of compounds and modulators of compound S1P1 | |
| CN104961724B (en) | A kind of vanguard technology for obtaining high-purity Desloratadine | |
| CN108997209B (en) | Preparation method of regorafenib | |
| CN106831768A (en) | A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine | |
| CN103896858B (en) | The preparation technology of cytosine | |
| CN105669651A (en) | Preparation technique of dabigatran methanesulfonate | |
| CN103130700B (en) | Preparation method of azelnidipine intermediate | |
| CN106008392B (en) | A kind of preparation method of the intermediate of cancer therapy drug Dasatinib | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN107722007B (en) | Preparation method of apixaban impurity | |
| CN112125889A (en) | Preparation method of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline | |
| CN105237529A (en) | Refining method for high-purity anhydrous dasatinib | |
| CN108341770A (en) | A kind of preparation method of Sorafenib compound | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |