CN108690000A - A kind of process for purification of avanaphil - Google Patents
A kind of process for purification of avanaphil Download PDFInfo
- Publication number
- CN108690000A CN108690000A CN201810694514.XA CN201810694514A CN108690000A CN 108690000 A CN108690000 A CN 108690000A CN 201810694514 A CN201810694514 A CN 201810694514A CN 108690000 A CN108690000 A CN 108690000A
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- Prior art keywords
- avanaphil
- purification
- heat
- temperature
- crude product
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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
Abstract
The present invention relates to a kind of process for purification of avanaphil, include the following steps:(1)Avanaphil crude product is added in organic solvent, temperature rising reflux to solid dissolves;(2)To step(1)Solution in be added activated carbon, decolourize 0.1 ~ 1 hour, heat filtering;(3)By step(2)Obtained filtrate cooling crystallization, then washed, dry obtained avanaphil highly finished product.The impurity of avanaphil highly finished product produced by the present invention is few, high income.Thus this method has apparent economic benefit, is advantageously implemented industrialized production.
Description
Technical field
The invention belongs to medication chemistry technologies to synthesize field, and in particular to a kind of process for purification of avanaphil.
Background technology
Avanaphil, structural formula are:
Avanaphil is developed by day Honda side drugmaker of Mitsubishi and VIVUS companies, and in April, 2012 FDA approvals Vivus is public
The avanaphil piece of department lists, and trade name is respectively (U.S.) Stendra, Spedra (European Union), Zepeed (South Korea).Clinic is used
In treatment male erectile dysfunction (ED), this is the ED drugs for a kind of unique onset time of FDA approvals being as short as 15 minutes.It should
Medicine has multiple specifications available (including 50mg, 100mg and 200mg).(such as silaenafil is commonly called as with other anti-ED drugs
" vigour ") it compares, the sharpest edges of avanaphil are rapid-action, and patient should take for 30 minutes before sexual behaviour.Avanaphil
Quick acting makes the enjoyment sexual love that ED patient at any time can be comfortable, without taking medicine in advance too early, and without apparent secondary work
With.In November, 2016 Hainan Meilan Shike Pharmaceutical Co., Ltd. receive state food pharmaceuticals administration general bureau check and approve sign and issue Ah
Cut down that non-, avanaphil dispersible tablet"Clinical drug trial official written reply".
CN106336401A discloses a kind of process for purification of avanaphil, needs the combination for using two kinds of solvents,
One is intensive polar solvent, and another is middle polarity or nonpolar solvent, so that cost is higher, in addition, the yield of the patent
Only up to 83.5%.
Invention content
In order to overcome the problems, such as in the prior art, the present invention provides a kind of process for purification of the avanaphil of high income.
In order to solve the above technical problems, the present invention adopts the following technical scheme that:
A kind of process for purification of avanaphil, includes the following steps:
(1) avanaphil crude product is added in organic solvent, temperature rising reflux to solid dissolves;
(2) activated carbon is added into the solution of step (1), decolourizes 0.1~1 hour, heat filtering;
(3) the filtrate cooling crystallization obtained step (2), then washed, dry obtained avanaphil highly finished product.
Preferably, in step (1), the organic solvent is methanol/or ethyl alcohol.
Preferably, in step (1), the quality that feeds intake of the organic solvent is the 13 of the avanaphil crude product quality
~32 times, further preferably 30~32 times.
Preferably, in step (1), the temperature of temperature rising reflux is 65~85 DEG C.
Preferably, in step (2), the temperature of heat filtering is 65~85 DEG C.
Preferably, in step (2), after carrying out the heat filtering, the filter cake is washed using the pure water of heat,
Merging filtrate carries out the processing of step (3).
It is further preferred that in step (2), the temperature of the pure water of the heat is 70~75 DEG C.
It is further preferred that in step (2), the dosage of the pure water of the heat is the avanaphil crude product quality
8~15 times, more preferably 9~11 times.
Preferably, in step (3), the temperature for the crystallization that cools down is 5~20 DEG C, further preferably 10~15 DEG C.
Preferably, in step (3), the time for the crystallization that cools down is 9~11 hours.
Avanaphil crude product and the related standard of physical of highly finished product
| Project | Avanaphil crude product | Avanaphil highly finished product |
| Impurity A | ≤ 0.2% | ≤ 0.1% |
| Other are single miscellaneous | ≤ 0.2% | ≤ 0.1% |
| It is total miscellaneous | ≤ 1.0% | ≤ 0.5% |
| Purity | >=99.0% | >=99.5% |
Note:The structural formula of impurity A is:
Compared with prior art, the invention has the advantages that:
The impurity of avanaphil highly finished product produced by the present invention is few, high income.Thus this method has apparent economic effect
Benefit is advantageously implemented industrialized production.
Specific implementation mode
Below in conjunction with specific embodiment, invention is further described in detail.
Embodiment 1
The avanaphil crude product 20g that purity is 99.37% is added in 1000ml reaction bulbs, and 340ml ethyl alcohol, heating is added
Flow back (80 ± 2 DEG C) 0.5h, and 1g activated carbon decolorizings are added 30 minutes in dissolved clarification, 70 DEG C of heat filterings, gradually has white solid on filter cake
(after testing, the white solid of precipitation is avanaphil) is precipitated, crystal solution slow cooling is cooled to 15~20 DEG C of stirring and crystallizings
10h, filtering, the washing of 50ml ethyl alcohol obtain avanaphil highly finished product 16.8g, yield 84% in 45~50 DEG C of vacuum drying.Matter
Measure situation:Related substance:Impurity A (≤0.1%):0.10%;Other single miscellaneous (≤0.1%):0.09%;Total miscellaneous (≤0.5%):
0.31%.Other quality index meet regulation.
Note:The related substance situation of avanaphil crude product used:
| Project | Standard | Avanaphil crude product |
| Impurity A | ≤ 0.2% | 0.13% |
| Other are single miscellaneous | ≤ 0.2% | 0.11% |
| It is total miscellaneous | ≤ 1.0% | 0.63% |
| Purity | >=99.0% | 99.37% |
Embodiment 2
The avanaphil crude product 20g that purity is 99.37% is added in 1000ml reaction bulbs, and the methanol of 340ml is added, adds
1g activated carbon decolorizings are added 30 minutes in heat reflux (70 ± 2 DEG C) 0.5h, dissolved clarification, 70 DEG C of heat filterings, gradually have white solid on filter cake
(after testing, the white solid of precipitation is avanaphil) is precipitated in body, and crystal solution slow cooling is cooled to 15~20 DEG C of stirring and crystallizings
10h, filtering, the washing of 50ml absolute methanols obtain avanaphil highly finished product 17g, yield 85% in 45~50 DEG C of vacuum drying.
Quality condition:Related substance:Impurity A (≤0.1%):0.09%;Other single miscellaneous (≤0.1%):0.08%;Always miscellaneous (≤
0.5%):0.29%.Other quality index meet regulation.
Embodiment 3
The avanaphil crude product 20g that purity is 99.37% is added in 1000ml reaction bulbs, and the methanol of 800ml is added, adds
1g activated carbon decolorizings are added 30 minutes in heat reflux (70 ± 2 DEG C) 0.5h, dissolved clarification, 70 DEG C of heat filterings, are precipitated without solid on filter cake,
Crystal solution slow cooling is cooled to 10~15 DEG C of stirring and crystallizing 10h, filtering, 50ml absolute methanols washing, in 45~50 DEG C of vacuum
It is dry, obtain avanaphil highly finished product 17.7g, yield 88.5%.Quality condition:Related substance:Impurity A (≤0.1%):
0.05%;Other single miscellaneous (≤0.1%):0.04%;Total miscellaneous (≤0.5%):0.18%.Other quality index meet regulation.
Embodiment 4
The avanaphil crude product 20g that purity is 99.37% is added in 1000ml reaction bulbs, and the methanol of 800ml is added, adds
1g activated carbon decolorizings are added 30 minutes in heat reflux (70 ± 2 DEG C) 0.5h, dissolved clarification, 70 DEG C of heat filterings, are precipitated without solid on filter cake,
With the purifying water washing filter cake of 200ml temperature 70 Cs, filtrate merges washing lotion slow cooling and is cooled to 10~15 DEG C of stirring and crystallizings
10h, filtering, the washing of 50ml absolute methanols obtain avanaphil highly finished product 18.5g in 45~50 DEG C of vacuum drying.Yield
92.5%, quality condition:Related substance:Impurity A (≤0.1%):0.04%;Other single miscellaneous (≤0.1%):0.03%;It is total miscellaneous
(≤0.5%):0.14%.Other quality index meet regulation.
The present invention is described in detail above, its object is to allow the personage for being familiar with this field technology that can understand this
The content of invention is simultaneously implemented, and it is not intended to limit the scope of the present invention, and the present invention is not limited to above-mentioned implementations
, equivalent change or modification made by all Spirit Essences according to the present invention should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of process for purification of avanaphil, it is characterised in that:Include the following steps:
(1)Avanaphil crude product is added in organic solvent, temperature rising reflux to solid dissolves;
(2)To step(1)Solution in be added activated carbon, decolourize 0.1 ~ 1 hour, heat filtering;
(3)By step(2)Obtained filtrate cooling crystallization, then washed, dry obtained avanaphil highly finished product.
2. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(1)In, described is organic molten
Agent is methanol/or ethyl alcohol.
3. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(1)In, described is organic molten
The quality that feeds intake of agent is 13 ~ 32 times of the avanaphil crude product quality.
4. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(1)In, the temperature of temperature rising reflux
Degree is 65 ~ 85 DEG C.
5. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(2)In, the temperature of heat filtering
It is 65 ~ 85 DEG C.
6. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(2)In, carry out the heat
After filtering, the filter cake is washed using the pure water of heat, merging filtrate carries out step(3)Processing.
7. the process for purification of avanaphil according to claim 6, it is characterised in that:Step(2)In, the described heat it is pure
The temperature of water is 70 ~ 75 DEG C.
8. the process for purification of avanaphil according to claim 6, it is characterised in that:Step(2)In, the described heat it is pure
The dosage of water is 8 ~ 15 times of the avanaphil crude product quality.
9. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(3)In, the temperature for the crystallization that cools down
Degree is 5 ~ 20 DEG C.
10. the process for purification of avanaphil according to claim 1, it is characterised in that:Step(3)In, cool down crystallization
Time is 9 ~ 11 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810694514.XA CN108690000A (en) | 2018-06-29 | 2018-06-29 | A kind of process for purification of avanaphil |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810694514.XA CN108690000A (en) | 2018-06-29 | 2018-06-29 | A kind of process for purification of avanaphil |
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| CN108690000A true CN108690000A (en) | 2018-10-23 |
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| CN201810694514.XA Pending CN108690000A (en) | 2018-06-29 | 2018-06-29 | A kind of process for purification of avanaphil |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN106336401A (en) * | 2015-07-15 | 2017-01-18 | 山东诚创医药技术开发有限公司 | Refining method for avanafil |
-
2018
- 2018-06-29 CN CN201810694514.XA patent/CN108690000A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN106336401A (en) * | 2015-07-15 | 2017-01-18 | 山东诚创医药技术开发有限公司 | Refining method for avanafil |
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| CB02 | Change of applicant information |
Address after: 215212 No. 6 Jinzi Road, Lili Town, Wujiang District, Suzhou City, Jiangsu Province Applicant after: Suzhou Shengda Pharmaceutical Co., Ltd. Address before: 215212 No. 9 Jiaotong East Road, Lili Town, Wujiang District, Suzhou City, Jiangsu Province Applicant before: China Union Chempharma (Suzhou) Co., Ltd. |
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Application publication date: 20181023 |
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