CN109053724A - The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity - Google Patents
The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity Download PDFInfo
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- CN109053724A CN109053724A CN201810960837.9A CN201810960837A CN109053724A CN 109053724 A CN109053724 A CN 109053724A CN 201810960837 A CN201810960837 A CN 201810960837A CN 109053724 A CN109053724 A CN 109053724A
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- structural formula
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of impurity prepared during Tadalafei, are compound shown in structural formula (2).The invention also discloses use of a compound shown in the preparation method of compound and the purification process of Tadalafei shown in the structural formula (2) and the structural formula (2).The beneficial effects of the present invention are the present invention provides a kind of new impurity of Tadalafei drug, and propose its preparation and purification method, as Tadalafei bulk pharmaceutical chemicals process impurity standard items or reference substance, can help to improve Tadalafei bulk pharmaceutical chemicals quality control system.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of impurity prepared during Tadalafei and the impurity
The purification process and purposes of preparation method and Tadalafei.
Background technique
Tadalafei (Tadalafil), shown in structure such as structural formula (1), trade name Xi Aili, Cialis, Tadalafil, by
Gift comes (EliLillv) and ICOS company cooperative research and development, and ratifies through FDA in U.S.'s list marketing in 2003.Tadalafei is
A kind of cyclic GMP-specific phosphodiesterase enzyme 5 (PDE5) inhibitor has high, rapid, long half time of action of selectivity etc.
Advantage, for treating male erectile dysfunction.Da Lafei drug effect is rapid and the duration is long, not by high fat diet and alcohol
Intake influences, and achieves brilliant market in ED therapy field and achieves.
The substance of any influence pharmaceutical purity is referred to as impurity.Miscellaneous Quality Research is an important content of drug research and development,
It includes selecting suitable analysis method, is accurately differentiated and the content of measurement impurity and comprehensive pharmacy, toxicity and clinical research
Result determine the reasonable limit of impurity.Whole process of this research through drug research and development.
Impurity in drug is generally divided into three classes by its physicochemical property: organic impurities, inorganic impurity and residual solvent.According to
Its source, impurity can be divided into process impurity (including synthesis in the complete reactant of unreacted and reagent, intermediate, by-product
Deng), catabolite, mixed impurity etc. from reactant and reagent.According to its toxicity category, impurity can be divided into toxic impurities again
With common impurities etc..Impurity can also be by its classification of chemical structure, such as steroidal, alkaloid, geometric isomer, optical isomer and poly-
Close object etc..Organic impurities includes the impurity introduced in technique and catabolite etc., it may be possible to known or unknown, volatile
Or fixedness.
European Pharmacopoeia (EP) 8.0 editions gives 9 kinds of related impurities such as A~I in the discussion of Tadalafei kind, for this
There are many related document report of a little impurity researchs, however available data has no research structure as shown in the compound of structural formula (2)
Tadalafei bulk pharmaceutical chemicals process impurity.It can be seen that the quality system and analytical standard of the research of Tadalafei bulk pharmaceutical chemicals still have
Need improvements.
Summary of the invention
In order to overcome the deficiencies in the prior art, Tadalafei is prepared one of the objects of the present invention is to provide a kind of
Impurity in the process.
The second object of the present invention is to provide a kind of preparation method of above-mentioned impurity.
The third object of the present invention is to provide a kind of purification process of Tadalafei.
The fourth object of the present invention is to provide a kind of above-mentioned impurity as Tadalafei bulk pharmaceutical chemicals process impurity standard items
Or the purposes of reference substance.
It is the compound of structural formula (2) as the impurity of first aspect present invention prepared during Tadalafei:
The preparation method of the compound of structural formula (2) as second aspect of the present invention, by structural formula (3) Ta Dala
Non- intermediate is dissolved in organic solvent, and methylamine water solution is added into system, is quickly stirred, and heat preservation to reaction is finished, cooling, dense
Contracting is evaporated removing solvent, residue with column chromatography scheme after purification, gained crude product it is secondarily purified structural formula (2) compound, instead
Answer formula as follows:
In a preferred embodiment of the invention, the structural formula (3) Tadalafei intermediate is that Tadalafei is normal
The key intermediate in preparation process is advised, is reported, can be made by kinds of processes method, example according to many existing ground documents and materials
Compound (3) institute is made through three-step reaction using D-trp as starting material in the method as described according to patent US5859006
It is as follows to be specifically prepared into route for the key intermediate shown:
In a preferred embodiment of the invention, the structural formula (3) Tadalafei intermediate with it is described organic molten
The mass volume ratio of agent is 1:5 (g:mL).
In a preferred embodiment of the invention, the organic solvent is methanol, ethyl alcohol, isopropanol, acetonitrile, dioxy
Any one in six rings or two or more mixing, preferably any one in acetonitrile or ethyl alcohol or two kinds of mixing.
In a preferred embodiment of the invention, the mass percent concentration of the methylamine water solution is 40%.
In a preferred embodiment of the invention, the system and the volume ratio of methylamine water solution are (4~5): 1.
In a preferred embodiment of the invention, the reaction temperature of the insulation reaction be 70~110 DEG C, preferably 80
~90 DEG C.
In a preferred embodiment of the invention, the reaction time of the insulation reaction is 2~3 hours.
In a preferred embodiment of the invention, column chromatography is silica gel column chromatography, wherein eluant, eluent ratio is
PE/EA/DCM=1/4/1.
In a preferred embodiment of the invention, the secondarily purified mode is mashing purifying.
In a preferred embodiment of the invention, mashing purifying is to carry out mashing purifying with ether solvent.
In a preferred embodiment of the invention, the ether solvent is petroleum ether, methyl tertiary butyl ether(MTBE), tetrahydro furan
It mutters, any one or two or more mixing in methyltetrahydrofuran, preferably methyl tertiary butyl ether(MTBE).
The third object of the present invention is to provide a kind of purification process of Tadalafei, which is characterized in that will contain structure
The compound Tadalafei crude product of formula (2) is dissolved in acetic acid, and organic solvent is added dropwise into system to a large amount of to dissolved clarification for heating stirring
White solid is precipitated, and drop finishes, and keeps the temperature crystallization, filters, and drying obtains sterling Tadalafei.
In a preferred embodiment of the invention, the organic solvent is methanol, the acetic acid and methanol volume ratio
Example is 1:(2~5), preferably 1:2.
In a preferred embodiment of the invention, the temperature of the heat preservation crystallization is 20~25 DEG C, time 4h.
The fourth object of the present invention is a kind of above-mentioned impurity as Tadalafei bulk pharmaceutical chemicals process impurity standard items or right
According to the purposes of product, can be used in improving Tadalafei bulk pharmaceutical chemicals quality control system.
Main innovation point of the invention is:
The present invention provides a kind of new impurity of Tadalafei drug, and propose its preparation and purification method, as
Tadalafei bulk pharmaceutical chemicals process impurity standard items or reference substance can help to improve Tadalafei bulk pharmaceutical chemicals quality control system.
Detailed description of the invention
Fig. 1 is the 1H NMR figure of according to embodiments of the present invention 6 preparation method gained target compound；
Fig. 2 is the LCMS figure of according to embodiments of the present invention 6 preparation method gained target compound.
Fig. 3 is impurity compound HPLC map shown in structural formula (2) in embodiment 12.
Fig. 4 is to identify HPLC map to the target impurity of Tadalafei bulk pharmaceutical chemicals in embodiment 12.
Specific embodiment
The present invention is further illustrated by the following examples, but these embodiments must not be used to explain to the present invention
Limitation.
Unless otherwise specified, product HPLC purity characterizing method instrument parameter referring to shown in table in embodiment.
One Tadalafei HPLC analysis method of table
Embodiment 1
5g intermediate (compound shown in structural formula (3)) is added in 50mL three-necked flask, it is solid that the dissolution of 25mL acetonitrile is added
Body opens stirring, is added 4.54g methylamine water solution (40%, 5eq), is warming up to 90 DEG C of back flow reactions, after 2h, TLC (PE/EA/
DCM=1/2/1) display raw material disappears, and stops reaction, cooling, 50 DEG C of reduced pressures are evaporated, residue obtained with column chromatographic purifying
(silica gel, PE/EA/DCM=1/4/1) obtains yellow solid 3.65g, the HPLC purity of compound shown in structural formula (2)
91.32%, yield 69.88%.
Embodiment 2
Process described in reference implementation example 1 is warming up to 72 DEG C of back flow reactions using methanol as reaction dissolvent.Residue is with column layer
Analysis purifying (silica gel, PE/EA/DCM=1/4/1), obtains the yellow solid 1.77g, HPLC of compound shown in structural formula (2)
Purity 90.12%, yield 33.44%.
Embodiment 3
Process described in reference implementation example 1 is warming up to 88 DEG C of back flow reactions using ethyl alcohol as reaction dissolvent.Residue is with column layer
Analysis purifying (silica gel, PE/EA/DCM=1/4/1), obtains the yellow solid 3.50g, HPLC of compound shown in structural formula (2)
Purity 90.45%, yield 66.37%.
Embodiment 4
Process described in reference implementation example 1 is warming up to 86 DEG C of back flow reactions using isopropanol as reaction dissolvent.Residue is with column
Chromatographic purifying (silica gel, PE/EA/DCM=1/4/1), obtains the yellow solid 2.74g of compound shown in structural formula (2),
HPLC purity 91.33%, yield 52.46%.
Embodiment 5
Process described in reference implementation example 1 is warming up to 108 DEG C of back flow reactions using dioxane as reaction dissolvent.Residue with
Column chromatographic purifying (silica gel, PE/EA/DCM=1/4/1), obtains the yellow solid 2.13g of compound shown in structural formula (2),
HPLC purity 89.23%, yield 39.84%.
Embodiment 6
Crude compound (HPLC purity 91.31%) shown in 3g structural formula (2) is added in 50mL three-necked flask, is added
20mL methyl tertiary butyl ether(MTBE) opens stirring, is warming up to reflux mashing 2h, filters while hot, filter cake is with the washing of 5mL methyl tertiary butyl ether(MTBE)
Twice, decompression drying obtains target compound 2.37g, HPLC purity shown in structural formula (2) 99.01%, receives to constant weight at 50 DEG C
Rate 85.81%.The 1H NMR of target compound is referring to Fig. 1.Referring to fig. 2, the MS data of target compound: [2M+1]=814.3,
[M-m]=214.3 (fragment peak).
Embodiment 7
Process described in reference implementation example 6 carries out mashing purifying by solvent of petroleum ether, obtains target shown in structural formula (2)
Compound 2.11g, HPLC purity 97.89%, yield 75.40%.
Embodiment 8
Process described in reference implementation example 6 carries out mashing purifying by solvent of tetrahydrofuran, obtains mesh shown in structural formula (2)
Mark compound 1.56g, HPLC purity 98.56%, yield 56.13%.
Embodiment 9
Process described in reference implementation example 6 carries out mashing purifying by solvent of methyltetrahydrofuran, obtains structural formula (2) institute
Show target compound 1.62g, HPLC purity 98.85%, yield 58.46%.
Embodiment 10
20g Tadalafei crude product (HPLC target impurity (chemical combination shown in structural formula (2) is added in 1000mL three-necked flask
Object) 1.41%), 260mL acetic acid is added, opens stirring, is warming up to 80 DEG C of solid dissolved clarifications, the heat preservation decoloration of 0.4g active carbon is added
0.5h is filtered while hot, and 520mL anhydrous methanol is slowly added dropwise in filtrate under 50 DEG C of keeping warm modes, and a large amount of solids are precipitated, and drop finishes, room
Temperature (20-25 DEG C) crystallization 4h is filtered, dry, obtains Tadalafei 17.89g, HPLC detect target impurity without.
Embodiment 11
Process described in reference implementation example 10 after decoloration, filters while hot, and filtrate is slowly dripped under room temperature (20-25 DEG C) state
Adding 520mL anhydrous methanol, a large amount of solids are precipitated, and drop finishes, room temperature crystallization 4h, filter, and it is dry, obtain Tadalafei 17.89g, HPLC
Detect target impurity 0.02%.
Embodiment 12
Using compound shown in structural formula (2) as working reference substance, contain to the impurity in Tadalafei bulk pharmaceutical chemicals is ground certainly
Amount is measured.The accurately weighed reference substance, compound concentration are the reference substance solution of 100ug/ml, and compound concentration is 1mg/ml's
Test solution is carried out HPLC analysis, is calculated using external standard method, grinds impurity compound A in bulk pharmaceutical chemicals certainly as the result is shown
Content be 0.03%, be less than report limit (referring to Fig. 3, Fig. 4).The compound is the content of the impurity in Tadalafei bulk pharmaceutical chemicals
Research provides Research foundation, the impurity working reference substance that can be used in the quality control of Tadalafei bulk pharmaceutical chemicals.
Claims (17)
1. the impurity during preparing Tadalafei, which is characterized in that be the compound of structural formula (2):
2. the preparation method of the compound of structural formula (2) described in claim 1, by structural formula (3) Tadalafei intermediate
It is dissolved in organic solvent, methylamine water solution is added into system, quickly stir, heat preservation to reaction is finished, and cooling, concentration, which is evaporated, to remove
Remove solvent, residue with column chromatography scheme after purification, gained crude product it is secondarily purified structural formula (2) compound, reaction equation is as follows:
3. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that be with D-trp
Beginning raw material is made key intermediate shown in compound (3) through three-step reaction, it is as follows to be specifically prepared into route:
4. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the structural formula (3)
The mass volume ratio of Tadalafei intermediate and the organic solvent is 1:5 (g:mL).
5. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the organic solvent
For any one or the two or more mixing in methanol, ethyl alcohol, isopropanol, acetonitrile, dioxane.
6. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the methylamine is water-soluble
The mass percent concentration of liquid is 40%.
7. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the system and methylamine
The volume ratio of aqueous solution is (4~5): 1.
8. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the insulation reaction
Reaction temperature is 70~110 DEG C.
9. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the insulation reaction
Reaction time be 2~3 hours.
10. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the column chromatography is silicon
Plastic column chromatography, wherein eluant, eluent ratio is PE/EA/DCM=1/4/1.
11. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that described is secondarily purified
Mode is mashing purifying.
12. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the mashing purifying
It is that mashing purifying is carried out with ether solvent.
13. the preparation method of the compound of structural formula (2) as claimed in claim 2, which is characterized in that the ether solvent
For any one or the two or more mixing in petroleum ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, methyltetrahydrofuran, preferably
For methyl tertiary butyl ether(MTBE).
14. a kind of purification process of Tadalafei, which is characterized in that the compound Tadalafei crude product of structural formula (2) will be contained
It is dissolved in acetic acid, heating stirring to dissolved clarification is added dropwise organic solvent to a large amount of white solids into system and is precipitated, and drop finishes, heat preservation analysis
Crystalline substance filters, and drying obtains sterling Tadalafei.
15. a kind of purification process of Tadalafei as claimed in claim 14, which is characterized in that the organic solvent is first
Alcohol, the acetic acid and methanol volume ratio are 1:2~5.
16. a kind of purification process of Tadalafei as claimed in claim 14, which is characterized in that the temperature of the heat preservation crystallization
It is 20~25 DEG C, time 4h.
17. a kind of purposes of compound of structural formula (2) as Tadalafei bulk pharmaceutical chemicals process impurity standard items or reference substance, energy
It is enough in and improves Tadalafei bulk pharmaceutical chemicals quality control system.
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| CN201810960837.9A CN109053724A (en) | 2018-08-22 | 2018-08-22 | The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity |
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Cited By (3)
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| CN109796461A (en) * | 2018-12-30 | 2019-05-24 | 杭州康本医药科技有限公司 | A kind of preparation process of Tadalafei impurity I |
| CN110734443A (en) * | 2019-12-04 | 2020-01-31 | 重庆植恩药业有限公司 | Preparation method of tadalafil-related substances I |
| CN110804055A (en) * | 2019-11-27 | 2020-02-18 | 株洲千金药业股份有限公司 | Preparation method of tadalafil impurity G |
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| CN109796461A (en) * | 2018-12-30 | 2019-05-24 | 杭州康本医药科技有限公司 | A kind of preparation process of Tadalafei impurity I |
| CN110804055A (en) * | 2019-11-27 | 2020-02-18 | 株洲千金药业股份有限公司 | Preparation method of tadalafil impurity G |
| CN110734443A (en) * | 2019-12-04 | 2020-01-31 | 重庆植恩药业有限公司 | Preparation method of tadalafil-related substances I |
| CN110734443B (en) * | 2019-12-04 | 2022-06-03 | 植恩生物技术股份有限公司 | Preparation method of tadalafil-related substance I |
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