CN109734775A - A kind of refining methd of enalapril maleate - Google Patents
A kind of refining methd of enalapril maleate Download PDFInfo
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- CN109734775A CN109734775A CN201811650284.3A CN201811650284A CN109734775A CN 109734775 A CN109734775 A CN 109734775A CN 201811650284 A CN201811650284 A CN 201811650284A CN 109734775 A CN109734775 A CN 109734775A
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- enalapril maleate
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Abstract
The invention belongs to field of medicine preparing technology, are related to a kind of refining methd of enalapril maleate.The refining methd comprises the following processes: enalapril maleate crude product is added in water-organic solvent mixed solvent system, it is heated to 30-80 DEG C and stirs dissolution, after stirring 30 minutes, it is cooled to 0-20 DEG C of crystallization, filtering, with 0-10 DEG C of mixed solvent filter wash cake is cooled to twice, 20-60 DEG C of vacuum drying obtains enalapril maleate of the purity 99.5% or more.Compared with prior art, the refining methd of enalapril maleate of the present invention refines enalapril maleate with the method that temperature control combines using the difference of enalapril maleate dissolution properties in all kinds of solvents, the quality of products obtained therefrom is stablized, yield and purity further improve, yield is 84% or more, and quality is higher than standards of pharmacopoeia, detects through HPLC, purity is greater than 99.5%, and total impurities content is lower than 0.04.
Description
Technical field
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of purification side of enalapril maleate
Method.
Background technique
Enalapril maleate (Enalapril Maleate) also known as Cinvoril, CAS registration number: 76095-16-4 changes
Scientific name: N- [(s)-ethoxycarbonyl-3-phenylpropyl]-L-Ala-L-Pro maleate, chemical structural formula are as follows:
Enalapril maleate is one of the main component of Oral glucose tolerance test Enalapril, and Enalapril is by Mo Shadong system
Medicine company (Merck&Co Inc) develops, and is approved for treating each phase essential hypertension, renovascular hypertension, each
Grade heart failure, prevention symptomatic heart failure and prevention left ventricular insufficiency patient coronary ischemia event.
Enalapril maleate can reduce the blood pressure of hypertensive patient, and can improve the symptom and body of chronic heart failure
Sign.Enalapril maleate is angiotensin converting enzyme inhibitor, is hydrolyzed into enalaprilat in vivo after oral
(Enalaprilat).The latter inhibits Angiotensin-Converting, reduces angiotensinⅡ content, causes systemic vasodilatation,
And generate the effect to reduce blood pressure.
The report of synthetic method about enalapril maleate, including patent document US4374829, periodical literature
Drugs Fut 1982,7 (8), 556 and Nature 1980,288,280-283, wherein being not directed to enalapril maleate
Purifying, refining methd.
Chinese patent CN1274362A discloses a kind of refining methd for preparing high-purity enalapril maleate, this method
Enalapril maleate crude product is dissolved in alkaline solution, adjust pH to 6.0 ± 0.5, then with acid neutralize adjusting PH to 2.3 ±
0.5, cooling precipitates crystal, filtration washing, and enalapril maleate finished product is obtained after vacuum drying.
It can be seen that the purifying of enalapril maleate, refining methd are all made of the place of " alkali-soluble acid analysis " in the prior art
Reason method, however, should need to carry out sternly the addition speed of acid and the pH value of solution in " alkali-soluble acid analysis " method operating process
The control of lattice, so that operating procedure and production cost are increased, in addition, enalapril is in an acidic solution compared with facile hydrolysis, degradation
For enalaprilat, i.e. N- [(S) -1- carboxyl -3- phenylpropyl]-L-Ala-L-Pro；2,4 dichloro benzene base -2- (- 1H-
Imidazoles) ethyl alcohol.Use the method for " alkali-soluble acid analysis " when refining to enalapril maleate, to enalapril maleate
In alkaline solution when acid adding, it may appear that the acid too strong situation in the part of solution in the short time causes enalapril difficult to understand to hydrolyze, raw
At enalaprilat.Therefore, traditional " alkali-soluble acid analysis " refining methd can not steadily, fully remove the impurity.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of simple process, at low cost, safe and reliable, stability is good,
Convenient for the Aceglutamide and sodium chloride injection and preparation method thereof of clinical use.
A kind of refining methd of enalapril maleate of the present invention, the refining methd comprise the following processes: will
Enalapril maleate crude product is added in water-organic solvent mixed solvent system, is heated to 30-80 DEG C and is stirred dissolution, stirring 30
After minute, it is cooled to 0-20 DEG C of crystallization, is filtered, with 0-10 DEG C of mixed solvent filter wash cake is cooled to twice, 20-60 DEG C of vacuum is dry
The dry enalapril maleate for obtaining purity 99.5% or more.
A kind of refining methd of enalapril maleate of the present invention, the organic solvent are selected from methanol, ethyl alcohol, third
Ketone, second eyeball, normal propyl alcohol, isopropanol, n-butanol, isobutanol, ethylene glycol, methylene chloride, dimethyl sulfoxide, tetrahydrofuran, N, N- bis-
One or more of methylformamide or DMAC N,N' dimethyl acetamide.
A kind of refining methd of enalapril maleate of the present invention, the weight of the enalapril maleate and water
Than for 1:10-40, the volume ratio of polar organic solvent and water is 0.1-50:1.
A kind of refining methd of enalapril maleate of the present invention, the weight of the enalapril maleate and water
Than for 1:10-40, the volume ratio of polar organic solvent and water is 0.1-50:1.
The temperature of a kind of refining methd of enalapril maleate of the present invention, the heating stirring dissolution is 20-
90 DEG C, the temperature of cooling crystallization is 0-20 DEG C.
A kind of refining methd of enalapril maleate of the present invention, the enalapril maleate and washing filter cake
Weight ratio in the mixed solvent water is 1:10-40, and the volume ratio of polar organic solvent and water is 0.1-50:1, cleaning solution temperature
Degree is 0-20 DEG C.
A kind of refining methd of enalapril maleate of the present invention, the vacuum drying temperature are 20-60 DEG C.
Research is found: at different temperatures, dissolution properties has enalapril maleate in solvent of different nature
Larger difference, thus the temperature of one precipitation process of dissolution by adjusting enalapril maleate and the variation of solvent property, are obtained
The product for obtaining high-purity and yield avoids it is not necessary that acid is added in subtractive process and uses " alkali-soluble acid analysis " in the prior art
Method leads to the problem of product hydrolysis, has the advantages that easy to operate, production cost is low, product purity is high, is suitable for industrializing
It produces and uses.
Compared with prior art, the refining methd of enalapril maleate of the present invention utilizes enalapril maleate
The difference of dissolution properties refines enalapril maleate with the method that temperature control combines in all kinds of solvents, products obtained therefrom
Quality is stablized, and yield and purity further improve, and yield is 84% or more, and quality is higher than standards of pharmacopoeia, examines through HPLC
It surveys, purity is greater than 99.5%, and total impurities content is lower than 0.04.
Detailed description of the invention
1 products obtained therefrom content detection result of Fig. 1 embodiment.2 products obtained therefrom content detection result of Fig. 2 embodiment.Fig. 3 is implemented
3 products obtained therefrom content detection result of example.4 products obtained therefrom content detection result of Fig. 4 embodiment.
Specific embodiment
The refining methd of enalapril maleate of the present invention is described further combined with specific embodiments below,
But the scope of protection of the present invention is not limited thereto.
Embodiment 1
20.0g enalapril maleate crude product is added in 320ml purified water, is heated to 60 DEG C, is stirred 2 hours, it is cold
But to 5 DEG C, crystallization 2 hours are stood, filtering, filter cake is washed twice with 5 DEG C of purified water, is dried in vacuo 4 hours, obtains at 50 DEG C
Enalapril maleate 18.0g, yield 90.0%.It is detected through HPLC, wherein appearance time 13.7 minutes are enalapril, peak
Area is 99.52%.
Embodiment 2
20.0g enalapril maleate crude product is added in 100ml acetonitrile-water (9:1), is heated to 80 DEG C, stirring is extremely
Solid continues stirring 30 minutes after being completely dissolved, be cooled to 10 DEG C, stands crystallization 4 hours, filtering, 10 DEG C of acetonitrile-of filter cake
Water (9:1) washes twice, and is dried in vacuo 4 hours at 30 DEG C, obtains enalapril maleate 18.2g, yield 91.0%.Through HPLC
Detection wherein appearance time 15.6 minutes is, enalapril, peak area 99.75%.
Embodiment 3
20.0g enalapril maleate crude product is added to 100ml methylene chloride-methanol-water of the river of blueness containing 0.5g rattan alkane A
In (5:3:2), 80 DEG C are heated to, stirring continues stirring 30 minutes after being completely dissolved to solid, be cooled to 3 DEG C, and it is small to stand crystallization 4
When, filtering, filter cake is washed twice with 3 DEG C of methylene chloride-methanol-water (5:3:2), is dried in vacuo 4 hours at 40 DEG C, obtains horse
Come sour enalapril 19.4g, yield 97.1%.It is detected through HPLC, wherein appearance time 13.7 minutes are enalapril, peak face
Product is 99.68%.
Embodiment 4
20.0g enalapril maleate crude product is added to 100ml methylene chloride-methanol-water of the river of blueness containing 0.5g rattan alkane B
In (5:3:2), 80 DEG C are heated to, stirring continues stirring 30 minutes after being completely dissolved to solid, be cooled to 3 DEG C, and it is small to stand crystallization 4
When, filtering, filter cake is washed twice with 3 DEG C of methylene chloride-methanol-water (5:3:2), is dried in vacuo 4 hours at 40 DEG C, obtains horse
Come sour enalapril 16.8g, yield 84.0%.It is detected through HPLC, wherein appearance time 13.7 minutes are enalapril, peak face
Product is 99.68%.
Using the purity of HPLC method measurement enalapril maleate in the present invention, chromatographic condition is as follows: chromatographic column:
RLRP-S100A 5μm 250*4.6μm；Mobile phase: mixture of acetonitrile-phosphate buffer (4:6)；Column temperature: 70 DEG C；Detection wavelength:
215nm；Sampling volume: 10 μ L；Flow velocity: 1.0ml/min.
Claims (10)
1. a kind of refining methd of enalapril maleate, which is characterized in that the refining methd comprises the following processes: by Malaysia
Sour enalapril crude product is added in water-organic solvent mixed solvent system, is heated to 30-80 DEG C and is stirred dissolution, stirs 30 minutes
Afterwards, it is cooled to 0-20 DEG C of crystallization, is filtered, with 0-10 DEG C of mixed solvent filter wash cake is cooled to twice, 20-60 DEG C is dried in vacuo
Enalapril maleate to purity 99.5% or more.
2. the refining methd of enalapril maleate according to claim 1, which is characterized in that the organic solvent is selected from
Methanol, ethyl alcohol, acetone, second eyeball, normal propyl alcohol, isopropanol, n-butanol, isobutanol, ethylene glycol, methylene chloride, dimethyl sulfoxide, tetrahydro
One or more of furans, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide.
3. the refining methd of enalapril maleate according to claim 1, which is characterized in that the maleic acid Yi Napu
Benefit and the weight ratio of water are 1:10-40, and the volume ratio of organic solvent and water is 0.1-50:1.
4. the refining methd of enalapril maleate according to claim 1, which is characterized in that the maleic acid Yi Napu
Benefit and the weight ratio of water are 1:0.5-20, and the volume ratio of organic solvent and water is 1-50:1.
5. the refining methd of enalapril maleate according to claim 1, which is characterized in that the heating stirring dissolution
Temperature be 20-90 DEG C, the temperature of cooling crystallization is 0-20 DEG C.
6. the refining methd of enalapril maleate according to claim 1, which is characterized in that the heating stirring dissolution
Temperature be 30-80 DEG C, the temperature of cooling crystallization is 0-10 DEG C.
7. the refining methd of enalapril maleate according to claim 1, which is characterized in that the maleic acid Yi Napu
Benefit is 1:10-40 with the weight ratio of in the mixed solvent water with washing filter cake, and the volume ratio of polar organic solvent and water is 0.1-
50:1, cleaning solution temperature are 0-20 DEG C.
8. the refining methd of enalapril maleate according to claim 1, which is characterized in that the maleic acid Yi Napu
Benefit is 1:10-40 with the weight ratio of in the mixed solvent water with washing filter cake, and the volume ratio of polar organic solvent and water is 0.1-
50:1, cleaning solution temperature are 0-10 DEG C.
9. the refining methd of enalapril maleate according to claim 1, which is characterized in that the vacuum drying temperature
Degree is 20-60 DEG C.
10. the refining methd of enalapril maleate according to claim 1, which is characterized in that described vacuum drying
Temperature is 30-50 DEG C.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4374829A (en) * | 1978-12-11 | 1983-02-22 | Merck & Co., Inc. | Aminoacid derivatives as antihypertensives |
| CN1234804A (en) * | 1997-07-22 | 1999-11-10 | 钟渊化学工业株式会社 | Process for preparing pharmacologically acceptable salts of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl amino acids |
| CN1274362A (en) * | 1998-07-21 | 2000-11-22 | 钟渊化学工业株式会社 | Method for crystallizing maleic acid salt of n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline |
| US6541635B1 (en) * | 2002-03-29 | 2003-04-01 | Everlight Usa, Inc. | Method for producing angiotensin converting enzyme inhibitor |
| JP2005060291A (en) * | 2003-08-11 | 2005-03-10 | Nitto Denko Corp | Enalapril analogue-containing plaster |
| WO2006099058A2 (en) * | 2005-03-09 | 2006-09-21 | Nitromed, Inc. | Organic nitric oxide enhancing salts of angiotensin ii antagonists, compositions and methods of use |
| CN104744404A (en) * | 2015-02-27 | 2015-07-01 | 张旻 | Stable hydrochlorothiazide crystalline compound, and composite enalapril maleate pharmaceutical composition thereof |
| CN108586572A (en) * | 2018-04-18 | 2018-09-28 | 日照市普达医药科技有限公司 | A kind of preparation method of high-purity enalapril maleate and its crystal form |
| CN109021064A (en) * | 2017-06-09 | 2018-12-18 | 扬子江药业集团有限公司 | A kind of preparation method of enalapril maleate |
-
2018
- 2018-12-31 CN CN201811650284.3A patent/CN109734775A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4374829A (en) * | 1978-12-11 | 1983-02-22 | Merck & Co., Inc. | Aminoacid derivatives as antihypertensives |
| CN1234804A (en) * | 1997-07-22 | 1999-11-10 | 钟渊化学工业株式会社 | Process for preparing pharmacologically acceptable salts of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl amino acids |
| CN1274362A (en) * | 1998-07-21 | 2000-11-22 | 钟渊化学工业株式会社 | Method for crystallizing maleic acid salt of n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline |
| US6541635B1 (en) * | 2002-03-29 | 2003-04-01 | Everlight Usa, Inc. | Method for producing angiotensin converting enzyme inhibitor |
| JP2005060291A (en) * | 2003-08-11 | 2005-03-10 | Nitto Denko Corp | Enalapril analogue-containing plaster |
| WO2006099058A2 (en) * | 2005-03-09 | 2006-09-21 | Nitromed, Inc. | Organic nitric oxide enhancing salts of angiotensin ii antagonists, compositions and methods of use |
| CN104744404A (en) * | 2015-02-27 | 2015-07-01 | 张旻 | Stable hydrochlorothiazide crystalline compound, and composite enalapril maleate pharmaceutical composition thereof |
| CN109021064A (en) * | 2017-06-09 | 2018-12-18 | 扬子江药业集团有限公司 | A kind of preparation method of enalapril maleate |
| CN108586572A (en) * | 2018-04-18 | 2018-09-28 | 日照市普达医药科技有限公司 | A kind of preparation method of high-purity enalapril maleate and its crystal form |
Non-Patent Citations (2)
| Title |
|---|
| 刘亚南等: "马来酸依那普利片稳定性研究", 《药学研究》 * |
| 王紫华: "马来酸依那普利片的制备工艺研究", 《当代医药论丛》 * |
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