A kind of refining methd of enalapril maleateTechnical field
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of purification side of enalapril maleateMethod.
Background technique
Enalapril maleate (Enalapril Maleate) also known as Cinvoril, CAS registration number: 76095-16-4 changesScientific 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 systemMedicine company (Merck&Co Inc) develops, and is approved for treating each phase essential hypertension, renovascular hypertension, eachGrade 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 failureSign.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 literatureDrugs Fut 1982,7 (8), 556 and Nature 1980,288,280-283, wherein being not directed to enalapril maleatePurifying, refining methd.
Chinese patent CN1274362A discloses a kind of refining methd for preparing high-purity enalapril maleate, this methodEnalapril 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 artReason 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 processThe control of lattice, so that operating procedure and production cost are increased, in addition, enalapril is in an acidic solution compared with facile hydrolysis, degradationFor 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 maleateIn 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, rawAt 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: willEnalapril maleate crude product is added in water-organic solvent mixed solvent system, is heated to 30-80 DEG C and is stirred dissolution, stirring 30After 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 dryThe 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, thirdKetone, 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 waterThan 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 waterThan 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 cakeWeight 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 temperatureDegree 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 natureLarger difference, thus the temperature of one precipitation process of dissolution by adjusting enalapril maleate and the variation of solvent property, are obtainedThe 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 artMethod 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 industrializingIt produces and uses.
Compared with prior art, the refining methd of enalapril maleate of the present invention utilizes enalapril maleateThe difference of dissolution properties refines enalapril maleate with the method that temperature control combines in all kinds of solvents, products obtained therefromQuality is stablized, and yield and purity further improve, and yield is 84% or more, and quality is higher than standards of pharmacopoeia, examines through HPLCIt 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 implemented3 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 coldBut 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 CEnalapril maleate 18.0g, yield 90.0%.It is detected through HPLC, wherein appearance time 13.7 minutes are enalapril, peakArea 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 extremelySolid 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 cakeWater (9:1) washes twice, and is dried in vacuo 4 hours at 30 DEG C, obtains enalapril maleate 18.2g, yield 91.0%.Through HPLCDetection 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 AIn (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 4When, 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 horseCome sour enalapril 19.4g, yield 97.1%.It is detected through HPLC, wherein appearance time 13.7 minutes are enalapril, peak faceProduct 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 BIn (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 4When, 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 horseCome sour enalapril 16.8g, yield 84.0%.It is detected through HPLC, wherein appearance time 13.7 minutes are enalapril, peak faceProduct 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.