CN105777626A - Preparation method of milrinone - Google Patents
Preparation method of milrinone Download PDFInfo
- Publication number
- CN105777626A CN105777626A CN201410804717.1A CN201410804717A CN105777626A CN 105777626 A CN105777626 A CN 105777626A CN 201410804717 A CN201410804717 A CN 201410804717A CN 105777626 A CN105777626 A CN 105777626A
- Authority
- CN
- China
- Prior art keywords
- methyl
- dihydro
- oxo
- pyridine radicals
- pyridine
- 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.)
- Pending
Links
Landscapes
- Pyridine Compounds (AREA)
Abstract
A preparation method of milrinone comprises the following steps: reacting n-butyl lithium with 4-methyl pyridine to generate pyridine methyl lithium, then reacting pyridine methyl lithium with propyl acetate to generate 1-(4-pyridyl)-acetone; reacting 1-(4-pyridyl)-acetone with tripropyl orthoformate and acetic anhydride to generate 1-propoxyl-2-(4-pyridyl)-vinyl methyl ketone; finally reacting 1-propoxyl-2-(4-pyridyl)-vinyl methyl ketone with cyanoacetamide in the presence of sodium ethoxide taken as the alkalizer, adding the reaction product into a mixed solution of dimethyl formamide and water, and carrying out recrystallization. The preparation method has the advantages that the yield of milrinone is prominently improved, the product purity is increased, and the color and crystal form of product are both improved.
Description
Technical field
The preparation method that the present invention relates to a kind of pyridine compounds and their, the preparation method particularly relating to a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN.
Background technology
1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN, its general milrinone by name, shown in the following formula I of its structural formula, for white or off-white color crystalline powder, odorless.It is almost insoluble in water or ethanol, slightly molten in dilute hydrochloric acid.
Milrinone is the congestive heart failure therapeutic agent of Sterling company of U.S. exploitation, is double; two pyridine derivates of amrinone (Amrinone), in December, 1987 U.S. approval listing.It is successively in Britain, France, Germany, Holland, country's list marketing such as Belgian and Brazilian.Intravenous injection milrinone has been widely used for improving the cardiac function of heart failure patient.Owing to the untoward reaction of tablet is too big, by market, current milrinone is substantially applied to patient injecting class dosage form.Milrinone injection has at home and abroad been applied for many years, and its curative effect and safety have obtained abundant checking.Abroad have(MilrinoneLactateInjection) Milrinone lactate injection；Domestic preparation has Milrinone injection, milrinone sodium chloride injection, milrinone glucose injection and injection milrinone.
Milrinone is removed mainly through kidney, and the half-life is 30min～60min, plasma protein binding rate 90%, and the medicine of about 80% is with original shape from urine ejection, and the half-life of severe heart failure or impaired renal function patient can extend.Clinical trial shows, along with the prolongation of drug delivery regimen, the milrinone content in tissue is gradually saturated, and effective half-life also correspondingly extends.Reach peak during the effect of single intravenous injection milrinone 5min upon administration, have after administration 30min and weaken, substantially close to level before medication after 120min.
Give Mouse oral milrinone 24 months with the dosage (being about 50 times of the oral therapeutic dose of body weight 50kg patient) of 40mg/kg/day, do not find carcinogenesis.Oral Administration in Rats is given 24 months with the dosage (being about 6 times of the oral therapeutic dose of people) of 5mg/kg/day, or give male rat oral 18 months with the dosage (being about 30 times of oral medication dosage) of 25mg/kg/day, oral 20 months of female rats, does not all find carcinogenesis.Depositing in case in metabolic activation system, Chinese Hamster Ovary chromosome aberration analysis is positive.In Salmonella reversion test, mouse lymphoma assay, micronucleus test and rat body, bone marrow analysis metaphase of cell division shows that milrinone is without mutagenic action.The reproductive system research of rat is shown, with the oral dose milrinone of 32mg/kg/day, on male and female fertility without impact.
Give pregnant Mus and the milrinone of oral 40mg/kg/day and the 12mg/kg/day of pregnant rabbit in period of organogenesis respectively, do not find teratogenesis.Milrinone to pregnant rats or pregnant rabbit intravenous injection 3mg/kg/day respectively (being about clinical recommend maximal dose 2.5 times) and 12mg/kg/day, although the latter's absorbance when vein is to 8mg/kg/day and 12mg/kg/day increases, but without teratogenesis.
Oral and vein gives rat and the milrinone of Canis familiaris L. toxic dose, causes that muscular degeneration of heart/fibrosis and endocardium are hemorrhage, major effect left ventricular papillary muscle.Canis familiaris L. is only occurred in the coronary injury that periarterial edema and inflammation are feature.The change that cardiac muscle/endocardial change causes to β-adrenergic receptor agonist such as isoproterenol is similar, and Blood vessel pattern is similar to the change that minoxidil and hydralazine cause.Within the scope of the recommended dose of clinical treatment congestive heart failure (1.13mg/kg/day), do not find that animal has obvious adverse reaction.
Milrinone injection prescription comprises principal agent milrinone, and adjuvant lactic acid is cosolvent and pH value regulator, and sodium chloride is osmotic pressure regulator.Milrinone listing specification is 5ml: 5mg, according to quantity, it is determined that the specification of this product is 5ml: 5mg.
Chinese invention patent application 201210447673.2 discloses the synthetic method of a kind of milrinone; with 4-picoline for raw material and acetic anhydride generation acetylization reaction; acetylate is direct and triethyl orthoformate generation condensation without purification, and condensation substance occurs ring-closure reaction to obtain milrinone with Cyanoacetyl-Cyacetazid again when dehydrated alcohol.
The preparation method that Chinese invention patent application 201310697502.X discloses a kind of milrinone, in the ethanol solution of ethoxy methylene malononitrile, the ethanol solution of dropping 1-(4-pyridine radicals)-2-acetone, under 20 DEG C～60 DEG C conditions, insulation 1～3h, it is warming up to 75 DEG C～85 DEG C again, after reacting completely, reactant liquor is cooled to 0 DEG C～50 DEG C, solid-liquid separation, collects solid, to obtain final product, wherein, the mass ratio of ethoxy methylene malononitrile: 1-(4-pyridine radicals)-2-acetone is 1.5～3: 1.5～2.5.
The preparation method that Chinese invention patent application 201410216735.8 discloses a kind of high-purity milrinone, it is by 1-ethyoxyl-2-(4-pyridine radicals)-ethenyl methyl ketone, Malonamide nitrile. and alkali-soluble are in unitary alcohol-water system, 15～18h is reacted in-5 DEG C～10 DEG C, 1.5 times of original volume it are diluted with water to after completion of the reaction in reactant liquor, it is subsequently added activated carbon, 15-25min is stirred under room temperature, filter, filtrate adjusts pH to 7 with hydrochloric acid solution, filter, washing filter cake is colourless to filtrate, filter cake 50vt% alcohol reflux dissolves, filter, namely filtrate obtain white solid milrinone in-5～10 DEG C of stirring and crystallizing.
Summary of the invention
The preparation method that it is an object of the present invention to provide a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN, to improve yield.
Further object is that the preparation method that a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN is provided, improve the purity of product.
The preparation method that it is yet a further object of the present invention to provide a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN, to improve the crystal formation of compound.
Another purpose of the present invention is in that the preparation method providing a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN so that the color of gained compound is improved.
The preparation method of a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN provided by the invention, its course of reaction such as formula II, comprise the steps:
First n-BuLi (relative 4-picoline 1.05 equivalent～1.2 equivalent) and 4-picoline are reacted generation picolyl lithium；
Then, picolyl lithium is reacted prepared 1-(4-pyridine radicals)-acetone with propyl acetate (relative 4-picoline 1.3 equivalent～2.0 equivalent)；
Then, 1mol1-(4-pyridine radicals)-acetone, 1.3mol～2.0mol tripropyl orthoformate, 15mol～25mol acetic acid and 20mol～35mol acetic anhydride obtain 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone；
Afterwards, with Sodium ethylate (relative 1-(4-pyridine radicals)-acetone), 2 equivalent～4 equivalents) as basifier, 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone and Malonamide nitrile. (relative 1-(4-pyridine radicals)-acetone) 1.2 equivalent～1.5 equivalents) it is obtained by reacting 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN.
The preparation method of another kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN provided by the invention, comprises the steps:
Step one, the synthesis of 1-(4-pyridine radicals)-acetone
Under argon shield, joining in reactor by diisopropylamine and oxolane, be cooled to less than 20 DEG C, start to be slowly added dropwise the hexane solution of 2mol/L～4mol/L n-BuLi, in dropping process, temperature is less than 20 DEG C；Stir 20 minutes after being cooled to 0 DEG C.Be slowly added dropwise again 4-picoline and oxolane mixed solution (as: 4-picoline and oxolane are 1: 1.5～3 by volume), in dropping process, temperature is less than 10 DEG C；Drip and finish, add HMPA (relative 4-picoline 0.05～0.1 equivalent), be cooled to 0 DEG C after adding and stir 1.5 hours；Dripping propyl acetate (relative 4-picoline 1.3～2.0 equivalent) again, in dropping process, temperature is less than 10 DEG C；Drip and finish, rise to and reaction 2.5 hour is stirred at room temperature；Reactant liquor ice bath is cooled to about 0 DEG C, starts to drip concentrated hydrochloric acid, and in dropping process, temperature is less than 10 DEG C；Dripping and finish, the solvent in reactant liquor is removed in 40 DEG C of decompressions, adds water and is dissolved by solid, and with dichloromethane extraction, anhydrous magnesium sulfate dries organic layer, concentration, obtains a light brown product liquid then rectification, collects the fraction of 115 DEG C～125 DEG C；
Step 2, the synthesis of 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone
1mol1-(4-pyridine radicals)-acetone, 1.3mol～2.0mol tripropyl orthoformate, 15mol～25mol acetic acid and 20mol～35mol acetic anhydride add in reaction vessel, seal room temperature (25 DEG C) and stir 20 hours.Low boiling point solvent (such as propyl acetate and acetic acid etc.) is removed in decompression, adds absolute methanol, continues to be decompressed to dry, obtains 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone.
Step 3, the synthesis of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN
By Sodium ethylate (relative 1-(4-pyridine radicals)-acetone) 2 equivalent～4 equivalents) join equipped with in the reaction vessel of ethanol, Malonamide nitrile. (relative 1-(4-pyridine radicals)-acetone) 1.2 equivalent～1.5 equivalents are added) after dissolving, until its molten clear after, again 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone is added, heating is to refluxing and keeping 90 minutes, it is cooled to 0 DEG C～5 DEG C after being cooled to room temperature, has solid to precipitate out；Sucking filtration, filter cake is soluble in water, add activated carbon, removing activated carbon after stirring 15 minutes, filtrate, with second acid for adjusting pH value to 6.5～7.0, precipitates out solid and washes, again with after a small amount of ethanol rinse and get final product, can also continue to use 80 DEG C of vacuum dryings to obtain faint yellow or yellow powder；
1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN that above-mentioned various method prepares, then with the aqueous solution of dimethylformamide (dimethylformamide and water by volume 8～15 mix) recrystallization.Its concrete grammar is as follows:
By 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines)-5-formonitrile HCN crude product inserts in container, add the dimethylformamide of 10 times amount volumes, after heating for dissolving, add the boiling water of 10～15 times amount volumes under agitation, be slowly stirred after being down to room temperature and be cooled to 0 DEG C～5 DEG C again, have crystal to precipitate out；First wash crystal with water, more namely obtain highly finished product with after a small amount of ethanol rinse, can also continue to use 80 DEG C of vacuum dryings to obtain off-white color product.
The beneficial effect that technical solution of the present invention realizes:
Milrinone preparation method provided by the invention, preparation method stably obtains high-purity milrinone (impurity does not detect, and purity is more than 99.9%), improves color and the crystal formation of product.
Various compositions provided by the invention, is specifically designed for the skin that children's is tender and lovely, heat-clearing and toxic substances removing, and dampness removing is antipruritic, gentle non-stimulated, and not easily allergy has no drug resistance, it is easy to accepted by infant and the head of a family.
Various compositions provided by the invention; natural plant material is adopted to treat infantile eczema as medicine portion evident in efficacy; without stimulation component; being conducive to the skin that protection infant is tender and lovely, safety is gentle, has no side effect; clear curative effect; easy to use, the prices of raw materials are cheap, are suitable to large-scale promotion clinically.
Detailed description of the invention
Technical scheme described in detail below.The embodiment of the present invention is only in order to illustrate technical scheme and unrestricted, although the present invention being described in detail with reference to preferred embodiment, it will be understood by those within the art that, the technical scheme of invention can be modified or equivalent replacement, without deviating from the spirit and scope of technical solution of the present invention, it all should be encompassed in scope of the presently claimed invention.
Embodiment 1
(1) synthesis of 1-(4-pyridine radicals)-acetone
Under argon shield, being joined by diisopropylamine 805mL and oxolane 4000mL in the reactor of 20L, be cooled to less than 20 DEG C, start to be slowly added dropwise the hexane solution 2500mL of 2.5M n-BuLi, in dropping process, temperature is less than 20 DEG C；0 DEG C of stirring 20min it is cooled to after adding.Being slowly added dropwise the mixed solution of 4-picoline 556mL and oxolane 1000mL again, in dropping process, temperature is less than 10 DEG C；Drip and finish, add HMPA 70.5mL, after adding, be cooled to 0 DEG C of stirring 1.5h；Dripping propyl acetate 975.3mL again, in dropping process, temperature is less than 10 DEG C；Drip and finish, be raised to and reaction 2.5h is stirred at room temperature；Reactant liquor ice bath is cooled to about 0 DEG C, starts to drip concentrated hydrochloric acid 1050mL, and in dropping process, temperature is less than 10 DEG C；Drip and finish, 40 DEG C of decompressions steam the solvent in reactant liquor, adding water to be dissolved by solid, extract with dichloromethane (3500mL × 3), anhydrous magnesium sulfate dries organic layer, concentration, obtain light brown product liquid 1-(4-pyridine radicals)-acetone then rectification, collect the fraction 329g of 115～125 DEG C, yield 42.7%, purity: 97.09%.
(2) synthesis of 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone
Successively 1-(4-pyridine radicals)-acetone 324g, tripropyl orthoformate 190.3ml, acetic acid 600ml and acetic anhydride 616ml are added sequentially in the flask of 2L, seal room temperature (25 DEG C) stirring 20h.Decompression boils off low boiling point solvent, adds 300ml absolute methanol, continues to remove under reduced pressure to doing and obtain 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone, at once directly as lower step raw material.
(3) synthesis of milrinone
Sodium ethylate 490g is joined equipped with in the 10L reaction bulb of 6480ml ethanol, after micro-heated and stirred is dissolved, adds the Malonamide nitrile. of 263g, until its molten clear after, then intermediate II is added, heating is to refluxing and keeping 90min.It is cooled to (0～5 DEG C) after being cooled to room temperature, has solid to precipitate out.Sucking filtration, filter cake is soluble in water, add activated carbon 40g, after stirring 15min, sucking filtration removes activated carbon, and filtrate with second acid for adjusting pH value to 6.5～7.0, precipitates out solid, and sucking filtration is washed, then with a small amount of ethanol rinse filter cake.80 DEG C of vacuum dryings obtain yellow powder 235g, yield: 46.4%.
(4) milrinone is refining
Milrinone crude product 235g is joined in 5L flask, add the dimethylformamide 2350ml of 10 times amount volumes, after heating for dissolving, add the boiling water 2350ml of 10 times amount volumes under agitation, it is slowly stirred after being down to room temperature and is cooled to (0 DEG C～5 DEG C) again, have crystal to precipitate out.Sucking filtration is washed, then with a small amount of ethanol rinse filter cake.80 DEG C of vacuum dryings obtain off-white color pressed powder 191g, and crystal formation is good, and impurity does not detect, yield: 81.3%.
(5) chemical constitution confirmation
Milrinone infrared absorption spectroscopy (IR) data obtained by the present embodiment are as shown in table 1 below, and hydrogen nuclear magnetic resonance modal data is as shown in table 2, and mass spectrum (ESI-MS) is as shown in table 3:
Table 1
The infrared absorption spectroscopy data parsing obtained is as follows:
[1]3472.10cm–1, 3414.82cm–1: the stretching vibration of N-H；1661.95cm–1:-C=O stretching vibration；1575.35cm–1: the bending vibration of amide N-H；1175.15cm–1: the stretching vibration of amide C-N；Prove that molecular structure has amide group.
[2]2929.61cm–1, 2863.75cm–1: the stretching vibration of methyl；1385.76cm–1: the symmetric curvature vibration of methyl, it was demonstrated that have-CH in molecular structure3。
[3]2221.65cm–1: the stretching vibration of C ≡ N, it was demonstrated that have C ≡ N in molecular structure.
[4]3023.37cm–1: the stretching vibration peak of=C-H.
[5]1595.52cm–1, 1489.29cm–1: aromatic ring C=C, C=N skeleton stretching vibration.
[6]832.21cm–1: three replace the hydrocarbon out-of-plane bending vibration peak of double bond.
Characteristic infrared absorption and milrinone structure match.
Table 2
Referring to formula III, hydrogen nuclear magnetic resonance spectrum data parsing is as follows:
Milrinone1H-NMR(DMSO-d6) stave is bright, removes outside solvent peak and impurity peaks, has 5 groups of peaks, its integration ratio (by low field to High-Field) is 1: 2: 1: 2: 3, has 9 protons.
Add D2After O, owing to the active H of aromatic secondary amine is exchanged by heavy hydrogen, N-H proton peak disappears, it was demonstrated that milrinone1H-NMR(DMSO-d6) δ 12.7843ppm is secondary amine Hydrogen Proton signal in spectrum.
The ownership of this product Hydrogen Proton combines chemical displacement value, various two-dimensional spectrums etc., and its result is as follows:
(1) δ 8.5890-8.6011ppm, double doublet, 2H, on hsqc spectrum and δ 149.702ppm (C-2 ', 6 ') directly related, in HMBC spectrum with δ 124.025ppm (C-3 ', 5 '), δ 143.683ppm (C-4 ') and δ 149.702ppm (C-2 ', 6 ') 5 carbon atoms are correlated with, and can be attributed to H-2 ', and 6 '.
(2) δ 8.1295ppm, unimodal, 1H, on hsqc spectrum, itself and δ 149.480ppm (C-4) are directly related, in HMBC spectrum relevant with δ 100.460ppm (C-5), δ 116.223ppm (itrile group C), 5 carbon atoms such as δ 143.683ppm (C-4 '), δ 151.477ppm (C-2) and δ 159.988ppm (C-6), H-4 can be attributed to.
(3) δ 7.3958-7.4080ppm, double doublet, 2H, on hsqc spectrum and δ 124.025ppm (C-3 ', 5 ') directly related, in HMBC spectrum with δ 115.761ppm (C-3), δ 124.025ppm (C-3 ', 5 '), δ 149.480ppm (C-4) and δ 149.702ppm (C-2 ', 6 ') etc. 6 carbon atoms are correlated with, and can be attributed to H-3 ', and 5 '.
(4) δ 2.3101ppm, unimodal, 3H, on hsqc spectrum and δ 18.240ppm (methyl C) directly related, in HMBC spectrum and δ 18.240ppm (methyl C), δ 100.460ppm (C-5), δ 115.761ppm (C-3), δ 116.223ppm (itrile group C), δ 149.480ppm (C-4), δ 149.702ppm (C-2 ', 6 ') relevant with 8 carbon atoms such as δ 151.477ppm (C-2), methyl H can be attributed to.
So far, all hydrogen atoms have all had rational ownership.
Table 3
From mass spectrometric data it can be seen that [M-H] that the peak of mass-to-charge ratio 210.0 is milrinone-Peak, it is known that the molecular weight of milrinone is 211.0, consistent with the molecular weight of milrinone.Mass-to-charge ratio 143.4 is [M-H-C3HON]-Peak, meets the architectural feature of milrinone.
Claims (10)
1. the preparation method of dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN, it is characterised in that comprise the steps:
First the n-BuLi of 4-picoline with relative described 4-picoline 1.05～1.2 equivalent is reacted generation picolyl lithium；
Then, picolyl lithium and propyl acetate are reacted prepared 1-(4-pyridine radicals)-acetone；
Then, 1-(4-pyridine radicals)-acetone is obtained 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone with tripropyl orthoformate and acetic anhydride；
Afterwards, using Sodium ethylate as basifier, 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone and Malonamide nitrile. are obtained by reacting 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN.
2. the preparation method of a kind of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN according to claim 1, it is characterised in that
Described n-BuLi relative 4-picoline 1.05 equivalent～1.2 equivalent；
Described propyl acetate relative 4-picoline 1.3 equivalent～2.0 equivalent；
Described 1-(4-pyridine radicals)-acetone is 1mol, and described tripropyl orthoformate is 1.3mol～2.0mol, described acetic acid is 15mol～25mol and described acetic anhydride is 20mol～35mol；
The relative 1-of described Sodium ethylate (4-pyridine radicals)-acetone) 2 equivalent～4 equivalents, described 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone 1-relative to Malonamide nitrile. (4-pyridine radicals)-acetone) 1.2 equivalent～1.5 equivalents.
3. the preparation method of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN according to claim 1, it is characterised in that described 1-(4-pyridine radicals)-acetone prepares as follows:
Under argon shield, joining in reactor by diisopropylamine and oxolane, be cooled to less than 20 DEG C, start to be slowly added dropwise the hexane solution of 2mol/L-4mol/L n-BuLi, in dropping process, temperature is less than 20 DEG C；Stir 20 minutes after being cooled to 0 DEG C.Being slowly added dropwise the mixed solution of 4-picoline and oxolane again, in dropping process, temperature is less than 10 DEG C；Drip and finish, add the HMPA of relatively described 4-picoline 0.05～0.1 equivalent, be cooled to 0 DEG C after adding and stir 1.5 hours；Dripping the propyl acetate of relatively described 4-picoline 1.3～2.0 equivalent again, in dropping process, temperature is less than 10 DEG C；Drip and finish, rise to and reaction 2.5 hour is stirred at room temperature；Reactant liquor ice bath is cooled to about 0 DEG C, starts to drip concentrated hydrochloric acid, and in dropping process, temperature is less than 10 DEG C；Dripping and finish, the solvent in reactant liquor is removed in 40 DEG C of decompressions, adds water and is dissolved by solid, with dichloromethane extraction, anhydrous magnesium sulfate dries organic layer, concentration, obtains a light brown product liquid, rectification again, collects the fraction of 115 DEG C～125 DEG C, obtains 1-(4-pyridine radicals)-acetone.
4. according to claim 11,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines) preparation method of-5-formonitrile HCN, it is characterised in that described 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone prepares as follows:
1mol1-(4-pyridine radicals)-acetone, 1.3mol～2.0mol tripropyl orthoformate, 15mol～25mol acetic acid and 20mol～35mol acetic anhydride are added in reaction vessel, seal room temperature (25 DEG C) and stir 20 hours.Low boiling point solvent is removed in decompression, adds absolute methanol, continues to be decompressed to dry, obtains 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone.
5. according to claim 11, 6-dihydro-2-methyl-6-oxo-(3, 4 '-two pyridines) preparation method of-5-formonitrile HCN, it is characterized in that relatively described 1-(4-pyridine radicals)-acetone) Sodium ethylate of 2～4 equivalents joins equipped with in the reaction vessel of ethanol, relatively described 1-(4-pyridine radicals)-acetone is added after dissolving) Malonamide nitrile. of 1.2～1.5 equivalents, until its molten clear after, again described 1-propoxyl group-2-(4-pyridine radicals)-ethenyl methyl ketone is added, heating is to refluxing and keeping 90 minutes, 0 DEG C～5 DEG C it are cooled to after being cooled to room temperature, solid is had to precipitate out；Sucking filtration, filter cake is soluble in water, add activated carbon, removing activated carbon after stirring 15 minutes, filtrate, with second acid for adjusting pH value to 6.5～7.0, precipitates out solid and washes, again with namely obtaining 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN after a small amount of ethanol rinse.
6. according to claim 11,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines) preparation method of-5-formonitrile HCN, it is characterized in that described 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines)-5-formonitrile HCN inserts in container, then obtains highly finished product with the aqueous solution recrystallization of dimethylformamide.
7. the preparation method of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN according to claim 5, it is characterised in that described dimethylformamide and water 8～15 are obtained by mixing by volume.
8. according to claim 11,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines) preparation method of-5-formonitrile HCN, it is characterised in that by 1,6-described dihydro-2-methyl-6-oxo-(3,4 '-two pyridines)-5-formonitrile HCN inserts in container, add the dimethylformamide of 10 times amount volumes, after heating for dissolving, add the boiling water of 10～15 times amount volumes under agitation, it is slowly stirred after being down to room temperature and is cooled to 0 DEG C～5 DEG C again, have crystal to precipitate out；First wash crystal with water, more namely obtain highly finished product with after a small amount of ethanol rinse.
9. according to claim 11,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines) preparation method of-5-formonitrile HCN, it is characterised in that it is 1: 1.5～3 form mixed solution by volume by described 4-picoline and described oxolane.
10. the preparation method of 1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-formonitrile HCN according to claim 1, it is characterised in that by one or more selected from propyl acetate and acetic acid of described low boiling point solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410804717.1A CN105777626A (en) | 2014-12-18 | 2014-12-18 | Preparation method of milrinone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410804717.1A CN105777626A (en) | 2014-12-18 | 2014-12-18 | Preparation method of milrinone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105777626A true CN105777626A (en) | 2016-07-20 |
Family
ID=56385486
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410804717.1A Pending CN105777626A (en) | 2014-12-18 | 2014-12-18 | Preparation method of milrinone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105777626A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111484450A (en) * | 2019-01-28 | 2020-08-04 | 上海隆盛化工有限公司 | Preparation method of medical intermediate milrinone |
| WO2021184609A1 (en) * | 2020-03-20 | 2021-09-23 | 鲁南制药集团股份有限公司 | Method for preparing milrinone intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143844A (en) * | 2007-01-16 | 2008-03-19 | 张刘森 | Method of preparing milrinone lactate |
| CN103288725A (en) * | 2013-05-27 | 2013-09-11 | 南京健友生化制药股份有限公司 | Method for synthesising milrinone |
-
2014
- 2014-12-18 CN CN201410804717.1A patent/CN105777626A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143844A (en) * | 2007-01-16 | 2008-03-19 | 张刘森 | Method of preparing milrinone lactate |
| CN103288725A (en) * | 2013-05-27 | 2013-09-11 | 南京健友生化制药股份有限公司 | Method for synthesising milrinone |
Non-Patent Citations (2)
| Title |
|---|
| DAVID W. ROBERTSON ET AL.,: "Bipyridine Cardiotonics: The Three-Dimensional Structures of Amrinone and Milrinone", 《J. MED. CHEM.》 * |
| 徐芳等: "米力农的合成", 《中国药科大学学报》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111484450A (en) * | 2019-01-28 | 2020-08-04 | 上海隆盛化工有限公司 | Preparation method of medical intermediate milrinone |
| WO2021184609A1 (en) * | 2020-03-20 | 2021-09-23 | 鲁南制药集团股份有限公司 | Method for preparing milrinone intermediate |
| CN113493406A (en) * | 2020-03-20 | 2021-10-12 | 鲁南制药集团股份有限公司 | Preparation method of milrinone intermediate |
| CN113493406B (en) * | 2020-03-20 | 2024-06-14 | 鲁南制药集团股份有限公司 | Preparation method of milrinone intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102329325B (en) | Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors | |
| CN104024228A (en) | Imidazolidinedione compounds and their uses | |
| CN105968093A (en) | Preparation method for trelagliptin succinate | |
| CN106632080A (en) | Flucytosine manufacturing process | |
| CN107337675A (en) | A kind of improved method for preparing ticagrelor | |
| CN109912676A (en) | A kind of preparation method of 3 β-ursodesoxycholic acid | |
| CN103087017B (en) | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product | |
| CN105777626A (en) | Preparation method of milrinone | |
| CN102503829B (en) | Preparation methods for sitagliptin intermediates | |
| CN104945436B (en) | Minodronic acid preparing method | |
| CN102285909B (en) | Preparation method of benzpyrole-2-ketone compound | |
| CN104098505A (en) | Preparation method for saxagliptin | |
| CN103804453B (en) | The method preparing ursodesoxycholic acid for raw material with Fel Sus domestica | |
| CN102532024A (en) | Sinomenine derivative | |
| CN101921225B (en) | Pirfenidone compound, preparation method and application thereof | |
| CN102174012B (en) | Preparation method of nimodipine | |
| CN108218789A (en) | 13 deuterated methyl Telmisartan of carbon and its preparation method and application | |
| CN104098487A (en) | Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine | |
| CN102911123A (en) | Preparation method of 2-chloro trifluoromethyl pyrimidine compound | |
| CN104761508A (en) | High yield preparation method of ligustrazine | |
| CN102532138A (en) | Synthesis method of anticoccidial drug adprin | |
| CN102372749A (en) | Method for preparing D-glucosamine hydrochloride by utilizing sleeve-fish sheathes | |
| CN108383831B (en) | Preparation method of bepotastine important intermediate | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| CN101492413A (en) | Fine purification method for carprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160720 |
|
| WD01 | Invention patent application deemed withdrawn after publication |