CN103965101A - Preparation method of high-purity milrinone - Google Patents
Preparation method of high-purity milrinone Download PDFInfo
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- CN103965101A CN103965101A CN201410216735.8A CN201410216735A CN103965101A CN 103965101 A CN103965101 A CN 103965101A CN 201410216735 A CN201410216735 A CN 201410216735A CN 103965101 A CN103965101 A CN 103965101A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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Abstract
The invention discloses a preparation method of high-purity milrinone. The method comprises the steps of dissolving 1-ethoxyl-2-(4-pyridyl) methyl vinyl ketone, cyanoacetamide and alkali into a monohydric alcohol-water system, reacting for 15-18 hours at -5 DEG C to 10 DEG C, adding water into reaction liquid and diluting to 1.5 times of the original volume after completing reaction, then adding activated carbon, stirring for 15-25 minutes at room temperature, filtering, regulating the pH value of filtrate to be 7 by using a hydrochloric acid solution, filtering, washing a filter cake by using water until the filtrate is colorless, refluxing and dissolving the filter cake by using 50vt% ethanol, filtering, and stirring and crystallizing the filtrate at -5 DEG C to 10 DEG C to obtain white solid milrinone with the purity of more than 99.9%. The method disclosed by the invention is simple and fast in process, high in yield and pure in product, and is more suitable for industrial production.
Description
One, technical field
The present invention relates to the preparation method of known medicine, specifically a kind of preparation method of high purity milrinone, belongs to medical technical field.
Two, background technology
Milrinone (Milirinone, formula (I)), chemistry 1,6-dihydro-2-methyl-6-oxygen by name-(the two pyridines of 3,4'-)-5-formonitrile HCN, is developed successfully by U.S. Sterling company the earliest, within 1987, goes on the market first in the U.S..Milrinone is heart phosphodiesterase inhibitor, is applicable to the short that routine maintains the severe congestive heart failure patient who fails to respond to any medical treatment, and curative effect is stronger than amrinone (amirinone), and untoward reaction is few.At aspects such as treatment congestive heart failure (CHF) and periphery expansion blood vessels, brought into play more and more important effect.
The synthetic route of milrinone is more, typical synthetic method is: 1-(4-pyridyl)-2-acetone (formula (II)) makes 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone (formula (III)) with triethyl orthoformate condensation, and formula (III) is reacted with Malonamide nitrile or propane dinitrile and made milrinone (formula (I)).This method is raw materials used cheap and easy to get, and operation is simple, is current more general method, and synthetic route is as follows:
The synthesis technique of formula (II) is simple, and concrete preparation method is existing detailed report in US Patent No. 4681944.
Formula (III) is liquid, easy oxidation discoloration, and US4413127 adopts its enriched material directly and propane dinitrile refluxes in ethanol, and cyclization makes milrinone, but the milrinone band look making is rubescent, refining can not removing; CN1253439C adopt its enriched material directly and Malonamide nitrile in cyclization below 0 ℃, make milrinone finished color and purity and be slightly improved, but still micro-redness.Though it is the milrinone of 99.98% (HPLC detection) that CN201110448840.0 adopts DMF/ crystal system to obtain purity, but this method decolorizing effect is limited, can not once remove and adopt the synthetic contained a small amount of pigment of milrinone crude product of CN1253439C method, need to repeatedly do over again, the residual difficulty of finished product DMF is removed, total recovery is low, and cost is high; Dai Xuyong etc. (Chinese Pharmaceutical Journal, 2007,9 (42), P1436-1437.) adopt methyl alcohol/sodium methylate to reflux refining, good decolorizing effect, increases obviously purity not high (99.7%) but alkali destroys impurity.
Bibliographical information (Milrila Injection10mg, pharmaceuticals イ Application タ ビ ュ ー フ ォ ー system, 2009) injection milrinone bulk drug is that white is to micro-yellow crystal powder.The milrinone color that prior art is produced is darker, need to repeatedly refine decolouring and just can reach the requirement of injection bulk drug, and cost is high; Force decolouring can increase impurity again, reduce purity.
Three, summary of the invention
The present invention aims to provide a kind of preparation method of high purity milrinone, make it meet the requirement of injection milrinone bulk drug, and method is simple to improve the purity of milrinone, is easy to produce.
Contriver is carrying out in screening process the synthetic technological condition of milrinone, find that 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone (formula II) and Malonamide nitrile carry out cyclization in the alkaline alcohol aqueous solution, only have reaction when reaction system alcohol water viscosity is greater than 2mPaS to be just easy to carry out, in alcohol-water, Methanol-Ethanol-Water, isopropanol-water, methyl alcohol-isopropanol-water, n-propyl alcohol-water and methyl alcohol-n-propyl alcohol-aqueous systems, easily occur, and do not react in methanol-water system.
Further research finds that in alcohol-water system, alcohol content is when 30～80vt% (volumn concentration, lower same), and synthetic milrinone color, purity all meet the requirement of injection milrinone bulk drug.Alcohol too high levels (being greater than 80vt%), product colour is intensification trend with the increase of alcohol content, though reaction system as used in CN1253439C contains ethanol, water, ethanol content is greater than 85vt%, product tape look inevitable; Alcohol content too low (being less than 50vt%), product colour is constant, and product yield reduces and is reduction trend with alcohol content.
In addition, contriver finds that by test the contained colored foreign of milrinone is after activated carbon decolorizing, washing, 50vt% alcohol crystal, foreign pigment can be removed efficiently, and therefore, the inventive method comprises uses activated carbon decolorizing, washing, 50vt% alcohol crystal process successively.
The preparation method of high purity milrinone of the present invention is as follows:
1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone (formula III), Malonamide nitrile and alkali are dissolved in monobasic alcohol-water system, in-5～10 ℃ of reaction 15～18h, after completion of the reaction to being diluted with water to 1.5 times of original volume in reaction solution, add subsequently gac, under room temperature, stir 15-25min, filter, filtrate is adjusted pH to 7 with hydrochloric acid soln, filter, washing filter cake is colourless to filtrate, filter cake dissolves with 50vt% alcohol reflux, filters, and filtrate obtain white solid milrinone (formula I) in-5～10 ℃ of stirring and crystallizing.
Reaction equation is as follows:
Described monobasic alcohol-water system is the mixed solvent system that monohydroxy-alcohol and water form; In described monobasic alcohol-water system, the volumn concentration of monohydroxy-alcohol is 50～80vt%, preferred 60～80vt%, further preferred 70～75vt%.
Described monohydroxy-alcohol is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol; Described monohydroxy-alcohol preferred alcohol/methyl alcohol, Virahol/methyl alcohol, ethanol or Virahol; Wherein ethanol/methyl alcohol refers to ethanol and methanol mixed alcohol, the volumn concentration >=50vt% of ethanol; Virahol/methyl alcohol refers to Virahol and methanol mixed alcohol, the volumn concentration >=40vt% of Virahol.
The mol ratio of described 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone and Malonamide nitrile is 1:1.1～1.5; The mol ratio of 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone and sodium hydroxide is 1:3～5.
The mass volume ratio of described filter cake and 50vt% ethanol is 1g:20～25mL.
The addition of described gac is 0.25 times of 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone quality.
The milrinone that the present invention makes is white crystals.
The milrinone that the present invention makes adopts impurity counter point to detect, and known impurities A, impurity B, impurity C, impurity D and impurity E all do not detect, and purity is greater than 99.9% (HPLC method), the results are shown in Table 1, and color atlas is shown in Fig. 1～3.Analytical procedure is as follows:
Chromatographic column: Ecosil C8 (250mm * 4.6mm, 5.0 μ m)
Moving phase: dipotassium hydrogen phosphate solution (get dipotassium hydrogen phosphate 2.7g, add after water 800ml dissolving, add triethylamine 2.4ml, with phosphorus acid for adjusting pH value to 7.5)-acetonitrile (85:15)
Detect wavelength: 220nm
Sample concentration: 1mg/ml
Flow velocity: 1ml/min
Sample size: 20 μ l
Table 1 milrinone related substance detected result
| Title | Relative retention time | Before 50vt% alcohol crystal | After 50vt% alcohol crystal |
| Impurity G | 0.27 | 0.009％ | Do not detect |
| Impurity E | 0.30 | 0.009％ | Do not detect |
| Impurity D | 0.43 | Do not detect | Do not detect |
| Impurity A | 0.64 | 0.059％ | 0.022％ |
| Impurity H | 0.73 | Do not detect | Do not detect |
| Milrinone | 1.0 | 99.895％ | 99.978％ |
| Impurity B | 1.19 | Do not detect | Do not detect |
| Impurity F | 1.46 | Do not detect | Do not detect |
| Impurity C | 2.27 | Do not detect | Do not detect |
| Other are maximum single assorted | / | 0.021％ | Do not detect |
| Total assorted | / | 0.105％ | 0.022％ |
The milrinone that the present invention makes adopts vapor-phase chromatography to detect residual solvent levels, and result solvent residual amount all meets existing pharmacopeia regulation.
Compared with prior art, the invention has the beneficial effects as follows: change milrinone synthesis reaction solvent system, with monobasic alcohol-water system, replace existing ethanol, tetrahydrofuran (THF), sodium methylate-DMF, sodium methylate-methanol system, from source, control the generation of foreign pigment, simplified technological operation step; Decoloration process is incorporated in post-reaction treatment process, use successively activated carbon decolorizing, washing, 50% alcohol crystal, decolouring improves product purity simultaneously, has saved production cost, product colour meets the requirement of injection milrinone bulk drug, and product purity is greater than 99.9% (HPLC method); The dissolvent residual of avoiding using the high boiling solvents such as DMF the to bring problem that exceeds standard.
Four, accompanying drawing explanation
Fig. 1 is milrinone impurity location HPLC color atlas.
Fig. 2 is HPLC color atlas before milrinone 50vt% alcohol crystal.
Fig. 3 is HPLC color atlas after milrinone 50vt% alcohol crystal.
Five, embodiment
Below technical scheme of the present invention is described, so that those skilled in the art understand.
Embodiment 1:
Get 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone 200g (1.05mol), adding 80vt% ethanol 2L dissolves, drop into Malonamide nitrile 97g (1.15mol), stirring and dissolving, the 80vt% ethanolic soln 630ml (sodium hydrate content 126g) that drips sodium hydroxide, temperature control is below 0 ℃; After dripping off, in-5～0 ℃ of stirring reaction 16h, reaction solution adds water 1.3L, adds gac 50g, stirring at room 20min, filters, and filtrate is adjusted pH to 7 with hydrochloric acid soln, filter, washing filter cake is colourless to filtrate, obtains milrinone wet product 200g, add 50vt% ethanol 4L backflow and dissolve, filter filtrate-5～0 ℃ stirring and crystallizing 6h, filter, 60～70 ℃ of dry 6h, obtain white crystals milrinone 183g, yield 82.8%, purity 99.97% (HPLC method).
Embodiment 2:
Get 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone 2kg (10.5mol), adding 70vt% ethanol 22L dissolves, drop into Malonamide nitrile 1kg (11.9mol), stirring and dissolving, the 80% ethanolic soln 6.5L (sodium hydrate content 1.3kg) that drips sodium hydroxide, temperature control is below 0 ℃; After dripping off, in-5～0 ℃ of stirring 16h, reaction solution adds water 15L, adds gac 500g, stirring at room 20min, filters, and filtrate is adjusted pH to 7 with dilute hydrochloric acid, filter, washing filter cake is colourless to filtrate, obtains milrinone wet product 2.2kg, add 50vt% ethanol 45L backflow and dissolve, filter, crystallization 6h is stirred in filtrate-5～0 ℃, filter, 60～70 ℃ of dry 6h, obtain white crystals milrinone 1.86kg, yield 84.2%, purity 99.93% (HPLC method).
Embodiment 3:
Get 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone 2kg (10.5mol), adding 60vt% ethanol 22L dissolves, drop into Malonamide nitrile 1kg (11.9mol), stirring and dissolving, the 80% ethanolic soln 6.5L (sodium hydrate content 1.3kg) that drips sodium hydroxide, temperature control is below 0 ℃; After dripping off, in-5～0 ℃ of stirring 16h, reaction solution adds water 15L, adds gac 500g, stirring at room 20min, filters, and filtrate is adjusted pH to 7 with dilute hydrochloric acid, filter, washing filter cake is colourless to filtrate, obtains milrinone wet product 2.1kg, add 50vt% ethanol 42L backflow and dissolve, filter, crystallization 6h is stirred in filtrate-5～0 ℃, filter, 60～70 ℃ of dry 6h, obtain white crystals milrinone 1.79kg, yield 81.0%, purity 99.96% (HPLC method).
Embodiment 4:
Get 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone 200g (1.05mol), the ratio of 50:50:25 adds ethanol-methanol-water mixing solutions 2L to dissolve by volume, drop into Malonamide nitrile 97g (1.15mol), stirring and dissolving, the 80vt% ethanolic soln 630ml (sodium hydrate content 126g) that drips sodium hydroxide, temperature control is below 0 ℃; After dripping off, in-5～0 ℃ of stirring reaction 16h, reaction solution adds water 1.3L, adds gac 50g, stirring at room 20min, filters, and filtrate is adjusted pH to 7 with hydrochloric acid soln, filter, washing filter cake is colourless to filtrate, obtains milrinone wet product 192g, add 50vt% ethanol 3.9L backflow and dissolve, filter filtrate-5～0 ℃ stirring and crystallizing 6h, filter, 60～70 ℃ of dry 6h, obtain white crystals milrinone 178g, yield 80.6%, purity 99.91% (HPLC method).
Embodiment 5:
Get 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone 200g (1.05mol), the ratio of 40:60:25 adds Virahol-methanol-water mixing solutions 2L to dissolve by volume, drop into Malonamide nitrile 97g (1.15mol), stirring and dissolving, the 80vt% aqueous isopropanol 630ml (sodium hydrate content 126g) that drips sodium hydroxide, temperature control is below 0 ℃; After dripping off, in-5～0 ℃ of stirring reaction 16h, reaction solution adds water 1.3L, adds gac 50g, stirring at room 20min, filters, and filtrate is adjusted pH to 7 with hydrochloric acid soln, filter, washing filter cake is colourless to filtrate, obtains milrinone wet product 195g, add 50vt% ethanol 3.9L backflow and dissolve, filter filtrate-5～0 ℃ stirring and crystallizing 6h, filter, 60～70 ℃ of dry 6h, obtain white crystals milrinone 176g, yield 79.7%, purity 99.94% (HPLC method).
Embodiment 6:
Get 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone 200g (1.05mol), adding 75vt% Virahol 2L dissolves, drop into Malonamide nitrile 97g (1.15mol), stirring and dissolving, the 80vt% aqueous isopropanol 630ml (sodium hydrate content 126g) that drips sodium hydroxide, temperature control is below 0 ℃; After dripping off, in-5～0 ℃ of stirring reaction 16h, reaction solution adds water 1.3L, adds gac 50g, stirring at room 20min, filters, and filtrate is adjusted pH to 7 with hydrochloric acid soln, filter, washing filter cake is colourless to filtrate, obtains milrinone wet product 198g, add 50vt% ethanol 4L backflow and dissolve, filter filtrate-5～0 ℃ stirring and crystallizing 6h, filter, 60～70 ℃ of dry 6h, obtain white crystals milrinone 180g, yield 81.5%, purity 99.93% (HPLC method).
Claims (9)
1. a preparation method for high purity milrinone, is characterized in that:
1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone, Malonamide nitrile and alkali are dissolved in monobasic alcohol-water system, in-5～10 ℃ of reaction 15～18h, to being diluted with water to 1.5 times of original volume in reaction solution, add subsequently gac after completion of the reaction, under room temperature, stir 15-25min, filter, filtrate is adjusted pH to 7 with hydrochloric acid soln, filters, washing filter cake is colourless to filtrate, filter cake dissolves with 50vt% alcohol reflux, filters, and filtrate obtain white solid milrinone in-5～10 ℃ of stirring and crystallizing;
The mol ratio of described 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone and Malonamide nitrile is 1:1.1～1.5; The mol ratio of 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone and alkali is 1:3～5.
2. preparation method according to claim 1, is characterized in that:
Described monobasic alcohol-water system is the mixed solvent system that monohydroxy-alcohol and water form; In described monobasic alcohol-water system, the volumn concentration of monohydroxy-alcohol is 50～80vt%.
3. preparation method according to claim 2, is characterized in that:
In described monobasic alcohol-water system, the volumn concentration of monohydroxy-alcohol is 60～80vt%.
4. preparation method according to claim 2, is characterized in that:
In described monobasic alcohol-water system, the volumn concentration of monohydroxy-alcohol is 70～75vt%.
5. preparation method according to claim 2, is characterized in that:
Described monohydroxy-alcohol is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol.
6. preparation method according to claim 5, is characterized in that:
Described monohydroxy-alcohol is selected from ethanol/methyl alcohol, Virahol/methyl alcohol, ethanol or Virahol.
7. preparation method according to claim 1, is characterized in that:
Described alkali is sodium hydroxide.
8. preparation method according to claim 1, is characterized in that:
The mass volume ratio of described filter cake and 50vt% ethanol is 1g:20～25mL.
9. preparation method according to claim 1, is characterized in that:
The addition of gac is 0.25 times of 1-oxyethyl group-2-(4-pyridyl) ethenyl methyl ketone quality.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106243032A (en) * | 2016-07-20 | 2016-12-21 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of preparation method of milrinone |
| CN108440395A (en) * | 2018-04-04 | 2018-08-24 | 梯尔希（南京）药物研发有限公司 | A kind of preparation method of milrinone impurity |
| CN111484450A (en) * | 2019-01-28 | 2020-08-04 | 上海隆盛化工有限公司 | Preparation method of medical intermediate milrinone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106243032A (en) * | 2016-07-20 | 2016-12-21 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of preparation method of milrinone |
| CN108440395A (en) * | 2018-04-04 | 2018-08-24 | 梯尔希（南京）药物研发有限公司 | A kind of preparation method of milrinone impurity |
| CN111484450A (en) * | 2019-01-28 | 2020-08-04 | 上海隆盛化工有限公司 | Preparation method of medical intermediate milrinone |
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| CN103965101B (en) | 2016-07-06 |
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