CN113493410A - Preparation process of milrinone - Google Patents
Preparation process of milrinone Download PDFInfo
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- CN113493410A CN113493410A CN202010201253.0A CN202010201253A CN113493410A CN 113493410 A CN113493410 A CN 113493410A CN 202010201253 A CN202010201253 A CN 202010201253A CN 113493410 A CN113493410 A CN 113493410A
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- Prior art keywords
- milrinone
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- solution
- cyanoacetamide
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- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 229960003574 milrinone Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 30
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 93
- 239000000243 solution Substances 0.000 claims description 70
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
- 239000007787 solid Substances 0.000 claims description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 34
- -1 SM-2 Chemical compound 0.000 claims description 28
- 230000008569 process Effects 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 150000007529 inorganic bases Chemical class 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- ILRVKOYYFFNXDB-UHFFFAOYSA-N 1-pyridin-4-ylpropan-2-one Chemical compound CC(=O)CC1=CC=NC=C1 ILRVKOYYFFNXDB-UHFFFAOYSA-N 0.000 abstract description 14
- 238000010438 heat treatment Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 81
- 238000003756 stirring Methods 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000001035 drying Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007788 liquid Substances 0.000 description 17
- 229960000583 acetic acid Drugs 0.000 description 16
- 238000000926 separation method Methods 0.000 description 16
- 239000008213 purified water Substances 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 10
- 239000012346 acetyl chloride Substances 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 238000002386 leaching Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 206010019280 Heart failures Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960002105 amrinone Drugs 0.000 description 3
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- ZLVJIUUJDJDJQG-SNAWJCMRSA-N (e)-2-cyano-3-ethoxyprop-2-enamide Chemical compound CCO\C=C(/C#N)C(N)=O ZLVJIUUJDJDJQG-SNAWJCMRSA-N 0.000 description 2
- RDYIQPJUVJSNKC-UHFFFAOYSA-N 1-(1-acetylpyridin-4-ylidene)propan-2-one Chemical compound CC(=O)C=C1C=CN(C(C)=O)C=C1 RDYIQPJUVJSNKC-UHFFFAOYSA-N 0.000 description 2
- RWNXXQFJBALKAX-UHFFFAOYSA-N 1-(dipropoxymethoxy)propane Chemical compound CCCOC(OCCC)OCCC RWNXXQFJBALKAX-UHFFFAOYSA-N 0.000 description 2
- OEICGMPRFOJHKO-UHFFFAOYSA-N 2-(ethoxymethylidene)propanedinitrile Chemical compound CCOC=C(C#N)C#N OEICGMPRFOJHKO-UHFFFAOYSA-N 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229940124975 inotropic drug Drugs 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- FJLBFSROUSIWMA-UHFFFAOYSA-N metyrapone Chemical compound C=1C=CN=CC=1C(C)(C)C(=O)C1=CC=CN=C1 FJLBFSROUSIWMA-UHFFFAOYSA-N 0.000 description 1
- 229960004465 metyrapone Drugs 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of milrinone, belonging to the technical field of drug synthesis. The method takes 1- (4-pyridyl) -2-acetone as a raw material to react with alpha- (substituted methylene) cyanoacetamide by heating under an alkaline condition to obtain milrinone. The method for preparing milrinone has the advantages of simple and convenient operation, high safety and high yield, and is suitable for industrial large-scale production. The obtained milrinone finished product has the appearance and the purity reaching the standard.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of milrinone.
Background
Milrinone (Milrinone), also known as metyrapone, has the CAS number: 78415-72-2, is the common name of 1, 6-dihydro-2-methyl-6-oxo- [3,4' -bipyridine ] -5-carbonitrile, was first developed and developed by Sterling corporation in the United states, was first approved by the FDA in the United states in 1987, was officially marketed in the United states in 1992, was subsequently marketed in countries such as the United kingdom, France, Germany, the Netherlands, Belgium and Brazil, and was clinically used as a lactate salt, mainly for the treatment of refractory heart failure and heart failure patients who have undergone digitalis intoxication, and recent studies showed that Milrinone can also be used for low-cardiac-ejection syndrome after cardiac surgery extracorporeal circulation, relief of bypass vasospasm, improvement of heart function and anti-inflammatory response in heart orthotopic transplantation patients, improvement of visceral blood flow perfusion, and the like. The chemical structural formula is as follows:
the product is a syngeneic drug of Amrinone, is a positive inotropic drug of non-digitalis cardiac glycoside and non-catecholamine, can selectively inhibit phosphodiesterase III (PDE III) in cardiac muscle cells, change the transport of calcium ions inside and outside the cells, enhance myocardial contractility, and play more and more important roles in treating Congestive Heart Failure (CHF), dilating blood vessels and the like. The efficacy of the compound is 10-30 times stronger than that of amrinone, and adverse reactions such as thrombocytopenia and hypotension of the amrinone are avoided.
The currently reported synthesis process of milrinone mainly comprises the following steps:
one approach is to use a "straight line" synthetic route (e.g., US4469871A, US4413127A, EP0095152, US4313951A, j.med. chem.,1986,29,635-640, CN103288725B, CN104387320B, CN1253439C, CN106243032A, CN105777626A, CN104526975A, CN101143844A, etc.): the reaction can be realized through two paths, wherein the first path is to react with ethyl acetate under the condition of n-butyl lithium or phenyl lithium, but the reaction condition is harsh, the requirement on water is strict, exothermic reaction is easy to occur when meeting oxygen when meeting water, the reaction is easy to combust in air, once the reaction is heated and expanded, explosion is easy to cause, so the operation is difficult, the price is relatively expensive, and the risk of generating benzene with high toxicity is generated in the reaction process, so the method is not suitable for industrial production. The second route is to react with acetyl chloride at room temperature for 16h, although the reaction conditions are mild, the reaction time is too long. Meanwhile, saturated sodium carbonate is used for adjusting the pH value of the system in the post-treatment, and the consumption of a water phase with the reaction volume more than 10 times is found to cause difficult operation, 3 times of extraction and reduced pressure concentration are used in the whole post-treatment of the reaction, the post-treatment is more complicated, the reaction time of the second step is longer, and the production cost is increased.
Then reacting the 1- (4-pyridyl) -2-acetone with trialkyl orthoformate or N, N-dimethylformamide dimethyl acetal (DMF-DMA), reacting with alpha-cyanoacetamide or malononitrile in one pot to obtain a milrinone crude product, and recrystallizing to obtain an injection-grade fine milrinone. In the process, a Soxhlet extractor is adopted for extraction and recrystallization, and the operation is complicated; in the final cyclization step, the malononitrile used is more toxic than α -cyanoacetamide and is also more expensive than α -cyanoacetamide, so that the production process using malononitrile is less safe and the production cost is also higher.
Another approach is to use a "convergent" synthetic route (e.g., Heterocycles, Vol.23, NO.6,1985,1479-1482, CN103664773A, etc.): the method also uses 4-methylpyridine as a starting material to prepare 1- (4-pyridyl) -2-acetone, then uses malononitrile and triethyl orthoformate as raw materials to prepare alpha-ethoxymethylene malononitrile, finally reacts the 1- (4-pyridyl) -2-acetone and the alpha-ethoxymethylene malononitrile to prepare a milrinone crude product, and finally obtains fine milrinone through recrystallization. The method needs three steps of reaction to prepare the milrinone and cannot be realized by a 'one-pot' method, so the route is relatively long, the reaction yield of the last step is only 34 percent lower, the yield is not obviously superior to that of 70 percent of other routes, and the prepared milrinone is red in color and cannot be eliminated by refining.
Summarizing the preparation process of milrinone in the prior art, 1- (4-pyridyl) -2-acetone is prepared by utilizing 4-methylpyridine, and then the milrinone is prepared by taking 1- (4-pyridyl) -2-acetone as a raw material. The preparation method of milrinone reported by Cheng Shuangwei et al (research on synthesis process of milrinone, Chinese Journal of Medicinal Chemistry, Vol.19No.4p.241, Aug 2009Sum90) uses 4-methylpyridine as raw material to prepare 1- (4-pyridyl) -2-acetone, and then prepares the milrinone from the 1- (4-pyridyl) -2-acetone, and the final yield is only 52.9%. The reaction route is as follows:
the raw material 1- (4-pyridyl) -2-acetone is light yellow liquid, and according to the report of the improvement of the synthetic process of (1- (4-pyridyl) -2-acetone, Journal of Chemical Industry & Engineering, Vol.30No.4Aug,2009)1- (4-pyridyl) -2-acetone needs to be distilled at 100-102 ℃/267Pa (2mmHg), and the operation condition is harsh and the yield is not high. In industrial mass production, high-temperature reduced-pressure distillation has high requirements on process operating conditions and equipment, low operational safety, and low yield and purity. On the other hand, compared with the preparation method in which 1- (4-pyridyl) -2-acetone in a liquid state is used as a raw material, the operation is difficult and the feeding amount is difficult to control.
In conclusion, the reported milrinone preparation method has many defects in the aspects of safe process, simple and convenient operation and the like, so that the research and search of a reaction route which is mild in reaction condition, simple and convenient in operation process, high in product yield, high in purity and low in production cost and is suitable for industrial production of milrinone still needs to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing milrinone preparation technology, the invention provides a novel preparation method of milrinone. The method has the advantages of mild reaction conditions, simple and convenient operation process and low production cost, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a preparation method of milrinone comprises the following steps of reacting an intermediate compound I with alpha- (substituted methylene) cyanoacetamide, namely SM-2 to obtain milrinone, wherein the reaction formula is as follows:
wherein X is one of C1-C6 alkoxy and dimethylamino; the C1-C6 alkoxy group is preferably methoxy, ethoxy or propoxy.
A preparation method of milrinone comprises the following steps:
adding the intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH value of the solution, controlling the temperature to react, adding acid to adjust the pH value of the solution after the reaction is finished, and stirring to separate out a solid to obtain the milrinone.
Preferably, the further step of preparing milrinone comprises:
adding the intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH of the solution, controlling the temperature until the reaction is finished, adding acid to adjust the pH of the solution, separating out a solid, and filtering to obtain the milrinone.
Preferably, the feeding molar ratio of the intermediate compound I to the alpha- (substituted methylene) cyanoacetamide is 1:1.1 to 1.7, preferably 1: 1.3.
preferably, the reaction solvent is one or two of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.
Preferably, the feeding mass-to-volume ratio of the intermediate compound I to the reaction solvent is 1: 5-10, wherein the mass is in g and the volume is in ml.
Preferably, the base is an inorganic base or an organic base, wherein the inorganic base is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, and the inorganic base can be a base or an aqueous solution thereof; the organic base is one or the combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide; sodium hydroxide is preferred.
Preferably, the pH value of the solution is adjusted to 12-14 by adding alkali.
Preferably, the temperature-controlled reaction temperature is the temperature when the reaction solution reaches the reflux temperature.
Preferably, the acid is one or a combination of formic acid, acetic acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, and acetic acid is preferred.
Preferably, the pH value of the solution is adjusted to 6-7 by adding acid.
In one embodiment, when R is dimethylamino, adding acid to adjust the pH value of the solution to separate out a solid, filtering, pulping a filter cake with purified water at 40-50 ℃, and filtering to obtain a white-like solid milrinone.
The intermediate compound I of the present invention can be prepared by:
4-methylpyridine, namely SM-1 is taken as a raw material to prepare a solid intermediate compound I under the action of acetyl chloride and acetic anhydride, and the reaction formula is as follows:
the preparation of the intermediate I comprises the following steps:
adding 4-methylpyridine and acetyl chloride into a solvent, stirring for reaction, adding alkali to adjust the pH of a reaction solution after the reaction is finished, collecting an organic phase, carrying out reduced pressure distillation, recovering 4-methylpyridine to obtain a concentrated viscous liquid, and carrying out post-treatment to obtain a solid 1- (1-acetylpyridine-4 (1H) -ylidene) -2-acetone, namely an intermediate compound I.
Preferably, the further preparation step of intermediate I comprises:
adding 4-methylpyridine into dichloromethane, adding acetyl chloride, and reacting at controlled temperature until the reaction is finished; adding purified water, adding alkali while stirring to adjust the pH of the reaction solution, separating liquid, collecting an organic phase, extracting with aqueous phase dichloromethane, combining the organic phases, drying a drying agent, filtering, controlling the temperature of the filtrate, distilling under reduced pressure until no fraction flows out, and recovering 4-methylpyridine; and continuously heating the concentrated solution, decompressing and concentrating to obtain viscous liquid, and performing post-treatment to obtain solid 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely the intermediate compound I.
Preferably, the mass-to-volume ratio of the 4-methylpyridine to the dichloromethane is 1: 1.5-4, wherein the mass is g, and the volume is ml.
Preferably, the feeding molar ratio of the 4-methylpyridine to the acetyl chloride is 1: 1.2-3, preferably 1: 2.2.
In a preferred scheme, the temperature can be controlled during the process of adding the acetyl chloride or not, and the temperature can be controlled to be 15-25 ℃.
Preferably, the temperature-controlled reaction temperature is 20-30 ℃.
Preferably, the temperature of adding the purified water is controlled to be 0-20 ℃.
Preferably, the base is an inorganic base or an organic base, wherein the inorganic base is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, and the inorganic base can be a base or an aqueous solution thereof; the organic base is one or the combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide; sodium hydroxide is preferred.
Preferably, the pH value of the reaction solution is adjusted to 12-14 by adding alkali.
Preferably, the temperature of the reduced pressure distillation is 50-60 ℃.
Preferably, the temperature for continuously heating and decompressing concentration is 70-80 ℃.
In a preferred embodiment, the post-treatment step is: and respectively adding ethyl acetate and acetic anhydride into the viscous liquid, stirring to separate out a solid, filtering, leaching and drying after the separation is finished, thus obtaining a solid compound intermediate I.
Preferably, the amount of the ethyl acetate is 2-5 times of the volume of the viscous liquid.
Preferably, the acetic anhydride is added at a controllable temperature in the adding process, wherein the controllable temperature is 0-25 ℃.
Preferably, the feeding amount of the acetic anhydride is 5-10 times of the volume of the viscous liquid.
Preferably, the leaching solvent is absolute ethyl alcohol.
The SM-2 of the invention is 2-cyano-3-alkoxy acrylamide, i.e. when X is alkoxy, it can be prepared by reacting alpha-cyanoacetamide with trialkyl orthoformate, and the reaction formula is as follows:
wherein R is C1-C6 alkyl, preferably methyl, ethyl and propyl.
In a preferred embodiment, when R is ethyl, the specific reaction steps for the preparation of SM-2 are:
adding alpha-cyanoacetamide and triethyl orthoformate into a mixed solvent of acetic anhydride and glacial acetic acid, controlling the temperature to be 40-45 ℃, reacting for 3-4 hours, adding absolute ethyl alcohol to quench the acetic anhydride, stirring for 10-15 minutes, controlling the temperature to be 50-60 ℃, concentrating under reduced pressure until no distillate flows out, continuously heating to be 75-80 ℃, concentrating under reduced pressure until the mixture is dried, and recrystallizing to obtain white solid 2-cyano-3-ethoxyacrylamide.
Preferably, the feeding molar ratio of the alpha-cyanoacetamide to the triethyl orthoformate is 1: 1.1-2.
PreferablyThe alpha-cyanoacetamide and a mixed solvent (m)Acetic anhydride：mGlacial acetic acid1:10) is 1: 5-6.
Preferably, the heavy crystal system is a n-hexane-ethanol system, and the volume ratio of n-hexane to ethanol is preferably 3: 1.
when R in the present invention is a methoxy group or a propoxy group, 2-cyano-3-methoxyacrylamide or 2-cyano-3-propoxylacrylamide can be prepared by reacting alpha-cyanoacetamide with trimethyl orthoformate or tripropyl orthoformate, respectively, according to the above-mentioned method for preparing 2-cyano-3-ethoxyacrylamide.
In one embodiment, when SM-2 of the present invention is 2-cyano-3-dimethylamino acrylamide, i.e., R is dimethylamino, it can be prepared by reacting alpha-cyanoacetamide with N, N-dimethylformamide dimethyl acetal, i.e., DMF-DMA, according to the following reaction scheme:
preferably, the specific reaction steps are:
adding alpha-cyanoacetamide and N, N-dimethylformamide dimethyl acetal into 1, 4-dioxane, controlling the temperature to be 95-100 ℃ for reaction, and after the reaction is detected to be finished, adding the reaction liquid into purified water at the temperature of 0-5 ℃ to separate out solids; and continuously stirring for crystallization for 1-2 hours, filtering, dissolving the obtained filter cake with a dilute hydrochloric acid solution, washing with dichloromethane, adding a sodium hydroxide solution into a water layer to adjust the pH value to 11-12, continuously stirring for crystallization for 1-2 hours, and filtering to obtain the 2-cyano-3-dimethylamino acrylamide.
Preferably, the molar charge ratio of the alpha-cyanoacetamide to the N, N-dimethylformamide dimethyl acetal is 1: 1.1-2.5.
Preferably, the mass-volume ratio of the alpha-cyanoacetamide to the 1, 4-dioxane is 1: 5-10, wherein the mass is g, and the volume is ml.
The invention has the beneficial effects that:
the invention provides a new milrinone preparation method, which uses a solid intermediate compound 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone to replace the liquid 1- (4-pyridyl) -2-acetone in the prior art to prepare milrinone, and has simple operation and easy control of the feeding amount; compared with the intermediate compound 1- (4-pyridyl) -2-acetone which needs to be obtained by high-temperature reduced pressure distillation, the intermediate compound is simple and easy to obtain, and the purity of the prepared intermediate compound I is high by utilizing the recrystallization effect of acetic anhydride; compared with the prior art, the milrinone preparation process has the advantages of shortened process route, simple and safe operation and is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The invention adopts HPLC to measure the purity of milrinone, and the chromatographic conditions are as follows:
a chromatographic column: agilent ZORBAX Rx-C8(4.6mm×250mm,5.0μm)；
Mobile phase: dipotassium phosphate buffer (2.7g K)2HPO4+2.4ml triethylamine +800ml water, over H3PO4pH was adjusted to 7.5) -acetonitrile (80: 20) (ii) a
Column temperature: 30 ℃;
detection wavelength: 220 nm;
flow rate: 1.0 ml/min;
sample introduction amount: 20 μ l.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 11 preparation of- (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
Adding 4-methylpyridine (93.08g, 1.0mol) into dichloromethane (200ml), controlling the temperature to be 15-20 ℃, adding acetyl chloride (172.72g, 2.2mol), controlling the temperature to be 20-30 ℃ after the addition is finished, and reacting for 5 hours, wherein the reaction is finished; adding purified water (400ml) at the temperature of 10-15 ℃, adding a sodium hydroxide solution (about 7.5mol/ml) while stirring to adjust the pH value of a reaction solution to 13-14, separating, collecting an organic phase, extracting a water phase dichloromethane (100ml multiplied by 2), combining the organic phases, drying anhydrous sodium sulfate, filtering, controlling the temperature of a filtrate to be 50-60 ℃, distilling under reduced pressure until no fraction flows out, continuously heating a concentrated solution to be 70-80 ℃, and concentrating under reduced pressure to obtain a viscous liquid (55.85 g of recovered 4-methylpyridine, wherein the recovery rate is 60%); adding ethyl acetate (45ml) into the viscous liquid, controlling the temperature to be 0-10 ℃, adding acetic anhydride (110ml), stirring to separate out a solid, filtering after separation is finished, leaching with absolute ethyl alcohol (50ml multiplied by 2), and drying to obtain a solid 1- (1-acetylpyridine-4 (1H) -ylidene) -2-acetone, namely an intermediate compound I, wherein the yield is 93.5% (calculated by the actual 4-methylpyridine participating in the reaction, namely the input amount minus the recovery amount); the purity is 99.85%.
Example 21 preparation of- (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
Adding 4-methylpyridine (93.12g, 1.0mol) into dichloromethane (150ml), controlling the temperature to be 20-25 ℃, adding acetyl chloride (94.24g, 1.2mol), controlling the temperature to be 20-30 ℃ after the addition is finished, and reacting for 6 hours, wherein the reaction is finished; controlling the temperature to be 0-10 ℃, adding purified water (400ml), adding a sodium hydroxide solution (about 7.5mol/ml) while stirring to adjust the pH value of a reaction solution to 13-14, separating, collecting an organic phase, extracting a water phase dichloromethane (100ml multiplied by 2), combining the organic phases, drying anhydrous sodium sulfate, filtering, controlling the temperature of a filtrate to be 50-60 ℃, distilling under reduced pressure until no fraction flows out, continuously heating a concentrated solution to be 70-80 ℃, and concentrating under reduced pressure to obtain a viscous liquid (57.73 g of recovered 4-methylpyridine, wherein the recovery rate is 62%); adding ethyl acetate (40ml) into the viscous liquid, controlling the temperature to be 10-15 ℃, adding acetic anhydride (100ml), stirring to separate out a solid, filtering after separation is finished, leaching with absolute ethyl alcohol (50ml multiplied by 2), and drying to obtain a solid 1- (1-acetylpyridine-4 (1H) -ylidene) -2-acetone, namely an intermediate compound I, wherein the yield is 90.4% (calculated by actual 4-methylpyridine participating in the reaction, namely the input amount minus the recovery amount); the purity is 99.78%.
Example 31 preparation of (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
Adding 4-methylpyridine (93.07g, 1.0mol) into dichloromethane (300ml), controlling the temperature to be 20-25 ℃, adding acetyl chloride (235.54g, 3mol), controlling the temperature to be 20-30 ℃ after the addition is finished, and reacting for 5 hours, wherein the reaction is finished; adding purified water (500ml) at the temperature of 15-20 ℃, adding a sodium hydroxide solution (about 7.5mol/ml) while stirring to adjust the pH value of a reaction solution to 13-14, separating, collecting an organic phase, extracting a water phase dichloromethane (150ml multiplied by 2), combining the organic phases, drying anhydrous sodium sulfate, filtering, controlling the temperature of a filtrate to be 50-60 ℃, distilling under reduced pressure until no fraction flows out, continuously heating a concentrated solution to be 70-80 ℃, and concentrating under reduced pressure to obtain a viscous liquid (54.91 g of recovered 4-methylpyridine, with the recovery rate of 59%); adding ethyl acetate (50ml) into the viscous liquid, controlling the temperature to be 20-25 ℃, adding acetic anhydride (115ml), stirring to separate out a solid, filtering after separation is finished, leaching with absolute ethyl alcohol (50ml multiplied by 2), and drying to obtain a solid 1- (1-acetylpyridine-4 (1H) -ylidene) -2-acetone, namely an intermediate compound I, wherein the yield is 918% (calculated by actual 4-methylpyridine participating in the reaction, namely the input amount minus the recovery amount); the purity is 99.82%.
Example 41 preparation of (1-acetylpyridin-4 (1H) -ylidene) -2-propanone
Adding 4-methylpyridine (93.05g, 1.0mol) and acetyl chloride (172.75g, 2.2mol) into dichloromethane (250ml), controlling the temperature to be 20-30 ℃ to react for 5 hours after the addition is finished, and finishing the reaction; adding purified water (500ml) into the reaction solution, adding a sodium hydroxide solution (about 7.5mol/ml) while stirring to adjust the pH value of the reaction solution to 12-13, separating, collecting an organic phase, extracting water-phase dichloromethane (150ml multiplied by 2), combining the organic phases, drying anhydrous sodium sulfate, filtering, controlling the temperature of a filtrate to be 50-60 ℃, distilling under reduced pressure until no fraction flows out, continuously heating the concentrated solution to be 70-80 ℃, concentrating under reduced pressure to obtain viscous liquid (55.83 g of recovered 4-methylpyridine, and the recovery rate of 60%); adding ethyl acetate (50ml) into the viscous liquid, controlling the temperature to be 20-25 ℃, adding acetic anhydride (115ml), stirring to separate out a solid, filtering after separation is finished, leaching with absolute ethyl alcohol (50ml multiplied by 2), and drying to obtain a solid 1- (1-acetylpyridine-4 (1H) -ylidene) -2-acetone, namely an intermediate compound I, wherein the yield is 90.2% (calculated by actual 4-methylpyridine participating in the reaction, namely the input amount minus the recovery amount); the purity is 99.87%.
EXAMPLE 5 preparation of alpha- (ethoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.04g, 1.0mol), triethyl orthoformate (162.83g, 1.1mol) were added to acetic anhydride and glacial acetic acid (415.84g, m)Acetic anhydride:mGlacial acetic acid1:10) in a mixed solventReacting for 3 hours at the temperature of 40-45 ℃, adding absolute ethyl alcohol (300ml) to quench acetic anhydride, stirring for 10-15 minutes, controlling the temperature of 50-60 ℃, concentrating under reduced pressure until no fraction flows out, continuously heating to 75-80 ℃, concentrating under reduced pressure until the mixture is dry, and adding n-hexane-ethanol (500ml, V)N-hexane:VEthanol2-cyano-3-ethoxy acrylamide was obtained as a white solid by recrystallization in a ratio of 3:1), with a yield of 91.4% and a purity of 99.45%.
EXAMPLE 6 preparation of alpha- (ethoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.06g, 1.0mol), triethyl orthoformate (236.84g, 1.6mol) were added to acetic anhydride and glacial acetic acid (456.58g, m)Acetic anhydride:mGlacial acetic acid1:10), reacting for 4 hours at the temperature of 40-45 ℃, adding absolute ethyl alcohol (350ml) to quench acetic anhydride, stirring for 10-15 minutes, then controlling the temperature of 50-60 ℃, concentrating under reduced pressure until no fraction flows out, continuously heating to 75-80 ℃, concentrating under reduced pressure until dry, and adding n-hexane-ethanol (500ml, V)N-hexane:VEthanol2-cyano-3-ethoxy acrylamide was obtained as a white solid by recrystallization in a ratio of 3:1), yield 94.2% and purity 99.68%.
EXAMPLE 7 preparation of alpha- (ethoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.03g, 1.0mol), triethyl orthoformate (296.08g, 2.0mol) were added to acetic anhydride and glacial acetic acid (498.03g, m)Acetic anhydride:mGlacial acetic acid1:10), reacting for 4 hours at the temperature of 40-45 ℃, adding anhydrous ethanol (400ml) to quench acetic anhydride, stirring for 10-15 minutes, concentrating under reduced pressure at the temperature of 50-60 ℃ until no fraction flows out, continuously heating to 75-80 ℃, concentrating under reduced pressure until dry, and adding n-hexane-ethanol (500ml, V)N-hexane:VEthanol2-cyano-3-ethoxy acrylamide was obtained as a white solid by recrystallization in a ratio of 3:1), yield 93.8% and purity 99.57%.
EXAMPLE 8 preparation of alpha- (methoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.05g, 1.0mol), trimethyl orthoformate (169.63g, 1.6mol) were added to acetic anhydride and glacial acetic acid (456.54g, m)Acetic anhydride:mGlacial acetic acid1:10) in a mixed solvent, controlling the temperature to be 40-45 ℃ and reacting 4After the reaction is carried out for 10 to 15 minutes, adding absolute ethyl alcohol (350ml) to quench acetic anhydride, stirring, controlling the temperature to be 50 to 60 ℃, carrying out reduced pressure concentration until no fraction flows out, continuously heating to be 75 to 80 ℃, carrying out reduced pressure concentration until the mixture is dried, and adding n-hexane-ethyl alcohol (500ml, V)N-hexane:VEthanol2-cyano-3-methoxyacrylamide was obtained as a white solid by recrystallization in a ratio of 3:1), yield 93.8% and purity 99.65%.
EXAMPLE 9 preparation of alpha- (propoxymethylene) cyanoacetamide
Alpha-cyanoacetamide (83.05g, 1.0mol), tripropylorthoformate (304.07g, 1.6mol) were added to acetic anhydride and glacial acetic acid (456.52g, m)Acetic anhydride:mGlacial acetic acid1:10), reacting for 4 hours at the temperature of 40-45 ℃, adding anhydrous ethanol (400ml) to quench acetic anhydride, stirring for 10-15 minutes, concentrating under reduced pressure at the temperature of 50-60 ℃ until no fraction flows out, continuously heating to 75-80 ℃, concentrating under reduced pressure until dry, and adding n-hexane-ethanol (500ml, V)N-hexane:VEthanol2-cyano-3-propoxylacrylamide was obtained as a white solid by recrystallization from 3:1), yield 93.5% and purity 99.62%.
Example 10 α - (N, N-dimethylaminomethyl) cyanoacetamide
Adding alpha-cyanoacetamide (83.05g, 1.0mol) and N, N-dimethylformamide dimethyl acetal (130.94g, 1.1mol) into 1, 4-dioxane (450ml), controlling the temperature to be 95-100 ℃ for reaction, after the reaction is detected, adding the reaction liquid into purified water (600ml) at the temperature of 0-5 ℃, and separating out solids; and continuously stirring for crystallization for 1 hour, filtering, dissolving the obtained filter cake with a dilute hydrochloric acid solution (300ml), washing with dichloromethane (100ml multiplied by 2), adding a sodium hydroxide solution into a water layer to adjust the pH value to 11-12, continuously stirring for crystallization for 1 hour, and filtering to obtain the 2-cyano-3-dimethylamino acrylamide with the yield of 92.4% and the purity of 99.38%.
Example 11 α - (N, N-dimethylaminomethyl) cyanoacetamide
Adding alpha-cyanoacetamide (83.02g, 1.0mol) and N, N-dimethylformamide dimethyl acetal (214.22g, 1.8mol) into 1, 4-dioxane (600ml), controlling the temperature to be 95-100 ℃ for reaction, after the reaction is detected to be finished, adding the reaction liquid into purified water (800ml) at 0-5 ℃, and separating out solids; and continuously stirring for crystallization for 2 hours, filtering, dissolving the obtained filter cake with a dilute hydrochloric acid solution (300ml), washing with dichloromethane (100ml multiplied by 2), adding a sodium hydroxide solution into a water layer to adjust the pH value to 11-12, continuously stirring for crystallization for 2 hours, and filtering to obtain the 2-cyano-3-dimethylamino acrylamide with the yield of 94.3% and the purity of 99.58%.
Example 12 α - (N, N-dimethylaminomethyl) cyanoacetamide
Adding alpha-cyanoacetamide (83.05g, 1.0mol) and N, N-dimethylformamide dimethyl acetal (297.53g, 2.5mol) into 1, 4-dioxane (800ml), controlling the temperature to be 95-100 ℃ for reaction, after the reaction is detected, adding the reaction liquid into purified water (1000ml) at 0-5 ℃, and separating out solids; and continuously stirring for crystallization for 2 hours, filtering, dissolving the obtained filter cake with a dilute hydrochloric acid solution (300ml), washing with dichloromethane (100ml multiplied by 2), adding a sodium hydroxide solution into a water layer to adjust the pH value to 11-12, continuously stirring for crystallization for 2 hours, and filtering to obtain the 2-cyano-3-dimethylamino acrylamide with the yield of 93.6% and the purity of 99.42%.
EXAMPLE 13 preparation of milrinone
Adding the intermediate compound I (177.04g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (182.06g, 1.3mol) into ethanol (1200ml), uniformly stirring, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 93.4% and the purity is 99.97%.
EXAMPLE 14 preparation of milrinone
Adding the intermediate compound I (177.06g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (154.05g, 1.1mol) into methanol (900ml), uniformly stirring, and adding 7.0mol/L potassium hydroxide solution to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding dilute hydrochloric acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 92.5% and the purity is 99.93%.
EXAMPLE 15 preparation of milrinone
Adding the intermediate compound I (177.01g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (140.03g, 1.0mol) into ethanol (900ml), uniformly stirring, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 88.5%, and the purity is 99.90%.
EXAMPLE 16 preparation of milrinone
Adding the intermediate compound I (177.02g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (238.12g, 1.7mol) into ethanol (1500ml), stirring uniformly, and adding sodium ethoxide to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, after the reaction is finished, cooling the reaction liquid to room temperature, adding hydrobromic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering, and drying to obtain a white-like solid milrinone, wherein the yield is 92.7%, and the purity is 99.95%.
EXAMPLE 17 preparation of milrinone
Adding the intermediate compound I (177.08g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (252.03g, 1.8mol) into ethanol (1500ml), stirring uniformly, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 91.8 percent, and the purity is 99.92 percent
EXAMPLE 18 preparation of milrinone
Adding the intermediate compound I (177.03g, 1.0mol) and alpha- (N, N-dimethylaminomethyl) cyanoacetamide (180.74g, 1.3mol) into ethanol (1200ml), uniformly stirring, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; and (3) carrying out temperature-controlled reflux reaction, after the reaction is finished, cooling the reaction solution to room temperature, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering after the separation is finished, pulping a filter cake by using purified water (500ml) at the temperature of 40-50 ℃, filtering, and drying to obtain a white-like solid milrinone, wherein the yield is 92.3%, and the purity is 99.98%.
EXAMPLE 19 preparation of milrinone
Adding the intermediate compound I (177.02g, 1.0mol) and alpha- (N, N-dimethylaminomethyl) cyanoacetamide (152.96g, 1.1mol) into isopropanol (1200ml), uniformly stirring, and adding sodium isopropoxide to adjust the pH value to 12-13; and (3) controlling the temperature to carry out reflux reaction, after the reaction is finished, cooling the reaction solution to room temperature, adding hydroiodic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering after the separation is finished, pulping a filter cake by using purified water (500ml) at the temperature of 40-50 ℃, filtering, and drying to obtain a white-like solid milrinone, wherein the yield is 91.4%, and the purity is 99.96%.
EXAMPLE 20 preparation of milrinone
Adding the intermediate compound I (177.07g, 1.0mol) and alpha- (N, N-dimethylaminomethyl) cyanoacetamide (236.37g, 1.7mol) into tert-butyl alcohol (1000ml), uniformly stirring, and adding sodium tert-butoxide to adjust the pH value to 12-13; and (3) carrying out temperature-controlled reflux reaction, after the reaction is finished, cooling the reaction solution to room temperature, adding formic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering after the separation is finished, pulping a filter cake by using purified water (500ml) at the temperature of 40-50 ℃, filtering, and drying to obtain a white-like solid milrinone, wherein the yield is 92.1%, and the purity is 99.95%.
EXAMPLE 21 preparation of milrinone
Adding the intermediate compound I (177.02g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (182.04g, 1.3mol) into ethanol (1200ml), uniformly stirring, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 11-12; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 85.8%, and the purity is 99.92%.
EXAMPLE 22 preparation of milrinone
Adding the intermediate compound I (177.06g, 1.0mol) and alpha- (ethoxymethylene) cyanoacetamide (182.03g, 1.3mol) into ethanol (1200ml), uniformly stirring, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 5-6, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 87.5 percent and the purity is 99.85 percent.
EXAMPLE 23 preparation of milrinone
Adding the intermediate compound I (177.06g, 1.0mol) and alpha- (methoxymethylene) cyanoacetamide (163.84g, 1.3mol) into ethanol (1000ml), uniformly stirring, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 92.5%, and the purity is 99.90%.
EXAMPLE 24 preparation of milrinone
Adding the intermediate compound I (177.04g, 1.0mol) and alpha- (propoxymethylene) cyanoacetamide (200.23g, 1.3mol) into ethanol (1500ml), stirring uniformly, and adding 7.5mol/L sodium hydroxide solution to adjust the pH value to 13-14; and (3) controlling the temperature to carry out reflux reaction, cooling the reaction solution to room temperature after the reaction is finished, adding acetic acid to adjust the pH value of the solution to 6-7, stirring to separate out a solid, filtering and drying after the separation is finished to obtain a white-like solid milrinone, wherein the yield is 91.6%, and the purity is 99.98%.
Claims (10)
1. A preparation method of milrinone, 1- (1-acetylpyridine-4 (1H) -subunit) -2-acetone, namely an intermediate I, and alpha- (substituted methylene) cyanoacetamide, namely SM-2, react to obtain the milrinone, and the reaction formula is as follows:
wherein X is one of methoxyl, ethoxyl, propoxyl and dimethylamino.
2. The method for preparing milrinone according to claim 1, comprising the steps of:
and adding the intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH value of the solution, and controlling the temperature to react to obtain the milrinone.
3. The method for preparing milrinone according to claim 1 or 2, comprising the steps of:
adding the intermediate compound I and alpha- (substituted methylene) cyanoacetamide into a reaction solvent, adding alkali to adjust the pH of the solution, controlling the temperature until the reaction is finished, adding acid to adjust the pH of the solution, separating out a solid, and filtering to obtain the milrinone.
4. The process according to claim 3, wherein the molar ratio of the intermediate compound I to the α - (substituted methylene) cyanoacetamide is 1:1.1 to 1.7.
5. The method for preparing milrinone according to claim 3, wherein the pH of the solution is adjusted to 12-14 by adding alkali.
6. The method for preparing milrinone according to claim 3, wherein the base is an inorganic base or an organic base, wherein the inorganic base is one or a combination of sodium hydroxide, potassium hydroxide and barium hydroxide, and the inorganic base can be a base or an aqueous solution thereof; the organic base is one or the combination of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide.
7. The process of claim 3, wherein the reaction temperature is controlled to a temperature at which the reaction solution is refluxed.
8. The method for preparing milrinone according to claim 3, wherein the pH value of the solution is adjusted to 6-7 by adding acid.
9. The method of claim 3, wherein the acid is one or a combination of formic acid, acetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid.
10. The method according to claim 3, wherein the reaction solvent is one or two of methanol, ethanol, isopropanol and tert-butanol.
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| CN113979945A (en) * | 2021-11-15 | 2022-01-28 | 湖北理工学院 | Novel method for preparing 3-aminopyrazole-4-formamide hemisulfate |
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| CN1629141A (en) * | 2003-12-17 | 2005-06-22 | 鲁南制药股份有限公司 | Process for preparing milrinone |
| CN104326975A (en) * | 2014-10-20 | 2015-02-04 | 郑州四环医药用品有限公司 | Preparation method of high-purity milrinone |
| 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 |
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