CN114773341A - Preparation method of olprinone hydrochloride - Google Patents
Preparation method of olprinone hydrochloride Download PDFInfo
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- CN114773341A CN114773341A CN202210508365.XA CN202210508365A CN114773341A CN 114773341 A CN114773341 A CN 114773341A CN 202210508365 A CN202210508365 A CN 202210508365A CN 114773341 A CN114773341 A CN 114773341A
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- imidazo
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- 229950005421 olprinone Drugs 0.000 title claims abstract description 62
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 20
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 16
- FXPMFQUOGYGTAM-UHFFFAOYSA-N 6-bromoimidazo[1,2-a]pyridine Chemical compound C1=C(Br)C=CC2=NC=CN21 FXPMFQUOGYGTAM-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 imidazo [1, 2-a ] pyridine-6-yl Chemical group 0.000 claims abstract description 14
- 125000005394 methallyl group Chemical group 0.000 claims abstract description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 9
- 238000007670 refining Methods 0.000 claims abstract description 8
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000012065 filter cake Substances 0.000 claims description 21
- 239000000706 filtrate Substances 0.000 claims description 16
- 238000000967 suction filtration Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001291 vacuum drying Methods 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 239000013067 intermediate product Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 5
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 claims description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 claims description 3
- OHXAOPZTJOUYKM-UHFFFAOYSA-N 3-Chloro-2-methylpropene Chemical compound CC(=C)CCl OHXAOPZTJOUYKM-UHFFFAOYSA-N 0.000 claims description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical group [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- NSFXGEUOJPPNLI-FMIVXFBMSA-N (Z)-4-(dimethylamino)-3-imidazo[1,2-a]pyridin-6-ylbut-3-en-2-one Chemical compound CN(C)\C=C(/C(C)=O)c1ccc2nccn2c1 NSFXGEUOJPPNLI-FMIVXFBMSA-N 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- HTBIAUMDQYXOFG-UHFFFAOYSA-N 3-methyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentanoic acid Chemical compound CCC(C)C(C(O)=O)N(C)C(=O)OC(C)(C)C HTBIAUMDQYXOFG-UHFFFAOYSA-N 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 239000000376 reactant Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- KEHXBISWXRCSIL-UHFFFAOYSA-N 1-imidazo[1,2-a]pyridin-6-ylpropan-2-one Chemical compound C1=C(CC(=O)C)C=CC2=NC=CN21 KEHXBISWXRCSIL-UHFFFAOYSA-N 0.000 description 4
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- IGUKSQJRFIRUAT-UHFFFAOYSA-N 6-(2-nitroprop-1-enyl)imidazo[1,2-a]pyridine Chemical compound C1=C(C=C(C)[N+]([O-])=O)C=CC2=NC=CN21 IGUKSQJRFIRUAT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of olprinone hydrochloride, belonging to the technical field of chemical pharmacy. The method specifically comprises the following steps: step one, preparing 6-bromoimidazo [1, 2-a ] pyridine through cyclization reaction; step two, preparing 6- (2-methylallyl) imidazo [1, 2-a ] pyridine through coupling reaction; step three, preparing 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone through oxidation reaction; step four, performing a methylene reaction to prepare (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-buten-2-one; step five, preparing olprinone through cyclization reaction; and step six, salifying and refining the olprinone hydrochloride. The preparation method has the advantages of wide raw material sources, mild reaction conditions, low reaction cost, good reproducibility, high product yield, high purity, low impurity content, safe and nontoxic reaction process, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of olprinone hydrochloride.
Background
Olprinone Hydrochloride (Olprinone Hydrochloride) is white to light yellow crystalline powder with chemical name of 1, 2-dihydro-5-imidazo [1, 2-a ]]Pyridin-6-yl-6-methyl-2-oxo-3-pyridinecarbonitrile hydrochloride monohydrate having the formula C14H11ClN4O, molecular weight 286.72, CAS registry number 119615-63-3, and the structural formula is as follows:
olprinone hydrochloride can selectively block specific Phosphodiesterase (PDEIII) of cyclic adenosine monophosphate, is phosphodiesterase III (PDEIII) inhibitor, has the effects of enhancing cardiac contractility and dilating blood vessels, is a medicine for treating heart failure, and is clinically suitable for short-term treatment of acute heart failure with poor curative effect by using other medicines.
In the prior art, the synthesis route of olprinone hydrochloride is mainly two, wherein one route takes dichloromethane as a solvent and uses dibutylaluminum hydride to reduce imidazo [1, 2-a ]]Pyridine-6-carboxylic acid methyl ester (1) gives the corresponding aldehyde (2); refluxing in ethanol under the action of butylamine, (2) condensing with nitroethane to obtain 6- (2-nitro-1-propenyl) imidazo [1, 2-a]Pyridine (3); (3) with Fe-FeCl in Hot ethanol-Water2Reaction with HCl to give 1- (imidazo [1, 2-a)]Pyridin-6-yl) -2-propanone (4); (4) with N, N-dimethylformamide dimethyl acetal in hot DMF (N, N-dimethylformamide)Amine) to obtain 4- (dimethylamino) -3- (imidazo [1, 2-a)]Pyridin-6-yl) -3-buten-2-one (5); and (5) cyclizing the intermediate product with cyanoacetamide in hot DMF under the catalysis of sodium methoxide to generate the olprinone (6). The reaction conditions of the above reaction schemes are severe, such as: (1) the reaction to (2) needs to be carried out for 3 hours at-60 ℃ under the protection of nitrogen; (2) the reaction to (3) takes more than 30 hours; the yield from starting material (1) to intermediate (4) is low: (1) the yield of the reactions (2) to (2) was only 17.2%, and the yield of the reactions (2) to (3) was only 11.9%. The other route is as follows: 6-bromoimidazo [1, 2-a ]]Pyridine (1) and potassium acetylacetonate are condensed under the catalytic action of KI and CuI to obtain an intermediate (2); (2) hydrolyzing with sodium hydroxide, and acidifying with hydrochloric acid to obtain 1- (imidazo [1, 2-a)]Pyridin-6-yl) -2-propanone (3); (3) reacting with N, N-dimethyl formamide dimethyl acetal in hot DMF to obtain 4- (dimethylamino) -3- (imidazo [1, 2-a)]Pyridin-6-yl) -3-buten-2-one (4); then cyclizing the intermediate with cyanoacetamide in hot DMF (4) under the catalysis of sodium methoxide to generate olprinone (5). Although the reaction conditions of the reaction route are mild and the reaction route is short, acetylacetone belongs to a third type of dangerous chemicals, potassium acetylacetonate needs to be prepared at present in use, and the yield from the raw material (1) to the intermediate (3) is low and is only 36%. The above reaction route is described in detail in chem.pharm.Bull, 39(6), 1556-]。
In conclusion, the existing olprinone hydrochloride synthesis process route has the defects of harsh reaction conditions, high raw material cost, low yield, difficult reagent acquisition and the like; therefore, the development of a preparation route of olprinone hydrochloride, which has the advantages of mild reaction conditions, simplicity, controllability, easily available raw materials, low cost, high yield, high product quality and capability of industrialization, is a technical problem to be solved at present.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention aims to provide the preparation method of the olprine hydrochloride, which has the advantages of mild reaction conditions, simplicity, controllability, easily available raw materials, low cost, high yield, high product quality and industrialization.
In order to achieve the purpose, the invention provides the following technical scheme:
one of the technical schemes of the invention is a preparation method of olprinone hydrochloride, which comprises the following steps:
performing cyclization reaction on 2-amino-5-bromopyridine and bromoacetaldehyde diethyl acetal under the protection of nitrogen to obtain 6-bromoimidazo [1, 2-a ] pyridine;
step two, the 6-bromoimidazo [1, 2-a ] pyridine prepared in the step one reacts with magnesium to generate an intermediate product (1), and the intermediate product (1) is coupled with methyl allyl chloride to obtain 6- (2-methyl allyl) imidazo [1, 2-a ] pyridine;
step three, carrying out oxidation reaction on the 6- (2-methylallyl) imidazo [1, 2-a ] pyridine prepared in the step two to obtain 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone;
step four, performing methylene reaction on the 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone prepared in the step three and N, N-dimethylformamide dimethyl acetal to obtain (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-butene-2-one;
step five, performing cyclization reaction on the (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-butylene-2-ketone prepared in the step four and cyanoacetamide to obtain olprinone;
reacting the olprinone prepared in the sixth step and the fifth step with a hydrogen chloride ethanol solution to obtain an olprinone hydrochloride crude product, and refining the olprinone hydrochloride crude product to obtain the olprinone hydrochloride;
the structural formula of the 6-bromoimidazo [1, 2-a ] pyridine is shown as a formula (I), the structural formula of the intermediate product (1) is shown as a formula (II), the structural formula of the 6- (2-methylallyl) imidazo [1, 2-a ] pyridine is shown as a formula (III), the structural formula of the 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone is shown as a formula (IV), the structural formula of the (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-butylene-2-ketone is shown as a formula (V), the structural formula of olprinone is shown as a formula (VI), and the structural formula of olprinone hydrochloride is shown as a formula (VII):
further, the cyclization reaction in the step one is refluxed for 20-40h, and chloroform or ethyl acetate is used for extraction after the cyclization reaction is finished, so that the yield is improved. The reaction process of the first step is shown as a reaction formula (1):
further, the refluxing time of the cyclization reaction in the step one is preferably 22h, and the cyclization reaction is preferably extracted by ethyl acetate after completion.
Further, in the second step, the reaction of 6-bromoimidazo [1, 2-a ] pyridine with magnesium is carried out in a mixture of ethyl bromide and Tetrahydrofuran (THF). The reaction process of the second step is shown as a reaction formula (2):
further, the oxidizing agent used in the oxidation reaction in the third step is ozone. The reaction process of the third step is shown as a reaction formula (3):
furthermore, the reaction temperature of the methylation reaction in the fourth step is 80-90 ℃, the reaction time is 1.5-4.5h, and the yield is high, the impurities are few and the cost is low under the condition of the methylation reaction.
Further, the reaction temperature of the methylene methylation reaction is preferably 85 ℃, the reaction time is preferably 3h, and the yield is highest, the impurities are least and the cost is lowest under the condition of the methylene methylation reaction.
Further, after the methylene reaction in the fourth step is completed, activated carbon is added for decoloring and purifying, so that the purity of the (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridin-6-yl) -3-buten-2-one can be improved, and the yield of the next reaction can be improved. The reaction process of the fourth step is shown as a reaction formula (4):
further, after the cyclization reaction in the step five is completed, treating the reaction liquid by using acetone to prepare the olprinone solid. Has the advantages of reducing potential harm caused by residual solvent of the raw material medicine and being more suitable for being made into a medicinal preparation. The reaction process of the fifth step is shown as a reaction formula (5):
further, the refining operation in the sixth step is as follows: adding the olprinone hydrochloride crude product into purified water for dissolving, then adding activated carbon, decoloring and performing suction filtration to obtain primary filtrate; crystallizing and filtering the filtrate to obtain a primary filter cake; adding the primary filter cake into purified water for dissolving, then adding activated carbon, decoloring and performing suction filtration to obtain secondary filtrate; crystallizing and filtering the secondary filtrate to obtain a secondary filter cake; and carrying out vacuum drying on the secondary filter cake to obtain the olprinone hydrochloride (high-purity olprinone hydrochloride). The olprinone hydrochloride is refined by purified water under specific conditions, decoloration is carried out by proper amount of activated carbon, impurities are adsorbed, the refined olprinone hydrochloride is more suitable for being made into a preparation, and the production cost is greatly reduced. The reaction process of the sixth step is shown as the reaction formula (6):
further, the temperature of the vacuum drying is 50 ℃, and the vacuum drying is carried out until the water content is 5.5-6.5%.
Further, phosphorus pentoxide is added in the vacuum drying process.
Compared with the prior art, the invention has the following beneficial effects:
(1) the olprinone hydrochloride prepared by the preparation method has the content of over 99.5 percent, the single impurity content of less than 0.1 percent, and the preparation method has the advantages of low impurity, high purity, high yield and the like. The invention takes the 2-amino-5-bromopyridine as the starting material, so that the raw material source is wider and easier to obtain, and the production cost is reduced; through verification of multiple batches, the synthesis process disclosed by the invention is mild in reaction conditions, good in reproducibility and very suitable for industrial production.
(2) The invention uses low-toxicity three solvents of ethyl acetate and acetone as reaction or extraction and purification solvents, which better meets the quality requirements of raw material medicines for human use; through multiple tests, the time and the temperature in the reaction condition are optimized, the reaction period is shortened, and the cost is reduced; the invention uses purified water to refine the crude product to replace a preparation column, is safe and nontoxic, and greatly simplifies the production process.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The description and examples are intended to be illustrative only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
Example 1
Step one, preparing 6-bromoimidazo [1, 2-a ] pyridine by cyclization reaction (carrying out preparation of 3 batches):
batch 1: sequentially adding 1350g of 2-amino-5-bromopyridine, 11.7L of n-butyl alcohol and 4680g of bromoacetaldehyde diethyl acetal into a 50L reaction bottle (air in the reaction bottle is replaced by nitrogen in advance), stirring and heating to reflux, sampling after 20 hours of reflux, observing by a TLC point plate, stopping heating after the reaction of the raw materials is finished, cooling to room temperature, and separating out brown solid; and (5) carrying out suction filtration to obtain a filter cake. Adding the filter cake into 900mL of purified water, adjusting the pH value to 8-9, adding ethyl acetate for extraction (5L multiplied by 2 times), combining organic phases, washing with saturated saline solution (4L multiplied by 2 times), then drying with anhydrous sodium sulfate, filtering out a drying agent, and concentrating the filtrate under reduced pressure to dryness to obtain a brown solid; adding 700mL of absolute ethyl alcohol, and concentrating under reduced pressure until the mixture is dry to obtain a solid; adding 10L of anhydrous ethanol, stirring for dissolving, adding appropriate amount of active carbon, heating, refluxing for decolorizing for 0.5h, and vacuum filtering to obtain filtrate; the mixture was concentrated to dryness under reduced pressure and dried under vacuum at 50 ℃ (a suitable amount of phosphorus pentoxide was added during vacuum drying) to give 883.2g of pale yellow to brown solid (6-bromoimidazo [1, 2-a ] pyridine), yield 57.4%. Wherein, the TLC monitoring conditions are as follows: according to the volume ratio, the ratio of ethyl acetate to petroleum ether is 3: 1, and the ratio of raw material rf is 0.7.
The preparation of batch 2 and batch 3 was carried out, the preparation method of batch 2 and batch 3 being identical to batch 1 except that the reflux time of batch 2 was 22 hours, ethyl acetate extraction; batch 3 was refluxed for 24 hours and extracted with chloroform. The yield of each batch is shown in table 1:
TABLE 1
Step two, preparing 6- (2-methallyl) imidazo [1, 2-a ] pyridine by coupling reaction (preparing 3 batches):
batch 1: under the protection of nitrogen, 1520mL of tetrahydrofuran and 467g of magnesium chips are sequentially added into a 50L reaction bottle, stirred, the temperature is controlled to be lower than 40 ℃, 156g of bromoethane is dropwise added, 924g of mixed liquid of 6-bromoimidazo [1, 2-a ] pyridine prepared in the step 1, 1407g of bromoethane and 4400mL of tetrahydrofuran is added after dropwise addition, and heating reflux reaction is carried out for 1.5 hours after dropwise addition; cooling to 50-55 ℃, dropwise adding a mixed solution of 1800g of methyl allyl chloride and 3660mL of tetrahydrofuran, heating and refluxing for 2h after dropwise adding, cooling to room temperature, stopping nitrogen, controlling the temperature to be less than 30 ℃, adding the reaction solution into 6160mL of saturated ammonium chloride solution, standing for layering after adding, extracting the water phase with ethyl acetate (4L multiplied by 3 times), combining the organic phases, drying with anhydrous sodium sulfate, and performing suction filtration to obtain a filtrate; the solvent was removed by concentration under reduced pressure to give a residue, which was distilled under reduced pressure to collect fractions to give 570.8g of a pale yellow oil (6- (2-methylallyl) imidazo [1, 2-a ] pyridine) in 70.7% yield.
The preparation of batch 2 and batch 3 was carried out, the preparation method of batch 2 and batch 3 being the same as batch 1 except that the reactant added in batch 2 was 6-bromoimidazo [1, 2-a ] pyridine prepared in step batch 2, and the reaction heating reflux time was 2 hours; batch 3 the reactant added was 6-bromoimidazo [1, 2-a ] pyridine prepared in step batch 3 and the time to settle and separate was extended. The yield of each batch is shown in table 2:
TABLE 2
Step three, preparing 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone through oxidation reaction (carrying out preparation of 3 batches):
batch 1: 569g of 6- (2-methylallyl) imidazo [1, 2-a ] pyridine prepared in the second batch 1 in the step, 1305mL of methanol, 1304g of concentrated hydrochloric acid and 1305mL of purified water are sequentially added into a reactor, the temperature is reduced to-5 to-10 ℃, ozone is introduced, and the reaction end point is controlled by a point plate TLC method; after the reaction is finished, dropwise adding an aqueous solution of sodium sulfite at the temperature of less than 30 ℃, slowly adding a saturated sodium carbonate solution to adjust the pH of the system to be 8-9, extracting with ethyl acetate (5L multiplied by 3 times), washing an organic phase with saturated salt solution (4L multiplied by 2 times), adding anhydrous sodium sulfate, drying, and performing suction filtration to obtain a filtrate; concentration to dryness under reduced pressure gave 429.4g of light brown to brown oil (1- (imidazo [1, 2-a ] pyridin-6-yl) -2-propanone) in 74.5% yield. Wherein, the TLC developing agent is: according to the volume ratio, ethyl acetate and cyclohexane are 2: 1, and a red anisaldehyde developer is used for developing color.
The preparation of batch 2 and batch 3 was carried out, the preparation of batch 2 and batch 3 being identical to batch 1 except that the reactant added in batch 2 was 6- (2-methylallyl) imidazo [1, 2-a ] pyridine prepared in step two, batch 2, the ethyl acetate extraction being 5 L.times.5 times; batch 3 the reactant added was 6- (2-methylallyl) imidazo [1, 2-a ] pyridine prepared in step two batch 3 and the ethyl acetate extraction mode was 5L × 4 times. The yield of each batch is shown in table 3:
TABLE 3
Step four, methylene reaction to prepare (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridin-6-yl) -3-buten-2-one (3 batches of preparation are carried out):
batch 1: 427g of 1- (imidazo [1, 2-a ] pyridin-6-yl) -2-propanone prepared in step three batches 1, 2518mL of DMF, 591g N, N-dimethylformamide dimethyl acetal were added in sequence to the reactor, stirred, heated and reacted at 80 ℃ for 1.5 hours; stopping reaction, cooling, adding 50g of activated carbon, keeping the temperature at 85 ℃ for 0.5h, and carrying out hot suction filtration to obtain filtrate; concentrating under reduced pressure to 1/10-1/8, putting into a refrigerator for cooling, separating out solids, and filtering; vacuum drying at 70 deg.C gave 310g of ((3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridin-6-yl) -3-buten-2-one) as a tan solid in 55.1% yield.
The preparation of batch 2 and batch 3 was carried out, with batch 2 and batch 3 being prepared in the same way as batch 1, except that the reactant added in batch 2 was 1- (imidazo [1, 2-a ] pyridin-6-yl) -2-propanone prepared in step three batch 2 and reacted at 85 ℃ for 3 hours; batch 3 the reactant added was 1- (imidazo [1, 2-a ] pyridin-6-yl) -2-propanone prepared in step three batch 3 and reacted at 90 ℃ for 4.5 hours. The yield of each batch is shown in table 4:
TABLE 4
Step five, preparing olprinone by cyclization reaction (preparing 3 batches):
batch 1: 308g of (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridin-6-yl) -3-buten-2-one prepared in the fourth step and 2726mL of N, N-dimethylformamide are sequentially added into a reactor, 168g of cyanoacetamide and 151g of sodium methoxide are added, and the temperature is raised to 80 ℃ for reaction for 1.5 h; cooling to room temperature, adjusting the pH value to 6.0-6.5 by using glacial acetic acid, separating out solids, stirring for 0.5h, and performing suction filtration to obtain a filter cake; adding the filter cake into 8L of acetone, stirring for 12h, and filtering to obtain a filter cake; adding the filter cake into 8L of acetone, stirring for 12h, and performing suction filtration to obtain a filter cake; adding the filter cake into 5.5L of 2.5% sodium hydroxide solution, stirring, heating for dissolving, adding 46g of activated carbon, and decolorizing at 60-70 ℃ for 0.5 h; carrying out suction filtration to obtain filtrate; adjusting the pH value to 7.0-7.5 by using glacial acetic acid, separating out light yellow solid, stirring for half an hour, performing suction filtration to obtain a filter cake, washing with a proper amount of acetone, and performing vacuum drying at 50 ℃ to obtain 245.3g of solid (olprinone) with the yield of 73%.
The preparation of batch 2 and batch 3 was carried out, with batch 2 and batch 3 being prepared in the same way as batch 1, except that the reactant added in batch 2 was (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridin-6-yl) -3-buten-2-one prepared in step four batch 2 and reacted at 85 ℃; batch 3 the reactant added was (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridin-6-yl) -3-buten-2-one prepared in step four batch 3 and reacted at 90 ℃. The yield of each batch is shown in table 5:
TABLE 5
Step six, preparing high-purity olprinone hydrochloride (preparing 3 batches):
batch 1: adding 242g of olprinone prepared in the step five batches 1 and 2665mL of N, N-dimethylformamide into a reaction bottle in sequence, stirring, heating to 90-95 ℃, dropwise adding 4845mL of 10% hydrogen chloride ethanol solution, separating out yellow solid, cooling to room temperature after dropwise adding, and performing suction filtration to obtain a filter cake; and (3) blowing and drying for 2h at 50 ℃ to obtain 240g of yellow solid (olprinone hydrochloride crude product) and the yield of the crude product is 81.4 percent. Adding the obtained 240g of olprinone hydrochloride crude product into a refined bottle, adding 1820mL of purified water, heating to dissolve under stirring, adding 48g of activated carbon, heating up, refluxing and decoloring for 40 minutes, and performing hot suction filtration to obtain light yellow primary filtrate; cooling to room temperature, crystallizing at 0-5 ℃, and filtering to obtain a white-like primary filter cake; adding the off-white primary filter cake into a refining bottle, adding 1430mL of purified water, stirring, heating to dissolve, adding 38g of activated carbon, heating, refluxing and decoloring for 40 minutes, and performing hot suction filtration to obtain a light yellow secondary filtrate; cooling to room temperature, crystallizing at 0-5 ℃, and filtering to obtain a white-like secondary filter cake; vacuum drying at 50 deg.C until water content is 5.5-6.5% (adding appropriate amount of phosphorus pentoxide) to obtain 138g of white solid (high purity olprinone hydrochloride), yield is 46.8%, and purity is 99.5%.
The preparation of batch 2 and batch 3 was carried out, the preparation method of batch 2 and batch 3 being the same as batch 1 except that the reactant added in batch 2 was olprinone prepared in step five, batch 2, and the addition of activated carbon during the refining process was increased by 5 wt% compared to batch 1; batch 3 the reactant added was olprinone prepared in step five, batch 3, and the activated carbon added during the refining process was reduced by 5 wt% compared to batch 1. The yield of each batch is shown in table 6:
TABLE 6
| Batches of | Feeding amount of olprinone/g | High-purity olprinone hydrochloride yield/g | Yield/% |
| 1 | 242.3 | 138.1 | 46.8 |
| 2 | 242.1 | 152.5 | 51.7 |
| 3 | 242.4 | 143.7 | 48.7 |
Effect verification
(1) Impurities and purity of high-purity olprinone hydrochloride obtained in example 1 the 3 batches of olprinone hydrochloride finally obtained in example 1 were subjected to property, clarity and color, impurities and purity measurements, and the specific results are shown in table 7:
TABLE 7
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The preparation method of olprinone hydrochloride is characterized by comprising the following steps:
performing cyclization reaction on 2-amino-5-bromopyridine and bromoacetaldehyde diethyl acetal under the protection of nitrogen to obtain 6-bromoimidazo [1, 2-a ] pyridine;
step two, the 6-bromoimidazo [1, 2-a ] pyridine prepared in the step one reacts with magnesium to generate an intermediate product (1), and the intermediate product (1) is coupled with methyl allyl chloride to obtain 6- (2-methyl allyl) imidazo [1, 2-a ] pyridine;
step three, the 6- (2-methylallyl) imidazo [1, 2-a ] pyridine prepared in the step two is subjected to oxidation reaction to obtain 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone;
step four, performing a methylene reaction on the 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone prepared in the step three and N, N-dimethylformamide dimethyl acetal to obtain (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-butene-2-ketone;
step five, performing cyclization reaction on the (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-butene-2-ketone prepared in the step four and cyanoacetamide to obtain olprinone;
reacting the olprinone prepared in the sixth step and the fifth step with a hydrogen chloride ethanol solution to obtain an olprinone hydrochloride crude product, and refining the olprinone hydrochloride crude product to obtain the olprinone hydrochloride;
the structural formula of the 6-bromoimidazo [1, 2-a ] pyridine is shown as a formula (I), the structural formula of the intermediate product (1) is shown as a formula (II), the structural formula of the 6- (2-methylallyl) imidazo [1, 2-a ] pyridine is shown as a formula (III), the structural formula of the 1- (imidazo [1, 2-a ] pyridine-6-yl) -2-acetone is shown as a formula (IV), the structural formula of the (3Z) -4- (dimethylamino) -3- (imidazo [1, 2-a ] pyridine-6-yl) -3-butylene-2-ketone is shown as a formula (V), the structural formula of olprinone is shown as a formula (VI), and the structural formula of olprinone hydrochloride is shown as a formula (VII):
2. the method for preparing olprinone hydrochloride according to claim 1, wherein the cyclization reaction in the step one is refluxed for 20-40h, and then is extracted by chloroform or ethyl acetate after the cyclization reaction is completed.
3. The method for preparing olprinone hydrochloride according to claim 1, wherein the reaction of 6-bromoimidazo [1, 2-a ] pyridine with magnesium in step two is carried out in a mixture of bromoethane and tetrahydrofuran.
4. The method for preparing olprinone hydrochloride according to claim 1, wherein the oxidizing agent used in the oxidation reaction in step three is ozone.
5. The method for preparing olprinone hydrochloride according to claim 1, wherein the reaction temperature of the methylene reaction in step four is 80-90 ℃ and the reaction time is 1.5-4.5 h.
6. The method for preparing olprinone hydrochloride according to claim 1, wherein activated carbon is added for decolorization and purification after the methylene reaction in step four.
7. The method for preparing olprinone hydrochloride according to claim 1, wherein after the cyclization reaction in the fifth step is completed, the reaction solution is treated with acetone to prepare an olprinone solid.
8. The method for preparing olprinone hydrochloride according to claim 1, wherein the refining in the sixth step is specifically performed by: adding the olprinone hydrochloride crude product into purified water for dissolving, then adding activated carbon, decoloring and performing suction filtration to obtain primary filtrate; crystallizing and filtering the filtrate to obtain a primary filter cake; adding the primary filter cake into purified water for dissolving, then adding activated carbon, decoloring and performing suction filtration to obtain secondary filtrate; crystallizing and filtering the secondary filtrate to obtain a secondary filter cake; and carrying out vacuum drying on the secondary filter cake to obtain the olprinone hydrochloride.
9. The method for preparing olprinone hydrochloride according to claim 8, wherein the temperature of vacuum drying is 50 ℃, and the vacuum drying is carried out until the water content is 5.5-6.5%.
10. The method for preparing olprinone hydrochloride according to claim 8, wherein phosphorus pentoxide is further added during the vacuum drying process.
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