CN103087059B - Preparation method for high-purity olprinone hydrochloride - Google Patents
Preparation method for high-purity olprinone hydrochloride Download PDFInfo
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- CN103087059B CN103087059B CN201110331082.4A CN201110331082A CN103087059B CN 103087059 B CN103087059 B CN 103087059B CN 201110331082 A CN201110331082 A CN 201110331082A CN 103087059 B CN103087059 B CN 103087059B
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- 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 59
- 229950005421 olprinone Drugs 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 10
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
- 238000007363 ring formation reaction Methods 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 8
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 7
- FXPMFQUOGYGTAM-UHFFFAOYSA-N 6-bromoimidazo[1,2-a]pyridine Chemical compound C1=C(Br)C=CC2=NC=CN21 FXPMFQUOGYGTAM-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000000284 extract Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 claims description 2
- OHXAOPZTJOUYKM-UHFFFAOYSA-N 3-Chloro-2-methylpropene Chemical compound CC(=C)CCl OHXAOPZTJOUYKM-UHFFFAOYSA-N 0.000 claims description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- MIVWORLDBCICSB-UHFFFAOYSA-N [K].C(C)C(=O)C(=O)C Chemical compound [K].C(C)C(=O)C(=O)C MIVWORLDBCICSB-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NSFXGEUOJPPNLI-FMIVXFBMSA-N CC(/C(/c(cc1)c[n]2c1ncc2)=C\N(C)C)=O Chemical compound CC(/C(/c(cc1)c[n]2c1ncc2)=C\N(C)C)=O NSFXGEUOJPPNLI-FMIVXFBMSA-N 0.000 description 1
- KEHXBISWXRCSIL-UHFFFAOYSA-N CC(Cc(cc1)c[n]2c1ncc2)=O Chemical compound CC(Cc(cc1)c[n]2c1ncc2)=O KEHXBISWXRCSIL-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PWTBMBAQRAOAFF-UHFFFAOYSA-N Olprinone hydrochloride Chemical group Cl.N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C PWTBMBAQRAOAFF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- KBLZFQBDODEHJH-UHFFFAOYSA-N dibutylalumane Chemical compound C(CCC)[AlH]CCCC KBLZFQBDODEHJH-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 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
- BTDBMFODXFTFIL-UHFFFAOYSA-N methyl imidazo[1,2-a]pyridine-6-carboxylate Chemical compound C1=C(C(=O)OC)C=CC2=NC=CN21 BTDBMFODXFTFIL-UHFFFAOYSA-N 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- TZMFJUDUGYTVRY-UHFFFAOYSA-N pentane-2,3-dione Chemical compound CCC(=O)C(C)=O TZMFJUDUGYTVRY-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method for high-purity olprinone hydrochloride, with 2-amino-5-bromopyridine as an initial raw material. A synthetic process of the high-purity olprinone hydrochloride has the advantages of wide raw material sources, mild reaction conditions, high stability/reappearance, high product yield, high purity and low impurity content. Besides, the synthetic process is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of medicinal chemicals, be specifically related to a kind of preparation method of high-purity hydrochloric acid olprinone.
Background technology
Olprinone HCl is phosphodiesterase iii (PDEIII) inhibitor, has the effect that strengthens contractile force and vasodilation, is treatment medicine in heart failure.Nineteen eighty-two the Olprinone HCl that abroad begun one's study, 1986 start clinical trial, within 1996, go on the market first in Japan.
The chemical name of Olprinone HCl (Olprinone Hydrochloride) is, 1,2-dihydro-5-imidazo [1,2-a] pyridine-6-base-6-methyl-2-oxo-3-pyridine carbonitrile hydrochloride monohydrate, and molecular formula is C
14h
11clN
4o, molecular weight is that 286.72, CAS registration number is 119615-63-3, structural formula is as follows:
Document [Chem.Pharm.Bull., 39 (6), 1556-1567 (1991)] reported the following synthetic route of Olprinone HCl: take methylene dichloride as solvent, with dibutyl aluminum hydride reduction imidazo [1,2-a] pyridine-6-carboxylate methyl ester (1), obtain corresponding aldehyde (2).Under the effect of butylamine, in ethanol, reflux, (2) obtain 6-(2-nitro-1-propenyl) imidazo [1,2-a] pyridine (3) with nitroethane condensation.In hot ethanol-water, react with Fe-FeCl2-HCl (3), generates 1-(imidazo [1,2-a] pyridine-6-yl)-2-acetone (4).And N (4), dinethylformamide dimethyl acetal reacts and obtains 4-(dimethylamino)-3-(imidazo [1 in hot DMF, 2-a] pyridine-6-yl)-3-butene-2-one (5), then in hot DMF 5 with malonamide nitrile cyclization under sodium methylate catalysis, generate olprinone (6).The severe reaction conditions of above-mentioned reaction scheme.As the reaction needed of (1) to (2) subzero 60 degree under nitrogen protection react 3 hours; (2) reaction needed that arrives (3) is more than 30 hours; lower to the yield of intermediate (4) from raw material (1): the yield of (1) to (2) reaction is only 17.2%, the yield of (2) to (3) reaction is only 11.9%.Concrete reaction scheme is as shown below:
Document also provides the synthetic route of Olprinone HCl: under the katalysis of KI and CuI, 6-bromine imidazo [1,2-a] pyridine (1) and the condensation of methyl ethyl diketone potassium obtain intermediate (2), and sodium hydroxide hydrolysis (2), hcl acidifying obtains 1-(imidazo [1,2-a] pyridine-6-yl)-2-acetone (3).And N (3), dinethylformamide dimethyl acetal reacts and obtains 4-(dimethylamino)-3-(imidazo [1 in hot DMF, 2-a] pyridine-6-yl)-3-butene-2-one (4), then (4) and malonamide nitrile cyclization under sodium methylate catalysis in hot DMF, generate olprinone (5).Although the reaction conditions of this reaction scheme is gentle, reaction scheme is shorter, and methyl ethyl diketone belongs to the 3rd class hazardous chemical, and methyl ethyl diketone potassium need to face the used time and now prepare, and lower to the yield of intermediate (3) from raw material (1), is only 36%.Reaction scheme is as follows:
Visible, about the synthesis technique of Olprinone HCl, there is many defects such as severe reaction conditions, yield is lower, reagent is more difficult to get in prior art.Therefore, exploitation reaction conditions is gentle, yield is higher, reagent is easy to get, olprinone production technique that can industrialization, is the technical problem that needs those skilled in the art to solve.
Summary of the invention
The invention provides a kind of preparation method of high-purity hydrochloric acid olprinone, comprise following technical scheme:
1, a preparation method for high-purity hydrochloric acid olprinone, comprises the steps:
1) 2-amino-5-bromopyridine and bromacetal carry out ring-closure reaction, obtain 6-bromo imidazo (1,2-a) pyridine;
2) 6-bromo imidazo (1,2-a) pyridine and methallyl chloride carry out linked reaction, obtain 6-(2-methacrylic) imidazo (1,2-a) pyridine;
3) 6-(2-methacrylic) imidazo (1,2-a) pyridine (OP-2), through oxidizing reaction, obtains 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone;
4) 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone (OP-3) and N, dinethylformamide dimethyl acetal carries out methene reaction, obtains (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone;
5) (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone (OP-4) carries out ring-closure reaction with malonamide nitrile, obtains olprinone.
2, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1, step 5 wherein) olprinone reacts with ethanol solution of hydrogen chloride, obtain Olprinone HCl crude product, purified water also adds proper amount of active carbon and refines, and obtains high-purity hydrochloric acid olprinone.
3, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1 or 2, wherein step 1) reactant ring-closure reaction backflow 20-24 hour.
4, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1 or 2, wherein step 1) nitrogen protection of ring-closure reaction process, after ring-closure reaction, by chloroform or ethyl acetate, extract.
5, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1 or 2, wherein step 4) temperature of reaction of metheneization reaction is 80-90 ℃, the reaction times is 1.5-4.5 hour.
7,, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 5, wherein the reaction times of metheneization reaction is 3 hours.
8, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1 or 2, wherein step 4) after metheneization reacted, add the gac purifying that decolours.
9, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1 or 2, wherein step 5) after ring-closure reaction, use acetone treatment reaction solution to carry out the preparation of olprinone solid.
10, according to the preparation method of the high-purity hydrochloric acid olprinone described in item 1 or 2, wherein step 1) reactant ring-closure reaction reflux 22 hours, the nitrogen protection of ring-closure reaction process, extracts by ethyl acetate after ring-closure reaction; Step 4) temperature of reaction of metheneization reaction is 85 ℃, and the reaction times is 3 hours, after metheneization has been reacted, adds the gac purifying that decolours.
Wherein, step 1) after ring-closure reaction, by chloroform or ethyl acetate, extract, advantage is to improve yield.
Wherein, step 4) temperature of reaction of metheneization reaction and time are 80-90 ℃ of reaction 1.5-4.5 hour, and advantage is that yield is high, and impurity is few.Cost is low.
Wherein, step 4) metheneization reaction is 3 hours 85 ℃ of reaction times.Advantage is, yield is the highest, and impurity is minimum.
Wherein, step 4), after metheneization has been reacted, add the gac purifying that decolours.Advantage is that purity is high, is conducive to improve the yield of next step reaction.
Wherein, step 5), after ring-closure reaction, use acetone treatment reaction solution to carry out the preparation of olprinone solid.Advantage is to reduce the potential hazard that bulk drug residual solvent brings.Be more suitable for making pharmaceutical preparation.
Wherein, step 5) olprinone (OP-5) further reacts with ethanol solution of hydrogen chloride, obtains Olprinone HCl crude product, and purified water also adds proper amount of active carbon and refines, and obtains high-purity hydrochloric acid olprinone.Advantage is, carries out under given conditions the refining of Olprinone HCl, and decolour and adsorb impurity by proper amount of active carbon by purified water, is not only Olprinone HCl and is more suitable for making preparation, and production cost reduces greatly.
Synthesis route of the present invention is as follows:
The Olprinone HCl that the present invention makes, content is all more than 99.5%, and single assorted content is all lower than 0.1%.Surprisingly, with select the present invention in the preparation technology of other parameter compare, above-mentioned 10) the hydrochloric acid Ao Puli product produced of preparation technology in many aspects such as purity, yields, there is obvious advantage.
The beneficial effect that the present invention obtains is also:
1) the present invention, by being pushed into 2-amino-5-bromopyridine before starting raw material, makes raw material sources more extensive, and production cost reduces.
2) the present invention uses the three kind solvent ethyl acetate, acetone of low toxicity as reaction or purification by liquid extraction solvent, more meets people with the specification of quality of bulk drug
3) the present invention, by test of many times, has optimized time and the temperature in reaction conditions, has reduced reaction time, has reduced cost.
4) the present invention replaces preparative column with the refining crude product of purified water, and production technique is greatly simplified.
5) through the checking of a plurality of batches, synthesis technique reaction conditions of the present invention is gentle, favorable reproducibility, is applicable to very much suitability for industrialized production.
Accompanying drawing explanation
Fig. 1: the infared spectrum of Olprinone HCl;
Fig. 2: the uv-spectrogram of Olprinone HCl;
Fig. 3: the nucleus magnetic hydrogen spectrum of Olprinone HCl;
Fig. 4: the nuclear-magnetism carbon spectrum of Olprinone HCl.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated, but this shall not be construed as any limitation of the invention.The various raw materials that the present invention relates to, reagent etc. are commercial.
Embodiment 1: ring-closure reaction is prepared 6-bromo imidazo (1,2-a) pyridine (OP-1)
Batch A: nitrogen replacement air, in 50L reaction flask, add 1350g 2-amino-5-bromopyridine, 11.7L propyl carbinol, 4680g bromacetal successively, stirring is warming up to backflow, after backflow 20h, sampling, TLC point plate is observed, raw material reaction is complete, stop heating, be cooled to room temperature, separate out brown solid.Suction filtration, obtains filter cake.Filter cake is added in 900mL purified water, adjust pH 8～9, add ethyl acetate extraction (5L * 2 time), merge organic phase, with saturated common salt water washing (4L * 2 time), then use anhydrous sodium sulfate drying, filter, filtering siccative, concentrate filtrate to dryly, obtain brown solid, add 700mL dehydrated alcohol, be evaporated to dryly, obtain solid.Add the absolute ethyl alcohol and stirring of 10L to dissolve, add proper amount of active carbon, temperature rising reflux decolouring 0.5h, suction filtration, obtains filtrate, be evaporated to dry, 50 ℃ of vacuum-dryings (Vanadium Pentoxide in FLAKES), obtain light yellow to brown solid 883.2g, yield 57.4%.Wherein, TLC monitoring condition is: ethyl acetate: sherwood oil=3: 1, and raw material rf=0.7.
According to the experimental technique of above-mentioned batch of A, the return time of batch B is 22 hours, ethyl acetate extraction; The return time of batch C is 24 hours, chloroform extraction.The yield situation of each batch is as follows:
| Lot number | 2-amino-5-bromopyridine charging capacity (gram) | OP-1 output (gram) | Yield |
| A | 1350.0 | 883.2 | 57.4％ |
| B | 1350.0 | 926.1 | 60.2％ |
| C | 1350.0 | 915.7 | 59.6％ |
Embodiment 2: linked reaction is prepared 6-(2-methacrylic) imidazo (1,2-a) pyridine (OP-2)
Batch A: nitrogen protection, to 50L reaction flask, add 1520mL tetrahydrofuran (THF) and 467g magnesium chips successively, stir, temperature control is less than 40 ℃, is added dropwise to 156g monobromethane, drips and finishes.The 6-bromo imidazo (1 that adds 924g embodiment 1 preparation, 2-a) pyridine, the tetrahydrofuran (THF) mixed solution of 1407g monobromethane and 4400mL, drip and finish, heating reflux reaction 1.5h, be cooled to 50～55 ℃, be added dropwise to the mixed solution of 1800g methallyl chloride and 3660mL tetrahydrofuran (THF), drip and finish, heating reflux reaction 2h, be cooled to room temperature, stop nitrogen, temperature control is less than 30 ℃ reaction solution is added in 6160mL saturated ammonium chloride solution, finish, stratification, water is extracted with ethyl acetate (4L * 3 time), merge organic phase, with anhydrous sodium sulfate drying, suction filtration, obtain filtrate, concentrating under reduced pressure is except desolventizing, obtain resistates, underpressure distillation, collect cut, obtain 570.8g light yellow oil, yield 70.7%.
According to the experimental technique of above-mentioned batch of A, it is 2 hours that batch B reaction reflux time is, and batch C has extended the time of stratification.The yield situation of each batch is as follows:
| Lot number | OP-1 charging capacity (gram) | OP-2 output (gram) | Yield |
| A | 924.1 | 570.8 | 70.7％ |
| B | 924.0 | 586.9 | 72.8％ |
| C | 924.7 | 572.9 | 71.0％ |
Embodiment 3: oxidizing reaction is prepared 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone (OP-3)
Batch A: successively to 6-(2-methacrylic) imidazo (1 that adds 569g embodiment 2 preparations in reactor, 2-a) pyridine, 1305mL methyl alcohol, 1304g concentrated hydrochloric acid, 1305mL purified water, be cooled to-5～-10 ℃, pass into ozone, point plate TLC method is controlled reaction end, react complete, temperature control is less than the aqueous solution that is added dropwise to S-WAT at 30 ℃, slowly adding saturated sodium carbonate solution to adjust system PH is 8～9, be extracted with ethyl acetate (5L * 3 time), saturated common salt water washing (4L * 2 time) for organic phase, add anhydrous sodium sulfate drying, suction filtration, obtain filtrate, be evaporated to dry, obtain light brown to brown oil 429.4g.Yield 74.5%.Wherein, TLC developping agent: ethyl acetate: hexanaphthene=2: 1, with red aubepine chromogenic reagent.
According to the experimental technique of above-mentioned batch of A, a batch B ethyl acetate extraction mode is 5L * 5 time; Batch C ethyl acetate extraction mode is 5L * 4 time.The yield situation of each batch is as follows:
| Lot number | OP-2 charging capacity (gram) | OP-3 output (gram) | Yield |
| A | 569.8 | 429.4 | 74.5％ |
| B | 569.4 | 443.5 | 77.0％ |
| C | 569.6 | 433.2 | 75.2％ |
Embodiment 4: metheneization reaction preparation (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone (OP-4)
Batch A: successively to 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone that adds 427g embodiment 3 preparations in reactor, 2518mL DMF, 591g DMF dimethyl acetal, stirs, heating, 80 ℃ are reacted 1.5 hours, stopped reaction, cooling, add 50g gac, 85 ℃ of insulation 0.5h, hot suction filtration, obtains filtrate, is evaporated to 1/10～1/8, put into refrigerator cooling, separate out solid, filter.70 ℃ of vacuum-dryings, obtain brown solid 310g.Yield 55.1%.
According to the experimental technique of above-mentioned batch of A, repeated B, C batch, batch B was 85 ℃ of reactions 3 hours; Batch C was 90 ℃ of reactions 4.5 hours.The yield situation of each batch is as follows:
| Lot number | OP-3 charging capacity (gram) | OP-4 output (gram) | Yield |
| A | 427.4 | 310.0 | 55.1％ |
| B | 427.3 | 330.2 | 58.7％ |
| C | 427.5 | 312.8 | 55.6％ |
Embodiment 5: ring-closure reaction is prepared olprinone (OP-5)
Batch A: successively to (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone that adds 308g embodiment 4 preparations in reactor, 2726mL N, dinethylformamide, add 168g malonamide nitrile, 151g sodium methylate, is warming up to 80～90 ℃ of reaction 1.5h, be cooled to room temperature, with Glacial acetic acid, adjust pH to 6.0～6.5, separate out solid, stir after 0.5h, suction filtration, obtains filter cake.Filter cake is added in 8L acetone, stir 12h, filter, obtain filter cake, then filter cake is added in 8L acetone and stirs 12h, suction filtration, obtains filter cake.Filter cake is added in 2.5% the sodium hydroxide solution of 5.5L, stir, heating for dissolving, adds the 46g gac 0.5h that decolours at 60-70 ℃.Suction filtration, obtains filtrate, and with Glacial acetic acid, adjusting pH is 7.0～7.5, separates out light yellow solid, stirs after half an hour, and suction filtration, obtains filter cake, proper amount of acetone washing, and 50 ℃ of vacuum-dryings, obtain solid 245.3g, yield 73%.
Experimental technique according to above-mentioned batch of A, has repeated B-C batch, and batch B is 85 ℃ of reactions, and batch C, at 90 ℃, has obtained olprinone (OP-5) equally.The yield situation of each batch is as follows:
| Lot number | OP-4 charging capacity (gram) | OP-5 output (gram) | Yield |
| A | 308.0 | 245.3 | 73.0％ |
| B | 308.1 | 264.1 | 78.6％ |
| C | 308.1 | 248.7 | 74.1％ |
Embodiment 6: the salify of Olprinone HCl, refining (OP)
Batch A: add 242g olprinone successively in reaction flask, 2665mLN, dinethylformamide, stir, be heated to 90～95 ℃, be added dropwise to 4845mL 10% ethanol solution of hydrogen chloride, separate out yellow solid, drip and finish, be cooled to room temperature, suction filtration, obtains filter cake, 50 ℃ of forced air drying 2h, obtain yellow solid 240g.Crude product yield 81.4%.
The 240g Olprinone HCl crude product obtaining is added in refining bottle, add 1820mL purified water, under stirring, be heated to dissolve, add 48g gac, temperature rising reflux decolouring 40 minutes, hot suction filtration, obtains light yellow filtrate, be cooled to room temperature, 0～5 ℃ of crystallization, filters, and obtains off-white color filter cake.White filter cake is added in refining bottle, add 1430mL purified water, under stirring, be heated to dissolve, add 38g gac, temperature rising reflux decolouring 40 minutes, hot suction filtration, obtains light yellow filtrate, is cooled to room temperature, and 0～5 ℃ of crystallization filters, and obtains off-white color filter cake.50 ℃ of vacuum-dryings are to moisture 5.5%～6.5% (adding appropriate Vanadium Pentoxide in FLAKES).Obtain white solid 138g, yield 46.8%, purity is 99.5%.
Experimental technique according to above-mentioned batch of A, has repeated B-C batch, and the consumption of gac floats upper and lower 5% respectively, has obtained equally high-purity hydrochloric acid olprinone.The yield situation of each batch is as follows:
| Lot number | OP-5 charging capacity | Output | Yield |
| A | 242.3 | 138.1 | 46.8％ |
| B | 242.1 | 152.5 | 51.7％ |
| C | 242.4 | 143.7 | 48.7％ |
The situations such as the impurity of Olprinone HCl prepared by the present invention, purity are as follows:
Accompanying drawing 1-4 is shown in by the structural identification collection of illustrative plates of the high-purity hydrochloric acid olprinone that the present invention obtains.
Claims (2)
1. a preparation method for Olprinone HCl, comprises the steps:
1) 2-amino-5-bromopyridine and bromacetal carry out ring-closure reaction, obtain 6-bromo imidazo (1,2-a) pyridine;
2) 6-bromo imidazo (1,2-a) pyridine and methallyl chloride carry out linked reaction, obtain 6-(2-methacrylic) imidazo (1,2-a) pyridine:
；
3) 6-(2-methacrylic) imidazo (1,2-a) pyridine, through oxidizing reaction, obtains 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone;
4) 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone and N, N-dimethyl formamide dimethyl acetal carries out methene reaction, obtains (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone;
5) (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone and malonamide nitrile carry out ring-closure reaction, obtain olprinone;
Wherein the olprinone of step 5) reacts with ethanol solution of hydrogen chloride, obtains Olprinone HCl crude product, and purified water also adds proper amount of active carbon and refines, and obtains Olprinone HCl.
2. the preparation method of Olprinone HCl according to claim 1, wherein the reactant ring-closure reaction backflow 20-24 hour of step 1).
3. the preparation method of Olprinone HCl according to claim 1 and 2, wherein step 1) ring-closure reaction process nitrogen protection, extracts by chloroform or ethyl acetate after ring-closure reaction.
4. the preparation method of Olprinone HCl according to claim 1 and 2, wherein the temperature of reaction of step 4) metheneization reaction is 80-90 ℃, the reaction times is 1.5-4.5 hour.
5. the preparation method of Olprinone HCl according to claim 4, wherein the reaction times of metheneization reaction is 3 hours.
6. the preparation method of Olprinone HCl according to claim 1 and 2, after wherein step 4) metheneization has been reacted, adds the gac purifying that decolours.
7. the preparation method of Olprinone HCl according to claim 1 and 2, wherein, after step 5) ring-closure reaction, uses acetone treatment reaction solution to carry out the preparation of olprinone solid.
8. the preparation method of Olprinone HCl according to claim 1 and 2, wherein the reactant ring-closure reaction of step 1) refluxes 22 hours, and the nitrogen protection of ring-closure reaction process, extracts by ethyl acetate after ring-closure reaction; The temperature of reaction of step 4) metheneization reaction is 85 ℃, and the reaction times is 3 hours, after metheneization has been reacted, adds the gac purifying that decolours.
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| CN110015988B (en) * | 2018-01-10 | 2020-06-23 | 新发药业有限公司 | Preparation method of 3-amino-4-methylpyridine |
| CN109575017A (en) * | 2018-11-01 | 2019-04-05 | 山东蒲济医药科技有限公司 | A kind of preparation method of Olprinone HCl compound |
| CN112194657B (en) * | 2020-10-16 | 2021-07-30 | 济川(上海)医学科技有限公司 | Heterocyclic compound, preparation method and application thereof |
| CN114773341A (en) * | 2022-05-10 | 2022-07-22 | 河北爱尔海泰制药有限公司 | Preparation method of olprinone hydrochloride |
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| CN111499631A (en) * | 2020-06-02 | 2020-08-07 | 山东美泰医药有限公司 | Preparation method of olprinone hydrochloride key intermediate |
| CN111499631B (en) * | 2020-06-02 | 2021-07-30 | 济南康桥医药科技有限公司 | Preparation method of olprinone hydrochloride key intermediate 1-imidazo [1,2-a ] pyridin-6-yl-2-acetone |
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