CN103087059A - Preparation method for high-purity olprinone hydrochloride - Google Patents
Preparation method for high-purity olprinone hydrochloride Download PDFInfo
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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, beginning clinical trial in 1986 was gone on the market in Japan in 1996 first.
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 are that 286.72, CAS registration number is 119615-63-3, and 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, obtain corresponding aldehyde (2) with dibutyl aluminum hydride reduction imidazo [1,2-a] pyridine-6-carboxylate methyl ester (1).Under the effect of butylamine, reflux in ethanol, (2) obtain 6-(2-nitro-1-propenyl) imidazo [1,2-a] pyridine (3) with the nitroethane condensation.(3) and Fe-FeCl2-HCl reaction, generate 1-(imidazo [1,2-a] pyridine-6-yl)-2-acetone (4) in hot ethanol-water.(4) and N, the dinethylformamide dimethyl acetal reacts in hot DMF and obtains 4-(dimethylamino)-3-(imidazo [1,2-a] pyridine-6-yl)-3-butene-2-ketone (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.Reaction needed subzero 60 degree under nitrogen protection as (1) to (2) reacted 3 hours; (2) to the reaction needed of (3) more than 30 hours; yield from raw material (1) to intermediate (4) is lower: the yield of (1) to (2) reaction is only 17.2%, and 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), (2) and sodium hydroxide hydrolysis, hcl acidifying obtains 1-(imidazo [1,2-a] pyridine-6-yl)-2-acetone (3).(3) and N, the dinethylformamide dimethyl acetal reacts in hot DMF and obtains 4-(dimethylamino)-3-(imidazo [1,2-a] pyridine-6-yl)-3-butene-2-ketone (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 the yield from raw material (1) to intermediate (3) is lower, is only 36%.Reaction scheme is as follows:
As seen, about the synthesis technique of Olprinone HCl, there are many defectives such as severe reaction conditions, yield is lower, reagent is more difficult to get in prior art.Therefore, the 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 kind of preparation method of high-purity hydrochloric acid olprinone, comprise 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, the dinethylformamide dimethyl acetal carries out the 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, the preparation method of high-purity hydrochloric acid olprinone described according to item 1, step 5 wherein) olprinone and ethanol solution of hydrogen chloride reaction, obtain the Olprinone HCl crude product, purified water also adds proper amount of active carbon and makes with extra care, and obtains the high-purity hydrochloric acid olprinone.
3, the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 1) reactant ring-closure reaction backflow 20-24 hour.
4, the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 1) nitrogen protection of ring-closure reaction process, extract with chloroform or ethyl acetate after ring-closure reaction.
5, the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 4) temperature of reaction of methene reaction is 80-90 ℃, the reaction times is 1.5-4.5 hour.
7, the preparation method of high-purity hydrochloric acid olprinone described according to item 5, wherein the reaction times of methene reaction is 3 hours.
8, the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 4) after the methene reaction completes, add the gac purifying that decolours.
9, the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 5) after ring-closure reaction, use the acetone treatment reaction solution to carry out the preparation of olprinone solid.
10, the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 1) the reactant ring-closure reaction refluxed 22 hours, the nitrogen protection of ring-closure reaction process extracts with ethyl acetate after ring-closure reaction; Step 4) temperature of reaction of methene reaction is 85 ℃, and the reaction times is 3 hours, after the methene reaction is completed, adds the gac purifying that decolours.
Wherein, step 1) extract with chloroform or ethyl acetate after ring-closure reaction, advantage is to improve yield.
Wherein, step 4) temperature of reaction of methene 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) the methene reaction is 3 hours 85 ℃ of reaction times.Advantage is, yield is the highest, and impurity is minimum.
Wherein, step 4) after the methene reaction is completed, 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 the acetone treatment reaction solution to carry out the preparation of olprinone solid.Advantage is to reduce the potential hazard that the bulk drug residual solvent brings.Be more suitable for making pharmaceutical preparation.
Wherein, step 5) olprinone (OP-5) further with the ethanol solution of hydrogen chloride reaction, obtain the Olprinone HCl crude product, purified water also adds proper amount of active carbon and makes with extra care, and obtains the high-purity hydrochloric acid olprinone.Advantage is, carries out under given conditions the refining of Olprinone HCl with purified water, and decolours and adsorb impurity with proper amount of active carbon, 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 are all more than 99.5%, and single assorted content is all lower than 0.1%.Beat allly be, 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 have obvious advantage in many aspects such as purity, yields.
The beneficial effect that the present invention obtains also is:
1) the present invention is pushed into 2-amino-5-bromopyridine before with starting raw material, makes raw material sources more extensive, and production cost reduces.
2) the present invention use low toxicity three kind solvent ethyl acetate, acetone as reaction or purification by liquid extraction solvent, more meet the specification of quality of human bulk drug
3) the present invention by test of many times, has optimized time and the temperature in the 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 fit to very much suitability for industrialized production.
Description of drawings
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
The present invention is further illustrated below in conjunction with embodiment, 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 prepares 6-bromo imidazo (1,2-a) pyridine (OP-1)
Batch A: nitrogen replacement air, add 1350g 2-amino-5-bromopyridine successively in the 50L reaction flask, 11.7L propyl carbinol, 4680g bromacetal, stirring is warming up to backflow, after backflow 20h, sampling, TLC point plate is observed, raw material reaction is complete, stopped heating is cooled to room temperature, separates out brown solid.Suction filtration gets filter cake.Filter cake is added in the 900mL purified water, transfer 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, the filtering siccative, filtrate decompression is concentrated into dried, gets brown solid, add the 700mL dehydrated alcohol, be evaporated to driedly, get solid.Add the absolute ethyl alcohol and stirring dissolving of 10L, add proper amount of active carbon, temperature rising reflux decolouring 0.5h, suction filtration gets filtrate, be evaporated to dried, 50 ℃ of vacuum-dryings (Vanadium Pentoxide in FLAKES), get light yellow to brown solid 883.2g, yield 57.4%.Wherein, TLC monitoring condition is: ethyl acetate: sherwood oil=3: 1, 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 prepares 6-(2-methacrylic) imidazo (1,2-a) pyridine (OP-2)
Batch A: nitrogen protection, add 1520mL tetrahydrofuran (THF) and 467g magnesium chips to the 50L reaction flask successively, stir, temperature control is added dropwise to the 156g monobromethane less than 40 ℃, drips to finish.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 adds to reaction solution in the 6160mL saturated ammonium chloride solution less than 30 ℃, finish, standing demix, water is with ethyl acetate extraction (4L * 3 time), merge organic phase, use anhydrous sodium sulfate drying, suction filtration, get filtrate, the concentrating under reduced pressure desolventizing, get resistates, underpressure distillation, collect cut, obtain the 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 standing demix.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 prepares 1-(imidazo (1,2-a) pyridine-6-yl)-2-acetone (OP-3)
batch A: 6-(2-methacrylic) imidazo (1 that adds successively 569g embodiment 2 preparations in the reactor, 2-a) pyridine, 1305mL methyl alcohol, the 1304g concentrated hydrochloric acid, the 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 under 30 ℃, slowly adding saturated sodium carbonate solution to transfer system PH is 8～9, with ethyl acetate extraction (5L * 3 time), organic phase is with saturated common salt water washing (4L * 2 time), add anhydrous sodium sulfate drying, suction filtration, get filtrate, be evaporated to dried, get 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: methene reaction preparation (3Z)-4-(dimethylamino)-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone (OP-4)
Batch A: add successively the 1-(imidazo (1,2-a) pyridine-6-yl) of 427g embodiment 3 preparations-2-acetone in the reactor, 2518mL DMF, 591g DMF dimethyl acetal stirs, heating, 80 ℃ were reacted 1.5 hours, stopped reaction, cooling, add the 50g gac, 85 ℃ of insulation 0.5h, hot suction filtration gets filtrate, is evaporated to 1/10～1/8, put into refrigerator cooling, separate out solid, filter.70 ℃ of vacuum-dryings get 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 prepares olprinone (OP-5)
Batch A: add successively (the 3Z)-4-(dimethylamino) of 308g embodiment 4 preparations-3-(imidazo (1,2-a) pyridine-6-yl)-3-butene-2 ketone in the reactor, 2726mL N, dinethylformamide, add the 168g malonamide nitrile, the 151g sodium methylate is warming up to 80～90 ℃ of reaction 1.5h, be cooled to room temperature, transfer pH to 6.0～6.5 with Glacial acetic acid, separate out solid, after stirring 0.5h, suction filtration gets filter cake.Filter cake is added in 8L acetone, stir 12h, filter, get filter cake, then filter cake is added in 8L acetone stir 12h, suction filtration gets 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 under 60-70 ℃.Suction filtration gets filtrate, and transferring pH with Glacial acetic acid is 7.0～7.5, separates out light yellow solid, and after stirring half an hour, suction filtration gets filter cake, the proper amount of acetone washing, and 50 ℃ of vacuum-dryings get solid 245.3g, yield 73%.
According to the experimental technique of above-mentioned batch of A, repeated B-C batch, batch B is 85 ℃ of reactions, and batch C has obtained olprinone (OP-5) equally at 90 ℃.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 the 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 gets filter cake, 50 ℃ of forced air drying 2h get yellow solid 240g.Crude product yield 81.4%.
The 240g Olprinone HCl crude product that obtains is added in refining bottle, add the 1820mL purified water, under stirring, be heated to dissolving, add the 48g gac, temperature rising reflux decolouring 40 minutes, hot suction filtration gets light yellow filtrate, be cooled to room temperature, 0～5 ℃ of crystallization filters, and gets the off-white color filter cake.White filter cake is added in refining bottle, add the 1430mL purified water, under stirring, be heated to dissolving, add the 38g gac, temperature rising reflux decolouring 40 minutes, hot suction filtration gets light yellow filtrate, is cooled to room temperature, and 0～5 ℃ of crystallization filters, and gets the off-white color filter cake.50 ℃ of vacuum-dryings are to moisture 5.5%～6.5% (adding appropriate Vanadium Pentoxide in FLAKES).Get white solid 138g, yield 46.8%, purity is 99.5%.
According to the experimental technique of above-mentioned batch of A, repeated B-C batch, the consumption of gac 5% floating up and down, has obtained the high-purity hydrochloric acid olprinone respectively equally.The yield situation of each batch is as follows:
| Lot number | The 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 the Olprinone HCl of the present invention's preparation, purity are as follows:
The structural identification collection of illustrative plates of the high-purity hydrochloric acid olprinone that the present invention obtains is seen accompanying drawing 1-4.
Claims (9)
1. the preparation method of a high-purity hydrochloric acid olprinone, comprise 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, the dinethylformamide dimethyl acetal carries out the 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. the preparation method of high-purity hydrochloric acid olprinone described according to item 1, step 5 wherein) olprinone and ethanol solution of hydrogen chloride reaction, obtain the Olprinone HCl crude product, purified water also adds proper amount of active carbon and makes with extra care, and obtains the high-purity hydrochloric acid olprinone.
3. the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 1) reactant ring-closure reaction backflow 20-24 hour.
4. the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 1) nitrogen protection of ring-closure reaction process, extract with chloroform or ethyl acetate after ring-closure reaction.
5. the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 4) temperature of reaction of methene reaction is 80-90 ℃, the reaction times is 1.5-4.5 hour.
6. the preparation method of high-purity hydrochloric acid olprinone described according to item 5, wherein the reaction times of methene reaction is 3 hours.
7. the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 4) after the methene reaction completes, add the gac purifying that decolours.
8. the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 5) after ring-closure reaction, use the acetone treatment reaction solution to carry out the preparation of olprinone solid.
9. the preparation method of high-purity hydrochloric acid olprinone described according to item 1 or 2, wherein step 1) the reactant ring-closure reaction refluxed 22 hours, the nitrogen protection of ring-closure reaction process extracts with ethyl acetate after ring-closure reaction; Step 4) temperature of reaction of methene reaction is 85 ℃, and the reaction times is 3 hours, after the methene reaction is completed, adds the gac purifying that decolours.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106349246A (en) * | 2016-08-29 | 2017-01-25 | 山东百诺医药股份有限公司 | Preparation method of olprinone and 9-azaindole-5-boric acid |
| 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 |
| CN110015988A (en) * | 2018-01-10 | 2019-07-16 | 新发药业有限公司 | A kind of simple and convenient process for preparing of low cost 3- amino-4-methylpyridine |
| CN112194657A (en) * | 2020-10-16 | 2021-01-08 | 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349246A (en) * | 2016-08-29 | 2017-01-25 | 山东百诺医药股份有限公司 | Preparation method of olprinone and 9-azaindole-5-boric acid |
| CN110015988A (en) * | 2018-01-10 | 2019-07-16 | 新发药业有限公司 | A kind of simple and convenient process for preparing of low cost 3- amino-4-methylpyridine |
| 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 |
| CN112194657A (en) * | 2020-10-16 | 2021-01-08 | 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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