CN102268009A - Preparation method for hydrogenated pyridine derivative - Google Patents
Preparation method for hydrogenated pyridine derivative Download PDFInfo
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- CN102268009A CN102268009A CN2011101562591A CN201110156259A CN102268009A CN 102268009 A CN102268009 A CN 102268009A CN 2011101562591 A CN2011101562591 A CN 2011101562591A CN 201110156259 A CN201110156259 A CN 201110156259A CN 102268009 A CN102268009 A CN 102268009A
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Abstract
The invention discloses a preparation method for a hydrogenated pyridine derivative, i.e., 5-(alpha-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-tetramethylene sulfide-o[3,2-C] pyridine (I). The method comprises the following steps of: undergoing a Grignard reaction on o-fluorobenzyl bromide and cyclopropyl cyanogen and undergoing a chlorination reaction to prepare a major intermediate, i.e., alpha-cyclopropyl carbonyl-2-luorobenzyl chloride (II); and undergoing a condensation reaction on (II) and 2-oxy-2,4,5,6,7,7alpha-hexahydro thiophene-o [3,2-C] pyridinium (III) to obtain 5-(alpha-cyclopropyl carbonyl-2-luorobenzyl)-2-oxy-2,4,5,6,7,7alpha-hexahydro thiophene-o [3,2-C] pyridine (I). The preparation method has the advantages of mild reaction temperature, small number of steps, using of low-toxicity reagent and solvent and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to hydrogenated pyridine derivative 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is the preparation method of [3,2-C] pyridines (I) also.
Background technology
The hydrogenated pyridine derivative as: ticlopidine and clopidogrel have been widely used in treating thrombosis and relative disease.And 2-ethanoyl-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-C] pyridines (I) is follow-on hydrogenated pyridine derivative, has good platelet aggregation restraining effect.Its acid addition salt (particularly hydrochloric acid or maleate) has a little less than good oral absorption, metabolic activity and the toxicity, is a kind of rising anti-freezing medicine therefore.5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-C] pyridines (I) are the key intermediates of this hydrogenated pyridine derivative anti-freezing medicine.
US5874581 has reported the synthetic method of a kind of preparation (I).By 2-siloxy-4,5,6,7,-tetramethylene sulfide also the tosilate of [3,2-C] pyridine and the coupling of α-cyclopropyl carbonyl-2-luorobenzyl chlorination thing has obtained 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-siloxy-4,5,6,7 ,-tetramethylene sulfide is [3,2-C] pyridine also.But this method need experience silylation one time, has increased the step of reaction, and this has increased the industrialization cost undoubtedly.
US 5288726 has reported and has utilized α-cyclopropyl carbonyl-2-luorobenzyl bromination thing and 2-oxygen-4,5,6, the 7-tetramethylene sulfide also coupling of the hydrochloride of [3,2-C] pyridine has obtained intermediate 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-4,5,6, the 7-tetramethylene sulfide is [3,2-C] pyridine also.But the yield of this method linked reaction is very low, and will use the bigger solvent C Cl of toxicity when carrying out bromo
4And the amount ratio of aceticanhydride is bigger, and this has all greatly limited large-scale industrial production.
Summary of the invention
For solving the defective that exists in the above-mentioned prior art, the present invention aim to provide a kind of simple to operate, reaction conditions is gentle, step is less, be fit to mass preparation hydrogenated pyridine derivative 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is the method for [3,2-C] pyridines (I) also.
Hydrogenated pyridine derivative 5-of the present invention (α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide also preparation method of [3,2-C] pyridines (I) comprises the steps:
(1) grignard reaction generation intermediate cyclopropyl-2-luorobenzyl ketone (VII) takes place with cyclopropyl cyanogen (VI) in adjacent fluorobenzyl bromide (V).
(2) chlorination generation intermediate α-cyclopropyl carbonyl-2-luorobenzyl chlorination thing (II) takes place in intermediate (VII).
(3) intermediate (II) and 2-oxygen-2,4,5,6, condensation reaction takes place and obtains intermediate 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2 in 7,7 α-six hydrogen thieno-[3,2-C] pyridinium salts (III) under the effect of additive and alkali, 4,5,6,7,7 α-six hydrogen thieno-[3,2-C] pyridines (IV).
Above-mentioned each reaction is represented by following reaction formula:
Wherein, in the described step (1), the preparation of described Grignard reagent is carried out in organic solvent, and used organic solvent has: the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, positive propyl ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether.
Wherein, in the described step (1), the consumption of MAGNESIUM METAL is 1～10 equivalent of substrate.
Wherein, in the described step (1), the temperature of preparation Grignard reagent is different with the difference of reagent, is generally 0～80 ℃, and the reaction times is also different with the difference of reagent, is generally 1～12h.
Wherein, in the described step (1), Grignard reagent and the temperature of the nucleophilic reaction of cyclopropyl cyanogen (VI) are different and different with reagent, are generally 0～100 ℃, and the reaction times is also different with the difference of reagent, is generally 1～24h.And the amount of encircling third cyanogen (VI) is 0.1～10 equivalent of substrate.
Wherein, in the described step (2), temperature of reaction is-20～60 ℃, and the reaction times is 1～24h.
Wherein, in the described step (3), linked reaction is carried out in appropriate solvent, and described solvent is one or more the combination in the following group: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin; Be selected from the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; N, dinethylformamide, N,N-dimethylacetamide, HMPA; Dimethyl sulfoxide (DMSO); Acetone or acetonitrile; The concentration of reaction is 0.01～10 mol.
Wherein, in the described step (3), linked reaction is carried out under the suitable additive effect, and described additive is the combination of following one or more: the inorganic salt of sodium iodide, potassiumiodide, lithium iodide, cesium iodide, Sodium Bromide, Potassium Bromide, lithiumbromide, cesium bromide, sodium-chlor, Repone K, lithium chloride, cesium chloride, sodium pyrosulfate, sal enixum, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium hydrogen phosphate, potassium primary phosphate etc.; The ammonia salt of tetramethyl ammonium chloride, tetramethyl-ammonia bromide, tetramethyl-iodate ammonia, TEA chloride, tetraethyl-ammonia bromide, tetraethyl-iodate ammonia, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride etc.The consumption of additive is 0.1～10 equivalent of substrate.
Wherein, in the described step (3), linked reaction is to carry out under suitable alkali effect, and described alkali is the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, calcium oxide, sodium hydride etc.; Triethylamine, diisopropyl ethyl amine, pyridine, 4-N, the organic bases of N-dimethyl aminopyridine etc.; And the consumption of alkali is 0.5～10 equivalent of substrate.
Wherein, in the described step (3), the temperature of reaction is 0～100 ℃, and the time of reaction is 1～24h.
The present invention and existing preparation hydrogenated pyridine derivative 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide also method of [3,2-C] pyridines (I) is compared advantage and the effect that has:
1, reaction conditions gentleness of the present invention, step is shorter, uses little reagent and the solvent of toxicity, and yield is high, is fit to suitability for industrialized production.
2, the present invention improves the yield and the final product quality of linked reaction by adding the mode of additive; And in esterification, only need to use general alkali and acylating reagent, effectively prevented the decomposition of this unstable compound, improved the yield of reaction.
Embodiment
Those skilled in the art below the present invention elaborated, so that can understand and implement the present invention better.
(1) by compound (V) and (VI) preparation compound (VII).
Adjacent fluorobenzyl bromide (V) reacts in organic solvent earlier with MAGNESIUM METAL and generates Grignard reagent.Used organic solvent is following a kind of: the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, positive propyl ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether.The consumption of MAGNESIUM METAL is 1～10 equivalent of substrate.Temperature of reaction is 0～80 ℃, and the reaction times is 1～12h.With ring third cyanogen (VI) nucleophilic reaction takes place after reaction is finished, the amount of encircling third cyanogen is 0.1～10 equivalent of substrate, and temperature of reaction is 0～100 ℃, and the reaction times is 1～24h.Reaction finishes the back with saturated aqueous ammonium chloride cancellation reaction, carries out purifying through vacuum fractionation or column chromatography, obtains compound (VII).Compound (VII) also can not purifiedly directly down be done.
(2) by compound (VII) preparation compound (II).
Chlorination takes place in compound (VII) and the SULPHURYL CHLORIDE organic solvent.Reaction solvent is the generation that can dissolve substrate and this reaction is free from side effects.Temperature of reaction is-20～60 ℃, and the reaction times is 1～24h.Carry out purifying by underpressure distillation or column chromatography after reaction is finished, obtain compound (II).Compound (II) also can not purifiedly directly down be done.
(3) by compound (II) and (III) preparation compound (I).
Compound (II) and (III) linked reaction takes place under the additive effect and generate compound (I).
This linked reaction is carried out in appropriate solvent, and solvent for use is one or more the combination in the following group: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin; Be selected from the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; N, dinethylformamide, N,N-dimethylacetamide, HMPA; Dimethyl sulfoxide (DMSO); Acetone; Or acetonitrile.The concentration of reaction is 0.01～10 mol.
Additive is the combination of following one or more: the inorganic salt of sodium iodide, potassiumiodide, lithium iodide, cesium iodide, Sodium Bromide, Potassium Bromide, lithiumbromide, cesium bromide, sodium-chlor, Repone K, lithium chloride, cesium chloride, sodium pyrosulfate, sal enixum, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium hydrogen phosphate, potassium primary phosphate etc.; The ammonia salt of tetramethyl ammonium chloride, tetramethyl-ammonia bromide, tetramethyl-iodate ammonia, TEA chloride, tetraethyl-ammonia bromide, tetraethyl-iodate ammonia, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride etc.The consumption of additive is 0.1～10 equivalent of substrate.
This linked reaction also is to carry out under suitable alkali effect, and used alkali is the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, calcium oxide, sodium hydride etc.; Triethylamine, diisopropyl ethyl amine, pyridine, 4-N, the organic bases of N-dimethyl aminopyridine etc.The consumption of alkali is 0.5～10 equivalent of substrate.
The temperature of this linked reaction is 0～100 ℃.
The time of this linked reaction is 1～24h.
Reaction can obtain compound (I) by crystallization after finishing.
Embodiment
Further describe technical scheme of the present invention below by embodiment, but protection scope of the present invention is not limited thereto.
Embodiment one:
Under nitrogen protection, add 9.6g Mg and dry methyl tertiary butyl ether 40mL in three-necked bottle, at room temperature, be added dropwise to the dry methyl tertbutyl ethereal solution of 300mL of the adjacent fluorobenzyl bromide of 75.6g.After dropwising, stirring at room 1 hour.Then, in reaction system, be added dropwise to the dry methyl tertbutyl ethereal solution of 300mL that 26.8g encircles third cyanogen.After dropwising, stirring at room 1 hour, reflux was 2 hours afterwards.After reaction finishes, in system, slowly be added dropwise to saturated aqueous ammonium chloride 300mL, use ethyl acetate extraction, after extraction liquid is used the saturated common salt water washing, anhydrous sodium sulfate drying, decompression desolventizes, (eluent is a sherwood oil to the oily matter that obtains: ethyl acetate=10: 1) carry out purifying through silica gel column chromatography, obtain compound (VII) 55.5g, be yellow oil, yield 70%.
Embodiment two:
Under nitrogen protection, add 131g compound (VII) and dry methylene chloride 500mL in three-necked bottle, at room temperature, slowly drip the 1000mL dichloromethane solution of 99.4g SULPHURYL CHLORIDE, temperature is no more than 30 ℃ in the control, drips at room temperature to stir 1 hour after complete.After reaction finishes, in system, slowly be added dropwise to saturated sodium bicarbonate aqueous solution 1500mL, use dichloromethane extraction, after extraction liquid is used the saturated common salt water washing, anhydrous sodium sulfate drying, decompression desolventizes, (eluent is a sherwood oil to the oily matter that obtains: ethyl acetate=20: 1) carry out purifying through silica gel column chromatography, obtain compound (II) 125g, be yellow oil, yield 82%.
Embodiment three:
Under nitrogen protection, add 106g compound (II), 163g compound (III), 138g salt of wormwood, 75g sodium iodide, 5.5g tetramethyl ammonium chloride in dry dimethyl sulfoxide (DMSO) 2500mL, stirred 14 hours down at 60 ℃.In system, add water, use ethyl acetate extraction.After extraction liquid is used the saturated common salt water washing, anhydrous sodium sulfate drying, decompression desolventizes, and obtains an oily matter.Oily matter isopropyl ether crystallization obtains compound (I) 116g, is light yellow solid, yield 70%.
Claims (10)
1. hydrogenated pyridine derivative 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is the preparation method of [3,2-C] pyridines (I) also, it is characterized in that described method comprises the steps:
(1) grignard reaction generation intermediate cyclopropyl-2-luorobenzyl ketone (VI) takes place with cyclopropyl cyanogen (V) in adjacent fluorobenzyl bromide (IV);
(2) chlorination generation intermediate α-cyclopropyl carbonyl-2-luorobenzyl chlorination thing (II) takes place in intermediate (VI);
(3) intermediate (II) and 2-oxygen-2,4, condensation reaction takes place and obtains (I) in 5,6,7,7 α-six hydrogen thieno-[3,2-C] pyridinium salts (III) under the effect of additive and alkali.
2. the method for claim 1, wherein, in the described step (1), the preparation of described Grignard reagent is carried out in organic solvent, and described organic solvent is following a kind of: the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, positive propyl ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether.
3. in the method for claim 1, wherein described step (1), the consumption of MAGNESIUM METAL is 1～10 equivalent of substrate.
4. in the method for claim 1, wherein described step (1), the temperature of preparation Grignard reagent is different with the difference of reagent, is generally 0～80 ℃, and the reaction times is also different with the difference of reagent, is generally 1～12h.
5. the method for claim 1, wherein, in the described step (1), Grignard reagent and the temperature of the nucleophilic reaction of cyclopropyl cyanogen (VI) are different and different with reagent, be generally 0～100 ℃, reaction times is also different with the difference of reagent, is generally 1～24h, and the amount of encircling third cyanogen (VI) is 0.1～10 equivalent of substrate.
6. in the method for claim 1, wherein described step (2), temperature of reaction is-20～60 ℃, and the reaction times is 1～24h.
7. in the method for claim 1, wherein described step (3), linked reaction is carried out in appropriate solvent, and described solvent is one or more the combination in the following group: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin; Be selected from the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; N, dinethylformamide, N,N-dimethylacetamide, HMPA; Dimethyl sulfoxide (DMSO); Acetone or acetonitrile; The concentration of reaction is 0.01～10 mol.
8. the method for claim 1, wherein, in the described step (3), linked reaction is carried out under the suitable additive effect, and described additive is the combination of following one or more: the inorganic salt of sodium iodide, potassiumiodide, lithium iodide, cesium iodide, Sodium Bromide, Potassium Bromide, lithiumbromide, cesium bromide, sodium-chlor, Repone K, lithium chloride, cesium chloride, sodium pyrosulfate, sal enixum, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium hydrogen phosphate, potassium primary phosphate etc.; The ammonia salt of tetramethyl ammonium chloride, tetramethyl-ammonia bromide, tetramethyl-iodate ammonia, TEA chloride, tetraethyl-ammonia bromide, tetraethyl-iodate ammonia, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride etc.; The consumption of additive is 0.1～10 equivalent of substrate.
9. the method for claim 1, wherein, in the described step (3), linked reaction is to carry out under suitable alkali effect, and described alkali is the mineral alkali that is selected from yellow soda ash or salt of wormwood or sodium bicarbonate or saleratus or cesium carbonate or sodium hydroxide or potassium hydroxide or lithium hydroxide or calcium hydroxide or calcium oxide or sodium hydride; Triethylamine or diisopropyl ethyl amine or pyridine or 4-N, the organic bases of N-dimethyl aminopyridine; And the consumption of alkali is 0.5～10 equivalent of substrate.
10. in the method for claim 1, wherein described step (3), the temperature of reaction is 0～100 ℃, and the time of reaction is 1～24h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101177430A (en) * | 2007-12-11 | 2008-05-14 | 鲁南制药集团股份有限公司 | Hydrogenated pyridine derivative and method for preparing salt thereof |
| WO2009122440A1 (en) * | 2008-03-31 | 2009-10-08 | Torrent Pharmaceuticals Ltd. | PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE |
| CN101888988A (en) * | 2007-11-27 | 2010-11-17 | 埃吉斯药物股份公开有限公司 | The method for preparing pharmaceutical intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101888988A (en) * | 2007-11-27 | 2010-11-17 | 埃吉斯药物股份公开有限公司 | The method for preparing pharmaceutical intermediate |
| CN101177430A (en) * | 2007-12-11 | 2008-05-14 | 鲁南制药集团股份有限公司 | Hydrogenated pyridine derivative and method for preparing salt thereof |
| WO2009122440A1 (en) * | 2008-03-31 | 2009-10-08 | Torrent Pharmaceuticals Ltd. | PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE |
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Application publication date: 20111207 |