CN102101827B - Method for preparing Prasugrel intermediate alpha-cyclopropyl carbonyl-2-fluorobenzyl halide - Google Patents
Method for preparing Prasugrel intermediate alpha-cyclopropyl carbonyl-2-fluorobenzyl halide Download PDFInfo
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- CN102101827B CN102101827B CN 201010544053 CN201010544053A CN102101827B CN 102101827 B CN102101827 B CN 102101827B CN 201010544053 CN201010544053 CN 201010544053 CN 201010544053 A CN201010544053 A CN 201010544053A CN 102101827 B CN102101827 B CN 102101827B
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Abstract
The invention discloses a method for preparing a Prasugrel intermediate alpha-cyclopropyl carbonyl-2-fluorobenzyl halide, and belongs to compound preparation in the fields of chemical engineering and pharmacy. The method is characterized in that: cyclopropyl-2-fluorobenzyl ketone (a) is taken as an initiative material, and is reacted with a halogenating reagent at the temperature of between 0 and 70DEG C for 0.5 to 3 hours in a solvent-free medium under the condition of stirring in the presence of a catalyst, so that the target product alpha-cyclopropyl carbonyl-2-fluorobenzyl halide is prepared. The method has the advantages of short halogenations time, low reaction temperature, high product purity and yield, stable and safe reaction, energy conservation, and contribution to environmental protection; an organic solvent is not used as a reaction medium, so that energy is saved and the environment is protected; a radical initiator is not adopted, so that defect that the radical reaction is violet and difficult to control is overcome; and the yield of the intermediate alpha-cyclopropyl carbonyl-2-fluorobenzyl halide is more than or equal to 95 percent generally, the purity is more than or equal to 93 percent, and the alpha-cyclopropyl carbonyl-2-fluorobenzyl halide is not needed to be separated and can be directly used for preparing Prasugrel.
Description
Technical field
The present invention is the preparation method of a kind of prasugrel intermediate α-cyclopropyl carbonyl-2-luorobenzyl halogen.Belong to the preparation of compound in chemical industry and the pharmacy field.
Background technology
The Thienopyridines medicine is ticlopidine for example, and clopidogrel has been used to treat the formation of thrombus and relevant disease.Prasugrel also goes on the market as the oral antiplatelet drug of thiophene pyridines of a new generation, and shown in the following formula II of its hydrochloride structural formula, traded commodity is called Effient.
EP0542411 has at first reported the method that synthetic prasugrel is of paramount importance, mainly with α-cyclopropyl carbonyl-2-luorobenzyl halogen (I) and 2-oxygen-2,4,5,6,7, and hydrochloride (IV) condensation of 7a-six hydrogen thieno-[3,2-c] pyridines and obtaining.
Be to obtain, be shown below by cyclopropyl-2-luorobenzyl ketone halogenation as the key intermediate compound I:
And existing halogenating reaction method is unsatisfactory, and the halogenation method of therefore seeking more simple, environmental protection, energy-saving safe seems particularly important.The patent WO2009068924 of people such as Mezei Tibor application has summed up the method for existing preparation α-cyclopropyl carbonyl-2-luorobenzyl halogen (I).
First kind with bromine brominated compound a in tetracol phenixin, methylene dichloride or acetic acid, long reaction time, of paramount importance is that the purity of compound I is low, which kind of solvent purity all is lower than 30%, and by product and product compound I structural similitude, be that column chromatography is separated or rectifying separation is all very difficult.Patent EP0542411 is this kind method that adopts, and patent US20100094013 is with chlorine chlorinated cpds a in methylene dichloride, and it is high that operational difficulty, industrial equipment require, yield only about 80%.
The bromide reagent of second method is NBS, catalyzer is benzoyl peroxide, Diisopropyl azodicarboxylate etc., solvent is tetracol phenixin, chloroform, long reaction time, back flow reaction temperature are higher, increase though compare first method purity, also just about 80%, yield only about 70%, wherein be very easy in the reaction process dash material, cause hazardous condition.At present the great majority report is this kind method that adopts, for example patent US6693115, WO2009062044, WO2009066326, and they are the same with first method, the separation and purification difficulty of compound I.And patent WO2009122440 has adopted new bromide reagent DBDMH, though yield can reach 93%, DBDMH large usage quantity, and does not report its purity, equally also needs to reflux, and the reaction times is longer.
Above-mentioned two kinds of common shortcomings of method are long reaction time, temperature of reaction height, reaction solvent toxicity height, and the environmental requirement height, the most important is that product purity is low, yield is not high, separation difficulty.
Mezei Tibor recognizes the various shortcoming of aforesaid method, and the industrialization difficulty, has therefore reported new bromination process in patent WO2009068924.They have adopted hydrogen halide solution and hydrogen peroxide is halide reagent, be halide reagent with halogenated alkali metal salt, sulfuric acid, hydrogen peroxide perhaps, being equipped with compound I purity according to this legal system is greatly improved, general purity is all greater than 85%, even can reach 95%, and of paramount importance is that impurity mainly is unreacted raw material, it does not participate in preparing next step reaction of prasugrel, therefore do not need to separate to remove, even if separate, so get final product by distillation owing to molecular weight differs greatly.But according to the 6th of its claims and the 7th as can be known: reaction still needs to add organic solvent soluble in water and phase-transfer catalyst, organic solvent is the alcohol of dioxane, acetic acid, tetrahydrofuran (THF), a 1-4 carbon for example, their requirements when in industrialization are big, same environmental pollution, and recovery soluble in water is difficult, reclaims power consumption greatly; Secondly the halogenating reaction temperature is higher, generally all at 80 ℃-90 ℃.
Above method catalyst system therefor mostly is radical initiator, so reaction mechanism substantially all is free radical reaction, in case that the shortcoming of free radical reaction is exactly initiation reaction is acutely wayward, hazard level is big, and side reaction is more, and this is that product purity is low, the reason that impurity is more.
In sum, also there is following deficiency in the prior art:
The halogenating reaction time long, the temperature of reaction height, product purity is low, productive rate is low.
2. adopting organic solvent is reaction medium, wastes energy contaminate environment.
3. employing radical initiator, so reaction mechanism substantially all is free radical reaction, should be violent, and wayward, have potential safety hazard, and side reaction is more, cause product purity low.
Summary of the invention
Summary of the invention
The objective of the invention is to avoid above-mentioned weak point of the prior art, and provide a kind of halogenating reaction time short, temperature of reaction is low, product purity height, yield height; Reacting balance, safety, save energy is of value to the preparation method of the prasugrel intermediate α-cyclopropyl carbonyl-2-luorobenzyl halogen of environment protection.
Purpose of the present invention can reach by following measure:
The preparation method of prasugrel intermediate α of the present invention-cyclopropyl carbonyl-2-luorobenzyl halogen, it is characterized in that: be starting raw material with cyclopropyl-2-luorobenzyl ketone (a), catalyzer exists and stirs down, in solvent-free medium, the control temperature of reaction is in 0～70 ℃ of scope, with halide reagent reaction 0.5～3 hour, preparation target product α-cyclopropyl carbonyl-2-luorobenzyl halogen (1), reaction formula is as follows:
In the formula, X is chlorine atom or bromine atoms.
The solvent-free method of the present invention, be catalyzer with toluene sulfonic acide or protonic acid or trifluoromethanesulfonic acid trimethyl silicane, variation has taken place in reaction mechanism, it no longer is free radical reaction, but be similar to the mechanism of ionic reaction, reaction is easy to control and the safety that becomes, and the few product purity height of impurity, and the reaction times is short.Possible reaction mechanism is as follows:
Mechanism 1:
Mechanism 2:
Mechanism 3:
Reasonable raw material proportioning in addition, suitable reaction is regulated, and carries out halogenating reaction under condition of no solvent, does not need solvent, temperature of reaction is low, the reaction times is short, environmental friendliness, yield height.Thereby finished task of the present invention.
Purpose of the present invention can also reach by following measure:
The preparation method of prasugrel intermediate α of the present invention-cyclopropyl carbonyl-2-luorobenzyl halogen, described halide reagent is a kind of in N-chlorosuccinimide (NCS), N-bromo-succinimide (NBS), C5H6Br2N2O2 (DBDMH), two chlordantoins (DCDMH).
The preparation method of prasugrel intermediate α of the present invention-cyclopropyl carbonyl-2-luorobenzyl halogen, in the described halide reagent, the mass ratio of halogen atom and compound a is 0.9～1.2: 1, is preferably 0.98～1.1: 1.
The preparation method of prasugrel intermediate α of the present invention-cyclopropyl carbonyl-2-luorobenzyl halogen, described halogenating reaction catalyzer is p-methyl benzenesulfonic acid (PTSA), any one in the trifluoromethanesulfonic acid trimethyl silicane (TMS-OTf).The amount of catalyzer is 5～15% of compound a quality, preferred 10%.
The disclosed technical scheme of preparation method of prasugrel intermediate α of the present invention-cyclopropyl carbonyl-2-luorobenzyl halogen has following positively effect compared to existing technology:
1. provide a kind of halogenating reaction time short, temperature of reaction is low, product purity height, yield height; Reacting balance, safety, save energy is of value to the preparation method of the prasugrel intermediate α-cyclopropyl carbonyl-2-luorobenzyl halogen of environment protection.
2. the halogenating reaction time lacks, and temperature of reaction is low, product purity height, productive rate height.
3. be reaction medium without organic solvent, save energy, protection environment.
4. do not adopt radical initiator, it is violent to have overcome free radical reaction, uppity drawback, and reacting balance, and also side reaction is few.
5. the intermediate α-cyclopropyl carbonyl that obtains-2-luorobenzyl halogen yield is general 〉=and 95%, and also purity 〉=93%, need not separate, can be directly used in the preparation prasugrel.
Embodiment
The present invention will now be further detailed embodiment:
Embodiment 1
Preparation α-cyclopropyl carbonyl-2-fluoro benzyl bromide
20.0g in cyclopropyl-2-luorobenzyl ketone, stir and add 22.0gNBS and 1.92gPTSA down, room temperature reaction 2 hours, add the 100ml hexanaphthene, add 10% Sodium Pyrosulfite 60ml, stirred 10 minutes, organic layer washs with 5% sodium bicarbonate 150ml, wash 100ml*2 again, dried over sodium sulfate, evaporate to dryness gets α-cyclopropyl carbonyl-2-fluoro benzyl bromide 28.1g.Yield 97.2%, HPLC purity 96.5%.
Embodiment 2
Preparation α-cyclopropyl carbonyl-2-fluorobenzyl chloride
20.0g in cyclopropyl-2-luorobenzyl ketone, stir and add 16.0gNCS and 1.92gPTSA down, 45 ℃ were reacted 2.5 hours, add the 100ml hexanaphthene, add 10% Sodium Pyrosulfite 60ml, stirred 10 minutes, organic layer washs with 5% sodium bicarbonate 150ml, wash 100ml*2 again, dried over sodium sulfate, evaporate to dryness gets α-cyclopropyl carbonyl-2-fluorobenzyl chloride 22.7g.Yield 95.1%, HPLC purity 94.6%.
Embodiment 3
Preparation α-cyclopropyl carbonyl-2-fluoro benzyl bromide
20.0g in cyclopropyl-2-luorobenzyl ketone, stir and add 16.0g DBDMH and 2.5g TMS-OTf down, 5 ℃ were reacted 0.5 hour, add the 100ml hexanaphthene, add 10% Sodium Pyrosulfite 60ml, stirred 10 minutes, organic layer washs with 5% sodium bicarbonate 150ml, wash 100ml*2 again, dried over sodium sulfate, evaporate to dryness gets α-cyclopropyl carbonyl-2-fluoro benzyl bromide 28.3g.Yield 98.1%, HPLC purity 93.5%.
Embodiment 4
Preparation α-cyclopropyl carbonyl-2-fluorobenzyl chloride
20.0g in cyclopropyl-2-luorobenzyl ketone, stir and add 11.0g DCDMH and 2.5g TMS-OTf down, 10 ℃ were reacted 1 hour, add the 100ml hexanaphthene, add 10% Sodium Pyrosulfite 60ml, stirred 10 minutes, organic layer washs with 5% sodium bicarbonate 150ml, wash 100ml*2 again, dried over sodium sulfate, evaporate to dryness gets α-cyclopropyl carbonyl-2-fluorobenzyl chloride 22.9g.Yield 96.1%, HPLC purity 94.1%.
Embodiment 5
Preparation α-cyclopropyl carbonyl-2-fluoro benzyl bromide
20.0g in cyclopropyl-2-luorobenzyl ketone, stir and add 21.0g NBS and 2.5g TMS-OTf down, room temperature reaction 3 hours, add the 100ml hexanaphthene, add 10% Sodium Pyrosulfite 60ml, stirred 10 minutes, organic layer washs with 5% sodium bicarbonate 150ml, wash 100ml*2 again, dried over sodium sulfate, evaporate to dryness gets α-cyclopropyl carbonyl-2-fluoro benzyl bromide 27.4g.Yield 95.1%, HPLC purity 93.5%.
Claims (3)
1. the preparation method of prasugrel intermediate α-cyclopropyl carbonyl-2-luorobenzyl halogen, it is characterized in that with cyclopropyl-2-luorobenzyl ketone (a) be starting raw material, catalyzer exists and stirs down, in solvent-free medium, the control temperature of reaction is in 0～70 ℃ of scope, with halide reagent reaction 0.5～3 hour, preparation target product α-cyclopropyl carbonyl-2-luorobenzyl halogen (I), reaction formula is as follows:
In the formula, X is chlorine atom or bromine atoms;
Described halide reagent is a kind of in N-chlorosuccinimide, N-bromo-succinimide, C5H6Br2N2O2, two chlordantoins, and the mass ratio of halogen atom and compound a is 0.9～1.2:1;
Described halogenating reaction catalyzer is p-methyl benzenesulfonic acid, any one in the trifluoromethanesulfonic acid trimethyl silicane, and the amount of catalyzer is 5～15% of compound a quality.
2. according to the preparation method of the prasugrel intermediate α-cyclopropyl carbonyl-2-luorobenzyl halogen of claim 1, it is characterized in that in the described halide reagent that the mass ratio of halogen atom and compound a is 0.98～1.1:1.
3. according to the preparation method of the prasugrel intermediate α-cyclopropyl carbonyl-2-luorobenzyl halogen of claim 1, it is characterized in that described catalyst consumption be compound a quality 10%.
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| CN101675058A (en) * | 2007-03-02 | 2010-03-17 | 第一三共株式会社 | Process for the preparation of high-purity prasugrel hydrochloride |
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| CN101675058A (en) * | 2007-03-02 | 2010-03-17 | 第一三共株式会社 | Process for the preparation of high-purity prasugrel hydrochloride |
Non-Patent Citations (4)
| Title |
|---|
| 孙志国等.普拉格雷的合成.《中国医药工业杂志》.2009,第40卷(第4期),第244-246页. |
| 普拉格雷中间体的合成研究;荆亚萍等;《广东药学院学报》;20090630;第25卷(第3期);第272-274页 * |
| 普拉格雷的合成;孙志国等;《中国医药工业杂志》;20091231;第40卷(第4期);第244-246页 * |
| 荆亚萍等.普拉格雷中间体的合成研究.《广东药学院学报》.2009,第25卷(第3期),第272-274页. |
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