CN104163778B - A kind of method preparing p-amino-benzamidine hydrochloride - Google Patents
A kind of method preparing p-amino-benzamidine hydrochloride Download PDFInfo
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- CN104163778B CN104163778B CN201410360670.4A CN201410360670A CN104163778B CN 104163778 B CN104163778 B CN 104163778B CN 201410360670 A CN201410360670 A CN 201410360670A CN 104163778 B CN104163778 B CN 104163778B
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Abstract
The present invention relates to field of pharmaceutical chemistry technology, provide a kind of method preparing p-amino-benzamidine hydrochloride, comprise (1) p-nitrobenzonitfile II and be obtained by reacting intermediate p-nitrophenyl azomethine acid esters III by amidineization in amidineization reagent I; (2) intermediate p-nitrophenyl azomethine acid esters III is obtained by reacting p-nitrophenyl carbonamidine IV by amidineization in amidineization reagent II; (3) p-nitrophenyl carbonamidine IV in acid condition, in reaction solvent II, obtain p-amino-benzamidine hydrochloride I by reductive agent reduction; In step (1), described amidineization reagent I is sulfur oxychloride, phosphorus trichloride or phosphorus pentachloride; In step (2), described amidineization reagent II is volatile salt, bicarbonate of ammonia or ammonium chloride; In step (3), described reaction solvent II is the mixed solvent of water and alcohols.Synthetic method of the present invention is safe and simple, and yield is high, good product quality.The preparation method of this p-amino-benzamidine hydrochloride is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, particularly relate to a kind of method preparing p-amino-benzamidine hydrochloride.
Background technology
P-amino-benzamidine hydrochloride is important industrial chemicals, pharmaceutical intermediate, is again the inhibitor of numerous enzyme such as trypsinase, urokinase.Up to now the competitive inhibitor of these enzymes many has been found, and one of p-amino-benzamidine hydrochloride several compounds that to be its Middle molecule minimum; Meanwhile, it also can be used as the probe of part in affinity chromatography and serine protease position.
Dabigatran etcxilate is a kind of new oral anticoagulation medicine being developed listing by German Boehringer Ingelheim company.P-amino-benzamidine hydrochloride is as the important source material of dabigatran etcxilate, and market demand increases.And the synthesis technique of current p-amino-benzamidine hydrochloride mainly contains: the direct ammoniation process of (1) p-aminophenyl formonitrile HCN (BrownEric.etal, Tetrahedronletters, 37:3317-3320 (1976)); (2) p-nitrobenzonitfile catalytic hydrogenation (FredC.etal, J.Org.Chem, 26 (2) 412-418 (1961)).
Synthesis technique (1)
Wherein synthesis technique (1) adopts immobilized enzyme catalysis cost higher and unstable products; And chemosynthesis condition is comparatively harsh, need at relatively high temperatures logical ammonia for a long time.
Synthesis technique (2)
Synthesis technique (2) palladium carbon shortening then needs pressurized vessel, high to equipment requirements; Difficult with the product aftertreatment of tin and Sold Stannous Chloride Catalyzes, not there is practical value.
So comprehensive above synthesis technique is considered, develop a kind of synthetic method safe and simple, yield is high, good product quality, and the route being applicable to suitability for industrialized production just seems and is even more important.
Summary of the invention
Not enough for prior art, the object of this invention is to provide a kind of synthetic method safe and simple, yield is high, good product quality, is applicable to the preparation method of the p-amino-benzamidine hydrochloride of suitability for industrialized production.
For achieving the above object, the invention provides a kind of method preparing p-amino-benzamidine hydrochloride, comprise the following steps:
(1) p-nitrobenzonitfile II is obtained by reacting intermediate p-nitrophenyl azomethine acid esters III by amidineization in amidineization reagent I;
(2) intermediate p-nitrophenyl azomethine acid esters III is obtained by reacting p-nitrophenyl carbonamidine IV by amidineization in amidineization reagent II;
(3) p-nitrophenyl carbonamidine IV in acid condition, in reaction solvent II, obtain p-amino-benzamidine hydrochloride I by reductive agent reduction;
In step (1), described amidineization reagent I is sulfur oxychloride, phosphorus trichloride or phosphorus pentachloride;
In step (2), described amidineization reagent II is volatile salt, bicarbonate of ammonia or ammonium chloride;
In step (3), described reaction solvent II is the mixed solvent of water and alcohols, and nitro-reduction reaction generally adopts water to make solvent, but p-nitrophenyl carbonamidine IV solubleness in water is on the low side, adds a certain amount of ethanol, is conducive to the rapid dissolving of material.
Preferably, in step (1), described amidineization reagent I is sulfur oxychloride.
Preferably, in step (1) and step (2), described amidineization reaction is carried out in reaction solvent I, and described reaction solvent I is dehydrated alcohol or methyl alcohol.Reaction solvent I is best with dehydrated alcohol.
Preferably, after molecular sieve is dried 4-5 hour in 300 DEG C of retort furnaces, put into commercial anhydrous ethanol or methyl alcohol water suction within more than 12 hours, obtain described dehydrated alcohol or methyl alcohol.
Preferably, in step (2), described amidineization reagent II is volatile salt.
Preferably, in step (3), in described reaction solvent II, the volume ratio of water and alcohols is 1:0.5 ~ 2.
Preferably, in step (3), described reaction solvent II is the mixed solvent of water and ethanol.
Preferably, in described reaction solvent II, the volume ratio of water and ethanol is 1:1, and this solvent burden ratio is beneficial to material dissolution most.
Preferably, in step (3), described acidic conditions acidity regulator used is Glacial acetic acid; Described reductive agent is iron powder or zinc powder, best with iron powder.The reductibility of zinc powder is stronger than iron powder, and the reductive agent adopting zinc powder to do this reaction can make reaction very exothermic, and be unfavorable for controlling speed of response, have tarry impurity to generate, yield is lower than iron powder.
Preferably, in step (3), described p-nitrophenyl carbonamidine IV is 1:2 ~ 5 with the mol ratio of reductive agent, and preferred mol ratio is 1:4.
Preferably, after described reduction reaction terminates, regulate reaction solution to pH value to be 11 ~ 12 rear filtrations with sodium hydroxide, filtrate regulates pH value for 1 ~ 2 with concentrated hydrochloric acid, concentrated post crystallization.By regulating pH value to alkalescence, iron acetate in reaction solution is become ironic hydroxide flocks (having certain removal of impurities effect), excessive iron powder and flocks is filtered by crossing, reaction solution after filtration, by regulating pH value to acid, obtains p-amino-benzamidine hydrochloride crystallization.
Compared with prior art, the present invention has the following advantages:
1, the amidineization reaction handy and safe of this synthetic route, avoids the expensive metal catalyst etc. used in other documents;
2, amidineization reactions steps (1) if in have water to exist, then the azomethine perester radical of compound III will become formyl chloro, destroy original synthesis intention.Amidineization reactions steps (2) if in have water to exist, then the amidino of compound IV will become formamido-, cannot obtain predetermined product.So amidineization reaction emphasis is anhydrous, and commercial anhydrous ethanol or methyl alcohol are still containing a small amount of moisture content, for realizing this goal, after molecular sieve is dried 4-5 hour in 300 DEG C of retort furnaces, put into commercial anhydrous ethanol or methyl alcohol water suction within more than 12 hours, obtain amidineization reaction dehydrated alcohol or methyl alcohol.
3, existing nitro-reduction reaction is improved, improve productive rate by reaction solvent mixture, be applicable to industrialized production.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1 amidineization is reacted
Pour in there-necked flask by the anhydrous methanol of 240ml, logical nitrogen protection under ice-water bath, when interior temperature drop to 8 DEG C, magnetic agitation drips 80ml sulfur oxychloride, ensures that in dropping process, temperature is lower than 20 DEG C.24g p-nitrobenzonitfile II is added, jam-pack bottle stopper after the logical nitrogen of stopping, stirring at room temperature reaction 24h under dripping off magnetic agitation condition.60 DEG C of vacuum rotary steams, to dry, obtain light yellow solid intermediate III.This solid room temperature magnetic agitation in 400ml anhydrous methanol is dissolved, uncoveredly adds the excessive volatile salt of 33g, continue stirring at room temperature reaction 16h.Suction filtration, filtrate is revolved at 60 DEG C and is steamed to dry, and damp product are dried at 80 DEG C, and obtaining white solid is p-nitrophenyl carbonamidine IV, about 18.7g, and yield is 70.0%, HPLC:97.56%.
Embodiment 2 amidineization is reacted
Pour in there-necked flask by the dehydrated alcohol of 300ml, logical nitrogen protection under ice-water bath, when interior temperature drop to 5 DEG C, magnetic agitation drips 70ml sulfur oxychloride, ensures that in dropping process, temperature is lower than 20 DEG C.20g p-nitrobenzonitfile is added, jam-pack bottle stopper after the logical nitrogen of stopping, stirring at room temperature reaction 20h under dripping off magnetic agitation condition.60 DEG C of vacuum rotary steams, to dry, obtain light yellow solid intermediate III.This solid room temperature magnetic agitation in 400ml dehydrated alcohol is dissolved, uncoveredly adds the excessive volatile salt of 27g, continue stirring at room temperature reaction 20h.Suction filtration, filtrate is revolved at 60 DEG C and is steamed to dry, and damp product are dried at 80 DEG C, and obtaining white solid is p-nitrophenyl carbonamidine IV, about 16.5g, and yield is 74.0%, HPLC:98.14%.
Embodiment 3 amidineization is reacted
Embodiment 3 is compared with embodiment 2, and distinctive points is only in the present embodiment, and amidineization reaction adopts phosphorus trichloride to replace sulfur oxychloride, and other are constant, and the present embodiment final product yield is 41%, HPLC:82.43%.
Embodiment 4 amidineization is reacted
Embodiment 4 is compared with embodiment 2, and distinctive points is only in the present embodiment, and amidineization reaction adopts phosphorus pentachloride to replace sulfur oxychloride, and other are constant, and the present embodiment final product yield is 56%, HPLC:85.06%.
Embodiment 5 amidineization is reacted
Embodiment 5 is compared with embodiment 2, and distinctive points is only in the present embodiment, and amidineization reaction adopts bicarbonate of ammonia to replace volatile salt, and other are constant, and the present embodiment final product yield is 60.50%, HPLC:95.21%.
Embodiment 6 amidineization is reacted
Embodiment 6 is compared with embodiment 2, and distinctive points is only in the present embodiment, and amidineization reaction adopts ammonium chloride to replace volatile salt, and other are constant, and the present embodiment final product yield is 67.74%, HPLC:97.15%.
Embodiment 7 reduction reaction
In the there-necked flask having reflux condensing tube and mechanical stirring device, add the p-nitrophenyl carbonamidine IV that 18.0g is obtained by embodiment 1,24ml Glacial acetic acid, 50ml water and 50ml ethanol (V water: V ethanol=1:1), at 60 DEG C, backflow is stirred to entirely molten, add the iron powder (n p-nitrophenyl carbonamidine IV: n iron powder=1:2) of 11.3g again, be warming up to 80 DEG C of stirred at reflux reaction 4h, filter.Filtrate 20%NaOH adjust ph is a large amount of flocculent undissolved substance of 11 ~ 12 rear appearance, and filtering rear is 1 ~ 2 by concentrated hydrochloric acid adjust ph, places crystallization after concentrated, tide product are dried at 100 DEG C, obtain white solid p-amino-benzamidine hydrochloride I 14.0g, yield is 61.7%, HPLC:98.02%.
Embodiment 8 reduction reaction
In the there-necked flask having reflux condensing tube and mechanical stirring device, add the p-nitrophenyl carbonamidine IV that 15.0g is obtained by embodiment 2,20ml Glacial acetic acid, 45ml water and 45ml ethanol (V water: V ethanol=1:1), at 60 DEG C, backflow is stirred to entirely molten, add the iron powder (n p-nitrophenyl carbonamidine IV: n iron powder=1:3) of 15.3g again, be warming up to 80 DEG C of stirred at reflux reaction 4h, filter.Filtrate 20%NaOH adjust ph is a large amount of flocculent undissolved substance of 11 ~ 12 rear appearance, and filtering rear is 1 ~ 2 by concentrated hydrochloric acid adjust ph, places crystallization after concentrated, tide product are dried at 100 DEG C, obtain white solid p-amino-benzamidine hydrochloride I 14.1g, yield is 74.6%, HPLC:98.51%.
Embodiment 9 reduction reaction
In the there-necked flask having reflux condensing tube and mechanical stirring device, add the p-nitrophenyl carbonamidine IV that 15.0g is obtained by embodiment 2,20ml Glacial acetic acid, 45ml water and 45ml ethanol (V water: V ethanol=1:1), at 60 DEG C, backflow is stirred to entirely molten, add the iron powder (n p-nitrophenyl carbonamidine IV: n iron powder=1:4) of 20.3g again, be warming up to 80 DEG C of stirred at reflux reaction 4h, filter.Filtrate 20%NaOH adjust ph is a large amount of flocculent undissolved substance of 11 ~ 12 rear appearance, and filtering rear is 1 ~ 2 by concentrated hydrochloric acid adjust ph, places crystallization after concentrated, tide product are dried at 100 DEG C, obtain white solid p-amino-benzamidine hydrochloride I 17.9g, yield is 94.7%, HPLC:99.51%.
Embodiment 10 reduction reaction
In the there-necked flask having reflux condensing tube and mechanical stirring device, add the p-nitrophenyl carbonamidine IV that 18.0g is obtained by embodiment 1,24ml Glacial acetic acid, 50ml water and 50ml ethanol (V water: V ethanol=1:1), at 60 DEG C, backflow is stirred to entirely molten, (n p-nitrophenyl carbonamidine IV: n iron powder=1:5 is warming up to 80 DEG C of stirred at reflux reaction 4h, filters to add the iron powder of 30.5g again.Filtrate 20%NaOH adjust ph is a large amount of flocculent undissolved substance of 11 ~ 12 rear appearance, and filtering rear is 1 ~ 2 by concentrated hydrochloric acid adjust ph, places crystallization after concentrated, tide product are dried at 100 DEG C, obtain white solid p-amino-benzamidine hydrochloride I 20.9g, yield is 92.1%, HPLC:99.02%.
Embodiment 11 reduction reaction
Embodiment 11 is compared with embodiment 9, and distinctive points is only in the present embodiment, V water in reduction reaction: V ethanol=1:0.5, and other are constant, and the present embodiment final product yield is 69.80%, HPLC:98.17%.
Embodiment 12 reduction reaction
Embodiment 12 is compared with embodiment 9, and distinctive points is only in the present embodiment, V water in reduction reaction: V ethanol=1:2, and other are constant, and the present embodiment final product yield is 67.43%, HPLC:99.05%.
Embodiment 13 reduction reaction
Embodiment 13 is compared with embodiment 7, and distinctive points is only in the present embodiment, and reductive agent adopts zinc powder to replace iron powder, and other are constant, and reaction very exothermic, have tarry matters to generate, the present embodiment final product yield is 51.02%, HPLC:81.60%.
Although above with general explanation, embodiment and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (7)
1. prepare a method for p-amino-benzamidine hydrochloride, comprise the following steps:
(1) p-nitrobenzonitfile II is obtained by reacting intermediate p-nitrophenyl azomethine acid esters III by amidineization in amidineization reagent I;
(2) intermediate p-nitrophenyl azomethine acid esters III is obtained by reacting p-nitrophenyl carbonamidine IV by amidineization in amidineization reagent II;
(3) p-nitrophenyl carbonamidine IV in acid condition, in reaction solvent II, obtain p-amino-benzamidine hydrochloride I by reductive agent reduction;
In step (1), described amidineization reagent I is sulfur oxychloride, phosphorus trichloride or phosphorus pentachloride;
In step (2), described amidineization reagent II is volatile salt, bicarbonate of ammonia or ammonium chloride;
In step (3), described reaction solvent II is the mixed solvent of water and alcohols;
In step (1) and step (2), described amidineization reaction is carried out in reaction solvent I, and described reaction solvent I is dehydrated alcohol or anhydrous methanol;
Described dehydrated alcohol or anhydrous methanol are by after molecular sieve is dried 4-5 hour in 300 DEG C of retort furnaces, put into commercial anhydrous ethanol or anhydrous methanol water suction acquisition in more than 12 hours;
In step (3), in described reaction solvent II, the volume ratio of water and alcohols is 1:0.5 ~ 2;
In step (3), described acidic conditions acidity regulator used is Glacial acetic acid; Described reductive agent is iron powder or zinc powder.
2. method according to claim 1, is characterized in that, in step (1), described amidineization reagent I is sulfur oxychloride.
3. method according to claim 1, is characterized in that, in step (3), described reaction solvent II is the mixed solvent of water and ethanol.
4. method according to claim 3, is characterized in that, in step (3), in described reaction solvent II, the volume ratio of water and ethanol is 1:1.
5. method according to claim 1, is characterized in that, in step (3), described p-nitrophenyl carbonamidine IV is 1:2 ~ 5 with the mol ratio of reductive agent.
6. method according to claim 5, is characterized in that, in step (3), described p-nitrophenyl carbonamidine IV is 1:4 with the mol ratio of reductive agent.
7. method according to claim 1, is characterized in that, after described reduction reaction terminates, regulate reaction solution to pH value to be 11 ~ 12 rear filtrations with sodium hydroxide, filtrate regulates pH value for 1 ~ 2 with concentrated hydrochloric acid, concentrated post crystallization.
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| 亚氨酸酯的少污染低成本制备法;王哲清;《中国医药工业杂志》;20091231;第40卷(第4期);第253-254页 * |
| 对氨基苯甲脒二盐酸盐合成工艺改进;韦长梅;《化工时刊》;19981231;第29-31页 * |
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