CN104163778A - Method for preparing p-amino-benzamidine hydrochloride - Google Patents
Method for preparing p-amino-benzamidine hydrochloride Download PDFInfo
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- CN104163778A CN104163778A CN201410360670.4A CN201410360670A CN104163778A CN 104163778 A CN104163778 A CN 104163778A CN 201410360670 A CN201410360670 A CN 201410360670A CN 104163778 A CN104163778 A CN 104163778A
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Abstract
The invention relates to the technical field of pharmaceutical chemistry and provides a method for preparing p-amino-benzamidine hydrochloride. The method comprises the following steps: (1) p-nitrobenzonitfile II undergoes an amidining reaction in an amidining reagent I to obtain an intermediate p-nitrobenzene methylenimine III; (2) the intermediate p-nitrobenzene methylenimine III undergoes an amidining reaction in an amidining reagent II to obtain p-nitrobenzamidine IV; and (3) under an acidic condition, p-nitrobenzamidine IV undergoes a reduction reaction in a reaction solvent II by the use of a reducing agent to obtain p-amino-benzamidine hydrochloride. In the step (1), the amidining reagent I is thionyl chloride, phosphorus trichloride or phosphorus pentachloride; in the step (2), the amidining reagent II is ammonium carbonate, ammonium bicarbonate or ammonium chloride; and in the step (3), the reaction solvent II is a mixed solvent of water and alcohols. The synthetic method provided by the invention is safe and simple and has advantages of high yield and good product quality. The preparation method of p-amino-benzamidine hydrochloride is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, relate in particular to a kind of method of preparing p-amino-benzamidine hydrochloride.
Background technology
P-amino-benzamidine hydrochloride is important industrial chemicals, pharmaceutical intermediate, is again the inhibitor of numerous enzymes such as trypsinase, urokinase.Up to now found the competitive inhibitor of many these enzymes, and p-amino-benzamidine hydrochloride is one of several compounds of wherein molecule minimum; Meanwhile, it also can be used as part in affinity chromatography and the probe of serine protease position.
Dabigatran etcxilate is a kind of new oral anticoagulation medicine by the exploitation listing of 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 (Brown Eric.et al, Tetrahedron letters, 37:3317-3320 (1976)); (2) p-nitrobenzonitfile catalytic hydrogenation (Fred C.et al, J.Org.Chem, 26 (2) 412-418 (1961)).
Synthesis technique (1)
Wherein synthesis technique (1) adopts the higher and unstable products of immobilized enzyme catalysis cost; And chemosynthesis condition is comparatively harsh, need under comparatively high temps, lead to for a long time ammonia.
Synthesis technique (2)
Synthesis technique (2) needs pressurized vessel with palladium carbon shortening, high to equipment requirements; Product aftertreatment difficulty with tin and Sold Stannous Chloride Catalyzes, does not have practical value.
So comprehensive above synthesis technique consideration, develops a kind of synthetic method safe and simple, yield is high, good product quality, and the route that is 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, the preparation method of the p-amino-benzamidine hydrochloride of applicable suitability for industrialized production.
For achieving the above object, the invention provides a kind of method of preparing p-amino-benzamidine hydrochloride, comprise the following steps:
(1) p-nitrobenzonitfile II obtains intermediate p-nitrophenyl azomethine acid esters III by amidineization reaction in amidineization reagent I;
(2) intermediate p-nitrophenyl azomethine acid esters III obtains p-nitrophenyl carbonamidine IV by amidineization reaction in amidineization reagent II;
(3) p-nitrophenyl carbonamidine IV, under acidic conditions, is reduced and is obtained p-amino-benzamidine hydrochloride I by reductive agent in reaction solvent II;
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, by molecular sieve is dried after 4-5 hour in 300 ℃ of retort furnaces, put into commercially available dehydrated alcohol or methyl alcohol 12 hours above described dehydrated alcohol or the methyl alcohol of obtaining that absorbs water.
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 that adopts zinc powder to do this reaction can make to react very exothermic, is unfavorable for controlling speed of response, has tarry impurity to generate, and yield is lower than iron powder.
Preferably, in step (3), the mol ratio of described p-nitrophenyl carbonamidine IV and reductive agent is 1:2～5, and preferred mol ratio is 1:4.
Preferably, after described reduction reaction finishes, with sodium hydroxide, regulating reaction solution to pH value is 11～12 rear filtrations, and filtrate take concentrated hydrochloric acid, and to regulate pH value be 1～2, concentrated post crystallization.By regulating pH value to alkalescence, iron acetate in reaction solution is become to ironic hydroxide flocks (having certain removal of impurities effect), by removing by filter excessive iron powder and flocks, the 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 of this synthetic route reaction handy and safe, has avoided the expensive metal catalyst that uses in other documents etc.;
2, amidineization reactions steps (1) if in have water to exist, the azomethine perester radical of compound III will become formyl chloro, has destroyed original synthetic intention.Amidineization reactions steps (2) if in have water to exist, the amidino of compound IV will become formamido-, cannot obtain predetermined product.So amidineization reaction emphasis is anhydrous, and commercially available dehydrated alcohol or methyl alcohol still contain a small amount of moisture content, for realizing this goal, by molecular sieve is dried after 4-5 hour in 300 ℃ of retort furnaces, put into commercially available dehydrated alcohol or methyl alcohol 12 hours above amidineization dehydrated alcohol or the methyl alcohol for reaction of obtaining that absorbs water.
3, existing nitro-reduction reaction is improved, by reaction solvent, be mixed and improved productive rate, be applicable to industrialized production.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Embodiment 1 amidineization reaction
The anhydrous methanol of 240ml is poured in there-necked flask, logical nitrogen protection under ice-water bath, when interior temperature drop to 8 ℃, magnetic agitation drips 80ml sulfur oxychloride, guarantees in dropping process that temperature is lower than 20 ℃.Drip off under magnetic agitation condition and add 24g p-nitrobenzonitfile II, stop jam-pack bottle stopper after logical nitrogen, stirring at room reaction 24h.60 ℃ of vacuum rotary steams, to dry, obtain light yellow solid intermediate III.This solid room temperature magnetic agitation in 400ml anhydrous methanol is dissolved, and the uncovered excessive volatile salt of 33g that adds, continues stirring at room reaction 16h.Suction filtration, filtrate is revolved and is steamed to dry at 60 ℃, and damp product are dried at 80 ℃, and obtaining white solid is p-nitrophenyl carbonamidine IV, about 18.7g, yield is 70.0%, HPLC:97.56%.
Embodiment 2 amidineization reactions
The dehydrated alcohol of 300ml is poured in there-necked flask, logical nitrogen protection under ice-water bath, when interior temperature drop to 5 ℃, magnetic agitation drips 70ml sulfur oxychloride, guarantees in dropping process that temperature is lower than 20 ℃.Drip off under magnetic agitation condition and add 20g p-nitrobenzonitfile, stop jam-pack bottle stopper after logical nitrogen, stirring at room reaction 20h.60 ℃ of vacuum rotary steams, to dry, obtain light yellow solid intermediate III.This solid room temperature magnetic agitation in 400ml dehydrated alcohol is dissolved, and the uncovered excessive volatile salt of 27g that adds, continues stirring at room reaction 20h.Suction filtration, filtrate is revolved and is steamed to dry at 60 ℃, and damp product are dried at 80 ℃, and obtaining white solid is p-nitrophenyl carbonamidine IV, about 16.5g, yield is 74.0%, HPLC:98.14%.
Embodiment 3 amidineization reactions
Embodiment 3 compares with embodiment 2, and distinctive points is only in the present embodiment, amidineization reaction employing phosphorus trichloride replacement sulfur oxychloride, and other are constant, and the present embodiment final product yield is 41%, HPLC:82.43%.
Embodiment 4 amidineization reactions
Embodiment 4 compares with embodiment 2, and distinctive points is only in the present embodiment, amidineization reaction employing phosphorus pentachloride replacement sulfur oxychloride, and other are constant, and the present embodiment final product yield is 56%, HPLC:85.06%.
Embodiment 5 amidineization reactions
Embodiment 5 compares with embodiment 2, and distinctive points is only in the present embodiment, amidineization reaction employing bicarbonate of ammonia replacement volatile salt, and other are constant, and the present embodiment final product yield is 60.50%, HPLC:95.21%.
Embodiment 6 amidineization reactions
Embodiment 6 compares with embodiment 2, and distinctive points is only in the present embodiment, amidineization reaction employing ammonium chloride replacement volatile salt, and other are constant, and the present embodiment final product yield is 67.74%, HPLC:97.15%.
Embodiment 7 reduction reactions
In having the there-necked flask of reflux condensing tube and mechanical stirring device, the p-nitrophenyl carbonamidine IV that adds 18.0g to be made by embodiment 1,24ml Glacial acetic acid, 50ml water and 50ml ethanol (V water: V ethanol=1:1), at 60 ℃, refluxing, it is entirely molten to be stirred to, iron powder (the n p-nitrophenyl carbonamidine IV: n iron powder=1:2), be warming up to stirring reaction 4h under 80 ℃ of backflows, filter that adds again 11.3g.It is a large amount of flocculent undissolved substances of 11～12 rear appearance that filtrate regulates pH value with 20%NaOH, and after filtration, with concentrated hydrochloric acid, regulating pH value is 1～2, the concentrated rear crystallization of placing, tide product are dried at 100 ℃, obtain white solid p-amino-benzamidine hydrochloride I 14.0g, yield is 61.7%, HPLC:98.02%.
Embodiment 8 reduction reactions
In having the there-necked flask of reflux condensing tube and mechanical stirring device, the p-nitrophenyl carbonamidine IV that adds 15.0g to be made by embodiment 2,20ml Glacial acetic acid, 45ml water and 45ml ethanol (V water: V ethanol=1:1), at 60 ℃, refluxing, it is entirely molten to be stirred to, iron powder (the n p-nitrophenyl carbonamidine IV: n iron powder=1:3), be warming up to stirring reaction 4h under 80 ℃ of backflows, filter that adds again 15.3g.It is a large amount of flocculent undissolved substances of 11～12 rear appearance that filtrate regulates pH value with 20%NaOH, and after filtration, with concentrated hydrochloric acid, regulating pH value is 1～2, the concentrated rear crystallization of placing, tide product are dried at 100 ℃, obtain white solid p-amino-benzamidine hydrochloride I 14.1g, yield is 74.6%, HPLC:98.51%.
Embodiment 9 reduction reactions
In having the there-necked flask of reflux condensing tube and mechanical stirring device, the p-nitrophenyl carbonamidine IV that adds 15.0g to be made by embodiment 2,20ml Glacial acetic acid, 45ml water and 45ml ethanol (V water: V ethanol=1:1), at 60 ℃, refluxing, it is entirely molten to be stirred to, iron powder (the n p-nitrophenyl carbonamidine IV: n iron powder=1:4), be warming up to stirring reaction 4h under 80 ℃ of backflows, filter that adds again 20.3g.It is a large amount of flocculent undissolved substances of 11～12 rear appearance that filtrate regulates pH value with 20%NaOH, and after filtration, with concentrated hydrochloric acid, regulating pH value is 1～2, the concentrated rear crystallization of placing, tide product are dried at 100 ℃, obtain white solid p-amino-benzamidine hydrochloride I 17.9g, yield is 94.7%, HPLC:99.51%.
Embodiment 10 reduction reactions
In having the there-necked flask of reflux condensing tube and mechanical stirring device, the p-nitrophenyl carbonamidine IV that adds 18.0g to be made by embodiment 1,24ml Glacial acetic acid, 50ml water and 50ml ethanol (V water: V ethanol=1:1), at 60 ℃, refluxing, it is entirely molten to be stirred to, iron powder (the n p-nitrophenyl carbonamidine IV: n iron powder=1:5, is warming up to stirring reaction 4h under 80 ℃ of backflows, filtration that adds again 30.5g.It is a large amount of flocculent undissolved substances of 11～12 rear appearance that filtrate regulates pH value with 20%NaOH, and after filtration, with concentrated hydrochloric acid, regulating pH value is 1～2, the concentrated rear crystallization of placing, tide product are dried at 100 ℃, obtain white solid p-amino-benzamidine hydrochloride I 20.9g, yield is 92.1%, HPLC:99.02%.
Embodiment 11 reduction reactions
Embodiment 11 compares 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 reactions
Embodiment 12 compares 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 reactions
Embodiment 13 compares with embodiment 7, and distinctive points is only in the present embodiment, reductive agent employing zinc powder replacement iron powder, and other are constant, and reaction very exothermic has tarry matters to generate, and the present embodiment final product yield is 51.02%, HPLC:81.60%.
Although, above used general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a method of preparing p-amino-benzamidine hydrochloride, comprises the following steps:
(1) p-nitrobenzonitfile II obtains intermediate p-nitrophenyl azomethine acid esters III by amidineization reaction in amidineization reagent I;
(2) intermediate p-nitrophenyl azomethine acid esters III obtains p-nitrophenyl carbonamidine IV by amidineization reaction in amidineization reagent II;
(3) p-nitrophenyl carbonamidine IV, under acidic conditions, is reduced and is obtained p-amino-benzamidine hydrochloride I by reductive agent in reaction solvent II;
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.
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 (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.
4. method according to claim 3, is characterized in that, described dehydrated alcohol or methyl alcohol are by molecular sieve is dried after 4-5 hour in 300 ℃ of retort furnaces, puts into commercially available dehydrated alcohol or methyl alcohol 12 hours above acquisitions that absorb water.
5. method according to claim 1, is characterized in that, in step (3), in described reaction solvent II, the volume ratio of water and alcohols is 1:0.5～2.
6. method according to claim 5, is characterized in that, in step (3), described reaction solvent II is the mixed solvent of water and ethanol.
7. method according to claim 6, is characterized in that, in step (3), in described reaction solvent II, the volume ratio of water and ethanol is 1:1.
8. method according to claim 1, is characterized in that, in step (3), described acidic conditions acidity regulator used is Glacial acetic acid; Described reductive agent is iron powder or zinc powder.
9. method according to claim 8, is characterized in that, in step (3), the mol ratio of described p-nitrophenyl carbonamidine IV and reductive agent is 1:2～5, and preferred mol ratio is 1:4.
10. method according to claim 1, is characterized in that, after described reduction reaction finishes, with sodium hydroxide, regulating reaction solution to pH value is 11～12 rear filtrations, and filtrate take concentrated hydrochloric acid, and to regulate pH value be 1～2, concentrated post crystallization.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146349A (en) * | 2015-04-07 | 2016-11-23 | 中国科学院大连化学物理研究所 | A kind of method that aromatic aldehyde catalyzed conversion prepares amidine |
| CN117586546A (en) * | 2024-01-18 | 2024-02-23 | 常州六次方纳米科技有限公司 | Preparation method of single-walled carbon nanotube modified antistatic coating |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1800168A (en) * | 2006-01-16 | 2006-07-12 | 同济大学 | 5-n-propyl-2-(3,5-difluophenyl)pyridine preparation method |
| JP2007051098A (en) * | 2005-08-18 | 2007-03-01 | Hoyu Co Ltd | Aminopyrimidine derivative and hair-dyeing agent composition containing the same |
-
2014
- 2014-07-25 CN CN201410360670.4A patent/CN104163778B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007051098A (en) * | 2005-08-18 | 2007-03-01 | Hoyu Co Ltd | Aminopyrimidine derivative and hair-dyeing agent composition containing the same |
| CN1800168A (en) * | 2006-01-16 | 2006-07-12 | 同济大学 | 5-n-propyl-2-(3,5-difluophenyl)pyridine preparation method |
Non-Patent Citations (2)
| Title |
|---|
| 王哲清: "亚氨酸酯的少污染低成本制备法", 《中国医药工业杂志》 * |
| 韦长梅: "对氨基苯甲脒二盐酸盐合成工艺改进", 《化工时刊》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146349A (en) * | 2015-04-07 | 2016-11-23 | 中国科学院大连化学物理研究所 | A kind of method that aromatic aldehyde catalyzed conversion prepares amidine |
| CN106146349B (en) * | 2015-04-07 | 2018-02-13 | 中国科学院大连化学物理研究所 | A kind of method that aromatic aldehyde catalyzed conversion prepares amidine |
| CN117586546A (en) * | 2024-01-18 | 2024-02-23 | 常州六次方纳米科技有限公司 | Preparation method of single-walled carbon nanotube modified antistatic coating |
| CN117586546B (en) * | 2024-01-18 | 2024-04-12 | 常州六次方纳米科技有限公司 | Preparation method of single-walled carbon nanotube modified antistatic coating |
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