CN102584628A - Method for synthesizing N-carboxymethyl pentamidine - Google Patents
Method for synthesizing N-carboxymethyl pentamidine Download PDFInfo
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- CN102584628A CN102584628A CN2011104576736A CN201110457673A CN102584628A CN 102584628 A CN102584628 A CN 102584628A CN 2011104576736 A CN2011104576736 A CN 2011104576736A CN 201110457673 A CN201110457673 A CN 201110457673A CN 102584628 A CN102584628 A CN 102584628A
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Abstract
The invention discloses a method for synthesizing N-carboxymethyl pentamidine which is shown as a formula (II). The method comprises the following steps of: performing esterification on valeronitrile and carbinol which are used as raw materials to obtain penta imidic acid methyl ester hydrochloride which is shown as a formula (I), wherein valeronitrile is shown as a formula (IV), dissociating penta imidic acid methyl ester hydrochloride to obtain penta imidic acid methyl ester alkali which is shown as a formula (V), performing amidine reaction on the penta imidic acid methyl ester alkali and glycine to obtain N-carboxymethyl pentamidine which is shown as a formula (II), wherein in the esterification, valeronitrile which is shown as the formula (IV) and carbinol are fully reacted under the action of acetylchloride to form penta imidic acid methyl ester hydrochloride, and the obtained reaction liquid A is directly used for next reaction. The method is safe and environment-friendly, and is convenient to operate, and the obtained product is high in yield and quality; and the method is suitable for industrial production.
Description
Technical field
The present invention relates to industry and go up key intermediate---the compound method of N-ethyloic penta amidine of producing the husky smooth raw material imidazole aldehyde of cardiovascular agent network.
Background technology
N-ethyloic penta amidine (structure is shown in (II)) is that the key intermediate of producing the husky smooth raw material imidazole aldehyde of cardiovascular agent network (compound III) is gone up in industry now.Losartan is obvious because of its antihypertensive effect, and better tolerance has unique curative effect and provide protection to cardiovascular disorder, has become one of the most general antihypertensive drug of clinical use.Along with the continuous increase of losartan demand, thereby develop a kind of safe, convenient and to be suitable for the better synthetic imidazole aldehyde of method of industrial N-ethyloic penta amidine necessary.
The synthetic route of the imidazole aldehyde (structure is shown in (III)) that present document is reported to mainly contains following four:
Route one (1, US4355040 (1982); 2, EP0403159A2 (1990); 3, Synthetic Communications, 2971-2977,
22 (20), 1992:4, Chinese pharmaceutical chemistry magazine, 271-276,
8 (04), 1998):
Route two (5, Chinese Chemical Letters, 269-270,
20 (03), 2009):
Route three (6, J.Org.Chem., 8084-8089,
64 (22), 1999):
Route four (7, Chinese Journal of New Drugs, 1948-1950,
15 (22), 2006; 8, Guangxi light industry, 8-10,
(02), 2008; 9, CN101781255A (2010)):
In the above-mentioned route, route one is longer, and complicated operation needs hydrogen chloride gas, ammonia to participate in reaction, and is reflected under the condition of high voltage and carries out, and certain danger is arranged, and yield is low, is unfavorable for suitability for industrialized production.
Noble metal catalyst has been adopted in route two reactions, and production cost is high, is unfavorable for suitability for industrialized production.
Route three reactions have more by product, and route is longer, and production cost is high.
The main technological line four synthetic imidazole aldehydes (compound III) that adopt are gone up in industry at present, and this technology and compared with techniques have in the past been simplified technological process, have shortened the reaction times, have improved production efficiency, are the conventional route of industrial production imidazole aldehyde now.
But obviously not enough below route four also exists:
The first step in A, the route four is led to hydrogen chloride gas, can be made by the vitriol oil, phosphorus trichloride etc. and concentrated hydrochloric acid or sodium-chlor reaction in the industry usually, but this method causes very big environmental pollution;
B, we find in experiment, and are dry bad like hydrogen chloride gas, can produce the impurity methyl valerate, thereby further influence the purity and the yield of imidazole aldehyde;
The hydrogen chloride gas of C, this step reaction will arrive certain amount, just can react completely, and the metering of the hydrogen chloride gas in industry difficulty; Operation and running cost high (molar ratio of bibliographical information valeronitrile and hydrogen chloride gas be 1.0: 1.37 preferable; Like [Guangxi light industry, 8-10
(02), 2008]).
Summary of the invention
The technical problem that the present invention will solve provide a kind of safety, environmental protection, easy to operate, products obtained therefrom yield high quality is good, be fit to key intermediate---the compound method of N-ethyloic penta amidine of producing the husky smooth raw material imidazole aldehyde of cardiovascular agent network in the industry of suitability for industrialized production.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
The compound method of N-ethyloic penta amidine shown in a kind of formula (II); Comprise the steps: that with valeronitrile shown in the formula (IV) and methyl alcohol be raw material; Obtain penta imidic acid methyl ester hydrochloride shown in the formula (I) through esterification; Said penta imidic acid methyl ester hydrochloride obtains penta imidic acid methyl esters alkali shown in the formula V through free, and said penta imidic acid methyl esters alkali and glycocoll make N-ethyloic penta amidine shown in the formula (II) through the amidineization reaction;
Described esterification is to be raw material with valeronitrile shown in the formula (IV) and methyl alcohol, and under the effect of Acetyl Chloride 98Min., fully reaction generates penta imidic acid methyl ester hydrochloride, and gained reaction solution A directly is used for next step reaction.
Further, said esterification reaction temperature is-10～15 ℃, and reaction time of esterification is 10～20 hours.
Further, said esterification reaction temperature is-5～5 ℃.
Further again, said esterification reaction temperature is 0～5 ℃.
The most preferably said esterification of the present invention was 0～5 ℃ of reaction 12 hours.
Further, in the said esterification, said valeronitrile, methyl alcohol and Acetyl Chloride 98Min. three's mol ratio is 1: 2～5: 1～3; More preferably 1: 3～4: 1～2, most preferably be 1.00: 3.47: 1.42.
Among the present invention, describedly free comprise the steps: in gained reaction solution A, to add benzene kind solvent, and adding alkali lye, to be neutralized to the pH value be 8～10, obtains the solution of penta imidic acid methyl esters alkali.
Further, the preferred toluene of described benzene kind solvent.Described alkali lye can use conventional reagent such as sodium hydroxide solution.
Further; Be to improve product purity, describedly freely comprise the steps: that also said reaction solution A adds after alkali lye is neutralized to the pH value and is 8～10 standing demix; Isolated organic layer steams methyl acetate and the methyl alcohol that removes wherein, obtains the solution of penta imidic acid methyl esters alkali.
Among the present invention; Described amidineization reaction comprises the steps: in the solution of penta imidic acid methyl esters alkali, to add methyl alcohol, sodium methylate and glycocoll; Said penta imidic acid methyl esters alkali and glycocoll react under sodium methylate catalysis; Fully reaction back conditioned reaction liquid pH to 6～8 obtain N-ethyloic penta amidine through separating.In the said reaction,, increase its solvability as solvent so add methyl alcohol because glycocoll is insoluble to benzene kind solvents such as toluene.
Further, said amidineization temperature of reaction is 0～5 ℃, and the amidineization reaction times is 15～20 hours.
Further, the glycocoll that the amidineization reaction is used and the mol ratio of valeronitrile are 1.0: 1.0～1.2, and the mol ratio of sodium methylate and glycocoll is 0.05～0.1: 1.
The present invention is with respect to the advantage of prior art: the environmental pollution of 1, having avoided direct feeding hydrogen chloride gas to be brought.2, easy to operate, steady quality is more suitable in industrial production.3, the products obtained therefrom yield is high, purity is good.
Embodiment
Following type reaction is used for illustrating the present invention.Within the technical scheme that those skilled in that art all belong to the present invention to the simple replacement done of invention or improvement etc. and protected.
Synthesizing of embodiment 1N-ethyloic penta amidine:
In the there-necked flask, add valeronitrile 30 grams (0.36mol) and anhydrous methanol 40 grams (1.25mol), mix; Cryosel is bathed and is cooled to 0 ℃; Slowly drip 40 the gram Acetyl Chloride 98Min. (0.51mol), drip off, 0～5 ℃ the reaction about 12 hours to valeronitrile content less than 2% (GC tracking); Reaction finishes, and gets penta imidic acid methyl ester hydrochloride solution.Gained penta imidic acid methyl ester hydrochloride solution adds toluene 150 grams, and 0 ℃ is used liquid caustic soda to regulate pH down is 9, stirs 15 minutes; Standing demix, water layer, with 50 gram extracted in toluene once; Merge organic layer, 100 gram saturated salt washings are after the organic layer decompression steams methyl acetate and methyl alcohol; For use, this is the toluene solution of penta imidic acid methyl esters free alkali.
In the above-mentioned solution, add methyl alcohol 80 grams, sodium methylate 1 gram is chilled to 0～5 ℃; Slowly add glycocoll 26.3 grams (0.35mol), temperature control reacts about 20 hours to penta this disappearance of imidic acid methyl esters base below 5 ℃, and sulfuric acid is transferred pH=7; Methyl alcohol is removed in underpressure distillation, and cooling is filtered, and gets N-ethyloic penta amidine 47.9 grams of white solid; Yield: 84.2%, purity: 98.3% (in valeronitrile), fusing point: 199.2～200.8 ℃.The hydrogen spectrum (
1H-NMR) (D
2O, 400MHz): δ 0.91 (t, 3H, J=7.2Hz), 1.38 (m, 2H), 1.66 (m, 2H), 2.52 (t, 2H, J=7.6Hz), 3.86 (s, 2H), mass spectrum (ESI-MS): 159 (M+1), infrared IR (KBr, cm
-1): 787,1334,1385,1626,2959,3354, ultimate analysis (C
7H
14N
2O
2, %) (measured value/calculated value): C53.22/53.15, H8.92/8.98, N17.71/17.55.
Embodiment 2-10
Change esterification raw material consumption and condition among the embodiment 1, thereby the product result who obtains is as shown in table 1.
Table 1
Claims (10)
1. the compound method of N-ethyloic penta amidine shown in the formula (II); Described compound method comprises the steps: that with valeronitrile shown in the formula (IV) and methyl alcohol be raw material; Obtain penta imidic acid methyl ester hydrochloride shown in the formula (I) through esterification; Said penta imidic acid methyl ester hydrochloride obtains penta imidic acid methyl esters alkali shown in the formula V through free, and said penta imidic acid methyl esters alkali and glycocoll make N-ethyloic penta amidine shown in the formula (II) through the amidineization reaction;
It is characterized in that: described esterification is to be raw material with valeronitrile shown in the formula (IV) and methyl alcohol, and under the effect of Acetyl Chloride 98Min., fully reaction generates penta imidic acid methyl ester hydrochloride, and gained reaction solution A directly is used for next step reaction.
2. the compound method of N-ethyloic penta amidine as claimed in claim 1, it is characterized in that: esterification reaction temperature is-10～15 ℃, reaction time of esterification is 10～20 hours; Said valeronitrile, methyl alcohol and Acetyl Chloride 98Min. three's mol ratio is 1: 2～5: 1～3.
3. the compound method of N-ethyloic penta amidine as claimed in claim 2, it is characterized in that: esterification reaction temperature is-5～5 ℃.
4. the compound method of N-ethyloic penta amidine as claimed in claim 1 is characterized in that: esterification reaction temperature is 0～5 ℃; Said valeronitrile, methyl alcohol and Acetyl Chloride 98Min. three's mol ratio is 1: 3～4: 1～2.
5. like the compound method of described N-ethyloic penta amidine of one of claim 1～4; It is characterized in that: described dissociating comprises the steps: in gained reaction solution A, to add benzene kind solvent; And adding alkali lye, to be neutralized to the pH value be 8～10, obtains the solution of penta imidic acid methyl esters alkali shown in the formula V.
6. the compound method of N-ethyloic penta amidine as claimed in claim 5 is characterized in that: described benzene kind solvent is a toluene.
7. the compound method of N-ethyloic penta amidine as claimed in claim 5; It is characterized in that: describedly free comprise the steps: that also said reaction solution A adds after alkali lye is neutralized to the pH value and is 8～10; Standing demix; Isolated organic layer steams methyl acetate and the methyl alcohol that removes wherein, obtains the solution of penta imidic acid methyl esters alkali.
8. the compound method of N-ethyloic penta amidine as claimed in claim 5; It is characterized in that: described amidineization reaction comprises the steps: in the solution of penta imidic acid methyl esters alkali, to add methyl alcohol, sodium methylate and glycocoll; Said penta imidic acid methyl esters alkali and glycocoll react under sodium methylate catalysis; Fully reaction back conditioned reaction liquid pH to 6～8 obtain N-ethyloic penta amidine shown in the formula (II) through separating.
9. the compound method of N-ethyloic penta amidine as claimed in claim 8 is characterized in that: the amidineization temperature of reaction is 0～5 ℃, and the amidineization reaction times is 15～20 hours.
10. the compound method of N-ethyloic penta amidine as claimed in claim 8 is characterized in that: the glycocoll that the amidineization reaction is used and the mol ratio of valeronitrile are 1.0: 1.00～1.20, and the mol ratio of sodium methylate and glycocoll is 0.05～0.1: 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4355040A (en) * | 1979-11-12 | 1982-10-19 | Takeda Chemical Industries, Ltd. | Hypotensive imidazole-5-acetic acid derivatives |
| CN1027504C (en) * | 1989-06-14 | 1995-01-25 | 史密丝克莱恩比彻姆公司 | Imidazolyl-alkenoic acids |
| CN101781255A (en) * | 2010-02-09 | 2010-07-21 | 江苏德峰医药化工有限公司 | Preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole |
-
2011
- 2011-12-30 CN CN201110457673.6A patent/CN102584628B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4355040A (en) * | 1979-11-12 | 1982-10-19 | Takeda Chemical Industries, Ltd. | Hypotensive imidazole-5-acetic acid derivatives |
| CN1027504C (en) * | 1989-06-14 | 1995-01-25 | 史密丝克莱恩比彻姆公司 | Imidazolyl-alkenoic acids |
| CN101781255A (en) * | 2010-02-09 | 2010-07-21 | 江苏德峰医药化工有限公司 | Preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole |
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Inventor after: You Jinzong Inventor after: Jiang Shanhui Inventor after: Tang Wei Inventor after: Cai Jinyuan Inventor after: Xu Huigang Inventor after: Ren Haihua Inventor after: He Jianshi Inventor after: Ye Rui Inventor before: Jiang Shanhui Inventor before: You Jinzong Inventor before: Tang Wei Inventor before: Cai Jinyuan Inventor before: Xu Huigang Inventor before: Ren Haihua Inventor before: He Jianshi Inventor before: Ye Rui |
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