CN100532362C - Process for preparing N-methyl quinoline compounds by ester reaction solvent - Google Patents
Process for preparing N-methyl quinoline compounds by ester reaction solvent Download PDFInfo
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- CN100532362C CN100532362C CNB2004100368024A CN200410036802A CN100532362C CN 100532362 C CN100532362 C CN 100532362C CN B2004100368024 A CNB2004100368024 A CN B2004100368024A CN 200410036802 A CN200410036802 A CN 200410036802A CN 100532362 C CN100532362 C CN 100532362C
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Abstract
The process of preparing N-methyl quinoline iodide compound with reactive ester solvent includes the following main steps: adding catalytically reactive ester solvent and quinoline in the volume ratio of 1-1000 into reactor in nitrogen atmosphere and reaction through stirring for 10-20 min; adding iodomethane in the same volume as quinoline through stirring in sealed reactor to react for 1-3 hr; adding iodomethane in the same volume to result in molar ratio between iodomethane and quinoline of 1-50 to react for further 1-10 hr while controlling the reaction temperature lower than the boiling point of the reactive ester solvent; letting the reaction system stand for 5-10 hr, separation, and crystallization to obtain the product. The present invention has high yield and product purity.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, specifically, it is the solvent that adopts ester class catalyzed reaction, quinoline reactant and iodomethane reaction there is very big catalytic effect, high yield and highly purified iodate 1-toluquinoline have been obtained, iodate 1-methylacridine, iodate 1-methyl-(3,4-N, N dimethyl) the N-methyl compound that replaces of acridine, iodate 1-methyl benzisoquinoline and iodate 1-tolimidazole and alkyl thereof.
Background technology
Iodate 1-toluquinoline compounds is a kind of intermediate commonly used in the organic synthesis, utilizes this intermediate can prepare many quinolines that important use is arranged, be medicine synthetic in the starting raw material of widespread use.Recently, JACS (Enrico, B.J.Am.Chem.Soc.2003,125,16444) etc. famous science magazine has been reported the photosensitization character of this compounds uniqueness, and iodate 1-toluquinoline can effectively activate ground state molecule oxygen under optical excitation, the non-thiophene organic sulfide of high selective oxidation Wei Ya Sulfone becomes the photosensitization reagent that available oxygen shifts.We find also that recently this compounds is the effective photosensitization oxygen of a thiophene-type sulfide transfer catalyst, and this separates sulfide for selective oxidation provides more efficient methods, as removing of sulphur in the FCC oil product.
The common method for making of this compounds is under logical nitrogen, methyl iodide and quinoline etc. is dissolved in realizes in the organic solvent that methylation reaction forms.Organic solvent commonly used is generally ether, benzene, methyl alcohol and ethanol etc., and wherein ether is comparatively commonly used.As solvent, with quinoline and excessive iodomethane reaction, productive rate can reach 62% to bibliographical information with ether.But because therefore the boiling point all very low (42.4 ℃ and 34 ℃) of methyl iodide and solvent ether will cause the loss of most of methyl iodide and solvent under the situation of logical nitrogen.Find that with being reflected in the system of deoxygenation sealing productive rate is lower, even prolong the productive rate that reaction also only can reach about 20% in 24 hours.Secondly, the product that generates in the reaction is serious absorption reaction thing quinoline in the ether medium, promptly uses a large amount of ether washings also can't remove the quinoline that adheres on the resultant (precipitation that obtains in the reaction) for several times, and product purity can not guarantee.Because ether is explosive, therefore carrying out the Soxhlet extraction with ether also has certain danger.
Summary of the invention
The purpose of this invention is to provide the method that a kind of ester reaction solvent prepares iodate N-toluquinoline compounds, mainly is to utilize a kind of reactive solvent to substitute ether to react.Principle is to adopt the aminolysis effect of esters solvent in raw material that adds, and promotes the catalyzed reaction that methylates of methyl iodide, and the hydroiodic acid HI of generation is the esterification of catalysis ester class dissolved again.The result shows, adopts same above-mentioned deoxygenation sealing method methyl iodide productive rate to bring up to more than 70% from 20%.Degree of purity of production is also than the height during as solvent with ether.From the product analysis result as can be known, can see almost there is not impurity on the HNMR spectrogram.Its purity of ultimate analysis can reach more than 99.5%, meets the pharmacopeia specified standards.Different when ether etc. is made medium, this system can be accelerated speed of reaction by heating up easily, and the reaction times can shorten to 1 hour from original 24 hours.
Technological core of the present invention is to utilize a kind of ester reaction solvent can obtain the 1-toluquinoline compounds of high yield, degree of purity of production improves when being medium than ether greatly, promptly obtain the product crystallization in such esters solvent, its surface is absorption reaction thing quinoline hardly.
Key of the present invention is the katalysis of this esters solvent to electrophilic substitution reaction, and such catalysis replaces the dynamic transesterify from esters solvent, and after substitution reaction finished, this esters solvent was finished esterification by the free hydroiodic acid HI again, returns to the solvent state.Secondly, the special solvent effect of reactant quinolines, the degree that makes unreacted quinoline remain in resultant crystals or surface is greatly suppressed, and can use this solvent to carry out Soxhlet formula purified product easily.
Realize among the present invention that this technology is with esters solvent and reactant hybrid reaction, crystallization deposition, filtration and Separation and Recovery solvent then, the present invention changes in the past inert solvent and becomes reactive solvents.
Reaction unit of the present invention is common reactor.
Esters solvent catalysis electrophilic substitution of the present invention is as follows by the concrete grammar that quinoline and methyl iodide class prepare the 1-toluquinoline:
Volume ratio by 1:1-1:1000 joins quinoline and esters solvent in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 10-20 minute.Add methyl iodide then, the molar ratio of methyl iodide and quinoline reactant is 50:1-1:1, reactor is sealed stirring reaction 1-3 hour after, add isopyknic methyl iodide again, continued sealed reaction 1-10 hour.Temperature of reaction is 10-25 ℃.The product of the productive rate more than 70% will promptly be obtained then in the static 5-10 of reaction system hour, product is iodate 1-toluquinoline, iodate 1-methylacridine, iodate 1-methyl-(3,4-N, N dimethyl) the N-methyl compound of acridine, iodate 1-methyl benzisoquinoline, iodate 1-tolimidazole or its replacement.Resulting product can be purified with the method that Soxhlet is extracted, and extracting solvent can be directly with the mother liquor behind the Reaction Separation crystalline product.
Of the present invention that esters solvent comprises saturated fatty class carboxylic acid esters such as methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate and butylacetate, esters of unsaturated carboxylic acids such as vinyl-acetic ester and aromatic ester class such as methyl benzoate and ethyl benzoate.
Ester class catalyzed reaction solvent of the present invention is meant the solvent that the n-formyl sarcolysine glycosylation reaction of quinoline reactant and methyl iodide is played katalysis.
Quinoline reactant of the present invention is the benzoglyoxaline of quinoline, acridine, different acridine, benzoglyoxaline and replacement.
Methylating reagent of the present invention is a methyl iodide.
Logical nitrogen deoxygenation of the present invention is meant the deoxygenation to reaction soln and reactor, also can carry out under the condition of a straight-through nitrogen.
Temperature when ester reaction solvent of the present invention and reactant reaction is controlled at 10-25 ℃, also can suitably improve temperature with the quickening speed of reaction, but must be lower than the boiling point of reaction soln.
Stirring operation in the reaction process of the present invention is necessary, and mixing speed is unsuitable too fast, otherwise generates to such an extent that particle too carefully causes filtration difficulty.
Product crystallization of the present invention can get final product according to general sepn process with separating.
Purification of products of the present invention can meet the requirements of purity with the mother liquor extracting behind the fractional crystallization.
Embodiment
Embodiment 1
Volume ratio by 1:25 joins quinoline and ethyl acetate in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 20 minutes.Add and the equimolar methyl iodide of quinoline, reactor was sealed stirring reaction 3 hours, add equimolar methyl iodide again, continued sealed reaction 3 hours.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained yellow crystals in static 10 hours, and productive rate can reach more than 70%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify, product purity can reach 99.5%.
Embodiment 2
Volume ratio by 1:50 joins quinoline and methyl benzoate in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 20 minutes.Adding is the methyl iodide of 1:5 with the quinoline mol ratio, and reactor was sealed stirring reaction 2 hours.Temperature of reaction is controlled to be 30 ℃.After reaction finished, system promptly obtained yellow crystals in static 10 hours, and productive rate can reach more than 70%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify, product purity can reach 99.5%.
Embodiment 3
Volume ratio by 1:1000 joins acridine and ethyl acetate in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 15 minutes.Adding is the methyl iodide of 1:5 with the acridine mol ratio, and reactor was sealed stirring reaction 3 hours.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained the deep yellow crystal in static 10 hours, and productive rate can reach more than 65%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify, product purity can reach 99.0%.
Embodiment 4
In the equal-volume ratio benzoglyoxaline and ethyl formate are joined in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, the time is 15 minutes.Adding is the methyl iodide of 1:30 with the benzoglyoxaline mol ratio, and reactor was sealed stirring reaction 1 hour.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained pale yellow crystals in static 10 hours, and productive rate can reach more than 80%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify, product purity can reach 99.2%.
Embodiment 5
The volume ratio of pressing 1:200 is 3,4-N, and N dimethyl-acridine and ethyl acetate join in the reactor that band stirs, the oxygen in the logical then nitrogen eliminating system, the time is 15 minutes.Adding is the methyl iodide of 1:5 with the acridine mol ratio, and reactor was sealed stirring reaction 3 hours.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained the deep yellow crystal in static 10 hours, and productive rate can reach more than 78%.
Embodiment 6
Volume ratio by 1:5 joins quinoline and ethyl acetate in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 20 minutes.Adding is the methyl iodide of 1:50 with the quinoline mol ratio, and reactor was sealed stirring reaction 1 hour.Temperature of reaction is controlled to be 25 ℃.System promptly obtained the deep yellow crystal in static 6 hours, and productive rate can reach more than 85%.
Reference examples 1
Volume ratio by 1:10 joins quinoline and ether in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 20 minutes.Add and the equimolar methyl iodide of quinoline, reactor was sealed stirring reaction after 3 hours, add equimolar methyl iodide again, continued sealed reaction 3 hours.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained yellow crystals in static 10 hours, and productive rate can reach 18%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify product purity 92.0%.
Reference examples 2
Volume ratio by 1:10 joins quinoline and methylene dichloride in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 20 minutes.Add and the equimolar methyl iodide of quinoline, reactor was sealed stirring reaction after 3 hours, add equimolar methyl iodide again, continued sealed reaction 3 hours.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained yellow crystals in static 10 hours, and productive rate can reach more than 10%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify, product purity can reach 89.5%.
Reference examples 3
Volume ratio by 1:10 joins quinoline and acetonitrile in the reactor of band stirring, the oxygen in the logical then nitrogen eliminating system, and the time is 20 minutes.Add and the equimolar methyl iodide of quinoline, reactor was sealed stirring reaction after 3 hours, add equimolar methyl iodide again, continued sealed reaction 3 hours.Temperature of reaction is controlled to be 25 ℃.After reaction finished, system promptly obtained yellow crystals in static 10 hours, and productive rate can reach more than 22%.With mother liquor resulting product is carried out the Soxhlet extracting method and purify, product purity can reach 95.0%.
Claims (5)
1. an ester reaction solvent prepares the method for iodate N-toluquinoline compounds, and its key step is:
A) under the nitrogen atmosphere, press the volume ratio 1000:1-1:1 of ester class catalyzed reaction solvent and quinoline reactant, join in the reactor, stirring reaction 10-20 minute;
B) add methyl iodide, the molar ratio of methyl iodide and quinoline reactant is 50:1-1:1, and reactor sealing stirring reaction 1-3 hour adds isopyknic methyl iodide again, continued sealed reaction 1-10 hour, control reaction temperature is lower than the boiling point of ester class catalyzed reaction solvent;
C) the static 5-10 of reaction system hour, crystallization separated, and obtains product;
Described ester class catalyzed reaction solvent is meant the solvent that the n-formyl sarcolysine glycosylation reaction of quinoline reactant and methyl iodide is played katalysis: ethyl acetate, methyl benzoate or ethyl formate;
Described quinoline reactant is quinoline, acridine or benzoglyoxaline.
2. preparation method as claimed in claim 1 is characterized in that, the temperature of reaction among the step b is 10-25 ℃.
3. the method for claim 1 is characterized in that, the method that step c products therefrom extracts with Soxhlet is purified.
4. method as claimed in claim 3 is characterized in that, the mother liquor of the solvent that uses in the described Soxhlet extracting method after as the fractional crystallization product.
5. the method for claim 1 is characterized in that, described product is iodate 1-toluquinoline, iodate 1-methylacridine or iodate 1-tolimidazole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100368024A CN100532362C (en) | 2004-04-13 | 2004-04-13 | Process for preparing N-methyl quinoline compounds by ester reaction solvent |
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| CNB2004100368024A CN100532362C (en) | 2004-04-13 | 2004-04-13 | Process for preparing N-methyl quinoline compounds by ester reaction solvent |
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| CN1683338A CN1683338A (en) | 2005-10-19 |
| CN100532362C true CN100532362C (en) | 2009-08-26 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070487A1 (en) * | 2001-03-01 | 2002-09-12 | Pharmacia & Upjohn Company | Substituted quinolinecarboxamides as antiviral agents |
| CN1398854A (en) * | 2002-08-21 | 2003-02-26 | 北京大学 | New iso quinoline compound with HIV-1 resisting activity |
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2004
- 2004-04-13 CN CNB2004100368024A patent/CN100532362C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070487A1 (en) * | 2001-03-01 | 2002-09-12 | Pharmacia & Upjohn Company | Substituted quinolinecarboxamides as antiviral agents |
| CN1398854A (en) * | 2002-08-21 | 2003-02-26 | 北京大学 | New iso quinoline compound with HIV-1 resisting activity |
Non-Patent Citations (2)
| Title |
|---|
| 1-(a-萘甲基)-2-甲基-6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐的化学研究和降压作用. 黄文龙等.中国药科大学学报,，第23,卷第6期. 1992 * |
| 取代苄基/萘甲基异喹啉类及有关季铵衍生物的合成与生物活性. 许国友等.药学学报,，第29,卷第2期. 1994 * |
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