CN101245069A - Process for producing cis-1.3 disubstituted benzyl imidazoline-2-ketone-2H-furo[3.4-d]imidazole-2,4,6- trione - Google Patents
Process for producing cis-1.3 disubstituted benzyl imidazoline-2-ketone-2H-furo[3.4-d]imidazole-2,4,6- trione Download PDFInfo
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- CN101245069A CN101245069A CNA2008100325046A CN200810032504A CN101245069A CN 101245069 A CN101245069 A CN 101245069A CN A2008100325046 A CNA2008100325046 A CN A2008100325046A CN 200810032504 A CN200810032504 A CN 200810032504A CN 101245069 A CN101245069 A CN 101245069A
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- disubstituted benzyl
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Abstract
The invention belongs to the technical field of organic chemistry, and more particularly relates to a preparation method of cis-1.3-disubstituted benzyl imidazoline-2-ketone-2H-furo (3.4-d) imidazole-2, 4, 6-triketone (cyclic anhydride, I). The prior art has the disadvantages of high unit consumption of acetic anhydride, incomplete reaction and poor product quality, etc. In the preparation method, 1, 3-disubstituted benzyl imidazoline-2-ketone-cis-4, 5-dicarboxylic acid and various acyl halide are subject to dehydration/ ring closure in an organic solvent or in a solvent-free way so as to obtain the cis-1.3-disubstituted benzyl imidazoline-2-ketone-2H-furo (3.4-d) imidazole-2, 4, 6-triketone (cyclic anhydride, I). The method can avoid the adoption of a great deal of acetic anhydride, and has mild reaction condition, product purity of more than 99 percent, low cost and less pollution to the environment, thus being suitable for industrial production.
Description
Technical field
The invention belongs to technical field of organic chemistry, being specifically related to a kind of is suitable-1.3-disubstituted benzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4,6-triketone (cyclic acid anhydride, I) preparation method.
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, p-methylphenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl or rubigan, Ar are phenyl, p-methylphenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, thienyl, furyl or naphthyl.
Background technology
(3aS, 6aR)-1,3-disubstituted benzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone (I) is the key intermediate of synthetic d-vitamin H (d-Biotin, vitamin H, vitamin H).United States Patent (USP) 2489232 has described 1; 3-dibenzyl imidazoline-2-ketone-suitable-4; 5-dicarboxylic acid and diacetyl oxide dehydration ring closure prepare suitable-1.3-dibenzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2; 4; 6-triketone (cyclic acid anhydride; I) preparation method; but reaction conditions and yield all do not disclose, (SCI, 2001 in our research process; 22; 1141), find 1,3-dibenzyl imidazoline-2-ketone-suitable-4; the mol ratio of 5-dicarboxylic acid and diacetyl oxide must just can be carried out reaction in 1: 3; yield 90%, yet, still have 5～10%1; 3-dibenzyl imidazoline-2-ketone-suitable-4; 5-dicarboxylic acid raw material unreacted is complete, is 90～93% only even the reaction times extends to 40h cyclic acid anhydride I content, is difficult to obtain highly purified product; and a large amount of diacetyl oxide and the acetate mixtures of reaction back formation, both are difficult for separation sleeve and use.(SCI such as Chen Fener; 2001; 22; 1141) phosphatase reaction that adds catalytic amount in above-mentioned system is almost quantitatively finished reaction in 3h, yield＞98%, but 1; 3-dibenzyl imidazoline-2-ketone-suitable-4; 5-dicarboxylic acid and diacetyl oxide mol ratio still need reaction in 1: 3 just can finish, otherwise reaction is difficult to carry out fundamentally do not properly settle these drawbacks fully.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provides a kind of efficient and suitable-1.3-disubstituted benzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4 cheaply, 6-triketone (cyclic acid anhydride, I) preparation method.
The present invention is 1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4, and 5-dicarboxylic acid and sour halogen dewater, close ring in organic solvent, promptly get suitable-1.3-disubstituted benzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4, the 6-triketone (cyclic acid anhydride, I).This method reaction conditions gentleness, product purity＞99.5%.Its reaction scheme is:
Among the present invention, used carboxylic acid halides is C
1～C
6Fat carboxylic acid halides or substituted aroma carboxylic acid halides, halogen is chlorine and bromine.
In the present invention, 1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4,5-dicarboxylic acid (naphthenic acid) is 1: 1～5 with the mol ratio of carboxylic acid halides, reaction can be carried out smoothly.
Used organic solvent is as any of aromatic hydrocarbon such as benzene,toluene,xylene or vinyl trichloride, 1,2,3-trichloropropane, zellon, 1,2, any of halohydrocarbon such as 3-tri chloropropene all is good solvents, and this two kind solvents convenient sources, price are all more cheap.1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4, the weightmeasurement ratio of 5-dicarboxylic acid and organic solvent is 1: 6～20g/ml, can reach the good solubility energy in reaction process.This reaction also can be carried out in solvent-free.
Among the present invention, temperature of reaction can be controlled in 20～135 ℃ of scopes.The suitable reaction times is 0.5～2h.
Optimum reaction condition of the present invention is:
1) 1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4,5-dicarboxylic acid (naphthenic acid) is that 1: 1.5～5 reactions can be finished smoothly with the mol ratio of Acetyl Chloride 98Min..
2) avoid with an organic solvent reducing cost, reduce and pollute.
3) temperature of reaction that this reaction is best is 45～60 ℃.Reaction times 1～2h is the most suitable.
Embodiment:
Embodiment 1 is 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the 5-dicarboxylic acid (35.5g, 0.10mol), Acetyl Chloride 98Min. (8.56mL, 0.12mol) and toluene (355mL) put in the reaction flask heated and stirred backflow 1h.Unnecessary Acetyl Chloride 98Min. and acetate are taken out in decompression, get white powder I (33.7g, 99%), 236～237 ℃ of mp. content 99.5% (HPLC).
IR(KBr)：v＝1805，1740，1687，1227cm
-1.
1H?NMR(CDCl
3)：δ＝4.21(s，2H，C
3a-H?and?C
6a-H)，4.19，5.10(dd，4H，J＝15Hz，2×CH
2C
6H
5)，7.26～7.39(m，10H，2×ArH)ppm.
EI-MS：(m/z，％)＝336(M
+，13.6)，264(15.6)，173(5.8)，132(10.9)，91(100).
Embodiment 2 is 1,3-dibenzyl imidazoline-2-ketone-suitable-4, and the 5-dicarboxylic acid (35.5g, 0.10mol), (14.3mL, 0.20mol) and 1, Acetyl Chloride 98Min. is put in the reaction flask, heated and stirred backflow 15h by 2-ethylene dichloride (650mL).Be cooled to room temperature, separate out solid, filter, drying gets white powder I (32g, 95%), 235～237 ℃ of .IR of mp,
1H NMR is consistent with embodiment with MS.
Embodiment 3 is 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the 5-dicarboxylic acid (35.5g, 0.10mol), propionyl chloride (17.4mL, 0.20mol) and toluene (710mL) put in the reaction flask heated and stirred backflow 8h.Be cooled to room temperature, separate out solid, filter, drying gets white powder I (33g, 98%), mp236～236.5 ℃ .IR,
1H NMR is consistent with embodiment with MS.
Embodiment 4 is 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the 5-dicarboxylic acid (35.5g, 0.10mol), Benzoyl chloride (29.3mL, 0.25mol) and toluene (710mL) put in the reaction flask heated and stirred backflow 8h.Be cooled to room temperature, separate out solid, filter, drying gets white powder I (32g, 95%), mp236～237 ℃ .IR,
1H NMR is consistent with embodiment with MS.
The invention is not restricted to the foregoing description.
Claims (7)
1 ,-and kind of suitable-1.3-dibenzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4,6-triketone preparation method, its structure are as shown in the formula (I):
R in the formula
1Be hydrogen, C
1～C
6Alkyl, phenyl, p-methylphenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl or rubigan, Ar are phenyl, p-methylphenyl, p-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-Dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, rubigan, thienyl, furyl or naphthyl;
It is characterized in that 1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4,5-dicarboxylic acid and carboxylic acid halides dewater, close ring in organic solvent or under solvent-free, promptly get suitable-1.3-disubstituted benzyl imidazoline-2-ketone-2H-furo [3.4-d] imidazoles-2,4, the 6-triketone.
2, preparation method as claimed in claim 1 is characterized in that used carboxylic acid halides is C
1～C
6Fat carboxylic acid halides or substituted aroma carboxylic acid halides, halogen is chlorine and bromine.
3, preparation method as claimed in claim 1 is characterized in that 1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4, and 5-dicarboxylic acid and carboxylic acid halides mol ratio are 1: 1～5.
4, preparation method as claimed in claim 1 is characterized in that organic solvent is aromatic hydrocarbon or halogenated hydrocarbon, 1, and 3-disubstituted benzyl imidazoline-2-ketone-suitable-4, the weightmeasurement ratio of 5-dicarboxylic acid and organic solvent is 1: 6～20g/ml.
6, preparation method as claimed in claim 1 is characterized in that temperature of reaction is 20～135 ℃, and the reaction times is 0.5～5h.
7, preparation method as claimed in claim 1 is characterized in that 1,3-disubstituted benzyl imidazoline-2-ketone-suitable-4, and 5-dicarboxylic acid (naphthenic acid) is 1: 1.5～5 with the mol ratio of carboxylic acid halides.
8, preparation method as claimed in claim 1 is characterized in that temperature of reaction is 45～60 ℃, and the reaction times is 1～2h.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100325046A CN101245069A (en) | 2008-01-10 | 2008-01-10 | Process for producing cis-1.3 disubstituted benzyl imidazoline-2-ketone-2H-furo[3.4-d]imidazole-2,4,6- trione |
| CN200880108194XA CN102282149A (en) | 2007-09-20 | 2008-09-22 | Process for the manufacture of (+)-biotin |
| PCT/CN2008/001635 WO2009049476A1 (en) | 2007-09-20 | 2008-09-22 | Process for the manufacture of (+)-biotin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100325046A CN101245069A (en) | 2008-01-10 | 2008-01-10 | Process for producing cis-1.3 disubstituted benzyl imidazoline-2-ketone-2H-furo[3.4-d]imidazole-2,4,6- trione |
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|---|---|
| CN101245069A true CN101245069A (en) | 2008-08-20 |
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| CNA2008100325046A Pending CN101245069A (en) | 2007-09-20 | 2008-01-10 | Process for producing cis-1.3 disubstituted benzyl imidazoline-2-ketone-2H-furo[3.4-d]imidazole-2,4,6- trione |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009049476A1 (en) * | 2007-09-20 | 2009-04-23 | Dsm Ip Assets B.V. | Process for the manufacture of (+)-biotin |
| CN101519407B (en) * | 2009-03-31 | 2012-09-05 | 复旦大学 | Synthesis method of cyclic acid anhydride capable of having substituent group |
-
2008
- 2008-01-10 CN CNA2008100325046A patent/CN101245069A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009049476A1 (en) * | 2007-09-20 | 2009-04-23 | Dsm Ip Assets B.V. | Process for the manufacture of (+)-biotin |
| CN102282149A (en) * | 2007-09-20 | 2011-12-14 | 帝斯曼知识产权资产管理有限公司 | Process for the manufacture of (+)-biotin |
| CN101519407B (en) * | 2009-03-31 | 2012-09-05 | 复旦大学 | Synthesis method of cyclic acid anhydride capable of having substituent group |
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