CN1434039A - Process for preparing 1,3-dibenzyl imidazoline-2-ketone-cis-4, 5-dicarboxylic acid (I) - Google Patents
Process for preparing 1,3-dibenzyl imidazoline-2-ketone-cis-4, 5-dicarboxylic acid (I) Download PDFInfo
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Abstract
The present invention provides a method for preparing 1,3-dibenzylimidazoline-2-ketone-cis-4,5- dicarboxylic acid, and is characterized by that it utilizes chlorine gas to make fumaric acid produce electrophilic addition reaction to obtain meso-2,3-dichlorosuccinic acid, in the pressence of phase transfer catalyst the meso-2,3-dichlorosuccinic acid and benzylamine are undergone the processes of benzylamination reaction in the solvent so as to synthesize cis-2,3-dibenzylamine succinic acid, the latter and solid carbonyl chloride and undergone the process of phase transfer catalytic ring-closing reaction in the potassium hydroxide solution so as to obtain the invented product. Its total yield rate is up to 74%.
Description
Technical field
The invention belongs to organic chemistry filed, is 1,3-dibenzyl imidazoline-2-ketone-suitable-4,5-dicarboxylic acid (naphthenic acid, preparation method I)
Background technology
1,3-dibenzyl imidazoline-2-ketone-suitable-4,5-dicarboxylic acid (I) is synthetic d-vitamin H (d-Biotin, vitamin H, vitamin H) important intermediate, foreign literature such as United States Patent (USP) 2489232,4659837, Japanese Patent 60-152469, it is the meso-2 of starting raw material preparation with the fumaric acid that 59-59668 etc. have all described, 3-dibromo-succinic acid and benzylamine carry out benzylamineization and change into meso-2 in ethanol, two (benzamido group) Succinic Acid of 3-, and then carry out phosgene with phosgene and close the method that cyclization becomes naphthenic acid (I).This technology exists benzylamine unit consumption height, uses a large amount of hypertoxic phosgene, and the harsh and a large amount of phosgene of labour protection conditional request transport and technological operation brings a series of problems that need solution to the product man that self does not produce phosgene.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provides a kind of easy, high purity and cheaply 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the industrial preparative method of 5-dicarboxylic acid (I).
The present invention is that starting raw material carries out electrophilic addition and prepares meso-2 in the mineral acid solvent with fumaric acid cheap and easy to get, 3-dichloro Succinic Acid (II), then in the presence of phase-transfer catalyst and mineral alkali, in organic solvent, carry out benzylamineization with benzylamine and change into suitable-2,3-dibenzylamine Succinic Acid (III), in the presence of phase-transfer catalyst and potassium hydroxide or sodium hydroxide solution, carry out ring closure reaction with cyclization reagent again, without separation, directly make naphthenic acid (I) with the mineral acid acidifying, total recovery is 77.4%, HPLC measures its content greater than more than 99.5%, and its synthetic route is as follows:
In chlorination reaction of the present invention, mineral acid can be 5%～30% hydrochloric acid, 40%～48% Hydrogen bromide, 36～50% acetate any all can obtain good result, temperature of reaction can be 65～100 ℃ of scopes.Use GC-MS or HPLC to follow the tracks of main fumaric acid disappearance in the reaction and be terminal point, the fumaric acid transformation efficiency reaches 95-98%.
In benzylamine reaction of the present invention, mineral alkali is that any of Anhydrous potassium carbonate, anhydrous sodium carbonate or Carbon Dioxide lithium, Carbon Dioxide caesium all is suitable as the benzylamine reaction base.Quaternary ammonium salt (A) has good phase-transfer catalysis effect, and the reaction conditions gentleness is easy and simple to handle, the yield height.The mol ratio of compound (II)/benzylamine/mineral alkali/phase-transfer catalyst is 1: 2.2～6.5: 2～4.5: 0.01～0.1, and reaction can be finished smoothly.Arenes such as organic solvent-benzene, toluene and dimethylbenzene all are suitable as benzylamineization
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl: X is Cl, Br,
F。The solvent of reaction, the cheap and easy to get and easy recovery set usefulness of this kind solvent.Temperature of reaction is 25～110 ℃.
Cyclization reagent is any of superpalite (trichloromethylchloroformate) or two (trichloromethyl) carbonic ether (triphosgene) in cyclization of the present invention, and this type of cyclization reagent is cheap and easy to get, convenient transportation and storage.Quaternary ammonium salt (A) and polyethylene glycols (B) but any equal catalytic cyclization reaction.Compound III/cyclization reagent/phase-transfer catalyst mol ratio is 1: 2～10: 0.01～0.1, and reaction can gentleness be finished.Suitable inorganic alkali solution is that the sodium hydroxide of 5～50% potassium hydroxide solution or this concentration is molten
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl: X is Cl, Br,
F。Liquid, this type of alkaline solution convenient sources, cheap and easy to get.Reaction soln pH8～14.Appropriate organic solvent is the solvent that arene equal solvents such as benzene, toluene and dimethylbenzene all can be used as the benzylamine reaction.Temperature of reaction is 20～70 ℃.
The better reaction conditions of the present invention is:
The mineral acid of chlorination reaction of the present invention is a 20-30% hydrochloric acid.
Chlorination reaction temperature of the present invention is 90～100 ℃.
The mineral alkali of benzylamine reaction of the present invention is an Anhydrous potassium carbonate, and phase-transfer catalyst is chlorination triethyl benzyl ammonium reaction effect the best, and both raw materials are cheap.
The Compound I I of benzylamine reaction of the present invention: benzylamine: Anhydrous potassium carbonate: the mol ratio of chlorination triethyl benzyl ammonium is the 1: 3～5: 2.1～3.2: 0.03～the 0.05th, best material ratio, reaction can be finished smoothly, and this temperature of reaction preferably is controlled at 100～110 ℃ of scopes.
The used organic solvent toluene of benzylamine reaction of the present invention is better, and its convenient sources reclaims easily.
The better reaction conditions of cyclization of the present invention is as follows:
Phase-transfer catalyst is a chlorination triethyl benzyl ammonium.
Compound III: cyclization reagent: the mol ratio of phase-transfer catalyst is 1: 3～5: 0.05～0.1.
Inorganic alkali solution of the present invention is 35～40% potassium hydroxide solutions, reaction soln pH9～11.
Organic solvent is a toluene.
35～40 ℃ of temperature of reaction.
The present invention has raw material and is easy to get, and the reaction conditions gentleness is easy and simple to handle, the yield height, and the low and product purity height of cost is suitable for suitability for industrialized production.
Embodiment
Embodiment
One, suitable-2, the preparation of 3-dichloro Succinic Acid (II)
Example 1 fumaric acid (116g, 1.0mol), 30% hydrochloric acid (400mL) is put in the reaction flask, after heated and stirred refluxes, feed chlorine (content that GC-MS follows the tracks of reaction II reaches more than 97.5%, and fumaric acid raw material peak disappears) to terminal rapidly, 4h Nei Tongbi continues insulated and stirred 0.5h.Reaction is finished, and is cooled to 5 ℃.Separate out solid, filter, washing, drying, white powder II (168.3g, 90%), mp217～219 ℃.
(116g, 1.0mol), put in the reaction flask, in 65 ℃, feeds chlorine (content that GC-MS follows the tracks of reaction II reaches more than 98%) to terminal under stirring rapidly, 2h Nei Tongbi, continuation insulated and stirred 2h by 40% Hydrogen bromide (350mL) with fumaric acid for example 2.Reaction is finished, and is cooled to 5～10 ℃.Separate out solid, filter, washing, drying, white powder II (159g, 85%), mp216～219 ℃.
Two, suitable-2, the preparation of 3-dibenzyl amido Succinic Acid (III)
Example 1 with II (18.7g, 0.1mol), benzylamine (32.1g, 0.30mol), chlorination triethyl benzyl ammonium (0.7g, 0.003mol), Anhydrous potassium carbonate (28.9g, 0.21mol) and toluene (200mL) put in the dry reaction bottle, in 45 ℃, stirring and refluxing 5h.Be cooled to room temperature, add entry (200mL), separate out solid, filter, drying gets white powder III (29.6g, 90%), mp220～224.
Example 2 with II (18.7g, 0.1mol), benzylamine (48.2g, 0.45mol), Tetrabutylammonium bromide (1.73g, 0.009mol), anhydrous sodium carbonate (54g, 0.5mol) and dimethylbenzene (300mL) put in the dry reaction bottle stirring and refluxing 15h.Be cooled to room temperature, add entry (300mL), separate out solid, filter, drying, white powder III (30g, 90%), mp222～225 ℃.
Three, 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the preparation of 5-dicarboxylic acid (I)
Example 1 is with III (117g, 0.36mol), 40% potassium hydroxide solution (200mL) and chlorination triethyl benzyl ammonium (3.5g, 0.18mol) put in the reaction flask, behind stirring at room 15min, add toluene (250mL) again, in 40 ℃, (320.8g 1.08mol) is dissolved in the solution of toluene (500mL), controls reaction solution pH9～11 with 40% potassium hydroxide solution again to drip triphosgene, in 2h, drip and finish, continue insulated and stirred 2h.Reaction is finished, and adds the Repone K dissolving that entry (400mL) generates reaction, standing demix, and water layer extracts with toluene (100mL * 3), and the buck layer transfers to pH1～2 with concentrated hydrochloric acid, separates out faint yellow oily thing, tells oily matter.Water layer uses ethyl acetate (120mL * 3) to extract again, merges oily matter and ethyl acetate layer, is washed to pH7, reclaim under reduced pressure ethyl acetate (about 400mL), solid is separated out in cooling, filters drying, white crystalline powder I (116.3g, 91%), mp173～175 ℃.IR(KBr)：v＝3417，2900，1709，1450，1418，1220cm
-1.
1H?NMR(DMSO-d
6)：δ＝4.07，4.78(dd，4H，J＝15.36Hz，2×CH
2C
6H
5)，4.16(s，2H，C
4-H?andC
5-H)，7.22～7.36(m，10H，2×ArH)，13.29(br?s，2H，2×COOH)ppm.EI-MS：(m/z，％)＝355(M
+，29)，309(43)，265(49)，154(45)，136(20)，91(100).
Example 2 is with III (32.9g, 0.1mol), 20% sodium hydroxide solution (100mL) and bromogeramine (2.7g, 0.007mol) put in the reaction flask, behind stirring at room 5min, add benzene (200mL) again, in 70 ℃, (178.2g 0.6mol) is dissolved in the solution of toluene (400mL), controls reaction solution pH10～12 with 20% sodium hydroxide solution again to drip triphosgene, in 1h, drip and finish, continue insulated and stirred 2.5h.Reaction is finished, and adds the sodium-chlor dissolving that entry (200mL) generates reaction, standing demix, and water layer extracts with toluene (80mL * 3), and the buck layer transfers to pH1～2 with concentrated hydrochloric acid, separates out faint yellow oily thing.Water layer uses ethyl acetate (100mL * 3) to extract again, merges oily matter and ethyl acetate layer, is washed to pH6～7, reclaim under reduced pressure ethyl acetate (about 200mL), solid is separated out in cooling, filters drying, white crystalline powder II (29.8g, 84%), mp171～174 ℃.IR,
1H NMR is all consistent with embodiment 1 with MS.
The invention is not restricted to above-mentioned example, above-mentioned example is the example of optimizing.
Claims (13)
1, a kind of preparation 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I
It is characterized in that fumaric acid and chlorine carry out electrophilic addition and prepares meso-2 in the mineral acid solvent, 3-dichloro Succinic Acid II, in the presence of phase-transfer catalyst and mineral alkali, Compound I I and benzylamine carry out benzylamine and change into suitable-2 in organic solvent, 3-dibenzylamine Succinic Acid III, the latter and cyclization reagent carry out phase-transfer catalysis pass ring and promptly get 1,3-dibenzyl imidazoline-2-ketone-suitable-4 in potassium hydroxide solution and organic solvent, 5-dicarboxylic acid I
Concrete preparation condition is:
When (1) preparing Compound I I by fumaric acid, mineral acid is 5～30% hydrochloric acid or 20～48% Hydrogen bromides or 36～50% acetate;
Temperature of reaction is 65 ℃～100 ℃ when (2) preparing Compound I I by fumaric acid;
Used mineral alkali was Anhydrous potassium carbonate or anhydrous sodium carbonate or Carbon Dioxide lithium or Carbon Dioxide caesium when (3) Compound I I prepared compound III;
(4) phase-transfer catalyst is quaternary ammonium salt A:
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl: X is Cl, Br, F;
Compound I I when (5) preparing compound III by Compound I I: benzylamine: mineral alkali: the mol ratio of phase-transfer catalyst is 1: 2.2～6.5: 2～4.5: 0.01～0.1:
Used organic solvent was an arene when (6) Compound I I prepared compound III;
Temperature of reaction was 25～110 ℃ when (7) Compound I I prepared compound III;
Used cyclization reagent was superpalite or two trichloromethyl carbonate when (8) compound III prepared Compound I;
Compound III when (9) compound III prepares Compound I: cyclization reagent: the phase-transfer catalyst mol ratio is 1: 2～10: 0.01～0.1;
Phase-transfer catalyst used when (10) compound III prepares Compound I is:
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl: X is Cl, Br, F;
Temperature of reaction is 20～70 ℃ when (11) preparing Compound I by compound III;
Used inorganic alkali solution was 5～50% potassium hydroxide solution or this concentration hydrogen sodium hydroxide solution when (12) compound III prepared Compound I, reaction soln pH8～14;
Used organic solvent is an arene when (13) preparing Compound I by compound III.
2, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, used acid is the hydrochloric acid of 20-30% when it is characterized in that preparing Compound I I by fumaric acid.
3, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I is characterized in that temperature of reaction is 90～100 ℃.
4, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I is characterized in that mineral alkali used when Compound I I prepares compound III is an Anhydrous potassium carbonate.
5, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, phase-transfer catalyst is a chlorination triethyl benzyl ammonium when it is characterized in that Compound I I prepares compound III.
6, according to claim 1,4,5 described preparations 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method of 5-dicarboxylic acid I, when it is characterized in that Compound I I prepares compound III, Compound I I: benzylamine: Anhydrous potassium carbonate: the mol ratio of chlorination triethyl benzylamine is 1: 3～5: 2.1～3.2: 0.03～0.05.
7, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, when it is characterized in that Compound I I prepares compound III, organic solvent is a toluene.
8, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I is characterized in that the temperature of reaction when Compound I I prepares compound III is 100～110 ℃.
9, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method of 5-dicarboxylic acid I, when it is characterized in that compound III prepares Compound I, compound III: cyclization reagent: the mol ratio of phase-transfer catalyst is 1: 3～5: 0.05～0.1.
10, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, when it is characterized in that compound III prepares Compound I, phase-transfer catalyst is a chlorination triethyl benzyl ammonium.
11, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, when it is characterized in that compound III prepares Compound I, 35～40 ℃ of temperature of reaction.
12, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, when it is characterized in that compound III prepares Compound I, inorganic alkali solution is 35～40% potassium hydroxide solutions, pH9～11.
13, preparation 1 according to claim 1,3-dibenzyl imidazoline-2-ketone-suitable-4, the method for 5-dicarboxylic acid I, when it is characterized in that compound III prepares Compound I, organic solvent is a toluene.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101417977B (en) * | 2007-10-24 | 2010-12-29 | 浙江医药股份有限公司新昌制药厂 | Method for synthesizing 1,3-dibenzyl-4,5-cis-dicarboxyl-2-imidazolinone |
| CN102219742A (en) * | 2011-04-14 | 2011-10-19 | 大丰海嘉诺药业有限公司 | Method for synthesizing 1,3-dibenzyl imidazoline-2-keto-cis-4,5-dicarboxylic acid |
| CN103553897A (en) * | 2013-10-23 | 2014-02-05 | 安徽省郎溪县联科实业有限公司 | Dicarboxylic acid refinement separation and drying method |
| CN105399677A (en) * | 2015-11-17 | 2016-03-16 | 蚌埠丰原医药科技发展有限公司 | Preparation method of trans-naphthenic acid |
| CN106831592A (en) * | 2017-03-15 | 2017-06-13 | 安徽泰格维生素实业有限公司 | A kind of preparation method of naphthenic acid |
| CN108164466A (en) * | 2017-12-12 | 2018-06-15 | 浙江工业大学 | Preparation method of cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid |
| CN111056937A (en) * | 2020-01-02 | 2020-04-24 | 大连凯飞化学股份有限公司 | Synthetic method of 2, 3-dichloro-2-methylpropanoic acid |
-
2003
- 2003-02-14 CN CNB031154166A patent/CN1152018C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101417977B (en) * | 2007-10-24 | 2010-12-29 | 浙江医药股份有限公司新昌制药厂 | Method for synthesizing 1,3-dibenzyl-4,5-cis-dicarboxyl-2-imidazolinone |
| CN102219742A (en) * | 2011-04-14 | 2011-10-19 | 大丰海嘉诺药业有限公司 | Method for synthesizing 1,3-dibenzyl imidazoline-2-keto-cis-4,5-dicarboxylic acid |
| CN103553897A (en) * | 2013-10-23 | 2014-02-05 | 安徽省郎溪县联科实业有限公司 | Dicarboxylic acid refinement separation and drying method |
| CN105399677A (en) * | 2015-11-17 | 2016-03-16 | 蚌埠丰原医药科技发展有限公司 | Preparation method of trans-naphthenic acid |
| CN105399677B (en) * | 2015-11-17 | 2019-02-22 | 蚌埠丰原医药科技发展有限公司 | A kind of preparation method of trans- naphthenic acid |
| CN106831592A (en) * | 2017-03-15 | 2017-06-13 | 安徽泰格维生素实业有限公司 | A kind of preparation method of naphthenic acid |
| CN108164466A (en) * | 2017-12-12 | 2018-06-15 | 浙江工业大学 | Preparation method of cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid |
| CN111056937A (en) * | 2020-01-02 | 2020-04-24 | 大连凯飞化学股份有限公司 | Synthetic method of 2, 3-dichloro-2-methylpropanoic acid |
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