CN101676276B - Method for preparing N-tert-butyloxycarbonylpiperazine acetic acid hydrochloride - Google Patents
Method for preparing N-tert-butyloxycarbonylpiperazine acetic acid hydrochloride Download PDFInfo
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Abstract
The invention relates to a method for preparing piperazine carboxylic acid hydrochloride, in particular to a method for preparing N-Boc-piperazine acetic acid hydrochloride, mainly aiming at solving the technical problems of low product yield and low weight content in the existing preparation method. The method has the technical scheme that conventional N-Boc-piperazine and ethyl bromoacetate which are easily obtained are taken as raw material, and the N-Boc-piperazine acetic acid hydrochloride can be obtained sequentially through two-step continuous reaction of substitution and hydrolyzation. The method is mainly used for preparing N-Boc-piperazine acetic acid which is a more important common medicine intermediate.
Description
Technical field:
The present invention relates to a kind of preparation method of piperazine carboxylic acid hydrochloride, the particularly preparation method of N-Boc-piperazine acetic acid hydrochloride, wherein Boc is tertbutyloxycarbonyl.
Background technology:
N-Boc-piperazine acetic acid is the common drug intermediate of outbalance, preparation for N-Boc-piperazine acetic acid, bibliographical information be take to the N-Boc-piperazine as raw material, reaction obtains N-Boc-piperazine ethyl acetate, (Bioorganic Medicinal Chemistry Letters with bromoethyl acetate under cesium carbonate or salt of wormwood condition; 13,4,2003; 723～728; WO2004/56782); Then by hydrolyzing N-Boc-piperazine ethyl acetate, utilize the acid-basicity of potassium hydrogen sulfate solution regulator solution to obtain the N-Boc-piperazine acetic acid of white powder, but the product yield that obtains by this method is low＜and 70%, and weight content not high (WO2004/63198).This is because product is very easily water-soluble, thereby is difficult to inorganic salt--sal enixum is separated from product.Just because of this, also there is not effectively to prepare at present the industrial preparative method of this product.Yet the N-Boc-piperazine acetic acid of hydrochloride form has good stability, and is easily separated, the characteristics of the good and easy purifying of crystal formation.Therefore, look for a kind of meet the synthetic needs of industry the method for preparing N-Boc-piperazine acetic acid hydrochloride, just become the key issue that the present invention need to solve.
Summary of the invention:
The object of the present invention is to provide a kind of preparation method of N-Boc-piperazine acetic acid hydrochloride, mainly solve the technical problem that product yield is low and weight content is not high that existing preparation method exists.This method of the present invention has short characteristics of reaction conditions gentleness, reaction times, is conducive to large-scale industrial production.
At the research and development initial stage, we screen different alkali, consequently: if yellow soda ash as alkali, then the speed of reaction is slower, and yield is on the low side; Cesium carbonate and salt of wormwood have better reaction effect; Contrast uses the cost of salt of wormwood to be lower than the use cesium carbonate, and we namely select salt of wormwood to carry out this reaction as alkali.Also reaction solvent is screened simultaneously, find that the yield that DMF and acetonitrile react when making solvent is higher, and other solvent (for example: ethyl acetate, toluene etc.) then is not suitable for this reaction and carries out.Consider DMF aftertreatment difficulty remove, select acetonitrile as the solvent of this reaction.Water cancellation after reaction finishes, the N-Boc-piperazine ethyl acetate that the conventional aftertreatment of process obtains need not to be further purified can carry out lower one-step hydrolysis reaction, and these are one of advantages of the present invention.In order to seek suitable hydrolysing agent, we have carried out the contrast experiment to sodium hydroxide and a hydronium(ion) oxidation lithium, although the result shows sodium hydroxide hydrolysis reaction are occured, and the reaction times is oversize, is not suitable for reaction and carries out; One hydronium(ion) oxidation lithium then can be finished at one to two hours reaction.
Technical scheme of the present invention:
The present invention obtains N-Boc-piperazine acetic acid hydrochloride by replacing and being hydrolyzed two step successive reactions successively take routine, the N-Boc-piperazine that is easy to get and bromoethyl acetate as raw material.
Concrete synthesis route of the present invention is as follows:
Described substitution reaction is: take N-Boc-piperazine and bromoethyl acetate as raw material, take second eyeball or DMF as solvent, do alkali with carbonate and prepare N-Boc-piperazine ethyl acetate, reaction is filtered after finishing, filter cake with water dissolution then the methylate tertbutyl ether extract, concentrate and namely make N-Boc-piperazine ethyl acetate, purity is more than 90%; Preferred solvent is the second eyeball, and preferred carbonate is salt of wormwood.The raw material molar ratio is the N-Boc-piperazine: bromoethyl acetate: salt of wormwood=1: 1: 2.Feed way is to drip, and namely the acetonitrile solution of bromoethyl acetate slowly is added drop-wise in the acetonitrile solution of N-Boc-piperazine.The temperature of reaction span of control that drips the acetonitrile solution of bromoethyl acetate can be 0～82 ℃.The reaction times that drips behind the acetonitrile solution of bromoethyl acetate is 1～2 hour.
Described hydrolysis reaction is: N-Boc-piperazine ethyl acetate through hydronium(ion) oxidation lithium hydrolysis, is filtered and is obtained white powdery solid N-Boc-piperazine acetic acid lithium salts in tetrahydrofuran (THF) and the aqueous solution.With dissolve with methanol and regulator solution pH=1～3, white solid N-Boc-piperazine acetic acid hydrochloride salts out, and filters post-drying and namely gets product, and purity is more than 97%, and yield can reach 85%～90%.The hydrolysising reacting temperature span of control is 0～25 ℃.Regulator solution pH value usefulness be the methyl tertbutyl ethereal solution of hydrogenchloride.
Beneficial effect of the present invention: the advantage of maximum of the present invention is to be embodied in the aftertreatment technology of reaction has been done larger improvement, bibliographical information generally is the pH value of utilizing the aqueous solution conditioned reaction system of sal enixum, thereby obtain thick product, because N-Boc-piperazine acetic acid excellence is water-soluble, the product that obtains by this method must contain a large amount of inorganic salt (sal enixum), if separate with soaking through constantly milling again, then must cause yield very low (about 38%).We utilize N-Boc-piperazine acetic acid hydrochloride in methyl alcohol and the very little characteristics of t-butyl methyl ether solvability, regulate the form that acid-basicity converts N-Boc-piperazine acetic acid lithium salts to N-Boc-piperazine acetic acid hydrochloride by the methyl tertbutyl ethereal solution that drips hydrogenchloride, and from reaction system, separate out, product purity reaches more than 97%, productive rate can reach 85～90%, and has obtained good white plates crystal or white powder solid.Preparation technology provided by the invention selects reasonable, whole yield is higher, technical process easy handling, less demanding to production unit; Because the required production time is shorter, has saved production cost; Both be fit to the short run preparation in laboratory, be fit to again carry out large-scale industrial production.
Embodiment:
Following embodiment illustrates content of the present invention better.But the present invention is not limited to following embodiment.
Example 1
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (1.5kg, 8.0mol) N-Boc-piperazine dissolved in 10 liters of reactors of acetonitrile (1.0L); Cool to 5-10 ℃ with ice bath; Add 1.5Kg salt of wormwood; Slowly drip again the acetonitrile solution (1.3Kg/1.0L) of bromoethyl acetate, warm below 25 ℃ in the control in the dropping process.After finishing dropping, reaction system stirred 2 hours at 20～25 ℃, filtered; Filter cake water (5.0L) and methyl tertiary butyl ether (5.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 10 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (5.0L); Add water (0.5L) and stirred 10 minutes; Add a water and lithium hydroxide (0.5Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 3L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (1.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (16L) in 20 liters of reactors, slowly drips again the methyl tertbutyl ethereal solution (0.6Kg/0.5L) of hydrogenchloride, warm below 25 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=1～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (2.0kg, HPLC purity: 97%, productive rate: 88%).
Example 2
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (1.5kg, 8.0mol) N-Boc-piperazine dissolved at acetonitrile (1.0L) in 10 liters of reactors; Cool to 5-10 ℃ with ice bath; Add 1.5Kg salt of wormwood; Slowly drip again the acetonitrile solution (1.3Kg/1.0L) of bromoethyl acetate, warm below 25 ℃ in the control in the dropping process.After finishing dropping, reaction system was stirring 2 hours below 82 ℃, filtered; Filter cake water (5.0L) and methyl tertiary butyl ether (5.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 10 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (5.0L); Add water (0.5L) and stirred 10 minutes; Add a water and lithium hydroxide (0.5Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 3L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (1.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (16L) in 20 liters of reactors, slowly drips again the methyl tertbutyl ethereal solution (0.6Kg/0.5L) of hydrogenchloride, warm below 25 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=1～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (1.92kg, HPLC purity: 97.1%, productive rate: 85%).
Example 3
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (1.5kg, 8.0mol) N-Boc-piperazine dissolved at acetonitrile (1.0L) in 10 liters of reactors; Cool to 5-10 ℃ with ice bath; Add 1.5Kg salt of wormwood; Slowly drip again the acetonitrile solution (1.3Kg/1.0L) of bromoethyl acetate, warm below 0 ℃ in the control in the dropping process.After finishing dropping, reaction system stirred 2 hours at 20～25 ℃, filtered; Filter cake water (5.0L) and methyl tertiary butyl ether (5.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 10 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (5.0L); Add water (0.5L) and stirred 10 minutes; Add a water and lithium hydroxide (0.5Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 3L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (1.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (16L) in 20 liters of reactors, slowly drips again the methyl tertbutyl ethereal solution (0.6Kg/0.5L) of hydrogenchloride, warm below 25 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=2～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (1.98kg, HPLC purity: 97.2%, productive rate: 87%).
Example 4
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (1.5kg, 8.0mol) N-Boc-piperazine dissolved at acetonitrile (1.0L) in 10 liters of reactors; Cool to 5-10 ℃ with ice bath; Add 1.5Kg salt of wormwood; Slowly drip again the acetonitrile solution (1.3Kg/1.0L) of bromoethyl acetate, warm below 25 ℃ in the control in the dropping process.After finishing dropping, reaction system stirred 1 hour at 20～25 ℃, filtered; Filter cake water (5.0L) and methyl tertiary butyl ether (5.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 10 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (5.0L); Add water (0.5L) and stirred 10 minutes; Add a water and lithium hydroxide (0.5Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 3L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (1.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (16L) in 20 liters of reactors, slowly drips again the methyl tertbutyl ethereal solution (0.6Kg/0.5L) of hydrogenchloride, warm below 25 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=2～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (1.91kg, HPLC purity: 97.1%, productive rate: 86%).
Example 5
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (1.5kg, 8.0mol) N-Boc-piperazine dissolved at acetonitrile (1.0L) in 10 liters of reactors; Cool to 5-10 ℃ with ice bath; Add 1.5Kg salt of wormwood; Slowly drip again the acetonitrile solution (1.3Kg/1.0L) of bromoethyl acetate, warm below 25 ℃ in the control in the dropping process.After finishing dropping, reaction system stirred 2 hours at 20～25 ℃, filtered; Filter cake water (5.0L) and methyl tertiary butyl ether (5.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 10 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (5.0L); Add water (0.5L) and stirred 10 minutes; Add a water and lithium hydroxide (0.5Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 4L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (1.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (16L) in 20 liters of reactors, slowly drips again the methyl tertbutyl ethereal solution (0.6Kg/0.5L) of hydrogenchloride, warm below 25 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=2～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (2.05kg, HPLC purity: 97.0%, productive rate: 89%).
Example 6
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (1.5kg, 8.0mol) N-Boc-piperazine dissolved at acetonitrile (1.0L) in 10 liters of reactors; Cool to 5-10 ℃ with ice bath; Add 1.5Kg salt of wormwood; Slowly drip again the acetonitrile solution (1.3Kg/1.0L) of bromoethyl acetate, warm below 25 ℃ in the control in the dropping process.After finishing dropping, reaction system stirred 2 hours at 20～25 ℃, filtered; Filter cake water (5.0L) and methyl tertiary butyl ether (5.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 10 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (5.0L); Add water (0.5L) and stirred 10 minutes; Add a water and lithium hydroxide (0.5Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 3L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (1.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (16L) in 20 liters of reactors, drips again the methyl tertbutyl ethereal solution (0.6Kg/0.5L) of hydrogenchloride, warm below 15 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=2～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (1.91kg, HPLC purity: 97.1%, productive rate: 86%).
Example 7
Synthesizing of N-Boc-piperazine acetic acid hydrochloride
Under mechanical stirring, with (3.0kg, 16.0mol) N-Boc-piperazine dissolved at acetonitrile (2.0L) in 20 liters of reactors; Cool to 5-10 ℃ with ice bath; Add 2.6Kg salt of wormwood; Slowly drip again the acetonitrile solution (2.68Kg/2.0L) of bromoethyl acetate, warm below 25 ℃ in the control in the dropping process.After finishing dropping, reaction system stirred 2 hours at 20～25 ℃, filtered; Filter cake water (10.0L) and methyl tertiary butyl ether (10.0LX2 time) dissolving are extracted, and the organic liquor of extraction and the filtrate of filtration merge, and underpressure distillation obtains N-Boc-piperazine ethyl acetate, and purity is more than 90%.Be directly used in lower one-step hydrolysis reaction.
Under mechanical stirring, in 20 liters of reactors, gained N-Boc-piperazine ethyl acetate is dissolved in tetrahydrofuran (THF) (10.0L); Add water (1.0L) and stirred 10 minutes; Add a water and lithium hydroxide (1.0Kg); Reaction system stirred 2 hours at 20～25 ℃, filtered; Filtrate steams 6L liquid under the condition of decompression, still adularescent N-Boc-piperazine lithium acetate salts out, and filters; Merge twice and filter filter cake, and wash with methyl tertiary butyl ether (2.0L); Gained N-Boc-piperazine acetic acid lithium salts is dissolved in methyl alcohol (30L) in 50 liters of reactors, slowly drips again the methyl tertbutyl ethereal solution (1.2Kg/1.0L) of hydrogenchloride, warm below 25 ℃ in the control in the dropping process; Finish the pH value that drips the afterreaction system=2～3, continue to stir 1 hour at 20～25 ℃, filtration, obtain white solid N-Boc-piperazine acetic acid hydrochloride (4.1kg, HPLC purity: 97.3%, productive rate: 90%).
Claims (9)
1. the preparation method of a N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride is characterized in that may further comprise the steps:
Take N-tertbutyloxycarbonyl-piperazine and bromoethyl acetate as raw material, obtain the N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride by replacing and being hydrolyzed two step successive reactions successively; Described substitution reaction is: take N-tertbutyloxycarbonyl-piperazine and bromoethyl acetate as raw material, take acetonitrile or DMF as solvent, do alkali with carbonate and prepare N-tertbutyloxycarbonyl-piperazine ethyl acetate, reaction is filtered after finishing, filter cake concentrates and namely makes N-tertbutyloxycarbonyl-piperazine ethyl acetate with then methylate tertbutyl ether extraction of water dissolution; Described hydrolysis reaction is: N-tertbutyloxycarbonyl-piperazine ethyl acetate through hydronium(ion) oxidation lithium hydrolysis, is filtered and is obtained white powdery solid N-tertbutyloxycarbonyl-piperazine acetic acid lithium salts in tetrahydrofuran (THF) and the aqueous solution; With methanol solvate dissolving and regulator solution pH=1～3, white solid N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride is separated out, and filters post-drying and namely gets product.
2. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 1 is characterized in that described solvent is acetonitrile.
3. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 1 is characterized in that described carbonate is salt of wormwood.
4. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 3 is characterized in that the raw material molar ratio is N-tertbutyloxycarbonyl-piperazine: bromoethyl acetate: carbonate=1: 1: 2.
5. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 1 is characterized in that the substitution reaction feed way is to drip, and namely the acetonitrile solution of bromoethyl acetate slowly is added drop-wise in the acetonitrile solution of N-tertbutyloxycarbonyl-piperazine.
6. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 5, the temperature of reaction span of control that it is characterized in that dripping the acetonitrile solution of bromoethyl acetate is 0～82 ℃.
7. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 5, the reaction times that it is characterized in that dripping behind the acetonitrile solution of bromoethyl acetate is 1～2 hour.
8. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 1 is characterized in that the hydrolysising reacting temperature span of control is 0～25 ℃.
9. the preparation method of N-tert-butyloxycarbonylpipeacetic acetic acid hydrochloride according to claim 1, what it is characterized in that regulator solution pH value usefulness is the methyl tertbutyl ethereal solution of hydrogenchloride.
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Non-Patent Citations (3)
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| Medicinal Chemistry Letters》.2003,第13卷(第4期),723–728. * |
| Wenrong Huang, et al..Design, Synthesis, and Structure–Activity Relationships of Unsubstituted Piperazinone-Based Transition State Factor Xa Inhibitors.《Bioorganic & * |
| WenrongHuang et al..Design |
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Effective date of registration: 20141215 Address after: 201507, No. three, No. 9, Jinshan District (West), Shanghai chemical industry zone, Shanghai, Jinshan District Patentee after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Address before: 201507, No. three, No. 9, Jinshan District (West), Shanghai chemical industry zone, Shanghai, Jinshan District Patentee before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Patentee before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. |