CN104086475B - A kind of preparation method of N-benzyloxycarbonyl group-L-prolineamide - Google Patents
A kind of preparation method of N-benzyloxycarbonyl group-L-prolineamide Download PDFInfo
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
A kind of preparation method of N benzyloxycarbonyl group L prolineamide, it is characterised in that: comprise the following steps: L proline, alkali are joined in solvent by (1)；Dropping benzyl chloroformate, reaction terminates post-heating extremely backflow, point water, cooling, obtains N benzyloxycarbonyl group L proline feed liquid；(2) in N benzyloxycarbonyl group L proline feed liquid, drip thionyl chloride, be heated to backflow, decompression distillation, obtain N benzyloxycarbonyl group L prolyl solutions of chlorine；(3) being passed through ammonia in N benzyloxycarbonyl group L prolyl solutions of chlorine, reaction is evaporated to solvent evaporated after terminating；Adding methylene chloride, after cooling, regulation system pH value is 12 ~ 13；Stand separatory, separate water layer, decolouring, filter, obtain distillation leftover, crystallize, filter, wash with petroleum ether, be dried, obtain product N benzyloxycarbonyl group L prolineamide.The preparation method operational approach of the present invention is simple, and yield is high, and product purity and optical purity are high, without inorganic salt, can produce N benzyloxycarbonyl group L prolineamide by large-scale industrial.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to the preparation method of a kind of N-benzyloxycarbonyl group-L-prolineamide.
Background technology
N-benzyloxycarbonyl group-L-prolineamide is the precursor of L-prolineamide, L-prolineamide is as a kind of important optical activity azole derivatives, can directly be catalyzed asymmetric Robinson cyclization, Aldol reaction etc., it is also possible to synthesize some chiral drug as chiral intermediate.
Prolineamide is the important intermediate in Peptide systhesis, is a kind of important chirality pharmaceutical intermediate compound.The preparation of prolineamide rarely has report at home, is mainly first made proline ester by proline abroad, and then the most long-time ammonia of ester solution or ammonia carry out ammonolysis.The method is the most, and productivity is low, purification difficult, and pole is not suitable for industrialized production；And due to prolineamide ortho position amide groups to electronic effect, ortho position amine-based basic is made to strengthen, thus it is easy to be combined into the form of salt, when processing with ammonia, ammonia or triethylamine, part HCl is had not dissociate, saliferous (US20050182262, US6271394, IN2010CH00225) in obtained product.
Another kind of synthetic method is that proline is first made proline ester, then is protected by its amino, then carries out amidatioon (US2005182262, US20110092415, EP176005).The same with former approach, ester ammonia or ammonia need to react when carrying out ammonolysis for a long time, and same inefficiency is not suitable for industrialized production；Owing to ammonium salt dissolubility in organic solvent is relatively big, actually it is difficult to be completely removed by the method filtered, causes product still contains substantial amounts of ammonium chloride.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of N-benzyloxycarbonyl group-L-prolineamide, to overcome in L-prolineamide in prior art or N-protected base-L-prolineamide product containing a large amount of inorganic salts, to make after ester ammonolysis efficiency lower and cannot the problem of industrialized production in a large number.The present invention uses one kettle way, and product intermediate directly carries out next step feed intake without separating, and product yield is high, and product quality is high, and not saliferous in product, production operation is convenient, can large-scale industrial production.
For reaching above-mentioned purpose, the technical solution used in the present invention is: the preparation method of a kind of N-benzyloxycarbonyl group-L-prolineamide, comprises the following steps:
The first step, joins in organic solvent by L-PROLINE, alkali, and the weight of organic solvent is 12 ~ 14 times of L-PROLINE weight；Then dripping benzyl chloroformate, react 1.5 ~ 2.5 hours after dripping off at 15 ~ 20 DEG C, reaction terminates post-heating extremely backflow, separates, with water knockout drum, the water that reaction generates, is cooled to 15 ~ 35 DEG C, and gained N-carbobenzyloxy-L-proline feed liquid is directly used in next step and feeds intake；
Wherein, described organic solvent is toluene, benzene or dimethylbenzene；Described alkali is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine；Described alkali is 1.5:1 ~ 2:1 with the mol ratio of L-PROLINE；Described benzyl chloroformate is 1.2 ~ 1.3:1 with the mol ratio of L-PROLINE；
Second step, at 10 ~ 30 DEG C, thionyl chloride is dripped in the N-carbobenzyloxy-L-proline feed liquid that the described first step obtains, drip off post-heating to backflow, it is incubated 3.5 ~ 4.5 hours, after terminating Deng reaction, the thionyl chloride that decompression distillation is complete to steam unreacted, gained N-benzyloxycarbonyl group-L-prolyl solutions of chlorine is directly used in next step reaction；
Wherein, the mol ratio of described thionyl chloride and L-PROLINE is 1.3:1 ~ 1.5:1；
3rd step, is passed through ammonia in the N-benzyloxycarbonyl group-L-prolyl solutions of chlorine that described second step obtains, and controlling temperature is 10 ~ 20 DEG C, and reaction is evaporated to be evaporated described organic solvent after terminating；Add dichloromethane, stirring and dissolving, after being cooled to 0 ~ 5 DEG C, dropping mass concentration be the sodium hydroxide solution of 30% with the pH value of regulation system 12 ~ 13, and then the HCl on N-benzyloxycarbonyl group-L-prolineamide that dissociates, wherein, the weight of described dichloromethane is 10 ~ 12 times of L-PROLINE weight；Stand separatory, separate water layer, in dichloromethane layer, add activated carbon decolorizing, filter, then dichloromethane layer is washed with water 2 times, after washing, again dichloromethane layer anhydrous magnesium sulfate is removed water, filter, steam dichloromethane, obtain distillation leftover, it is cooled to 5 ~ 10 DEG C, in distillation leftover, then drips petroleum ether crystallize, continue to stir 7.5 ~ 8.5 hours at 5 ~ 10 DEG C, filter, gained solid petroleum ether is washed, and is dried, finally gives product N-benzyloxycarbonyl group-L-prolineamide.
Relevant content in technique scheme is explained as follows:
1., in technique scheme, the described first step is cooled to 15 ~ 35 DEG C and i.e. refers to be cooled to room temperature.
2. in technique scheme, preferably technical scheme drips the dropping temperature of benzyl chloroformate in being the described first step is 10 ~ 15 DEG C.
3. in technique scheme, preferably technical scheme steams weight is dichloromethane inventory the 70% ~ 80% of dichloromethane in being described 3rd step.
The design principle of the present invention and beneficial effect: the reaction equation in preparation method of the present invention is as follows:
Use one kettle way, it is not necessary to separated by intermediate, directly carry out next step and feed intake；Ammonolysis speed is fast, and yield is high；Operational approach of the present invention is simple, and yield is high, and product purity and optical purity are high, without inorganic salt in product, it is provided that a kind of large-scale industrial that is available for produces the preparation method of N-benzyloxycarbonyl group-L-prolineamide.
Detailed description of the invention
The invention will be further described for example below:
Example below contributes to understanding the present invention, but is not limited to present invention.
Embodiment one: the preparation method of a kind of N-benzyloxycarbonyl group-L-prolineamide
The preparation of N-carbobenzyloxy-L-proline.Putting into toluene 1200kg in reactor, put into L-PROLINE 100kg, sodium bicarbonate 88kg, drip benzyl chloroformate 178kg at 10 ~ 15 DEG C, 1h drips off, and keeps 15 ~ 20 DEG C to stir after dripping off 2 hours.Having reacted post-heating extremely backflow, with fraction water device water-dividing to anhydrous outflow, gained feed liquid is cooled to room temperature, directly carries out next step and feeds intake.
The preparation of N-benzyloxycarbonyl group-L-prolyl chlorine.The N-carbobenzyloxy-L-proline solution that will obtain, stirring borehole cooling, to 10 ~ 30 DEG C of dropping thionyl chloride 135kg, drips off for 30 minutes, drips off post-heating extremely backflow, is incubated 4h, distillation of reducing pressure after having reacted, steams thionyl chloride and part toluene.
The preparation of N-benzyloxycarbonyl group-L-prolineamide.N-benzyloxycarbonyl group-L-prolyl the solutions of chlorine that will obtain, stirring borehole cooling, to 0 ~ 10 DEG C, controls temperature 10 ~ 20 DEG C and is passed through ammonia reaction 12 hours, and reaction terminates, and is evaporated to solvent and is evaporated.Add dichloromethane 1000kg, after stirring and dissolving, it is cooled to 0 ~ 5 DEG C, control temperature 10 ~ 15 DEG C dropping 30% sodium hydroxide and adjust pH12 ~ 13, continue 10 ~ 15 DEG C after dripping off to stir 1 hour, repetition measurement pH, stand, separatory, separate water layer, dichloromethane layer adds 10kg activated carbon, 20 ~ 25 DEG C are stirred 40 minutes, filter, gained dichloromethane solution with 200kg purify washing 2 times, dichloromethane layer adds the dehydration of 30kg anhydrous magnesium sulfate, filter, steam 800kg dichloromethane, it is cooled to 5 ~ 10 DEG C, dropping 500kg petroleum ether, solid separates out, continue 5 ~ 10 DEG C to stir 8 hours.Filtering, petroleum ether 50kg washs, and is dried, obtains white solid 177kg, yield 82.0%, purity 99.8%, optical purity 99.9%(HPLC area normalization method).mp 91~93℃；1H-NMR(500Hz, CDCl3) δ: 7.23-7.40 (m, 5H), 6.72 (s), 6.13 (s), 5.98 (s, 2H), 5.08-5.18 (m, 2H), 4.29-4.34 (m, 1H), 3.42-3.53 (m, 2H), 2.28 (s), 2.14 (s, 2H), 1.87-2.03 (m, 2H).
Embodiment two: the preparation method of a kind of N-benzyloxycarbonyl group-L-prolineamide
The preparation of N-carbobenzyloxy-L-proline.Putting into dimethylbenzene 1400kg in reactor, put into L-PROLINE 100kg, sodium bicarbonate 88kg, drip benzyl chloroformate 192kg at 10 ~ 15 DEG C, 1h drips off, and keeps 15 ~ 20 DEG C to stir after dripping off 2 hours.Having reacted post-heating extremely backflow, with fraction water device water-dividing to anhydrous outflow, gained feed liquid is cooled to room temperature, directly carries out next step and feeds intake.
The preparation of N-benzyloxycarbonyl group-L-prolyl chlorine.The N-carbobenzyloxy-L-proline solution that will obtain, stirring borehole cooling, to 10 ~ 30 DEG C of dropping thionyl chloride 135kg, drips off for 30 minutes, drips off post-heating extremely backflow, is incubated 4h, distillation of reducing pressure after having reacted, steams thionyl chloride and part dimethylbenzene.
The preparation of N-benzyloxycarbonyl group-L-prolineamide.N-benzyloxycarbonyl group-L-prolyl the solutions of chlorine that will obtain, stirring borehole cooling, to 0 ~ 10 DEG C, controls temperature 10 ~ 20 DEG C and is passed through ammonia reaction 10 hours, and reaction terminates, and is evaporated to solvent and is evaporated.Add dichloromethane 1000kg, after stirring and dissolving, it is cooled to 0 ~ 5 DEG C, control temperature 10 ~ 15 DEG C dropping 30% sodium hydroxide and adjust pH12 ~ 13, continue 10 ~ 15 DEG C after dripping off to stir 1 hour, repetition measurement pH, stand, separatory, separate water layer, dichloromethane layer adds 10kg activated carbon, 20 ~ 25 DEG C are stirred 40 minutes, filter, gained dichloromethane solution with 200kg purify washing 2 times, dichloromethane layer adds the dehydration of 30kg anhydrous magnesium sulfate, filter, steam 700kg dichloromethane, it is cooled to 5 ~ 10 DEG C, dropping 500kg petroleum ether, solid separates out, continue 5 ~ 10 DEG C to stir 8 hours.Filtering, petroleum ether 50kg washs, and is dried, obtains white solid 173kg, yield 80.2%, purity 99.7%, optical purity 100%(HPLC area normalization method).mp 91~93℃.
Above-described embodiment only for technology design and the feature of the present invention are described, its object is to allow person skilled in the art will appreciate that present disclosure and to implement according to this, can not limit the scope of the invention with this.All equivalence changes made according to spirit of the invention or modification, all should contain within protection scope of the present invention.
Claims (2)
1. the preparation method of a N-benzyloxycarbonyl group-L-prolineamide, it is characterised in that: described preparation method comprises the following steps:
The first step, joins in organic solvent by L-PROLINE, alkali, and the weight of organic solvent is 12 ~ 14 times of L-PROLINE weight；Then benzyl chloroformate is dripped, the dropping temperature of dropping benzyl chloroformate is 10 ~ 15 DEG C, react 1.5 ~ 2.5 hours at 15 ~ 20 DEG C after dripping off, reaction terminates post-heating to backflow, the water that reaction generates is separated with water knockout drum, being cooled to 15 ~ 35 DEG C, gained N-carbobenzyloxy-L-proline feed liquid is directly used in next step and feeds intake；
Wherein, described organic solvent is toluene, benzene or dimethylbenzene；Described alkali is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine；Described alkali is 1.5:1 ~ 2:1 with the mol ratio of L-PROLINE；Described benzyl chloroformate is 1.2 ~ 1.3:1 with the mol ratio of L-PROLINE；
Second step, at 10 ~ 30 DEG C, thionyl chloride is dripped in the N-carbobenzyloxy-L-proline feed liquid that the described first step obtains, drip off post-heating to backflow, it is incubated 3.5 ~ 4.5 hours, after terminating Deng reaction, the thionyl chloride that decompression distillation is complete to steam unreacted, gained N-benzyloxycarbonyl group-L-prolyl solutions of chlorine is directly used in next step reaction；
Wherein, the mol ratio of described thionyl chloride and L-PROLINE is 1.3:1 ~ 1.5:1；
3rd step, is passed through ammonia in the N-benzyloxycarbonyl group-L-prolyl solutions of chlorine that described second step obtains, and controlling temperature is 10 ~ 20 DEG C, and reaction is evaporated to be evaporated described organic solvent after terminating；Add dichloromethane, stirring and dissolving, after being cooled to 0 ~ 5 DEG C, dropping mass concentration be the sodium hydroxide solution of 30% with the pH value of regulation system 12 ~ 13, and then the HCl on N-benzyloxycarbonyl group-L-prolineamide that dissociates, wherein, the weight of described dichloromethane is 10 ~ 12 times of L-PROLINE weight；Stand separatory, separate water layer, in dichloromethane layer, add activated carbon decolorizing, filter, then dichloromethane layer is washed with water 2 times, after washing, again dichloromethane layer anhydrous magnesium sulfate is removed water, filter, steam dichloromethane, obtain distillation leftover, it is cooled to 5 ~ 10 DEG C, in distillation leftover, then drips petroleum ether crystallize, continue to stir 7.5 ~ 8.5 hours at 5 ~ 10 DEG C, filter, gained solid petroleum ether is washed, and is dried, finally gives product N-benzyloxycarbonyl group-L-prolineamide.
The preparation method of N-benzyloxycarbonyl group-L-prolineamide the most according to claim 1, it is characterised in that: described 3rd step steams weight is dichloromethane inventory the 70% ~ 80% of dichloromethane.
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| D-脯氨酰胺的不对称合成研究;王蓓等;《化工进展》;20051110;第24卷(第8期);第897-900页，第898页合成路线图，第898页实验部分1.4和1.5 * |
| Preparation of pyrrolidine-oxazoline containing ligands and their application in asymmetric transfer hydrogenation;Helen A.McManus等;《Tetrahedron》;20040405;第60卷(第15期);第3405-3416页，第3406页Scheme 1，第3409页左栏第2-3段 * |
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