CN115626925A - Synthesis method of bispidine - Google Patents
Synthesis method of bispidine Download PDFInfo
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Abstract
The invention relates to the field of chemical industry, and discloses a method for synthesizing bispidine, which comprises the steps of firstly, taking benzyl piperidone, paraformaldehyde, benzylamine and glacial acetic acid as raw materials, and reacting to obtain an intermediate product, namely the bis-benzyl bispiperidone; then under the action of diethylene glycol, strong base and hydrazine hydrate, reducing carbonyl to generate dibenzyl bispiperidine; finally, the bis-benzyl-bis-piperidine is synthesized into the bis-piperidine through Pd/C catalytic debenzylation reaction. The method has the advantages that a smooth synthetic route is formed by the three steps of the synthesis of the dibenzyl bispiperidone, the synthesis of the dibenzyl bispiperidine and the synthesis of the bispiperidine, and the method is simple and easy to popularize; the raw materials are easy to obtain, no harmful waste is generated in the production process, and the environment-friendly property is good; the accuracy of the synthesis reaction is ensured through process detection and quantitative analysis; higher GC purity and yield of the product are obtained.
Description
Technical Field
The invention relates to the field of chemical industry, and particularly relates to a method for synthesizing bipiperidine.
Background
The synthesis of chiral bispidine is of great significance in the field of catalysis, and as early as 1851, stenhouse firstly obtained cytisine (-) -sparteine by separation. (-) -Sparteine is a lupin alkaloid existing in nature, and can be widely applied to the field of asymmetric catalytic reaction as a chiral induction double-nitrogen ligand. For example, (-) -Sparteine can be used in different catalytic reactions such as Pd-catalyzed secondary alcohol aerobic oxidation kinetic resolution reaction, pyrrolidine asymmetric lithiation/deprotonation reaction, pd-catalyzed allylation reaction for keeping configuration, imine and organic lithium addition reaction and the like. (-) -Sparteine is a natural alkaloid, has extremely limited resources, is very difficult to artificially synthesize completely, and is found in the process of researching (-) -Sparteine, the (-) -Sparteine exists in a monopole mode in nature, does not exist enantiomers, can not be obtained by splitting, and is difficult to modify the structure by derivation. The research finds that the bispidine ring is an important central structure of (-) -sparteine, no substituent is arranged on the bridge ring, and the structure is very rigid. Due to the good catalytic performance of (-) -sparteine, scientists hope to replace or optimize the chiral catalytic system formed by (-) -sparteine by synthesizing compounds with similar structures.
(-) -Sparteine is a natural alkaloid, has good chiral induction effect, and can be widely used in the field of asymmetric catalytic reaction. Stenhouse successfully isolated (-) -spark for the first time in 1851. Since then, many people have been devoted to the study of cytisine. (-) -spark has a strong rigid structure, and the core part of the (-) -spark is a cage-shaped bipiperidine structure. However, the sparteine as a natural product has limited resources and great difficulty in total synthesis. Therefore, how to synthesize the bipiperidine by a simple and environment-friendly chemical method is an important technical problem.
Disclosure of Invention
Aiming at the technical problem, the invention provides a method for synthesizing bipiperidine, which adopts the technical scheme that:
a method for synthesizing bipiperidine, which comprises the following steps:
(1) Synthesis of bisbenzylbispiperidone: mixing glacial acetic acid and methanol, cooling in an ice water bath, and dropwise adding into a three-necked bottle containing benzyl piperidone and methanol to obtain a mixture A; under the protection of nitrogen, adding methanol and benzylamine into a four-mouth bottle, controlling the temperature by using an ice-water bath, dropwise adding glacial acetic acid, adding paraformaldehyde after dropwise adding, controlling the temperature by using a water bath, dropwise adding the mixture A into the mixture after dropwise adding, detecting and tracking the reaction process by using a GC (gas chromatography), stopping heating after reaction components do not change obviously any more, cooling and filtering, carrying out rotary evaporation and concentration on filtrate, adding cold water into residues, extracting with diethyl ether, then extracting with dichloromethane, drying extract liquid with anhydrous sodium sulfate, filtering, carrying out rotary evaporation and concentration to obtain wine red oily liquid, recrystallizing with ethyl acetate and n-hexane, and filtering to obtain white crystals, namely the dibenzylbispiperidone;
(2) Synthesis of bis-benzyl-bis-piperidine: under the protection of nitrogen, sequentially adding KOH, diethylene glycol, the dibenzyl bispiperidone obtained in the step (1) and hydrazine hydrate into a four-mouth bottle, heating and refluxing, evaporating a mixture of hydrazine and water to a first reaction temperature, refluxing again, continuously evaporating a mixture of hydrazine and water to a second reaction temperature, refluxing again, stopping the reaction, cooling to room temperature, adding cold water, extracting with diethyl ether, washing an extract liquid with a sodium hydroxide solution and a saturated salt aqueous solution in sequence, drying with anhydrous sodium sulfate, filtering to remove the solvent, evaporating the solvent from a filtrate to obtain a yellow viscous liquid, and distilling under reduced pressure to obtain a colorless transparent liquid, namely the dibenzyl bispiperidine;
(3) Synthesis of bispiperidine: under the protection of nitrogen, adding a Pd/C catalyst, acetic acid and the dibenzyl bispiperidine obtained in the step (2) into a three-necked bottle with magnetic stirring, controlling the temperature of a water bath, introducing hydrogen gas under stirring, detecting by TLC (thin layer chromatography) until the reaction is complete, filtering, carrying out rotary evaporation and concentration on filtrate, extracting a concentrated solution by using ether under the cooling of ice water, drying an extract by using anhydrous sodium sulfate, filtering to remove a drying agent, carrying out rotary evaporation on the filtrate to remove a solvent to obtain a light yellow oily substance, and carrying out reduced pressure distillation to obtain a colorless transparent liquid, namely the bispiperidine.
2. The method for synthesizing bipiperidine according to claim 1, wherein in the step (1), the benzyl piperidone is 16 to 19ml, the benzylamine is 8 to 12ml, and the paraformaldehyde is 10 to 14g; glacial acetic acid is firstly added to benzyl piperidone dropwise by 5.0-6.5ml, and is added to benzylamine dropwise by 4-7ml; the methanol is mixed with glacial acetic acid in sequence by 50-70ml, mixed with benzyl piperidone by 100-200ml and mixed with benzylamine by 100-200ml.
The temperature of the step (1) is controlled to be 5-10 ℃ by using an ice water bath; controlling the temperature to be 40-45 ℃ by using water bath; adding cold water to the residue, extracting with diethyl ether, and adjusting pH of the water phase with 31% KOH by mass to 12-14.
15-17g of white crystal, namely dibenzyl bispiperidone, obtained in the step (1), 45-55% of yield and mp.60-80 ℃.
The mass fraction of KOH in the step (2) is 80 percent, and the adding amount is 10-15g; the adding amount of diethylene glycol is 50-80ml; the adding amount of the dibenzyl bispidine is 5-8g; the mass fraction of hydrazine hydrate is 80 percent, and the adding amount is 4-8g; the cold water is added in an amount of 40-60ml.
Heating and refluxing for 3-5 hours in the step (2); the first reaction temperature is 140-160 ℃, and then reflux is carried out for 2-4 hours; the second reaction temperature is 180-200 ℃, and then the reflux is carried out for 3-5 hours.
The colorless transparent liquid obtained in the step (2), namely the dibenzyl bispidine is 4.0 to 5.0g, and the yield is 90 to 95 percent.
The mass fraction of the Pd/C catalyst in the step (3) is 10 percent, and the adding amount is 0.5-3g; the mass fraction of acetic acid is 85 percent, and the addition amount is 10-30ml; the amount of the added bis-benzyl bis-piperidine is 3-6g.
The temperature of the water bath in the step (3) is controlled to be 20-30 ℃; when the concentrated solution is cooled by ice water, the PH value is adjusted to 11-12 by KOH solution with the mass fraction of 40 percent.
The colorless transparent liquid obtained in the step (3) is 2-3g of bispidine, the GC purity is 89-93%, and the yield is 45-55%.
The invention mainly has the following beneficial technical effects:
1. the method forms a smooth synthetic route by three steps of synthesis of the dibenzyl bispiperidone, synthesis of the dibenzyl bispiperidine and synthesis of the bispiperidine, and is simple and easy to popularize.
2. The invention has the advantages of easily obtained raw materials, no harmful waste generated in the production process and good environmental protection.
3. The method adopts Gas Chromatography (GC) to detect the reaction process, judges the reaction end point, and qualitatively analyzes the structures of intermediate compounds and target products in the synthesis process through infrared and nuclear magnetism characterization so as to ensure the accuracy of the synthesis reaction.
4. The invention has high synthesis rate. According to the determination, the GC purity of the bipiperidine reaches 89-93%, and the yield reaches 45-55%.
Drawings
FIG. 1 is a schematic diagram of a synthesis process of dibenzyl bispiperidone according to the present invention;
FIG. 2 is a schematic diagram of a process for synthesizing bis-benzylbispiperidine according to the present invention;
FIG. 3 is a schematic diagram of the process for synthesizing bispiperidine according to the present invention.
Detailed Description
The present invention will be further described with reference to specific embodiments and drawings, illustrative embodiments and descriptions of which are provided herein to illustrate the invention, but not to limit the invention.
Example 1
A synthetic method of the synthesized bipiperidine comprises the following steps:
as shown in fig. 1, synthesis of dibenzylbispiperidone: 5.7ml (0.1 mol) of glacial acetic acid and 60ml of methanol are mixed and are added into a 500ml three-neck flask with 17.9ml (0.1 mol) of benzyl piperidone and 150ml of methanol in a dropwise manner under the cooling of an ice water bath to obtain a mixture A; under the protection of nitrogen, 150ml of methanol and 10.9ml (0.1 mol) of benzylamine are added into a four-mouth bottle, the temperature is controlled to be 8 ℃ by using an ice-water bath, 5.7ml (0.1 mol) of glacial acetic acid is dropwise added at the temperature, 12.6g (0.42 mol) of paraformaldehyde is added after dropwise addition is finished, the temperature of the water bath is controlled to be 42 ℃, the mixture A is dropwise added into the mixture, after the dropwise addition is finished, the reaction process is tracked by GC detection, after the reaction components do not obviously change any more, heating is stopped, cooling and filtering are carried out, filtrate is evaporated and concentrated in a rotary manner, the residue is extracted by cold water and diethyl ether, the pH value of an aqueous phase is adjusted to be 13 by KOH with the mass fraction of 31%, then dichloromethane is used for extraction, the extract liquid is dried by anhydrous sodium sulfate, filtered, evaporated and concentrated in a wine red viscous oily liquid is obtained, ethyl acetate and n-hexane are used for recrystallization, white crystals, namely 16.34g of dibenzylbispiperidone is obtained by filtration, the yield is 51%, and mp.79 ℃.
As shown in fig. 2, synthesis of bis-benzylbispiperidine: under the protection of nitrogen, 12.00g (0.176 mol) of 82% by mass of KOH, 70ml of diethylene glycol, 6.00g (0.022 mol) of dibenzylbispiperidone and 5.5g (0.088 mol) of 80% by mass of hydrazine hydrate are sequentially added into a four-necked flask, after heating and refluxing for 4 hours, a mixture of hydrazine and water is distilled out until the reaction temperature reaches 150 ℃, then refluxing for 3 hours, a mixture of hydrazine and water is continuously distilled out until the reaction temperature reaches 190 ℃, then refluxing for 4 hours is carried out, the reaction is stopped and cooled to room temperature, 50ml of cold water is added, ether is used for extraction (30ml 5), the extract is sequentially washed by sodium hydroxide solution (30ml 3) and saturated saline solution (30ml x 3), then anhydrous sodium sulfate is used for drying, the solvent is filtered, the filtrate is distilled off to obtain yellow viscous liquid, colorless transparent liquid, namely 4.65g of dibenzylbispiperidone is obtained by reduced pressure distillation, and the yield is 94%.
As shown in fig. 3, synthesis of bispiperidine: under the protection of nitrogen, 0.5g of a Pd/C catalyst with the mass fraction of 10%, 15ml of acetic acid with the mass fraction of 85% and 3.80 (0.0147 mmol) dibenzyl bispiperidine are added into a 100ml three-necked bottle with magnetic stirring, the water bath temperature is controlled to be 25 ℃, hydrogen is introduced under stirring, TLC detection is carried out until the reaction is completed, then filtration is carried out, filtrate is concentrated by rotary evaporation, the concentrated solution is adjusted to the pH value to be 11.5 by KOH solution with the mass fraction of 40% under the cooling of ice water, ether is extracted, extraction liquid is dried by anhydrous sodium sulfate, drying agent is removed by filtration, filtrate is removed by rotary evaporation to obtain light yellow oily matter, and colorless transparent liquid, namely the bispiperidine, is obtained by reduced pressure distillation, the GC purity is 90%, and the yield is 50%.
Example 2
A synthetic method of the synthesized bipiperidine comprises the following steps:
as shown in fig. 1, synthesis of dibenzylbispiperidone: mixing 5.0ml of glacial acetic acid and 50ml of methanol, and dropwise adding the mixture into a 500ml three-neck bottle containing 16ml of benzyl piperidone and 100ml of methanol under the cooling of an ice water bath to obtain a mixture A; under the protection of nitrogen, 100ml of methanol and 8ml of benzylamine are added into a four-mouth bottle, the temperature is controlled by an ice-water bath to be 5 ℃, 4ml of glacial acetic acid is dropwise added at the temperature, 10g of paraformaldehyde is added after the dropwise addition is finished, the temperature of the water bath is controlled to be 40 ℃, the mixture A is dropwise added into the mixture, the dropwise addition is finished, the reaction process is detected and tracked by GC, after the reaction components do not change obviously any more, the heating is stopped, the cooling and the filtration are carried out, the filtrate is evaporated and concentrated by rotation, the residue is added with cold water and extracted by ether, the pH value of the water phase is adjusted to be 12 by KOH with the mass fraction of 31 percent, then dichloromethane is used for extraction, the extract liquid is dried by anhydrous sodium sulfate, the filtration is carried out, the evaporation and the concentration is carried out to obtain wine red viscous oily liquid, the wine red viscous oily liquid is recrystallized by ethyl acetate and normal hexane, and the white crystal, namely 15.2g of dibenzyl bispiperidone, the yield is 45 mp percent and is obtained by the filtration.
As shown in fig. 2, synthesis of bis-benzylbispiperidine: under the protection of nitrogen, 10g of KOH with the mass fraction of 82%, 50ml of diethylene glycol, 5g of dibenzyl bispiperidone and 4g of hydrazine hydrate with the mass fraction of 80% are sequentially added into a four-mouth bottle, the mixture is heated and refluxed for 3 hours, the mixture of hydrazine and water is evaporated to the reaction temperature of 140 ℃, the reflux is carried out for 3 hours, the mixture of hydrazine and water is continuously evaporated to the reaction temperature of 180 ℃, the reflux is carried out for 3 hours, the reaction is stopped and the mixture is cooled to the room temperature, 40ml of cold water is added, ether is used for extraction (30ml. About.5), extract liquid is sequentially washed by sodium hydroxide solution (30ml. About.3) and saturated saline solution (30ml. About.3), anhydrous sodium sulfate is used for drying, the solvent is filtered, the filtrate is evaporated to obtain yellow viscous liquid, colorless transparent liquid, namely, 4.05g of dibenzyl bispiperidine is obtained by reduced pressure distillation, and the yield is 90%.
As shown in fig. 3, synthesis of bispiperidine: under the protection of nitrogen, adding 1.5g of a Pd/C catalyst with the mass fraction of 10%, 10ml of acetic acid with the mass fraction of 85% and 3g of bis-benzyl-bispiperidine into a 100ml three-mouth bottle with magnetic stirring, controlling the water bath temperature to be 20 ℃, introducing hydrogen gas while stirring, filtering after TLC detection till complete reaction, carrying out rotary evaporation and concentration on filtrate, adjusting the pH value of the concentrated solution to be 11 by using a KOH solution with the mass fraction of 40% under the cooling of ice water, extracting ether, drying the extract by using anhydrous sodium sulfate, filtering to remove a drying agent, carrying out rotary evaporation on the filtrate to remove a solvent to obtain a light yellow oily substance, carrying out reduced pressure distillation to obtain a colorless transparent liquid, namely 2.5g of bispiperidine, having the GC purity of 89% and the yield of 45%.
Example 3
A synthetic method of the synthesized bipiperidine comprises the following steps:
as shown in fig. 1, synthesis of dibenzylbispiperidone: mixing 6.5ml of glacial acetic acid and 70ml of methanol, and dropwise adding the mixture into a 500ml three-neck bottle containing 19ml of benzyl piperidone and 200ml of methanol under the cooling of an ice water bath to obtain a mixture A; under the protection of nitrogen, 200ml of methanol and 12ml of benzylamine are added into a four-mouth bottle, the temperature is controlled by an ice-water bath to be 10 ℃, 7ml of glacial acetic acid is dropwise added at the temperature, 14g of paraformaldehyde is added after the dropwise addition is finished, the temperature of the water bath is controlled to be 45 ℃, the mixture A is dropwise added into the mixture, the dropwise addition is finished, the reaction process is detected and tracked by GC, after the reaction components do not change obviously any more, heating is stopped, cooling and filtering are carried out, filtrate is evaporated and concentrated in a rotary mode, cold water is added into residues and is extracted by diethyl ether, the pH value of a water phase is adjusted to be 14 by KOH with the mass fraction of 31%, then dichloromethane is used for extraction, an extract liquid is dried by anhydrous sodium sulfate, filtering is carried out, the evaporated and concentrated in a rotary mode is carried out to obtain wine red viscous oily liquid, ethyl acetate and normal hexane are used for recrystallization, and white crystals, namely 16.95g of dibenzyl bispiperidone, the yield is 55 mp percent and is obtained by filtering.
As shown in fig. 2, synthesis of bis-benzylbispiperidine: under the protection of nitrogen, 15g of KOH with the mass fraction of 82%, 80ml of diethylene glycol, 8g of dibenzyl bispiperidone and 8g of hydrazine hydrate with the mass fraction of 80% are sequentially added into a four-mouth bottle, after heating and refluxing for 5 hours, a mixture of hydrazine and water is evaporated to the reaction temperature of 160 ℃, then refluxing is carried out for 3 hours, a mixture of hydrazine and water is continuously evaporated to the reaction temperature of 200 ℃, then refluxing is carried out for 5 hours, the reaction is stopped and the mixture is cooled to the room temperature, 60ml of cold water is added, ether is used for extraction (30ml. About.5), extract liquid is sequentially washed by sodium hydroxide solution (30ml. About.3) and saturated saline solution (30ml. About.3), then anhydrous sodium sulfate is used for drying, the solvent is filtered, the solvent is evaporated from filtrate to obtain yellow viscous liquid, and colorless transparent liquid, namely, 5.02g of dibenzyl bispiperidine is obtained through reduced pressure distillation, and the yield is 95%.
As shown in fig. 3, synthesis of bispiperidine: under the protection of nitrogen, 3g of a Pd/C catalyst with the mass fraction of 10%, 30ml of acetic acid with the mass fraction of 85% and 6g of bis-benzyl-bispiperidine are added into a 100ml three-mouth bottle with magnetic stirring, the temperature of a water bath is controlled to be 30 ℃, hydrogen is introduced under stirring, after TLC detection till complete reaction, filtration is carried out, filtrate is concentrated by rotary evaporation, the pH value of concentrated solution is adjusted to be 12 by KOH solution with the mass fraction of 40% under the cooling of ice water, ether is extracted, extract liquor is dried by anhydrous sodium sulfate, drying agent is removed by filtration, solvent is removed by rotary evaporation from filtrate to obtain faint yellow oily matter, colorless transparent liquid, namely bispiperidine is obtained by reduced pressure distillation, the GC purity is 93%, and the yield is 55%.
The invention adopts Gas Chromatography (GC) to detect the reaction process, judge the reaction end point and carry out qualitative analysis on the structures of intermediate compounds and target products in the synthesis process through infrared and nuclear magnetism characterization. The synthesis process of the above embodiment is shown in fig. 1, fig. 2 and fig. 3.
Claims (10)
1. A method for synthesizing bipiperidine is characterized by comprising the following steps:
(1) Synthesis of bisbenzylbispiperidone: mixing glacial acetic acid and methanol, cooling in an ice water bath, and dropwise adding into a three-necked bottle containing benzyl piperidone and methanol to obtain a mixture A; under the protection of nitrogen, adding methanol and benzylamine into a four-mouth bottle, controlling the temperature by using an ice-water bath, dropwise adding glacial acetic acid, adding paraformaldehyde after dropwise adding, controlling the temperature by using a water bath, dropwise adding the mixture A into the mixture after dropwise adding, detecting and tracking the reaction process by using a GC (gas chromatography), stopping heating after reaction components do not change obviously any more, cooling and filtering, carrying out rotary evaporation and concentration on filtrate, adding cold water into residues, extracting with diethyl ether, then extracting with dichloromethane, drying extract liquid with anhydrous sodium sulfate, filtering, carrying out rotary evaporation and concentration to obtain wine red oily liquid, recrystallizing with ethyl acetate and n-hexane, and filtering to obtain white crystals, namely the dibenzylbispiperidone;
(2) Synthesis of bis-benzyl-bis-piperidine: under the protection of nitrogen, sequentially adding KOH, diethylene glycol, the dibenzyl bispiperidone obtained in the step (1) and hydrazine hydrate into a four-mouth bottle, heating and refluxing, evaporating a mixture of hydrazine and water to a first reaction temperature, refluxing again, continuously evaporating a mixture of hydrazine and water to a second reaction temperature, refluxing again, stopping the reaction, cooling to room temperature, adding cold water, extracting with diethyl ether, washing an extract liquid with a sodium hydroxide solution and a saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering to remove the solvent, evaporating the solvent from a filtrate to obtain a yellow viscous liquid, and carrying out reduced pressure distillation to obtain a colorless transparent liquid, namely the dibenzyl bispiperidone;
(3) Synthesis of bispiperidine: under the protection of nitrogen, adding a Pd/C catalyst, acetic acid and the dibenzyl bispiperidine obtained in the step (2) into a three-necked bottle with magnetic stirring, controlling the temperature of a water bath, introducing hydrogen gas under stirring, detecting by TLC (thin layer chromatography) until the reaction is complete, filtering, carrying out rotary evaporation and concentration on filtrate, extracting a concentrated solution by using ether under the cooling of ice water, drying an extract by using anhydrous sodium sulfate, filtering to remove a drying agent, carrying out rotary evaporation on the filtrate to remove a solvent to obtain a light yellow oily substance, and carrying out reduced pressure distillation to obtain a colorless transparent liquid, namely the bispiperidine.
2. The method for synthesizing bipiperidine according to claim 1, wherein in the step (1), the benzyl piperidone is 16 to 19ml, the benzylamine is 8 to 12ml, and the paraformaldehyde is 10 to 14g; glacial acetic acid is firstly added to benzyl piperidone dropwise by 5.0-6.5ml, and is added to benzylamine dropwise by 4-7ml; the methanol is mixed with glacial acetic acid in sequence by 50-70ml, mixed with benzyl piperidone by 100-200ml and mixed with benzylamine by 100-200ml.
3. The method for synthesizing bipiperidine according to claim 2, wherein the temperature of step (1) is controlled to be 5-10 ℃ by using an ice water bath; controlling the temperature to be 40-45 ℃ by using water bath; adding cold water to the residue, extracting with diethyl ether, and adjusting pH of the water phase with 31% KOH solution to 12-14.
4. The method for synthesizing bispidine according to claim 3, wherein the amount of the white crystal, i.e. dibenzylbispiperidone, obtained in the step (1) is 15-17g, the yield is 45-55%, and the temperature is mp.60-80 ℃.
5. The method for synthesizing bipiperidine according to claim 1, wherein the mass fraction of KOH in the step (2) is 80%, and the addition amount is 10-15g; the addition amount of the diethylene glycol is 50-80ml; the adding amount of the dibenzyl bispidine is 5-8g; the mass fraction of hydrazine hydrate is 80 percent, and the adding amount is 4-8g; the cold water is added in an amount of 40-60ml.
6. The method for synthesizing bispidine according to claim 5, wherein the step (2) is performed for 3 to 5 hours under heating and refluxing; the first reaction temperature is 140-160 ℃, and then reflux is carried out for 2-4 hours; the second reaction temperature is 180-200 ℃, and then the reflux is carried out for 3-5 hours.
7. The method for synthesizing bis-piperidine according to claim 6, wherein the colorless transparent liquid obtained in step (2), i.e., bis-benzylbis-piperidine, is 4.0-5.0g, and the yield is 90-95%.
8. The method for synthesizing bipiperidine according to claim 1, wherein the mass fraction of the Pd/C catalyst in the step (3) is 10%, and the addition amount is 0.5-3g; the mass fraction of acetic acid is 85 percent, and the addition amount is 10-30ml; the amount of the bisbenzylbispiperidine added is 3 to 6g.
9. The method for synthesizing bipiperidine according to claim 8, wherein the water bath temperature in step (3) is controlled to be 20-30 ℃; when the concentrated solution is cooled by ice water, the PH value is adjusted to 11-12 by KOH solution with the mass fraction of 40 percent.
10. The method for synthesizing dipiperidine in claim 9, wherein the colorless transparent liquid obtained in step (3) is dipiperidine 2-3g, the GC purity is 89-93%, and the yield is 45-55%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995002599A1 (en) * | 1993-07-17 | 1995-01-26 | Basf Aktiengesellschaft | Method of preparing n,n'-dibenzylbispidine |
| CN1210521A (en) * | 1996-02-02 | 1999-03-10 | 日本新药株式会社 | Isoquinoline derivatives and drugs |
| WO2010028011A1 (en) * | 2008-09-05 | 2010-03-11 | Targacept, Inc. | Amides of diazabicyclononanes and uses thereof |
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- 2022-12-08 CN CN202211570117.4A patent/CN115626925A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995002599A1 (en) * | 1993-07-17 | 1995-01-26 | Basf Aktiengesellschaft | Method of preparing n,n'-dibenzylbispidine |
| CN1210521A (en) * | 1996-02-02 | 1999-03-10 | 日本新药株式会社 | Isoquinoline derivatives and drugs |
| WO2010028011A1 (en) * | 2008-09-05 | 2010-03-11 | Targacept, Inc. | Amides of diazabicyclononanes and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| JAN SPIELER等: "Synthesis of Chiral Amino Alcohols Embodying the Bispidine Framework and Their Application as Ligands in Enantioselectively Catalyzed Additions to C5O and C5C Groups", EUR. J. ORG. CHEM., pages 391 - 399 * |
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