CN106916097B - A kind of preparation method of the cis- -3,5- lupetidine of high-purity - Google Patents
A kind of preparation method of the cis- -3,5- lupetidine of high-purity Download PDFInfo
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- CN106916097B CN106916097B CN201710077728.8A CN201710077728A CN106916097B CN 106916097 B CN106916097 B CN 106916097B CN 201710077728 A CN201710077728 A CN 201710077728A CN 106916097 B CN106916097 B CN 106916097B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of high-purities cis- -3, the preparation method of 5- lupetidine, belong to organic synthesis field, with 3,5- lutidines for raw material, 3 are obtained through catalytic hydrogenation, 5- lupetidine crude product, be precipitated obtain after purification high-purity it is cis- -3,5- lupetidine, cis- gas chromatographic purity > 99.5%.The present invention changes the combination of Pyridine Molecules and catalyst molecule in hydrogenation process, is conducive to the generation of cis- body, can obtain the crude product for being directly used in medicine company production and application by introducing neutral alumina and alkali；The cis-isomer of purity > 99.5% can be obtained through handling, 3, there is no the reports of such high-purity for the cis- synthesis of 5- lupetidine and separation aspect, in the synthesizing and purifying and industrial production application aspect of piperidine derivative, with larger reference and higher commercial value.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to and a kind of high-purity is cis--the preparation side of 3,5- lupetidine
Method.
Background technique
Cis- -3,5- lupetidine is the derivative of piperidines, it is in preparing antifungal agent and plant growth regulator
It is widely used.
Cis- -3,5- lupetidine is also used as intermediate, prepares ammonia first heterocyclic pesticide compound and can
Adjust the compound of dietary behavior and related disease, disease relevant to dietary behavior includes that obesity, diabetes, cancer are (swollen
Tumor), inflammatory disease, depression, with nervous related disease and Alzheimer's disease.In addition, cis- -3,5- lupetidine is being made
In double hydrogen-dehydrogenation-(ring type amidogen) derivatives of the carbon -20- of standby macrolide antibiotics, during system with molecular sieve for preparing is standby also very
It is useful.
There are two ways to existing synthesis 3,5- lupetidine: Furanol method and hydrogenization method.Wherein Furanol method produces
Higher cost, therefore industrial production generally uses hydrogenization method to be prepared.
Cis- -3,5- the dimethyl generally obtained in the method that the hydrogenation of 3,5- lutidines prepares 3,5- lupetidine
The purity of piperidines is about 80 ± 3%, this purity is difficult to apply in pharmaceutical synthesis field.
The method that the prior art extracts cis- -3,5- lupetidine is as follows:
1) a kind of method, which discloses for the chloride of o- chlorobenzoyl to be added, contains cis- -3,5- lupetidine, three second
The solution of amine and methylene chloride.Disclose product is further recrystallized using hexane and methylene chloride it is pure cis- to obtain
Then amide distills by back flow reaction further in ethylene glycol and potassium hydroxide and is collected in evaporating for 100-195 DEG C of boiling
Point, obtain pure cis- -3,5- lupetidine.
2) a kind of method, which is disclosed, passes through commerical grade 3,5- lupetidine and anhydrous ether for the hydrogen chloride gas of boiling
Solution prepares hydrochloride salt.Salt is further processed using acetone and ether, to generate cis- -3,5- lupetidine,
It is mixed with≤5% transisomer.
3) a kind of method is disclosed water and 3, and the mixing of 5- lutidines carries out catalytic hydrogenation, uses still afterwards
Raw product is distilled, to remove trans- -3,5- lupetidine as the entrainer of water.
It is complex that the prior art improves cis ratio, therefore there is an urgent need to find simple suitable catalytic way for industrial production
And simple and effective way of purification, cis- -3,5- lupetidine of high-purity is obtained with this.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of preparation sides of the cis- -3,5- lupetidine of high-purity
Method, preparation process is simple, and 3,5- lupetidine crude products can reach total purity greater than 99.5%, cis- purity is 85 ± 3%,
Trans- purity is 15 ± 3%, which may be directly applied to pharmaceutical synthesis field, while be can be obtained by precipitation processing cis-
Gas phase purity is greater than 99.5% cis- -3,5- lupetidine, is deployed with mother liquor, cis- purity can be obtained in 70-
The product of any purity between 99.5%.
The technical scheme to solve the above technical problems is that a kind of cis- -3,5- lupetidine of high-purity
Preparation method, which comprises the following steps:
A, under the conditions of hydrogen shield, 3,5- lutidines, inorganic base, neutral alumina, catalyst are added to height
It is reacted in pressure reaction kettle, filters obtain 3,5- lupetidine crude product after completion of the reaction；
B, by 3 obtained in step A, 5- lupetidine crude product is mixed with organic solvent, is cooled down and is precipitated, and is obtained high-purity
Spend cis- -3,5- lupetidine.
Based on the above technical solution, the present invention can also be improved as follows.
Further, in step, the catalyst is one or more of platinum carbon, ruthenium carbon, nickel；It is active in catalyst
The loading of component is the 0.001~30.0% of catalyst quality.
Further, in step, 3, the 5- lutidines and the neutral alumina mass ratio are (8~10): 1；
The mass ratio of the neutral alumina and the catalyst is (1~10): 1；The inorganic base and total raw material mass ratio in step A
For (0.001~1): 100.
Further, in step, the neutral alumina partial size is 100~400 mesh.
Further, in step, the inorganic base be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium acetate,
One or more of aluminium hydroxide.
Further, in step, the reaction pressure that the autoclave is reacted is 0.1MPa~10.0MPa, instead
Answering temperature is 100~200 DEG C, and the reaction time is 2~20h.
Further, in stepb, the organic solvent is methanol, ethyl alcohol, the tert-butyl alcohol, petroleum ether, normal heptane, toluene, second
One or more of acetoacetic ester.
Further, in stepb, the organic solvent and 3, the 5- lupetidine crude product quality ratio be (0.1~
5): 1.
Further, in stepb, the cooling temperature control is at -80~20 DEG C.
The beneficial effects of the present invention are:
A, the present invention, using its fit effect, changes Pyridine Molecules in hydrogenation process by introducing neutral alumina and alkali
With the combination of catalyst molecule, the purity of cis- piperidines can be improved to a certain extent so that crude product can reach it is total pure
> 99.5% is spent, cis- purity is the purity that 85 ± 3%, trans- purity is 15 ± 3%, and yield > 95%, solvent-free participation can
Directly apply to pharmaceutical synthesis field；
B, cis- -3,5- lupetidine of gas phase purity > 99.5% can be obtained through simple process, process is simple, produces
Product purity is higher, is deployed with mother liquor, the product of any purity of the cis- purity between 70-99.5% can be obtained, in piperidines
The synthesizing and purifying and industrial production application aspect of derivative have larger reference and higher commercial value.
Specific embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
It is as follows about the related introduction of gas-chromatography instrument and experiment parameter condition in the present embodiment:
Gas-chromatography instrument model are as follows: Agilent 7820A；
Column model are as follows: HP-1 (30m, 0.32mm, 0.25 μm)；
Temperature program are as follows: 40 DEG C of holding 5.0min, be warming up to 300 DEG C with 15 DEG C/min；
Injector temperature are as follows: 300 DEG C；
Detector temperature are as follows: 320 DEG C (FID)；
Carrier gas are as follows: nitrogen；
Control model are as follows: constant pressure 10pis；
Split ratio are as follows: 50:1；
Sample volume are as follows: 0.2 μ L；
Embodiment 1
645.0g 3,5- lutidines, 77.4g neutral alumina, 12.9g potassium carbonate, 25.8g ruthenium carbon (are effectively contained
5%) amount is added in the autoclave of 2L.Autoclave is closed, nitrogen is replaced 6 times, and hydrogen is replaced 6 times.Pressurising is warming up to
Hydrogen Vapor Pressure is 9.0MPa, after 150 DEG C, and Hydrogen Vapor Pressure can be greatly reduced in reaction process, and heat-insulation pressure keeping reacts 5.0hr, detection
3,5- lutidines react completely, obtain crude reaction, yield 96.8% through filtering.Gas chromatographic analysis show it is cis--
3,5- lupetidine purity are 84.5%, and trans- -3,5- lupetidine purity is 15.2%.
2L there-necked flask is furnished with mechanical stirring, thermometer, drying tube.By above-mentioned crude reaction, 340.0g n-hexane, 35.0g
Dehydrated alcohol is added in 2L there-necked flask, and system is faint yellow clarified solution at room temperature, and stirring is cooled to -10 DEG C, there is white solid analysis
Out, keep the temperature 1.0hr, filter, the elution of a small amount of n-hexane, yield is 75.3% after transfer drying, gas chromatographic analysis show it is cis--
3,5- lupetidine purity is 99.8%.Mother liquor is recyclable.
Comparative example 1
645.0g 3,5- lutidines, 25.8g ruthenium carbon (effective content 5%) are added in the autoclave of 2L.It closes
Autoclave is closed, nitrogen is replaced 6 times, and hydrogen is replaced 6 times.After pressurising is warming up to Hydrogen Vapor Pressure as 9.0MPa, 150 DEG C, reaction
Hydrogen Vapor Pressure can be greatly reduced in the process, and heat-insulation pressure keeping reacts 5.0hr, and detection 3,5- lutidines reacts completely, through filtering
Obtain crude reaction, yield 96.8%.Gas chromatographic analysis shows that cis- -3,5- lupetidine purity is 80.3%, instead
Formula -3,5- lupetidine purity is 19.2%.
Comparative example 2
645.0g 3,5- lutidines, 12.9g potassium carbonate, 25.8g ruthenium carbon (effective content 5%) are added to the height of 2L
It presses in reaction kettle.Autoclave is closed, nitrogen is replaced 6 times, and hydrogen is replaced 6 times.Pressurising be warming up to Hydrogen Vapor Pressure be 9.0MPa,
After 150 DEG C, Hydrogen Vapor Pressure can be greatly reduced in reaction process, and heat-insulation pressure keeping reacts 24.0hr, hydrogen gas pressure stabilization, sampling inspection
It surveys, gas chromatographic analysis shows that 3,5- lutidines purity is 83.2%, and cis- -3,5- lupetidine purity is
13.5%, trans- -3,5- lupetidine purity is 2.8%.
Comparative example 3
2L is added in 645.0g 3,5- lutidines, 77.4g neutral alumina, 25.8g ruthenium carbon (effective content 5%)
Autoclave in.Autoclave is closed, nitrogen is replaced 6 times, and hydrogen is replaced 6 times.Pressurising is warming up to Hydrogen Vapor Pressure
9.0MPa, after 150 DEG C, Hydrogen Vapor Pressure can be greatly reduced in reaction process, and heat-insulation pressure keeping reacts 5.0hr, detect 3,5- dimethyl
Pyridine reacts completely, obtains crude reaction, yield 96.8% through filtering.Gas chromatographic analysis shows cis- -3,5- dimethyl
Piperidines purity is 81.7%, and trans- -3,5- lupetidine purity is 17.9%.
One crude product purity of table statistics
As shown in Table 1:
The present invention is by introducing neutral alumina and alkali, using its fit effect, change in hydrogenation process Pyridine Molecules with
The combination of catalyst molecule, can improve the purity of cis- -3,5- lupetidine to a certain extent, solvent-free participation,
It may be directly applied to pharmaceutical synthesis field；
Two embodiment of table, one purity statistics
As shown in Table 2:
Cis- -3,5- the lupetidine of gas phase purity > 99.5% can be obtained by simple process by the present invention.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (7)
1. a kind of high-purity is cis--preparation method of 3,5- lupetidine, which comprises the following steps:
A, under the conditions of hydrogen shield, 3,5- lutidines, potassium carbonate, neutral alumina, ruthenium carbon are added to reaction under high pressure
It is reacted in kettle, filters obtain 3,5- lupetidine crude product after completion of the reaction；
B, by 3 obtained in step A, 5- lupetidine crude product is mixed with organic solvent, is cooled down and is precipitated, it is suitable to obtain high-purity
Formula -3,5- lupetidine.
2. according to claim 1 a kind of high-purity it is cis--preparation method of 3,5- lupetidine, which is characterized in that
In step A, 3, the 5- lutidines and the neutral alumina mass ratio are (8~10): 1；The neutral alumina with
The mass ratio of the ruthenium carbon is (1~10): 1；The potassium carbonate is (0.001~1) with total raw material mass ratio in step A: 100.
3. according to claim 1 a kind of high-purity it is cis--preparation method of 3,5- lupetidine, which is characterized in that
In step A, the neutral alumina partial size is 100~400 mesh.
4. according to claim 1 a kind of high-purity it is cis--preparation method of 3,5- lupetidine, which is characterized in that
In step A, the reaction pressure that the autoclave is reacted is 0.1MPa~10.0MPa, and reaction temperature is 100~200
DEG C, the reaction time is 2~20h.
5. according to claim 1 a kind of high-purity it is cis--preparation method of 3,5- lupetidine, which is characterized in that
In step B, the organic solvent be one of methanol, ethyl alcohol, the tert-butyl alcohol, petroleum ether, normal heptane, toluene, ethyl acetate or
It is several.
6. according to claim 1 a kind of high-purity it is cis--preparation method of 3,5- lupetidine, which is characterized in that
In step B, the organic solvent and 3, the 5- lupetidine crude product quality ratio are (0.1~5): 1.
7. according to claim 1 a kind of high-purity it is cis--preparation method of 3,5- lupetidine, which is characterized in that
In step B, the cooling temperature control is at -80~20 DEG C.
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| CN201710077728.8A CN106916097B (en) | 2017-02-13 | 2017-02-13 | A kind of preparation method of the cis- -3,5- lupetidine of high-purity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB201810449D0 (en) | 2018-06-26 | 2018-08-08 | Johnson Matthey Plc | Hydrogenation process |
| CN113372262A (en) * | 2021-06-08 | 2021-09-10 | 安徽星宇化工有限公司 | Preparation method of trans-3, 5-dimethylpiperidine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1308152A (en) * | 1969-07-07 | 1973-02-21 | Ici Ltd | Process for the production of pyridines |
| CN1222531A (en) * | 1997-12-23 | 1999-07-14 | 蒙岱尔北美股份有限公司 | Catalyst for polymerization of alpha-olefins containing substituted amino silane compounds |
| WO2000073291A1 (en) * | 1999-05-26 | 2000-12-07 | Phillips Petroleum Company | Process for producing piperidine |
| CN101104146A (en) * | 2006-07-14 | 2008-01-16 | 常州艾坛化学有限公司 | Method for preparing cis-and-trans mixed isomers 3,5-dimethylpiperidine |
| CN102093283A (en) * | 2009-12-10 | 2011-06-15 | 中国科学院大连化学物理研究所 | Method for preparing piperidine and piperidine derivative |
-
2017
- 2017-02-13 CN CN201710077728.8A patent/CN106916097B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1308152A (en) * | 1969-07-07 | 1973-02-21 | Ici Ltd | Process for the production of pyridines |
| CN1222531A (en) * | 1997-12-23 | 1999-07-14 | 蒙岱尔北美股份有限公司 | Catalyst for polymerization of alpha-olefins containing substituted amino silane compounds |
| WO2000073291A1 (en) * | 1999-05-26 | 2000-12-07 | Phillips Petroleum Company | Process for producing piperidine |
| CN101104146A (en) * | 2006-07-14 | 2008-01-16 | 常州艾坛化学有限公司 | Method for preparing cis-and-trans mixed isomers 3,5-dimethylpiperidine |
| CN102093283A (en) * | 2009-12-10 | 2011-06-15 | 中国科学院大连化学物理研究所 | Method for preparing piperidine and piperidine derivative |
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Denomination of invention: A preparation method of high purity cis-3,5-dimethylpiperidine Effective date of registration: 20211202 Granted publication date: 20190607 Pledgee: Yantai Branch of China Merchants Bank Co.,Ltd. Pledgor: VALIANT Co.,Ltd. Registration number: Y2021980013807 |
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Date of cancellation: 20220823 Granted publication date: 20190607 Pledgee: Yantai Branch of China Merchants Bank Co.,Ltd. Pledgor: VALIANT Co.,Ltd. Registration number: Y2021980013807 |