CN106916097A - A kind of preparation method of cis 3,5 lupetidine of high-purity - Google Patents
A kind of preparation method of cis 3,5 lupetidine of high-purity Download PDFInfo
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- CN106916097A CN106916097A CN201710077728.8A CN201710077728A CN106916097A CN 106916097 A CN106916097 A CN 106916097A CN 201710077728 A CN201710077728 A CN 201710077728A CN 106916097 A CN106916097 A CN 106916097A
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- purity
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- lupetidines
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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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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of high-purity cis 3, the preparation method of 5 lupetidines, belong to organic synthesis field, with 3,5 lutidines are raw material, and 3 are obtained through catalytic hydrogenation, 5 lupetidine crude products, high-purity cis 3,5 lupetidines, its cis gas chromatographic purity ＞ 99.5% are obtained after purification through separating out.The present invention changes Pyridine Molecules and the combination of catalyst molecule in hydrogenation process by introducing neutral alumina and alkali, is conducive to the generation of cis body, can obtain being directly used in the crude product of medicine company production and application；The cis-isomer of purity ＞ 99.5% is can obtain through treatment, 3, the cis synthesis of 5 lupetidines and separation aspect do not have the report of such high-purity, in the synthesizing and purifying and industrial production application aspect of piperidine derivative, with larger reference and commercial value higher.
Description
Technical field
The invention belongs to organic synthesis field, and in particular to a kind of high-purity is cis-the preparation side of 3,5- lupetidines
Method.
Background technology
Cis -3,5- lupetidines are the derivatives of piperidines, and it is in antifungal agent and plant growth regulator is prepared
It is widely used.
Cis -3,5- lupetidines are also used as intermediate, prepare ammonia first heterocyclic pesticide compound and can
The compound of regulation dietary behavior and relevant disease, the disease related to dietary behavior includes that obesity, diabetes, cancer are (swollen
Knurl), inflammatory disease, depression, the disease relevant with anxiety and Alzheimer's disease.Additionally, cis -3,5- lupetidines are in system
In double hydrogen-dehydrogenation-(ring amino) derivatives of carbon -20- of standby macrolide antibiotics, during system with molecular sieve for preparing is standby also very
It is useful.
The method of existing synthesis 3,5- lupetidines has two kinds：Furanol method and hydrogenization method.Wherein Furanol method production
It is relatively costly, therefore industrial production is typically prepared using hydrogenization method.
It is general that the cis -3,5- dimethyl that the method for 3,5- lupetidines is obtained is prepared with the hydrogenation of 3,5- lutidines
The purity of piperidines is about 80 ± 3%, and this purity is difficult to apply in pharmaceutical synthesis field.
The method that prior art extracts cis -3,5- lupetidines is as follows：
1) a kind of method is disclosed and adds containing cis -3,5- lupetidines, three second the chloride of o- chlorobenzoyls
The solution of amine and dichloromethane.Disclose and obtain pure cis using hexane and dichloromethane recrystallization further to product
Acid amides, by the further back flow reaction in ethylene glycol and potassium hydroxide, then distills and is collected in evaporating for 100-195 DEG C of boiling
Point, obtain pure cis -3,5- lupetidines.
2) a kind of method discloses the hydrogen chloride gas that will be seethed with excitement by commerical grade 3,5- lupetidines and anhydrous ether
Solution, prepares hydrochloride salt.Salt is further processed using acetone and ether, to produce cis -3,5- lupetidines,
It is mixed with≤5% transisomer.
3) a kind of method discloses to mix in water and 3,5- lutidines carries out catalytic hydrogenation, afterwards using still
Distillation raw product, to remove trans -3, the 5- lupetidines as the entrainer of water.
Prior art raising cis ratio is complex, therefore industrial production is in the urgent need to finding simple suitable catalytic way
And simple and effective way of purification, cis -3, the 5- lupetidines of high-purity are obtained with this.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of preparation side of the cis -3,5- lupetidines of high-purity
Method, its preparation process is simple, 3,5- lupetidine crude products can reach total purity more than 99.5%, cis purity is 85 ± 3%,
Trans purity is 15 ± 3%, and the crude product is that may be directly applied to pharmaceutical synthesis field, while be can obtain by precipitation treatment cis
Cis -3,5- lupetidine of the gas phase purity more than 99.5%, allocates through with mother liquor, can obtain cis purity in 70-
The product of any purity between 99.5%.
The technical scheme that the present invention solves above-mentioned technical problem is as follows：A kind of cis -3,5- lupetidines of high-purity
Preparation method, it is characterised in that comprise the following steps：
A, under the conditions of hydrogen shield, 3,5- lutidines, inorganic base, neutral alumina, catalyst are added to height
Reacted in pressure reactor, suction filtration obtains 3,5- lupetidine crude products after completion of the reaction；
B, 3, the 5- lupetidine crude products that will be obtained in step A mix with organic solvent, lower the temperature and separate out, and obtain high-purity
Cis -3,5- the lupetidines of degree.
On the basis of above-mentioned technical proposal, the present invention can also do following improvement.
Further, in step, the catalyst is one or more in platinum carbon, ruthenium carbon, nickel；Activity 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 neutral alumina is (1~10) with the mass ratio of the catalyst：1；The inorganic base and total raw material mass ratio in step A
It is (0.001~1)：100.
Further, in step, the neutral alumina particle diameter is 100~400 mesh.
Further, in step, the inorganic base be potassium hydroxide, NaOH, sodium carbonate, potassium carbonate, potassium acetate,
One or more in aluminium hydroxide.
Further, in step, the reaction pressure that the autoclave is reacted is 0.1MPa~10.0MPa, instead
It is 100~200 DEG C to answer temperature, and the reaction time is 2~20h.
Further, in stepb, the organic solvent is methyl alcohol, ethanol, the tert-butyl alcohol, petroleum ether, normal heptane, toluene, second
One or more in acetoacetic ester.
Further, in stepb, the organic solvent and 3, the 5- lupetidines crude product quality ratio for (0.1~
5)：1.
Further, in stepb, the cooling temperature control is at -80~20 DEG C.
The beneficial effects of the invention are as follows：
A, the present invention, using its fit effect, change Pyridine Molecules in hydrogenation process by introducing neutral alumina and alkali
With the combination of catalyst molecule, can to a certain extent improve the purity of cis piperidines so that crude product be can reach it is total pure
Degree ＞ 99.5%, the purity that cis purity is 85 ± 3%, trans purity is 15 ± 3%, yield ＞ 95%, solvent-free participation can
Directly apply to pharmaceutical synthesis field；
B, it is cis -3, the 5- lupetidines that can obtain gas phase purity ＞ 99.5% through simple process, process is simple, produces
Product purity is higher, is allocated through with mother liquor, the product of any purity of the cis purity between 70-99.5% is can obtain, in piperidines
The synthesizing and purifying and industrial production application aspect of derivative, with larger reference and commercial value higher.
Specific embodiment
Principle of the invention and feature are described below, example is served only for explaining the present invention, is not intended to limit
Determine the scope of the present invention.
Related introduction and experiment parameter condition on gas-chromatography instrument in the present embodiment is as follows：
Gas-chromatography INSTRUMENT MODEL is：Agilent 7820A；
Chromatographic column model：HP-1(30m、0.32mm、0.25μm)；
Heating schedule is：40 DEG C keep 5.0min, are warming up to 300 DEG C with 15 DEG C/min；
Injector temperature is：300℃；
Detector temperature is：320℃(FID)；
Carrier gas is：Nitrogen；
Control model is：Constant pressure 10pis；
Split ratio is：50:1；
Sample size is：0.2μL；
Embodiment 1
645.0g 3,5- lutidines, 77.4g neutral aluminas, 12.9g potassium carbonate, 25.8g ruthenium carbon (are effectively contained
5%) amount is added in the autoclave of 2L.Autoclave is closed, nitrogen displacement 6 times, hydrogen is replaced 6 times.Pressurising is warming up to
Hydrogen Vapor Pressure is 9.0MPa, after 150 DEG C, Hydrogen Vapor Pressure can be greatly reduced in course of reaction, heat-insulation pressure keeping reaction 5.0hr, detection
3,5- lutidines are reacted completely, and crude reaction is obtained through suction filtration, and yield is 96.8%.Gas chromatographic analysis shows, cis-
3,5- lupetidine purity are 84.5%, and trans -3,5- lupetidines purity is 15.2%.
2L there-necked flasks are furnished with mechanical agitation, thermometer, drying tube.By above-mentioned crude reaction, 340.0g n-hexanes, 35.0g
Absolute ethyl alcohol is added in 2L there-necked flasks, and system is faint yellow clarified solution at room temperature, and stirring is cooled to -10 DEG C, has white solid to analyse
Go out, be incubated 1.0hr, suction filtration, a small amount of n-hexane drip washing, transfer drying after yield be 75.3%, gas chromatographic analysis show it is cis-
3,5- lupetidines purity is 99.8%.Mother liquor is recyclable.
Comparative example 1
By in 645.0g 3,5- lutidines, the autoclave of 25.8g rutheniums carbon (effective content 5%) addition 2L.Close
Autoclave is closed, nitrogen displacement 6 times, hydrogen is replaced 6 times.After pressurising is warming up to Hydrogen Vapor Pressure for 9.0MPa, 150 DEG C, reaction
During Hydrogen Vapor Pressure can be greatly reduced, heat-insulation pressure keeping reaction 5.0hr, detection 3,5- lutidines react completely, through suction filtration
Crude reaction is obtained, yield is 96.8%.Gas chromatographic analysis shows that cis -3,5- lupetidines purity is 80.3%, instead
Formula -3,5- lupetidines purity is 19.2%.
Comparative example 2
645.0g 3,5- lutidines, 12.9g potassium carbonate, 25.8g rutheniums carbon (effective content 5%) are added the height of 2L
In pressure reactor.Autoclave is closed, nitrogen displacement 6 times, hydrogen is replaced 6 times.Pressurising be warming up to Hydrogen Vapor Pressure for 9.0MPa,
After 150 DEG C, Hydrogen Vapor Pressure can be greatly reduced in course of reaction, heat-insulation pressure keeping reaction 24.0hr, hydrogen gas pressure stabilization, sampling inspection
Survey, gas chromatographic analysis shows, 3,5- lutidines purity are 83.2%, cis -3,5- lupetidine purity is
13.5%, trans -3,5- lupetidines purity is 2.8%.
Comparative example 3
645.0g 3,5- lutidines, 77.4g neutral aluminas, 25.8g rutheniums carbon (effective content 5%) are added into 2L
Autoclave in.Autoclave is closed, nitrogen displacement 6 times, 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 course of reaction, heat-insulation pressure keeping reaction 5.0hr, detect 3,5- dimethyl
Pyridine is reacted completely, and crude reaction is obtained through suction filtration, and yield is 96.8%.Gas chromatographic analysis shows, cis -3,5- dimethyl
Piperidines purity is 81.7%, and trans -3,5- lupetidines purity is 17.9%.
The crude product purity of table one is counted
As shown in Table 1：
The present invention by introducing neutral alumina and alkali, using its fit effect, change in hydrogenation process Pyridine Molecules with
The combination of catalyst molecule, can to a certain extent improve the purity of cis -3,5- lupetidines, solvent-free participation,
May be directly applied to pharmaceutical synthesis field；
The purity of two embodiment of table one is counted
As shown in Table 2：
The present invention is the cis -3,5- lupetidines that can obtain gas phase purity ＞ 99.5% by simple process.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all it is of the invention spirit and
Within principle, any modification, equivalent substitution and improvements made etc. should be included within the scope of the present invention.
Claims (9)
1. a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that comprise the following steps：
A, under the conditions of hydrogen shield, by 3,5- lutidines, inorganic base, neutral alumina, that catalyst is added to high pressure is anti-
Answer and reacted in kettle, suction filtration obtains 3,5- lupetidine crude products after completion of the reaction；
B, 3, the 5- lupetidine crude products that will be obtained in step A mix with organic solvent, lower the temperature and separate out, and obtain high-purity suitable
Formula -3,5- lupetidines.
2. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step A, the catalyst is one or more in platinum carbon, ruthenium carbon, nickel.
3. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step A, 3, the 5- lutidines is (8~10) with the neutral alumina mass ratio：1；The neutral alumina with
The mass ratio of the catalyst is (1~10)：1；The inorganic base is (0.001~1) with total raw material mass ratio in step A：
100。
4. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step A, the neutral alumina particle diameter is 100~400 mesh.
5. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step A, the inorganic base be potassium hydroxide, NaOH, sodium carbonate, potassium carbonate, potassium acetate, aluminium hydroxide in one kind or
It is several.
6. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised 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.
7. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step B, the organic solvent be methyl alcohol, ethanol, the tert-butyl alcohol, petroleum ether, normal heptane, toluene, ethyl acetate in one kind or
It is several.
8. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step B, the organic solvent is (0.1~5) with 3, the 5- lupetidines crude product quality ratio：1.
9. according to claim 1 a kind of high-purity it is cis-preparation method of 3,5- lupetidines, it is characterised in that
In step B, the cooling temperature control is at -80~20 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| 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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| CN106916097B CN106916097B (en) | 2019-06-07 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020002908A1 (en) | 2018-06-26 | 2020-01-02 | Johnson Matthey Public Limited Company | 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 | Preparation method of cis-trans mixed isomer 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 | Preparation method of cis-trans mixed isomer 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020002908A1 (en) | 2018-06-26 | 2020-01-02 | Johnson Matthey Public Limited Company | 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 |
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| Publication number | Publication date |
|---|---|
| CN106916097B (en) | 2019-06-07 |
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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 |