CN109305935A - A kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride - Google Patents
A kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride Download PDFInfo
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- CN109305935A CN109305935A CN201710624685.0A CN201710624685A CN109305935A CN 109305935 A CN109305935 A CN 109305935A CN 201710624685 A CN201710624685 A CN 201710624685A CN 109305935 A CN109305935 A CN 109305935A
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- amino
- piperidine dione
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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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two 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 directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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Abstract
The invention discloses a kind of preparation methods of 3- amino -2,6- piperidine dione hydrochloride, method includes the following steps: (1) is by L-Glutamine, the upper protection in alkaline medium obtains the tertiary fourth oxygen formoxyl-L-Glutamine of N-；(2) in anhydrous conditions, with N under 4-dimethylaminopyridine catalysis, N- carbonyl dimidazoles cyclization obtains tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N- to the tertiary fourth oxygen formoxyl-L-Glutamine of N- for obtaining step (1)；(3) tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N- for obtaining step (2) is deprotected in acid medium, and hydrochloric acid salt, obtains 3- amino -2,6- piperidine dione hydrochloride.Target product 3- amino -2,6- piperidine dione hydrochloride is obtained by upper protection, the ring of light, deprotection and at three step of salt, acquired product purity is high and quality is stablized.The method applied in the present invention, if three step of synthesis process, and also route is simple, and reaction condition is mild, does not need high-pressure hydrogenation condition, low in cost, it is easy to accomplish industrialization.
Description
Technical field
The present invention relates to pharmaceutical technology fields, are related to a kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride.
Background technique
3- amino -2,6- piperidine dione hydrochloride is the key intermediate for synthesizing lenalidomide and pomalidomide.
Lenalidomide (Lenalidomide/Revlimid) increases in FDA approval Revlimid in 2008 for treating marrow
Raw exception syndrome.What Food and Drug Adminstration of the US (FDA) had approved American Cell genome company carrys out that degree
(Lenalidomide/Revlimid).Revlimid is oral preparation, and Revlimid (Lenalidomide) is by Celgene
The drug for being used to treat lethal hematologic disease and cancer of company's research and development.The product are once to cause number with thousand for treating morning sickness
The strengthening version of the baby due defect Thalidomide (Thalidomide) of meter has anticancer potentiality.Compared with Thalidomide,
Less adverse effect, research have shown that it will not cause baby due defect.
Pomalidomide (Pomalidomide) is thalidomide analogs, has anti-tumor activity, and it is swollen to be able to suppress hematopoiesis
Oncocyte hyperplasia simultaneously induces cell apoptosis.In addition, pomalidomide can inhibit the multiple myeloma cell line of resistance to lenalidomide to increase
It is raw, it can be with dexamethasone co-induction apoptosis of tumor cells；Enhance the immune response that T cell and natural killer cells mediate, together
When inhibit monocyte generate pro-inflammatory cytokine.Pomalidomide is researched and developed by Sai Er gene (Celgene) company of the U.S.,
Acquisition FDA approval listing in 2 months 2013, for treating the invalid multiple bone of other medicines (such as lenalidomide, bortezomib)
Myeloma (Multiple Myeloma).
Pomalidomide (Pomalidomide) is after Thalidomide (Thalidomide), lenalidomide
(Lenalidomide) third spends amine drug afterwards, is mainly used for the patient to lenalidomide, bortezomib drug resistant, it is contemplated that should
Medicine is in 2017 annual sales amounts up to 1,000,000,000 dollars.
In the prior art, the synthetic route of 3- amino -2,6- piperidine dione hydrochloride has as follows:
The synthetic route that patent WO2008/7979 and WO2011/50962 are disclosed uses carbobenzyloxy as amino
Protecting group, this protecting group needs the method using high-pressure hydrogenation in deprotection reaction, but hydrogenation belong to it is extraordinary anti-
It answers, is unfavorable for general plant produced, while hydrogenation needs to use 10% palladium carbon as catalyst, catalyst price is higher,
Also the control of cost is influenced.
Summary of the invention
The present invention is insufficient according to prior art, provides a kind of preparation side of 3- amino -2,6- piperidine dione hydrochloride
Method, using cheap L-Glutamine as starting material, by upper protection, cyclization is deprotected and obtains mesh at three step of salt
Product 3- amino -2,6- piperidine dione hydrochloride is marked, acquired product purity is high and quality is stablized.
Above-mentioned technical problem of the invention is carried out by the following technical programs:
A kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride, method includes the following steps:
(1) by L-Glutamine, upper protection obtains the tertiary fourth oxygen formoxyl-L-Glutamine of N- in alkaline medium；
(2) make step (1) obtain the tertiary fourth oxygen formoxyl-L-Glutamine of N- in anhydrous conditions, in 4- dimethylamino
Pyridine catalysis is lower and N, N- carbonyl dimidazoles cyclization obtain tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N-；
(3) the tertiary fourth oxygen formoxyl -3- amino -2,6- piperidine dione remove-insurance in acid medium of N- for obtaining step (2)
Shield, and hydrochloric acid salt, obtain 3- amino -2,6- piperidine dione hydrochloride.
Synthetic route of the invention is as follows:
L-Glutamine is a kind of widely used important intermediate, and raw material is easy to get and price is very cheap.L- glutamy
Amine is deprotected through upper protection, cyclization and obtains target product 3- amino -2,6- piperidine dione hydrochloride at three step of salt.Condition
Mildly, easy to operate, and yield is very satisfied.
Preferably, alkaline medium described in step (1) is sodium hydrate aqueous solution, wet chemical or bicarbonate
The molar ratio range of sodium water solution, preferably sodium hydrate aqueous solution, the alkali and L-Glutamine is 1-4:1, and preferred scope is
2-3:1。
Preferably, being added with hydrotropy solvent in step (1), hydrotropy solvent used is, Isosorbide-5-Nitrae-dioxane, ethyl alcohol,
Any one in methanol, tetrahydrofuran, preferably Isosorbide-5-Nitrae-dioxane, hydrotropy solvent and water ratio are 1:0.1-0.4, preferably
1:02-0.3。
Preferably, the temperature range protected in step (1) is 10-80 DEG C, preferred scope is 20-40 DEG C.
Preferably, the range of the temperature of step (2) cyclization is 40-70 DEG C, preferred scope is 60-70 DEG C.
Preferably, the solvent of ring closure reaction described in step (2) is tetrahydrofuran, ethyl alcohol, methanol, Isosorbide-5-Nitrae-dioxy six
Ring, preferably tetrahydrofuran.
Preferably, step (2) is in ring closure reaction, the tertiary fourth oxygen formoxyl-L-Glutamine of N- and two miaow of N, N- carbonyl
The molar ratio of azoles is 1:1-1.5, preferred scope 1:1.2-1.3.
Preferably, step (2) is in ring closure reaction, the tertiary fourth oxygen formoxyl-L-Glutamine of N- and 4- dimethylamino pyrrole
The molar ratio of pyridine is 1:0.01-0.05, preferred scope 1:0.02-0.03.
Preferably, acid medium described in step (3) deprotection is the organic solution of hydrochloric acid, it is above-described organic molten
Liquid is methanol, ethyl alcohol, ethyl acetate, tetrahydrofuran, preferably methanol, solution concentration 2-4mol/L, preferred scope 2.5-
3.5mol/L。
Preferably, tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of step (3) N- is reacted with hydrochloric acid solution, remove-insurance
The temperature range of shield is 0-50 DEG C, and preferred scope is 10-30 DEG C.
The present invention have the characteristics that it is following and the utility model has the advantages that
By adopting the above technical scheme, using cheap L-Glutamine as starting material, by upper protection, cyclization,
It is deprotected and obtains target product 3- amino -2,6- piperidine dione hydrochloride, acquired product purity height and quality at three step of salt
Stablize；As long as in addition, three step of synthesis process, and route is simple, reaction condition is mild, and does not need high-pressure hydrogenation condition,
It is low in cost, it is easy to accomplish industrialization.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
Some embodiments of invention without any creative labor, may be used also for those of ordinary skill in the art
To obtain other drawings based on these drawings.
Fig. 1 is the 1H-NMR spectrogram that the present invention prepares resulting 3- amino -2,6- piperidine dione hydrochloride.
Specific embodiment
Specific embodiments of the present invention will be further explained below.It should be noted that for these implementations
The explanation of mode is used to help understand the present invention, but and does not constitute a limitation of the invention.In addition, invention described below
Technical characteristic involved in each embodiment can be combined with each other as long as they do not conflict with each other.
Embodiment 1
The present invention provides a kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride, this method includes following step
It is rapid:
(1) synthesis of the tertiary fourth oxygen formoxyl-L-Glutamine of N-
1.5 kilograms of L-Glutamines and 1.5 liters of Isosorbide-5-Nitrae-dioxane are added in 20 liters of reaction kettles, it is muddy to stir to get white
NaOH (1 kilogram)/H of preparation is added in turbid26 liters of O, clarified solution is stirred to get, ice bath is cooled to 0 DEG C, is added dropwise 2.25 kilograms
Di-tert-butyl dicarbonate after being added dropwise, is removed ice bath, is reacted at room temperature 4 hours, muddy, liquid chromatography detection reaction occurs
Terminal.Next day is concentrated under reduced pressure and removes Isosorbide-5-Nitrae-dioxane and part water (about 4 liters), adjusts PH=1 with 6mol/L hydrochloric acid, uses second
* 5 extractions of 5 liters of acetoacetic ester, take organic phase, and organic phase is dry with anhydrous sodium sulfate, be concentrated to dryness to obtain 2065 grams it is yellowish
The tertiary fourth oxygen formoxyl-L-Glutamine of color dope N-, yield: it is 97.3% that 90.7%, HPLC, which detect purity,.
(2) synthesis of tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N-
The addition tertiary fourth oxygen formoxyl-L-Glutamine of 2060 grams of N- in 20 liters of four-hole bottles, 34 grams of 4-dimethylaminopyridine,
With 11 liters of anhydrous tetrahydro furan stirring and dissolving, 1790 grams of N are added portionwise, N- carbonyl dimidazoles generate a large amount of foams, start to rise
For temperature to back flow reaction 4 hours, liquid chromatography detected reaction end.Reaction is finished, and is concentrated to dryness to obtain yellow solid, with 10
* 4 washings are risen, are filtered, vacuum drying obtains tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of 1520 grams of white solid N-, receives
Rate: it is 99.1% that 79.6%, HPLC, which detect purity,.
(3) synthesis of 3- amino -2,6- piperidine dione hydrochloride
6L methanol hydrochloride solution (2mol/L) is added in 20 liters of four-hole bottle, is cooled to 0 DEG C, 1520 grams of tertiary fourths of N- is added dropwise
The solution of oxygen formoxyl -3- amino -2,6- piperidine dione and 6 liters of methanol drips and finishes insulated and stirred 30 minutes, and room temperature reaction is stayed overnight,
Liquid chromatography detects raw material fully reacting.Next day is concentrated to dryness, and 5L ethyl acetate room temperature is added and is beaten 2 hours, filters
White solid is obtained, vacuum drying obtains 1040 grams of white solid 3- amino -2,6- piperidine dione hydrochloride, yield:
It is 99.5% that 94.8%, HPLC, which detect purity,.
As shown in Figure 1, preparing the 1H-NMR spectrogram of resulting 3- amino -2,6- piperidine dione hydrochloride by above-mentioned steps
Embodiment 2
The present embodiment the difference from embodiment 1 is that, alkali selected in step (1) be wet chemical, produced
Product yield is 88.4%.It is 90.2% that HPLC, which detects purity,.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 3
The present embodiment the difference from embodiment 1 is that, NaOH (1.2 kilograms)/H prepared is added in step (1)2O 6L,
Obtaining product yield is 79.2%.It is 96.3% that HPLC, which detects purity,.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 4
The present embodiment the difference from embodiment 1 is that, the selected hydrotropy solvent of step (1) be tetrahydrofuran, produced
The yield of product is that 72.3%, HPLC detection purity is 97.1%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 5
The present embodiment the difference from embodiment 1 is that, the temperature protected in step (1) be 70 DEG C, resulting product yield
Detecting purity for 51.8%, HPLC is 87.1%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 6
The present embodiment the difference from embodiment 1 is that, the temperature of step (2) cyclization is 40 DEG C, and resulting product yield is
It is 81.5% that 70.3%, HPLC, which detect purity,.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 7
The present embodiment the difference from embodiment 1 is that, solvent used in step (2) cyclization be methanol, resulting product receive
Rate is that 73.5%, HPLC detection purity is 98.2%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 8
The present embodiment the difference from embodiment 1 is that, N used in step (2), N- carbonyl dimidazoles amount be 1.5 kilograms, gained
Product yield be 66.3%, HPLC detection purity be 98.7%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 9
The present embodiment the difference from embodiment 1 is that, 4-dimethylaminopyridine amount used in step (2) be 51 grams, it is resulting
Product yield is that 77.3%, HPLC detection purity is 98.4%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 10
The present embodiment the difference from embodiment 1 is that, methanol hydrochloride solution used in step (3) changes hydrochloric ethyl acetate into
Solution, resulting product yield are that 80.3%, HPLC detection purity is 97.3%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 11
The present embodiment the difference from embodiment 1 is that, methanol hydrochloride solution concentration used in step (3) be 4mol/L, institute
The product yield obtained is that 88.3%, HPLC detection purity is 99.2%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Embodiment 12
The present embodiment the difference from embodiment 1 is that, step (3) deprotection temperature be 50 DEG C, resulting product yield
Detecting purity for 50.2%, HPLC is 97.8%.
In the present embodiment, other steps are same as Example 1, therefore without specifically writing.
Specific embodiment described in the present invention only illustrate the spirit of the present invention by way of example.The neck of technology belonging to the present invention
The technical staff in domain can make various modifications or additions or by a similar method to described specific embodiment
Instead of however, it does not deviate from the spirit of the invention or surmounts range defined in appended letter of authorization.Although having been done to the present invention
Go out and be described in detail and be cited some specific examples, but to those skilled in the art, as long as without departing from this hair
It is obvious that bright spirit and scope, which can make various changes or correct,.
Claims (10)
1. a kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride, method includes the following steps:
(1) by L-Glutamine, upper protection obtains the tertiary fourth oxygen formoxyl-L-Glutamine of N- in alkaline medium；
(2) make step (1) obtain the tertiary fourth oxygen formoxyl-L-Glutamine of N- in anhydrous conditions, in 4-dimethylaminopyridine
Catalysis is lower and N, N- carbonyl dimidazoles cyclization obtain tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N-；
(3) tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N- for obtaining step (2) is deprotected in acid medium, and
Hydrochloric acid salt obtains 3- amino -2,6- piperidine dione hydrochloride.
2. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
Alkaline medium in step (1) be any one in sodium hydrate aqueous solution, wet chemical and sodium bicarbonate aqueous solution or
A variety of, the molar ratio range of the alkaline medium and L-Glutamine is 1-4:1.
3. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
It is added with hydrotropy solvent in step (1), which is Isosorbide-5-Nitrae-dioxane, ethyl alcohol, methanol, any one in tetrahydrofuran
Kind, hydrotropy solvent and water ratio are 1:0.2-0.4.
4. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (1), the temperature range of upper protection is 10-80 DEG C.
5. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (2), ring closure reaction temperature is 40-70 DEG C.
6. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (2), the solvent of ring closure reaction is tetrahydrofuran, ethyl alcohol, methanol, Isosorbide-5-Nitrae-dioxane.
7. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (2), in ring closure reaction, the molar ratio of the tertiary fourth oxygen formoxyl-L-Glutamine of N- and N, N- carbonyl dimidazoles is
1:1-1.5。
8. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (2), in ring closure reaction, the molar ratio of the tertiary fourth oxygen formoxyl-L-Glutamine of N- and 4-dimethylaminopyridine is
1:0.01-0.05。
9. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (3), acid medium is hydrochloric acid/ethyl acetate solution, methanol hydrochloride solution, ethanol solution hydrochloride, solution concentration 2-
4mol/L。
10. the preparation method of 3- amino -2,6- piperidine dione hydrochloride according to claim 1, it is characterised in that: described
In step (3), tertiary fourth oxygen formoxyl -3- amino -2, the 6- piperidine dione of N- is reacted with hydrochloric acid solution, and the temperature range of deprotection is
0-50℃。
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| CN101665484A (en) * | 2009-07-20 | 2010-03-10 | 上海皓元生物医药科技有限公司 | Method for preparing lenalidomide |
| CN103193763A (en) * | 2013-04-10 | 2013-07-10 | 杭州百诚医药科技有限公司 | Novel preparation method of lenalidomide |
| CN104311536A (en) * | 2014-10-24 | 2015-01-28 | 上海应用技术学院 | Method for preparing lenalidomide |
| CN104910132A (en) * | 2014-03-14 | 2015-09-16 | 天津永生生物技术有限公司 | Preparation method of pomalyst and intermediate thereof |
| CN105440012A (en) * | 2014-08-07 | 2016-03-30 | 天津法莫西医药科技有限公司 | Lenalidomide and lenalidomide intermediate preparation method |
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2017
- 2017-07-27 CN CN201710624685.0A patent/CN109305935A/en active Pending
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| CN101665484A (en) * | 2009-07-20 | 2010-03-10 | 上海皓元生物医药科技有限公司 | Method for preparing lenalidomide |
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| CN104910132A (en) * | 2014-03-14 | 2015-09-16 | 天津永生生物技术有限公司 | Preparation method of pomalyst and intermediate thereof |
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