CN108276380A - A kind of synthetic method of pomalidomide - Google Patents
A kind of synthetic method of pomalidomide Download PDFInfo
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- CN108276380A CN108276380A CN201810268705.XA CN201810268705A CN108276380A CN 108276380 A CN108276380 A CN 108276380A CN 201810268705 A CN201810268705 A CN 201810268705A CN 108276380 A CN108276380 A CN 108276380A
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- pomalidomide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of synthetic methods of improved pomalidomide, belong to medicinal chemistry art.It is raw material with 3 halophthalic acids 1（F, Cl and Br）, it is condensed to yield phthalic acid acid anhydride compound 2 through acetic anhydride system, compound 2 and 3 amino, 2,6 piperidine dione reactant salt obtain phthalimide derivative 4；Compound 4 occurs amino with ammonium hydroxide and replaces to obtain pomalidomide.The present invention is starting material instead of 3 nitrophthalic acids reported at present using 3 halophthalic acids; halogen is directly replaced to prepare pomalidomide by ammonia; avoid high-pressure hydrogenation when nitro reduction; or the use of the metallic reducing agents such as iron powder; reaction process is simple to operation, pollutes small, high income; the recyclable recycling of solvent is conducive to scale industrial production.
Description
Technical field
The present invention relates to a kind of synthetic methods of pomalidomide, belong to medicinal chemistry art.
Background technology
Pomalidomide（pomalidomide）It is the new immunomodulator of Celgene drugmakers of U.S. exploitation, commodity
Entitled Pomalyst.On 2 8th, 2013, U.S.'s food and Drug Administration（FDA）Ratify the medicine for treating recurrent
And Refractory Multiple Myeloma.The immune response that T cell and natural killer cells mediate can be enhanced, while inhibiting monokaryon thin
Born of the same parents generate pro-inflammatory cytokine（Such as TNF-α, IL-6）.In addition, pomalidomide can inhibit tumor cell proliferation and induce thin
Born of the same parents' apoptosis also has stronger scar -derived fibroblast to act on the drug resistant multiple myeloma cell line of lenalidomide.
Pomalidomide Time To Market is shorter, and the synthetic method reported at present is few.Patent of invention US20130143922 A1
（Route 1）It reports using 3- nitrophthalic acids acid anhydride as raw material, prepares pomalidomide.Wherein final step will use palladium carbon and urge
The method for changing hydrogenation restores nitro.This method will use more harsh hydrogenation conditions and valuable palladium catalyst.
Route 1
As shown in Scheme 2, Tang Mei, Wu Han etc.（Chinese Journal of Pharmaceuticals, 2009,40（10）, 721-723）Use chiral original
Material synthesizes 3- amino -2,6- piperidine diones, and further prepares 3- nitro neighbours benzene two by raw material of 3- nitrophthalic acids
Formic anhydride, then use and 1 similar method of route, carry out the synthesis of pomalidomide.However the Fe/HCl systems of their uses
The method of reduction nitro has the generation of a large amount of solid waste.Wu Gang, Cen Junda etc.（Chinese journal of Medicinal Chemistry, 2013,2,
108-110）This method is improved, using ammonium formate as reducing agent, palladium carbon is catalyst to nitre for final step reduction
Base is restored, and reaction condition is more mild, good to operate, however this method also uses more valuable palladium catalyst.
Route 2
Patent of invention US20070004920A1 is reported prepares key intermediate 3- nitros by raw material of 3- nitrophthalic acids
Then phthalic anhydride prepares phthalimide intermediate with L-Glutamine reaction, then through nitro reduction, amidation
Cyclization prepares pomalidomide.However the route needs to use in the synthetic route, -30 DEG C of low temperature below, high pressure reduction etc. compared with
For harsh reaction condition.
In conclusion in the synthetic method for the pomalidomide reported, 3- nitrophthalic acids are mostly used as former
Material, prepares amino, reaction condition is more harsh, noble metal by the metallic reducing agents reduction such as high-pressure hydrogenation or iron powder
The use of catalyst increases cost, and the use of metallic reducing agent will produce a large amount of solid wastes, increase environmental pressure.It is urgently right at present
The synthetic method of pomalidomide is improved, and meets industrial production demand.
Invention content
Above-mentioned reaction reagent in the prior art is of high cost, condition is harsh the purpose of the present invention is overcoming, and it is existing that pollution is big etc.
The shortcomings that preparation method, provides a kind of improved synthetic method for preparing pomalidomide.
To achieve the purpose of the present invention, the present invention uses 3- halophthalic acids（Compound 1）For raw material, specifically grasping
Make that reaction dissolvent, reagent, reaction time and purification process etc. are screened and optimized in step, develops an operation
Convenient, yield is higher, and quality is preferable, and reaction condition is mild, is suitble to the synthetic method of industrialized production.
The technical solution adopted by the present invention is as follows：
（1）3- halophthalic acids are added in acetic anhydride, are heated.Cooling system after reaction, filtering wash to change
Close object 2；3- halophthalic acid quality（g）With the volume of acetic anhydride（mL）Than being 1：0.8~2.
The rate of charge of preferred compound 1 and acetic anhydride is 1g/mL, 80 DEG C of reaction temperature, cleaning solvent be petroleum ether, just oneself
One or more of alkane, hexamethylene.It is preferred that 3- bromophthalic acids are raw material.
（2）Compound 2 is heated to reflux with 3- amino -2,6- piperidine dione salt in acetic acid, sodium acetate system, and reaction terminates
Postcooling to room temperature, product is precipitated, and compound 4 is washed to obtain in filtering.Cleaning solvent is in water, methanol, ethyl alcohol, acetonitrile, acetone
It is one or more of；It is preferred that water, ethyl alcohol substep wash.
3- amino -2,6- piperidine dione the salt is its hydrochloride or trifluoroacetate；Compound 2 and 3- amino -2,6-
The molar ratio of piperidine dione salt is 1.3 ~ 1.1:1.（3）Compound 4, alkali, catalyst and ammonium hydroxide react in a solvent, after the completion mistake
Catalyst and solid base are filtered out, solvent evaporated obtains pomalidomide crude product.The solvent is using water, methanol, ethyl alcohol, DMF（N,N-
Dimethylformamide）, acetonitrile, DMSO（Dimethyl sulfoxide (DMSO)）Or THF（Tetrahydrofuran）；Alkali be sodium carbonate, potassium carbonate, cesium carbonate,
Sodium hydroxide；Catalyst is copper, cupric iodide, cuprous iodide, cuprous oxide, palladium bichloride or palladium.It is preferred that：Acetonitrile is to react molten
Agent, alkali are potassium carbonate, and cuprous oxide is catalyst.
It is preferred that：Reaction temperature is 20-100 DEG C；Compound 4 and the molar ratio of alkali are 1:1~2；The usage amount of catalyst is
0.5%-5%。
（4）It takes in pomalidomide crude product reaction kettle, good solvent is added, dissolving is stirred at room temperature, atent solvent, solid is added dropwise
It is gradually precipitated, is added dropwise and continues to stir.Filtering, washs, dries to obtain product.The good solvent be methanol, ethyl alcohol, acetone,
Acetonitrile, DMF, THF or DMSO, atent solvent are petroleum ether, n-hexane or water.Good solvent and atent solvent volume ratio are 1:
0.8~1.5。
It is preferred that：DMF and water, volume ratio 1 is respectively adopted in good solvent and atent solvent:1.1, the two can pass through rectifying
It detaches and can reuse.
Compared with prior art the invention has the advantages that：
（1）The present invention prepares pomalidomide using 3- halophthalic acids as raw material, through cyclization, substitution process, and reaction is used
Raw material it is inexpensively less toxic, environmental-friendly, reaction condition is mild, easy to operate, high income, up to 75% or more, is conducive to industrialized production.
（2）The process of substitution amination avoids the great number cost of more harsh high-pressure hydrogenation and noble metal catalyst；Also it avoids
The a large amount of solid wastes generated during the metallic reducing agents uses such as iron powder, reduce environmental pressure.（3）It is used in reaction process
The recyclable recycling of solvent, catalyst are recovered by filtration, can be recycled after activation, reduce production cost and environment
Pollution, is very suitable for industrialized production.
Description of the drawings
Fig. 1 is the pomalidomide X-ray powder diffraction collection that the present invention synthesizes.
Specific implementation mode
In order to preferably implement the present invention, now for embodiment, the invention will be further described, but these embodiments are only
For illustrating the present invention, the present invention is not limited.
Embodiment 1
60 g and 60mL acetic anhydrides of 3- phthalate bromines are added in 500 mL there-necked flasks, 3 h, point are stirred in 80 DEG C
Plate determines that the reaction was complete, is cooled to room temperature, and filters, and with 2 × 30 mL petroleum ethers, dries 3- bromo phthalic anhydrides, production
Rate 89%.
43.4 g of 3- bromos phthalic anhydride is added in 1 L single port bottles, the stirring of 300 mL acetic acid is added, successively
36.7 g of 3- amino -2,6- piperidine diones hydrochloride, sodium acetate 19.8 g, 3 h of reflux are added, is cooled to room temperature, filters, with 2
× 50 mL water and the washing of 30 mL ethyl alcohol, filtering drying obtain compound 4, yield 94.1%.
By 64.1 g compounds 4,500 mL acetonitriles, 18mL ammonium hydroxide, 40g potassium carbonate and 0.5g cuprous oxide in 1L obturators
It is reacted 6 hours for 50 DEG C in system.It is filtered to remove solid after completion of the reaction, is evaporated to obtain pomalidomide crude product.Crude solid is pure with 100mL
Water and the washing of 50mL ethyl alcohol, filtering drying.
It takes 46.8g pomalidomides crude product in 4L reaction kettles, 800mL DMF is added, dissolving is stirred at room temperature, 900mL is added dropwise
Pure water, yellow solid are gradually precipitated, and are added dropwise and continue to stir 2h.Filtering, solid are beaten filtration washing with 2 × 100mL pure water
Afterwards, 50 mL ethyl alcohol, which stir, washes, and filtering drying obtains 45.4g products, and yield 90%, purity 99.86%, list is miscellaneous to be less than 0.1%.
1H-NMR(DMSO-d6, 400 MHz, ppm): δ: 11.8 (1H, s), 7.45-7.47 (1H, t),
6.99-7.03 (2H, t), 6.52 (2H, s), 5.02-5.07 (1H, m), 2.84-2.89 (1H, m), 2.47-
2.57 (2H, m), 2.00-2.04 (1H, m)。
Claims (4)
1. a kind of method of synthesis pomalidomide, which is characterized in that include the following steps：
（1）3- halophthalic acids are added in acetic anhydride, heating reaction；Cooling system after reaction filters, washing
Obtain compound 2；
（2）Compound 2 is heated to reflux with 3- amino -2,6- piperidine dione salt in acetic acid, sodium acetate system, cold after reaction
But to room temperature, product is precipitated, and compound 4 is washed to obtain in filtering；
（3）Compound 4, alkali, catalyst and ammonium hydroxide react in a solvent, and Filtration of catalyst and solid base, are evaporated after the completion
Solvent obtains pomalidomide crude product；The solvent is using water, methanol, ethyl alcohol, DMF（N,N-dimethylformamide）, acetonitrile, DMSO
（Dimethyl sulfoxide (DMSO)）Or THF（Tetrahydrofuran）；Alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide；Catalyst is copper, iodate
Copper, cuprous iodide, cuprous oxide, palladium bichloride or palladium.
2. according to the synthetic method of the pomalidomide described in claim 1, which is characterized in that 3- halophthalic acids select 3-
Bromophthalic acid.
3. the synthetic method of the pomalidomide according to claim 1 or 2, which is characterized in that step（2）In 3- amino-
2,6- piperidine dione salt is its hydrochloride or trifluoroacetate.
4. the synthetic method of the pomalidomide according to claim 1 or 2, which is characterized in that step（1）The middle halogenated neighbours of 3-
Phthalic acid quality（g）With the volume of acetic anhydride（mL）Ratio is 1：0.8~2；Step（2）Compound 2 and 3- amino -2,6- piperazines
The molar ratio of pyridine diketone is 1.3 ~ 1.1:1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6830569B1 (en) * | 2019-08-23 | 2021-02-17 | 持田製薬株式会社 | Method for Producing Heterocyclidene Acetamide Derivative |
| WO2021039023A1 (en) * | 2019-08-23 | 2021-03-04 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivatives |
| JP2022153519A (en) * | 2019-08-23 | 2022-10-12 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivative |
| RU2813203C2 (en) * | 2019-08-23 | 2024-02-07 | Мотида Фармасьютикал Ко., Лтд. | Method of producing heterocyclidene acetamide derivative |
-
2018
- 2018-03-29 CN CN201810268705.XA patent/CN108276380A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6830569B1 (en) * | 2019-08-23 | 2021-02-17 | 持田製薬株式会社 | Method for Producing Heterocyclidene Acetamide Derivative |
| WO2021039023A1 (en) * | 2019-08-23 | 2021-03-04 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivatives |
| CN114206847A (en) * | 2019-08-23 | 2022-03-18 | 持田制药株式会社 | Process for producing heterocyclylideneacetamide derivative |
| JP2022153519A (en) * | 2019-08-23 | 2022-10-12 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivative |
| JP7320113B2 (en) | 2019-08-23 | 2023-08-02 | 持田製薬株式会社 | Method for producing heterocyclideneacetamide derivative |
| RU2813203C2 (en) * | 2019-08-23 | 2024-02-07 | Мотида Фармасьютикал Ко., Лтд. | Method of producing heterocyclidene acetamide derivative |
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