CN109776493A - A kind of preparation method of lenalidomide - Google Patents
A kind of preparation method of lenalidomide Download PDFInfo
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- CN109776493A CN109776493A CN201910212294.7A CN201910212294A CN109776493A CN 109776493 A CN109776493 A CN 109776493A CN 201910212294 A CN201910212294 A CN 201910212294A CN 109776493 A CN109776493 A CN 109776493A
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Abstract
The invention discloses a kind of preparation methods of lenalidomide, belong to organic synthesis field.By the way that using 2- methyl-3-nitro methyl benzoate and 3-N- benzyloxycarbonyl-L-Glutamine as starting material, 2- methyl-3-nitro methyl benzoate obtains important intermediate 2- bromomethyl -3- nitrobenzene methyl through bromo-reaction.3-N- benzyloxycarbonyl-L-Glutamine carries out cyclization reaction under catalytic action; generate 3-N- benzyloxycarbonyl amino -2; 6- dioxopiperidine; amino deprotection generates 3- amino -2; then 6- piperidine dione halogen acid salt obtains 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2 through aminolysis reaction with 2- bromomethyl -3- nitrobenzene methyl; lenalidomide is made through reduction reaction in 6- diketone.The route has many advantages, such as that cost of material is low, post-processing is easy, and the production cost of lenalidomide bulk pharmaceutical chemicals is greatly reduced in high income.The present invention is a kind of convenience, is efficiently suitable for industrial lenalidomide synthetic method.
Description
Technical field
The present invention relates to a kind of preparation methods of lenalidomide, belong to organic synthesis field.
Background technique
Lenalidomide, chemical name: RS-3- (4- amino -1- oxygen -1,3- dihydro -2H- iso-indoles -2- base) piperidines -2,6-
Diketone (Lenalidomide, (RS) -3- (4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)
Piperidine-2,6-dione), it is that lethal hematologic disease and cancer are treated by a kind of of Celgene company, U.S. research and development
Second generation immunomodulator.Product name: Revlimid, U.S. Food and Drug Administration (FDA) is in 2 months 2006 batches
Its quasi- listing, is mainly used for transfusion dependent caused by the myelodysplastic syndrome with 5q deletion cytogenetic exception
The treatment of Anemic patients.The chemical structural formula of lenalidomide are as follows:
Lenalidomide is the derivative of new generation of Thalidomide, but does not find its toxicity with aberration inducing, and medicine
It imitates 100 times stronger than Thalidomide.
The synthetic method of existing lenalidomide: 2- bromomethyl -3- is made by raw material of 2- methyl-3-nitro methyl benzoate
Nitrobenzene methyl；Using 3-N- benzyloxycarbonyl-L-Glutamine as raw material, cyclization generates benzyloxycarbonyl amino -2 3-N-,
6- dioxopiperidine, deamination protecting group generate 3- amino -2,6- piperidine dione halogen acid salt.
2- bromomethyl -3- nitrobenzene methyl and 3- amino -2,6- piperidine dione halogen acid salt are made in basic catalyst
With lower reaction, 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2,6- diketone is obtained, through reduction reaction system
Obtain lenalidomide.
Chemical equation are as follows:
In the existing preparation method of lenalidomide: 1. lenalidomide intermediates (III) are by starting material (I) through free bromide
Generation reaction obtains.1. US2003/139451A, WO2010/56344A1 are reported in 90~140 DEG C, with bromine or N- bromo amber
Amber acid imide and radical initiator benzoyl peroxide；②US2010/10060A1,Bioorg.Med.Chem.Lett.,14,
81 (2004) report uses azodiisobutyronitrile for radical initiator；3. US6335/349B1 report is caused anti-using illumination
It answers；4. US5534481A1 is reported while being used initiator and illumination initiation reaction.
In reaction atent solvent of the solvent for use containing chlorine for example carbon tetrachloride, chloroform, methylene chloride, 1,2- dichloroethanes,
1,1,2- trichloroethanes, chlorobenzene, dichloro-benzenes.These solvents are harmful to health and environment, expensive compared with not chloro-containing reagent,
And surcharge is also needed in terms of post-processing with environmental protection control.
US6335/349B1、WO2009/114601A1、WO2010/139266A1、WO2010/56384A1、WO2011/
50962、WO2011/27326A1、WO2011/69608A1、US2011/237802A1、US2011/223157A1、US2012/
71509A1, Bioorg.Med.Chem.Lett., 3,1019 (2001) are reported by 3- (4- nitro -1- oxo -1,3- dihydro -2H-
Iso-indoles -2- base) piperidines -2,6- diketone (VII) reduction prepares lenalidomide, and most common condition is the catalytic hydrogenation of nitro.
Catalytic hydrogenation needs transition-metal catalyst (Pd/C, PtO2) and hydrogen, consider that catalytic hydrogenation needs from secure context
Special installation and safeguard procedures are wanted, these can all increase production cost, it is also necessary to control the transition metal impurity in final product
Residual quantity.It also will form the partial reduction products and the nitroso disproportionation products of intermediate of nitro in reaction.The purifying of product
Cumbersome, yield is impacted, increased costs.
WO2010/61209A1 report, by 3- (4- nitro -1- oxo -1,3- dihydro -2H- iso-indoles -2- base) piperidines -2,
6- diketone (VII) prepares lenalidomide through non-catalytic hydrogenation method, such as ferrous acid restores to obtain lenalidomide hydrochloride, uses ammonium hydroxide
Handle to obtain lenalidomide (I).With iron powder reducing, there is security risk, generates a large amount of iron mud, post-processing trouble.
3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidine-2,6-diones (VII) have different preparation sides
Method and route.Bioorg.Med.Chem.Lett., 3,1019 (2001), Bioorg.Med.Chem.Lett., 9,1625
(1999), WO2010/100476A2, WO2011/27826A1, WO2011/111053A1, US2012/71509A1 report are intermediate
Body (VII) is carried out made from cyclization reaction as 2- bromomethyl -3- nitrobenzene methyl and 3- amino -2,6- piperidine dione.
WO2011/27326A1 is reported using glutamine or glutamate derivatives and 2- bromomethyl -3- nitrobenzoic acid
Another route of methyl esters synthetic intermediate (VII).This is to come that by raw material preparation of 2- bromomethyl -3- nitrobenzene methyl
The minimal path of amine is spent, totally 4 steps are reacted.
WO2010/139255A1 reports another synthetic route, and step is longer, is unfavorable for applying.The route includes 2-
The cyclization of bromomethyl -3- nitrobenzene methyl, nitro reduction, obtains 4- amino iso-indoles -1- ketone.2- bromine is used after protecting amino
Glutaric acid derivatives carry out hydrocarbylation to amide nitrogen atom, obtain compound (Ⅸ).Object is obtained through cyclization, Deprotection again
Lenalidomide (I).In document description reaction in most suitable protecting group first is that benzyloxycarbonyl group (Cbz), can use catalytic hydrogenolysis
Removing.
It is the weight for preparing lenalidomide (I) by 2- bromomethyl -3- nitrobenzene methyl known to the description of each route
Want intermediate.The intermediate occurs from the preliminary stage of synthetic route, and the amount needed is very big, synthesizes the compound and needs largely
Solvent containing halogen, makes that the production cost increases.It is low that therefore, it is necessary to research costs, environmental-friendly synthetic method, is suffered from meeting
The demand of person.
If using the method for catalytic hydrogenation, by 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2,
6- diketone (VII) is prepared lenalidomide (I), and a large amount of nitro moiety hydrogenated products and nitroso discrimination are usually had in final product
Change reaction product generation and remaining transition metal.The other product of pharmaceutical grade in order to obtain is needed using repeated recrystallize,
Or be transformed into salt, purifying, free method are refined.Most difficult task is removal metal impurities, since they are at end
Residual quantity in product is measured by ppm (hundred a ten thousandths).
If restoring 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2,6- two using iron powder-hydrochloric acid
Ketone (VII) prepares lenalidomide (I), and what is obtained is lenalidomide hydrochloride, is dissolved in aqueous solution, needs to solve to separate with molysite
The problem of.The free alkali of lenalidomide in order to obtain, is neutralized with highly basic, can generate a large amount of iron oxide, gives separating-purifying band
It bothers, causes yield to reduce, increased costs.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of lenalidomide, the present invention be it is a kind of simple,
Efficiently, in high yield, the lenalidomide synthetic method of high quality.
The technical solution used in the present invention is:
It uses acetonitrile to carry out the solvent of free radical bromo-reaction for 2- methyl-3-nitro methyl benzoate (II), can make
Reaction carries out at relatively low temperature (70 DEG C), and yield is up to 90%, and purity is higher, not purified up to 98%.Due to
2- bromomethyl -3- nitrobenzene methyl (III) is the important intermediate for synthesizing lenalidomide (I), and demand is larger, new method
It can be to avoid the use of the heavier solvent of the environmental pollution containing halogen, so as to reduce cost.
Use stannous chloride for reducing agent, by 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2,6-
Diketone (VII) prepares lenalidomide (I), and impurity content is low, and yield is up to 85%, and crude product purity is up to 98%.
The present invention is the synthetic method of a kind of easy, efficient environment and good type lenalidomide.
The present invention with 2- methyl-3-nitro methyl benzoate (II) be starting material, through bromination, with 3- amino -2,6- piperazine
Pyridine diketone carries out cyclization reaction, and key intermediate 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2 is made,
6- diketone (VII), then lenalidomide (I) is made through restoring.Raw material is easy to get, mild condition, easy to operate, and synthetic route is as follows:
Specific embodiment
Embodiment
The synthesis of 2- bromomethyl -3- nitrobenzene methyl (III)
It is added in 500ml reaction flask 2- methyl-3-nitro methyl benzoate 200g (1.02mol) and a certain amount of
NBS181.5g (1.02mol), AIBN24g, 200ml acetonitrile are uniformly mixed, and are warming up to 70 DEG C, keep the temperature 6h, and standing is cooled to
Room temperature is filtered to remove insoluble matter, and filtrate decompression boils off solvent, 200ml ethyl acetate is added in residue, successively with saturation sulfurous
Acid sodium aqueous solution 100ml washing, water (100ml × 2) washing, 2.5% sodium hydroxide solution 100ml washing, water 100ml washing.
It is filtered after being dried over anhydrous sodium sulfate, filtrate decompression boils off ethyl acetate, is recrystallized with ethyl acetate/ethyl alcohol (volume ratio 1: 1)
Obtain faint yellow solid product 253.3g, yield 90.6%, purity 98%.
The synthesis of 3-N- benzyloxycarbonyl amino -2,6- dioxopiperidine (V)
3-N- benzyloxycarbonyl-L-Glutamine 100g (0.357mol) and DMAP 6.5g is added in 2L reaction flask
(0.054mol), a certain amount of CDI 69.5g (0.43mol), Isosorbide-5-Nitrae-dioxane 1000ml are uniformly mixed, are warming up to
100 DEG C, 15h is kept the temperature, is cooled to room temperature, decompression boils off solvent, 200ml ethyl acetate is added in residue, is successively washed with water
(200ml × 3), 0.2mo1/L hydrochloric acid 200ml washing, water washing filter after being dried over anhydrous sodium sulfate, and filtrate decompression boils off second
Acetoacetic ester obtains white solid product.
The synthesis of 3- amino -2,6- piperidine dione hydrochloride (VI a)
3-N- benzyloxycarbonyl amino -2,6- dioxopiperidine 40g (0.153mol), 10% are sequentially added in adding hydrogen kettle
Pd/C 4g, methanol 2L, 2mol/L hydrochloric acid 1.5L, certain H2Pressure, 25 DEG C of holding 5h, is filtered, filtrate concentrated by rotary evaporation after pressure release
To doing, 500ml methanol is added, 0.5h is stirred, filters to obtain white solid 22.79g, yield 90.5%.
The synthesis of 3- amino -2,6- piperidine dione hydrobromate (VI b)
3-N- benzyloxycarbonyl amino -2,6- piperidine dione hydrochloride 40g (0.153mol) is added in 1L reaction flask, 40%
Hydrobromic acid solution 300ml, acetic acid 400ml, is uniformly mixed, and is warming up to 60 DEG C, keeps the temperature 1h, is cooled to room temperature, and decompression boils off molten
Ethyl acetate 1L is added in residue and stirs 0.5h, filters to obtain white solid product 30.4g, yield 95.2% for agent and water.
The synthesis of 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidine-2,6-diones (VII)
3- amino -2,6- piperidine dione hydrobromate 55.0g (0.263mol) is added in 1000ml reaction flask, triethylamine
75ml, 200ml acetonitrile, are stirred at room temperature uniformly mixed, are warming up to 80 DEG C, 2- bromomethyl -3- nitrobenzene methyl 72.1g is added
The mixed liquor of (0.263mol) and acetonitrile 150ml, insulation reaction 10h, are cooled to room temperature, are slowly added to water 200ml, stir 0.5h,
Filter to obtain product as off-white solid 49.6g, yield 65.2%.
The synthesis of lenalidomide (I)
3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidine-2,6-diones are added in 2L there-necked flask
At agitating and heating 15min to 35 DEG C, stannous chloride 532g is added in 197g (0.68mol), 95% alcohol 95 0ml.It is warming up to 55
~60 DEG C, Quan Rong.Continue to be heated to 80 DEG C of reaction 2h.For concentration of reaction solution to dry, addition ethyl acetate 1.5L dissolution, ice bath is cooling
Under be added dropwise to 2N sodium hydrate aqueous solution.Organic layer is separated, aqueous layer with ethyl acetate 900ml is extracted, and merges organic liquor, it washes,
Anhydrous sodium sulfate is dry.Solution is concentrated to dryness, and washs 30min with hot ethyl acetate 5L, and faint yellow solid is dried to obtain in filtering
150.9g, yield 85.6%, purity 99.6% (HPLC).
1H-NMR (500MHz, DMSO-d6), δ=2.01~2.07 (m, 1H), 2.28~2.32 (m, 1H), 2.59~2.63
(m, 1H), 2., 88~2.94 (m, 1H), 4.08~4.12 (dd, 2H, J1=36.9Hz, J2=18.8Hz), 5.09~5.12
(dd, 1H, J1=12.9Hz, J2=4.5Hz), 5.42 (br, s, 2H), 6.80 (d, 1H, J=7.5Hz), 6.91 (d, 1H, J=
8.1Hz), 7.19 (t, 1H), 11.00ppm (s, 1H).
Claims (11)
1. a kind of preparation method of lenalidomide, it is characterised in that following steps:
2- methyl-3-nitro methyl benzoate is put into solvent, at a certain temperature, stirring is reacted with bromide reagent, is completed
It is filtered to remove insoluble matter after reaction, ethyl acetate is added in residue in evaporating solvent under reduced pressure, successively water-soluble with saturated sodium sulfite
Liquid washing, water washing, aqueous slkali washing, water washing through drying, remove ethyl acetate under reduced pressure and obtain brown color crude product, recrystallize
Obtain faint yellow solid 2- bromomethyl -3- nitrobenzene methyl；
3-N-benzyloxycarbonyl-L-Glutamine carries out cyclization reaction under catalytic action, generates 3-N-benzyloxycarbonyl group ammonia
Base -2,6- dioxopiperidine, amino deprotection generate 3- amino -2,6- piperidine dione halogen acid salt；
2- bromomethyl -3- nitrobenzene methyl and 3- amino -2,6- piperidine dione halogen acid salt are acted in basic catalyst
Lower reaction obtains 3- (4- nitro -1- oxo -1,3- xylylenimine -2- base) piperidines -2,6- diketone, is made to come through reduction reaction
That degree amine.
2. a kind of preparation method of lenalidomide according to claim 1,2- bromomethyl -3- nitrobenzoic acid first
In the preparation of ester, which is characterized in that the solvent is one of ethyl acetate, DMF, acetonitrile, preferably acetonitrile.
3. a kind of preparation method of lenalidomide according to claim 1,2- bromomethyl -3- nitrobenzoic acid first
In the preparation of ester, which is characterized in that the reaction temperature is 25 DEG C~85 DEG C, preferably 70 DEG C.
4. a kind of preparation method of lenalidomide according to claim 1,2- bromomethyl -3- nitrobenzoic acid first
In the preparation of ester, which is characterized in that bromide reagent is carbon tetrachloride solution, the N-bromosuccinimide (NBS)/idol of bromine
One of nitrogen bis-isobutyronitrile, N-bromosuccinimide (NBS)/benzoyl peroxide, preferably N-bromosuccinimide
(NBS)/azodiisobutyronitrile.
5. a kind of preparation method of lenalidomide according to claim 1,2- bromomethyl -3- nitrobenzoic acid first
In the preparation of ester, which is characterized in that recrystallization solvent is ethyl acetate/ethyl alcohol (volume ratio 1: 1).
6. a kind of preparation method of lenalidomide according to claim 1,3-N-benzyloxycarbonyl amino -2,6- dioxo
In the preparation of piperidines, which is characterized in that solvent for use is tetrahydrofuran, dioxane, toluene and acetonitrile, preferably dioxane.
7. a kind of preparation method of lenalidomide according to claim 1,3-N-benzyloxycarbonyl amino -2,6- dioxo
In the preparation of piperidines, which is characterized in that with DMAP/CDI be catalyst, the optimum mole ratio with reaction substrate be 0.15: 1 and
1.2∶1。
8. a kind of preparation method of lenalidomide according to claim 1,3- amino -2,6- piperidine dione halogen acid salt
In preparation, which is characterized in that use one of hydrochloric acid, hydrobromic acid.
9. a kind of preparation method of lenalidomide according to claim 1,3- amino -2,6- piperidine dione hydrogen
In the preparation of halate, which is characterized in that the reaction of Deprotection be 5% or 10%Pd-C and hydrogen, then with hydrochloric acid at
Directly at hydrobromate after salt, 40% hydrobromic acid and acetic acid Deprotection.
10. a kind of preparation method of lenalidomide according to claim 1, which is characterized in that basic catalyst used is
Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and triethylamine, preferably triethylamine.
11. a kind of preparation method of lenalidomide according to claim 1, which is characterized in that reducing agent used be iron powder/
Sour (hydrochloric acid or acetic acid), zinc powder/acid (hydrochloric acid or acetic acid), Pd-C/H2、SnCl2。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101959856A (en) * | 2008-03-11 | 2011-01-26 | 雷迪博士实验室有限公司 | Preparation of lenalidomide |
| WO2016024286A2 (en) * | 2014-08-11 | 2016-02-18 | Avra Laboratories Pvt. Ltd. | An improved process for synthesis of lenalidomide |
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2019
- 2019-03-20 CN CN201910212294.7A patent/CN109776493A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101959856A (en) * | 2008-03-11 | 2011-01-26 | 雷迪博士实验室有限公司 | Preparation of lenalidomide |
| WO2016024286A2 (en) * | 2014-08-11 | 2016-02-18 | Avra Laboratories Pvt. Ltd. | An improved process for synthesis of lenalidomide |
Non-Patent Citations (2)
| Title |
|---|
| LIQIANG FU: "Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates", 《BIOORG. MED. CHEM. LETT.》 * |
| 卜龙: "来那度胺及其中间体的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
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