CN108191828A - A kind of synthetic method of lenalidomide metabolin - Google Patents
A kind of synthetic method of lenalidomide metabolin Download PDFInfo
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- CN108191828A CN108191828A CN201810300245.4A CN201810300245A CN108191828A CN 108191828 A CN108191828 A CN 108191828A CN 201810300245 A CN201810300245 A CN 201810300245A CN 108191828 A CN108191828 A CN 108191828A
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- lenalidomide
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a kind of synthetic methods of lenalidomide metabolin, belong to pharmaceutical synthesis field, and technological design is reasonable, and cost of material is cheap, and products therefrom purity is high.The present invention is using 4 hydroxyl, 2 methyl toluate as raw material; first protect phenolic hydroxyl group; nitrify hydroxyl again faces position; purification ＆ isolation product; then substitution reaction and ammonolysis cyclization occur with 3 amino, 2,6 piperidine dione, restores nitro to amino under palladium chtalyst for benzyl bromide; protecting group is finally taken off, obtains target molecule.Entire highway route design of the invention is reasonable, and the target product being prepared provides test sample for the metabolic mechanism research of lenalidomide, has important application value.
Description
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of synthetic methods of lenalidomide metabolin.
Background technology
Entitled 3- (4- amino -1,3- dihydro -1- oxo -2H- iso-indoles-the 2- of lenalidomide (Lenalidomide) chemistry
Base) -2,6- piperidine diones, No. CAS:191732-72-6, trade name: Revlimid.By the research and development of Celgene companies of the U.S.
A kind of new immunomodulator with antiangiogenic and antitumor property.Ratified to list in the U.S. for the first time in 2006, it is main
It is used to treat the myelodysplastic syndrome hypotype and Huppert's disease of No. 5 chromosome long arm missings, which is to be used for
The derivative of the Thalidomide for ten hundreds of baby due defect of vomiting during pregnancy, cause is treated, chemical property is more stable, has stronger
Agiogenesis inhibition, immunological regulation and direct the effects that killing tumor promotion, clinical practice is safer, and drug effect compares Sha Lidu
Amine is about 100 times strong, and currently without discovery aberration inducing effect.
With the progress in epoch, the raising of scientific and technological level, people to drug before marketing drugs to that must carry out quality, safety
Property and the importance of efficiency scientific evaluation etc., which have, more fully to be recognized, wherein with drug quality it is closely related be drug institute
Impure control.Impurity is often related with drug safety, and also related with efficiency in a few cases.Therefore, it controls miscellaneous
Matter level is increasingly paid attention to during drug development by medical personal.The synthesis side of lenalidomide metabolin
Method, there is not been reported, in order to which to lenalidomide clinic, pharmacology, pharmacokinetics, toxicity is comprehensively analyzed and researched, had very much
For necessity in prior art basis, the preparation method of lenalidomide metabolin is developed in design, for analysis lenalidomide comprehensively
Clinic, pharmacology, pharmacokinetics, toxicity provide the primary standard substance of analysis and research.
Invention content
The present invention provides a kind of synthetic method of lenalidomide metabolin, and this method reasonable design, raw material are cheap and easy to get, real
Test process control.
In order to achieve the above object, the present invention uses following technical scheme：
A kind of synthetic method of lenalidomide metabolin, includes the following steps：
(1) by raw material 1 at ambient temperature, with No. 3 positions of nitrating agent nitrification phenyl ring, mole of the raw material 1 and nitrating agent
Than being 1:0.5-1:2, separation isomers, purification obtain compound 2；
(2) compound 2 is taken to be dissolved in organic solvent, adds in alkali and phenolic hydroxyl protecting group, the molar ratio of compound 2 and alkali is 1:
1-1:7, the molar ratio of compound 2 and phenolic hydroxyl protecting group is 1:1-1:5, processing purification obtains compound 3；
(3) compound 3 is taken to be dissolved in organic solvent, with bromide reagent benzyl bromide, compound (3) and mole of bromide reagent
Than being 1:1-1:5, obtain compound 4；
(4) compound 4 is taken to be dissolved in organic solvent with compound 5, the molar ratio of compound 4 and compound 5 is 1:1-1:1.5
Organic base, the tracking of thin-layer chromatography contact plate are added in, processing purification obtains compound 6；
(5) compound 6 is taken to be dissolved in organic solvent, room temperature reduction nitro, the molar ratio of catalyst and compound 6 is 1:0.01-1:
0.5, processing is evaporated to obtain compound 7；
(6) compound 7 is taken to be dissolved in organic solvent, adds in desiliconization etherifying reagent in acid condition, processed pillar purifies to obtain
Target compound 8.
In step described above, step (1) described nitrating agent is concentrated nitric acid, and compound 1 is rubbed with the nitrating agent
You are than being 1:1, the reaction time is 2 hours, and reaction dissolvent is the concentrated sulfuric acid or acetic acid, the preferably concentrated sulfuric acid；Phenol hydroxyl described in step 2
Base protecting group is silicon ether protecting group（TBS/TMS）Or methoxy（MOM）, preferred methoxy protecting group, compound 2
Molar ratio with the phenolic hydroxyl protecting group is 1:3 reaction dissolvents be dimethylformamide or dimethyl sulfoxide (DMSO), preferably two
Methylformamide, reaction temperature are 65 DEG C, and the reaction time is 2 hours；Step (3) described organic solvent is carbon tetrachloride or dichloro
Ethane, the bromide reagent are cuprous bromide, triphenyl phosphorus/carbon tetrabromide or NBS/BPO（N- bromo-succinimides/peroxide
Change dibenzoyl）, NBS/AIBN (N- bromo-succinimides/azodiisobutyronitrile), preferably NBS/AIBN, compound 3 and bromine
The molar ratio for changing reagent is 1:1-1:3, reaction temperature is 77 DEG C, and the reaction time is 10 hours；Organic base is described in step (4)
The molar ratio of triethylamine, compound 4 and compound 5 is 1:1, reaction temperature is 80 DEG C, and the reaction time is 5 hours；Step (5)
The solvent be dimethylformamide or methanol, the reducing agent be zinc powder/ammonium chloride or palladium catalyst hydro-reduction, it is excellent
Select palladium catalyst hydro-reduction, the molar ratio of palladium catalyst and compound 6 is 1:0.1；Desiliconization etherifying reagent described in step (6)
For potassium fluoride or tetrabutyl ammonium fluoride, preferably tetrabutyl ammonium fluoride, reaction temperature is 65 DEG C, and the reaction time is 2 hours.
Beneficial effects of the present invention：The present invention provides a kind of synthetic method of lenalidomide metabolin, this method passes through
Six-step process obtains target product, and technological design is reasonable, and principle is cheap, cost-effective, and experimentation is controllable, operating method
Simply, the target product purity being prepared is high, and research of the lenalidomide metabolin of the invention prepared for lenalidomide
Test sample is provided, there is important value in CLINICAL PHARMACOKINETIS STUDY ON.
Description of the drawings
Fig. 1 is the synthetic route chart of lenalidomide metabolin preparation method of the present invention.
Specific embodiment
Embodiment 1
As shown in Figure 1, the preparation method of lenalidomide metabolin, includes the following steps：
The preparation of compound 2：
26 g4- hydroxy-2-methylbenzoic acid methyl esters are dissolved in the 80 mL concentrated sulfuric acids, and 65% that 15 mL are slowly added under ice bath is dense
Nitric acid, after being stirred at room temperature 2 hours, the reaction was complete, and a large amount of solids are precipitated, and suction filtration, solid are washed with water, and after drier drying, uses
Chromatographic column purifies to obtain 15.2 g compounds 2, yield 46%.
MS: 210[M-H-]；1H NMR: (400 MHz, DMSO-d6): δ 2.38 (s, 3 H), 3.81 (s, 3
H), 6.9 (dd, 1 H), 7.9 (dd, 1 H), 11.8 (brs, 1 H)).
The preparation of compound 3
10 g compounds 2 is taken to be dissolved in 120 mL dimethylformamides, add in 26 g potassium carbonate and 8 g chloromethyl methyl ethers, 65 DEG C anti-
It answers 2 hours, thin-layer chromatography shows that the reaction was complete, and reaction solution topples over water in ice, is extracted with ethyl acetate, sodium-chloride water solution washing
Afterwards, anhydrous sodium sulfate is dried, and is concentrated to give 11 g compounds 3, yield 88%.MS: 278 [M+Na+].
The preparation of compound 4
4.5 g compounds 3 is taken to be dissolved in 136 mL carbon tetrachloride, the AIBN of 6.3 grams of NBS and 1.7 g are added portionwise under ice bath, are reacted
Liquid is stirred overnight in 77 DEG C, and the reaction was complete for contact plate, and water quenching is added to go out reaction, and water phase continues to be extracted twice with dichloromethane, sodium sulphate
It is concentrated after drying, crude product is purified to obtain 5 g compounds 4, yield 85% with chromatographic column.
1H NMR: (400 MHz, DMSO-d6): δ 3.38 (s, 3 H), 3.89 (s, 3 H), 4.83 (s,
2 H), 5.44 (s, 2 H),7.51 (d, 1 H), 8.51 (d, 1 H)).
The preparation of compound 6
5 g compounds 4 is taken to be dissolved in 120 mL acetonitriles, add in 3.5 g potassium carbonate and 2.9 g 3- amino -2,6- piperidine diones, institute
Reaction solution stirs 5 hours in 80 DEG C, 100 mL water quenchings are gone out reaction, ethyl acetate extraction, organic phase with sodium sulphate it is dry, concentrate
Yellow oil is obtained, continues to be purified to obtain 3.5 g compounds 6, yield 67% with chromatographic column.MS: 372[M+Na+]。
The preparation of compound 7
3 g compounds 6 are dissolved in 30 mL dimethylformamides, then the lower palladium carbon for adding in 600 mg of nitrogen protection, in 25 DEG C/mono-
It is stirred 10 hours under a atmospheric pressure, thin-layer chromatography shows that the reaction was complete, and suction filtration removes catalyst, obtains 2.7 solvent concentration is dry
G compounds 7, yield 98%.
The preparation of compound 8
1.6 g compounds 7 is taken to be dissolved in 68 mL methanol, add in the dilute hydrochloric acid of 4 M of 6 mL, 65 DEG C is heated to and reacts 2 hours, it is thin
Layer chromatography shows that the reaction was complete, and 20 mL water are added in after reaction solution cooling, and after adding alkali neutralization, revolving removes methanol, water phase dichloro
Methane extracts, and crude product is purified to obtain 0.8 g compounds 8, yield 57% with chromatographic column.
MS: 274 [M-H-]；1H NMR: (400 MHz, DMSO-d6): δ1.99 (m, 1 H), 2.27 (m, 1
H), 2.61 (m, 1 H), 2.91 (m, 1 H),4.1-4.2 (dd, 2 H), 4.7-4.9 (brs, 2 H), 5.09
(m, 1 H), 6.2-6.5 (m, 2 H), 6.79-6.86 (Ar-H, 2 H), 9.76 (brs, 1 H), 10.96 (s,
1 H).
Embodiment 2
As shown in Figure 1, the preparation method of lenalidomide metabolin, includes the following steps：
The preparation of compound 2：
2.6 g4- hydroxy-2-methylbenzoic acid methyl esters are dissolved in the 8.0 mL concentrated sulfuric acids, and the 95% of 1.5mL is slowly added under ice bath
Concentrated nitric acid, after being stirred at room temperature 1 hour, the reaction was complete, and solid is precipitated, and suction filtration, solid are washed with water, after drier drying, solid
It is purified to obtain 1.3 g compounds 2, yield 43% with chromatographic column.
The preparation of compound 3
1 g compounds 2 is taken to be dissolved in 12 mL dimethylformamides, add in 2.5 g potassium carbonate and 0.78 g chloromethyl methyl ethers, 65 DEG C
Reaction 2 hours, thin-layer chromatography shows that the reaction was complete, and reaction solution topples over water in ice, is extracted with ethyl acetate, and sodium-chloride water solution is washed
After washing, anhydrous sodium sulfate drying is concentrated to give 1 g compounds 3, yield 87%.MS: 278 [M+Na+].
The preparation of compound 4
500 mg compounds 3 is taken to be dissolved in 1.4 mL carbon tetrachloride, be added portionwise under ice bath 0.6 g N- bromo-succinimides and
The azodiisobutyronitrile of 0.2 g, reaction solution are stirred overnight in 77 DEG C, and the reaction was complete for contact plate, and water quenching is added to go out reaction, continues to use dichloro
Methane is extracted twice, and is concentrated after sodium sulphate drying, crude product is purified to obtain 0.5 g compounds 4, yield 85% with chromatographic column.
The preparation of compound 6
0.5 g compounds 4 is taken to be dissolved in 2 mL acetonitriles, add in 0.3 g potassium carbonate and 0.3 g 3- amino -2,6- piperidine diones, institute
Reaction solution stirs 5 hours in 80 DEG C, 5 mL water quenchings are gone out reaction, ethyl acetate extraction, and the drying of organic phase sodium sulphate is concentrated to give
To yellow oil, purified to obtain 0.4 g compounds 6, yield 68% with chromatographic column.MS: 372[M+Na+]。
The preparation of compound 7
0.3 g compounds 6 are dissolved in 3 mL dimethylformamides, then the lower palladium carbon for adding in 60 mg of nitrogen protection, in 25 DEG C/mono-
It is stirred 10 hours under a atmospheric pressure, thin-layer chromatography shows that the reaction was complete, removes catalyst, obtains 0.3 gization solvent concentration is dry
Close object 7, yield 97%.
The preparation of compound 8
0.2 g compounds 7 is taken to be dissolved in 6.8 mL methanol, add in the dilute hydrochloric acid of 4 M of 1 mL, 65 DEG C is heated to and reacts 2 hours, it is thin
Layer chromatography shows that the reaction was complete, and 10 mL water are added in after reaction solution cooling, and after adding alkali neutralization, revolving removes methanol, and water phase continues to use
Dichloromethane extracts, and crude product is purified to obtain 0.1 g compounds 8, yield 55% with chromatographic column.
Embodiment 3
As shown in Figure 1, the preparation method of lenalidomide metabolin, includes the following steps：
The preparation of compound 2：
13 g 4- hydroxy-2-methylbenzoic acid methyl esters are dissolved in the 50 mL concentrated sulfuric acids, and 95% that 7 mL are slowly added under ice bath is dense
Nitric acid, after being stirred at room temperature 2 hours, the reaction was complete, there is solid precipitation, and suction filtration, solid are washed with water, and after drier drying, uses color
Spectrum column purifies to obtain 8 g compounds 2, yield 47%.MS: 210[M-H-]
The preparation of compound 3
5 g compounds 2 is taken to be dissolved in 60 mL dimethylformamides, add in 13 g potassium carbonate and 4 g chloromethyl methyl ethers, 65 DEG C of reactions 2
Hour, thin-layer chromatography shows that the reaction was complete, and reaction solution topples over water in ice, is extracted with ethyl acetate, after sodium-chloride water solution washing,
Anhydrous sodium sulfate is dried, and is concentrated to give 6 g compounds 3, yield 89%.MS: 278 [M+Na+].
The preparation of compound 4
2.2 g compounds 3 is taken to be dissolved in 65 mL carbon tetrachloride, are added portionwise the AIBN of 3 grams of NBS and 1 g under ice bath, reaction solution in
77 DEG C are stirred overnight, and the reaction was complete for contact plate, and under ice bath plus water quenching is gone out reaction, and water phase continues to be extracted twice with dichloromethane, merging
It is concentrated after organic phase, sodium sulphate drying, is purified to obtain 2.3 g compounds 4, yield 84% with chromatographic column.
The preparation of compound 6
2.3 g compounds 4 is taken to be dissolved in 55 mL acetonitriles, add in 1.7 g potassium carbonate and 1.5 g 3- amino -2,6- piperidine diones, instead
Liquid is answered to be stirred 5 hours in 80 DEG C, 40 mL water quenchings are gone out reaction, ethyl acetate extraction, and the drying of organic phase sodium sulphate is concentrated to give
Grease is purified to obtain 2 g compounds 6, yield 70% with chromatographic column.MS: 372[M+Na+]。
The preparation of compound 7
1.5 g compounds 6 are dissolved in 15 mL dimethylformamides, then add in the palladium carbon of 300 mg, in 25 DEG C/mono- atmospheric pressure
Lower stirring 10 hours, thin-layer chromatography shows that the reaction was complete, removes catalyst, and solvent concentration is dry to obtain 1.4 g compounds 7, yield
98%。
The preparation of compound 8
1.4 g compounds 7 is taken to be dissolved in 35 mL dimethyl sulfoxide (DMSO)s, add in the dilute hydrochloric acid of 4 M of 4 mL, 65 DEG C are reacted 2 hours, thin
Layer chromatography shows that the reaction was complete, and 10 mL water are added in after cooling, and revolving removes solvent after neutralization, is extracted with dichloromethane, crude product
It is purified to obtain 0.5 g compounds 8, yield 59% with chromatographic column.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (12)
1. a kind of synthetic method of lenalidomide metabolin, which is characterized in that include the following steps：
(1) by raw material (1) at room temperature, with No. 3 positions of nitrating agent nitrification phenyl ring, the raw material (1) and mole of nitrating agent
Than being 1:0.5-1:2, separation isomers, purification obtain compound (2)；
(2) compound is taken（2）It is dissolved in organic solvent, adds in alkali and phenolic hydroxyl protecting group, compound（2）With the molar ratio of alkali
It is 1:1-1:7, the molar ratio of compound (2) and phenolic hydroxyl protecting group is 1:1-1:5, processing purification obtains compound（3）；
(3) compound is taken（3）Organic solvent is dissolved in, with bromide reagent benzyl bromide, compound (3) is rubbed with bromide reagent
You are than being 1:1-1:5, obtain compound（4）；
(4) compound is taken（4）With compound（5）It is dissolved in organic solvent, the molar ratio of compound (4) and compound (5) is 1:
1-1:1.5, organic base, the tracking of thin-layer chromatography contact plate are added in, processing purification obtains compound（6）；
(5) compound is taken（6）Organic solvent is dissolved in, restores nitro at room temperature, the molar ratio of catalyst and compound (6) is 1:
0.01-1:0.5, processing is evaporated to obtain compound（7）；
(6) compound is taken（7）It is dissolved in organic solvent, adds in desiliconization etherifying reagent in acid condition, processed pillar purifies
To target compound（8）.
2. the synthetic method of lenalidomide metabolin according to claim 1, which is characterized in that step (1) described nitrification
Reagent is concentrated nitric acid, compound（1）Molar ratio with the nitrating agent is 1:1, reaction dissolvent is the concentrated sulfuric acid or acetic acid, is reacted
Time is 2 hours.
3. the synthetic method of lenalidomide metabolin according to claim 1 or 2, which is characterized in that step (1) is described anti-
It is the concentrated sulfuric acid to answer solvent.
4. the synthetic method of lenalidomide metabolin according to claim 1, which is characterized in that the phenol described in step (2)
Hydroxyl protection base be silicon ether protecting group or methoxy, compound（2）Molar ratio with the phenolic hydroxyl protecting group is 1:
3, the reaction dissolvent is dimethylformamide or dimethyl sulfoxide (DMSO), and reaction temperature is 65 DEG C, and the reaction time is 2 hours.
5. the synthetic method of the lenalidomide metabolin according to claim 1 or 4, which is characterized in that step (2) is described
Phenolic hydroxyl protecting group for methoxy protecting group, the reaction dissolvent is dimethylformamide.
6. the synthetic method of lenalidomide metabolin according to claim 1, which is characterized in that step (3) is described organic
Solvent is carbon tetrachloride or dichloroethanes, and the bromide reagent is cuprous bromide, triphenyl phosphorus/carbon tetrabromide or NBS/BPO（N-
Bromo-succinimide/dibenzoyl peroxide）, NBS/AIBN (N- bromo-succinimides/azodiisobutyronitrile), compound
(3) it is 1 with the molar ratio of bromide reagent:1-1:3, reaction temperature is 77 DEG C, and the reaction time is 10 hours.
7. the synthetic method of the lenalidomide metabolin according to claim 1 or 6, which is characterized in that step (3) is described to be had
Solvent is carbon tetrachloride, and the bromide reagent is NBS/AIBN (N- bromo-succinimides/azodiisobutyronitrile).
8. the synthetic method of lenalidomide metabolin according to claim 1, which is characterized in that step has described in (4)
Machine alkali be triethylamine, compound（4）And compound（5）Molar ratio be 1:1, reaction temperature is 80 DEG C, and the reaction time is small for 5
When.
9. the synthetic method of lenalidomide metabolin according to claim 1, which is characterized in that step (5) described solvent
For dimethylformamide or methanol, the reducing agent is zinc powder/ammonium chloride or palladium catalyst hydro-reduction, the reduction
Agent and compound（6）Molar ratio be 1:0.1.
10. the synthetic method of the lenalidomide metabolin according to claim 1 or 9, which is characterized in that step (5) is described
Reducing agent be palladium catalyst hydro-reduction.
11. the synthetic method of lenalidomide metabolin according to claim 1, which is characterized in that de- described in step (6)
Silicon etherifying reagent is potassium fluoride or tetrabutyl ammonium fluoride, and reaction temperature is 65 DEG C, and the reaction time is 2 hours.
12. the synthetic method of the lenalidomide metabolin according to claim 1 or 11, which is characterized in that step (6) is described
Desiliconization etherifying reagent be tetrabutyl ammonium fluoride.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
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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 |
| WO2016024286A2 (en) * | 2014-08-11 | 2016-02-18 | Avra Laboratories Pvt. Ltd. | An improved process for synthesis of lenalidomide |
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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 |
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| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
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