CN103588767B - The preparation method of Da Lafeini - Google Patents

The preparation method of Da Lafeini Download PDF

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CN103588767B
CN103588767B CN201310586872.6A CN201310586872A CN103588767B CN 103588767 B CN103588767 B CN 103588767B CN 201310586872 A CN201310586872 A CN 201310586872A CN 103588767 B CN103588767 B CN 103588767B
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fluorophenyl
difluorobenzenesulfonamide
lafeini
preparation
oxa
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CN103588767A (en
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许学农
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Beijing Hengtong innovation integrated housing assembly Co., Ltd
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Suzhou Miracpharma Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Present invention is disclosed the preparation method of a kind of Da Lafeini (Dabrafenib); it comprises the steps: for raw material, to obtain Da Lafeini (I) through steps such as sulfuryl amine, halo, thiazole cyclization, acidylate and pyrimidine cyclizations with 3-(3-amino-2-fluorophenyl)-3-oxa--propionic ester (II).This preparation method's raw material is easy to get, concise in technology, mild condition, adapts to suitability for industrialized production, promotes that the economic technology of this bulk drug develops.

Description

The preparation method of Da Lafeini
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of Da Lafeini preparation method.
Background technology
Da Lafeini (Dabrafenib) is silk Serineprotein kinase (BRAF) inhibitor developed by Britain's GlaxoSmithKline PLC (GSK) company, as one list medicine oral capsule, be applicable to carry the operation irresectability melanoma of BRAFV600E sudden change or the treatment of metastasis melanin tumor adult patient, Da Lafeini mesylate obtains the approval of FDA (Food and Drug Adminstration) (FDA) in May, 2013, in U.S.'s listing, commodity are called Tafinlar (Tamiflu is received).Due to European drug administration (EMA) people with the pharmaceutical prod council (CHMP) to the Positive evaluation of Tafinlar, make this medicine be expected to become second the BRAF inhibitor entering European market after the Wei Luofeini (Vemurafinib) under Roche.
The chemistry of Da Lafeini is called: N-[3-[5-(2-amino-4-pyrimidyl)-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide.
No. WO2009137391st, world patent, No. WO2011047238 and No. WO2012148588 pharmaceutical use and the synthetic method reporting Da Lafeini and composition thereof.According to the constructional feature of Da Lafeini and analogue thereof, the synthesis of such material at present has A, B and C tri-routes.
A route is synthetic route commonplace at present, first with 2,6-difluoro chloride (III), sulfonamide reaction occurs obtain intermediate (X) by 3-amino-2-fluorophenyl carbamate (IX); Condensation reaction is there is and obtains intermediate (XII) in intermediate (X) and the chloro-4-methylpyrimidine (XI) of 2-under highly basic effect; Intermediate (XII) bromo obtains intermediate (XIII); Intermediate (XIII) and 2,2-dimethyl thiopropionamide (VI) cyclisation obtain intermediate (XIV); Finally, intermediate (XIV) obtains target compound Da Lafeini (I) through ammonolysis reaction.
The difference of B route is first by the amido protecting of 3-amino-2-fluorophenyl carbamate (IX), and then carries out condensation, bromo and ring-closure reaction; Intermediate (XIV) is obtained again by amino deprotection and sulfuryl amine; Equally, intermediate (XIV) obtains target compound Da Lafeini (I) through ammonolysis reaction.
The design feature of C route is first to carry out ammonolysis reaction, then obtains target product by amino deprotection and sulfonamide reaction.Obviously, this design route is applicable to the ammonolysis reaction of some substituted-aminos, and is inapplicable for the compound that such as Da Lafeini etc. has a pyrimdinyl-amino structure.Reason is if the existence of two fragrant amidos can make the sulfonamide reaction of final step lose selectivity.
Investigate above-mentioned A and B two synthetic routes, although can target product be prepared, but still have that reactions steps is many, aftertreatment is difficult and the defect such as severe reaction conditions.So, seek Simplified flowsheet step, the preparation method that reduces environmental pollution and the new Da Lafeini (I) that reduces production cost can have very important realistic meaning.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Da Lafeini (I) of improvement, this preparation method's concise in technology, raw material is easy to get, quality controllable, is applicable to suitability for industrialized production.
For achieving the above object, present invention employs following main technical schemes: the preparation method of a kind of Da Lafeini (I),
It is characterized in that described preparation method comprises the steps: raw material 3-(3-amino-2-fluorophenyl)-3-oxa--propionic acid alkyl (R 1) ester (II) and 2,6-difluoro chlorides (III) sulfonamide reaction occur and obtains intermediate 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-3-oxa--propionic acid alkyl (R 1) ester (IV); Intermediate (IV) obtains intermediate 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-2-halogen (X)-3-oxa--propionic acid alkyl (R through halogen (X) replacement 1) ester (V); There is thiazole cyclization and be obtained by reacting intermediate N [3-[5-formic acid alkyl (R in intermediate (V) and 2,2-dimethyl thiopropionamide (VI) 1) ester-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide (VII); Intermediate (VII) obtains intermediate N [3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 through acetylization reaction; 6-difluorobenzenesulfonamide (VIII); intermediate (VIII) is obtained by reacting Da Lafeini (I) with DMF dimethylacetal (DMF-DMA) and the cyclization of Guanidinium nitrate generation pyrimidine.
In addition, the present invention also comprises following attached technical scheme:
Described raw material 3-(3-amino-2-fluorophenyl)-3-oxa--propionic acid alkyl (R 1) alkyl R in ester (II) 1for phenyl, preferable methyl or the ethyl of methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, the tertiary butyl, benzyl, phenyl or replacement.
Described halogen (X) is fluorine, chlorine, bromine or iodine, preferred chlorine or bromine.
Described 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-2-halogen (X)-3-oxa--propionic acid alkyl (R 1) ester (V) without the need to be separated directly can carry out thiazole ring-closure reaction, its reactant 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-3-oxa--propionic acid alkyl (R 1) molar ratio of ester (IV), halogenating agent and 2,2-dimethyl thiopropionamide (VI) is 1:1-3:1-2, preferred 1:2:1.2.
Described acetylization reaction is N-[3-[5-formic acid alkyl (R 1) ester-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2; 6-difluorobenzenesulfonamide (VII) first adds alkali backflow in ethyl acetate solution; add concentrated hydrochloric acid backflow again; obtained N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide (VIII).
The alkali of described acetylization reaction is sodium hydroxide, potassium hydroxide, sodium methylate, lithium methoxide, potassium tert.-butoxide, tert-butyl alcohol magnesium, sodium tert-butoxide, salt of wormwood or sodium carbonate, particular methanol sodium or potassium hydroxide.
N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 in described pyrimidine ring-closure reaction; 6-difluorobenzenesulfonamide (VIII), N; the molar ratio of dinethylformamide dimethylacetal (DMF-DMA) and Guanidinium nitrate is 1:1-3:1-5, preferred 1:2:1.
The solvent of described pyrimidine ring-closure reaction is methyl alcohol, ethanol, Virahol, propyl carbinol, toluene, chloroform, methyl-sulphoxide, DMF or acetonitrile, preferred propyl carbinol or toluene.
The temperature of described pyrimidine ring-closure reaction is 90-150 DEG C, preferably 120 DEG C.
Compared to prior art; the invention has the advantages that: the preparation method of Da Lafeini provided by the present invention; target compound can be obtained by steps such as sulfuryl amine, halo, thiazole cyclization, acidylate and pyrimidine cyclizations; improve Atom economy, the selectivity of reaction and the controllability of operation; make the production of Da Lafeini more controlled; quality product increases, and promotes the development of the economic technology of this bulk drug.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
3-(3-amino-2-fluorophenyl)-3-oxa--ethyl propionate (II) (11.3g is added in there-necked flask, 50mmol), the DMAP (DMAP) of pyridine 10mL, catalytic amount and methylene dichloride 200mL, after stirring and dissolving, 2 are dripped at 0 DEG C, the methylene dichloride 50mL solution of 6-difluoro chloride (III) (11.7g, 55mmol), drips and finishes, room temperature reaction 16 hours, TLC detection reaction terminates.Add water washing, gained organic phase uses salt water washing again, anhydrous sodium sulfate drying, vacuum distillation recovered solvent, gained crude product petroleum ether, obtain off-white color solid 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-3-oxa--ethyl propionate (IV) 12.4g, yield is 60.5%.
Embodiment two:
To 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-3-oxa--ethyl propionate (IV) (10g, 25mmol) He in methylene dichloride 150mL add N-bromosuccinimide (NBS) (8.9g, 50mmol), the red solution stirring at room temperature formed is after 30 minutes, concentrating under reduced pressure, gained resistates dioxane 100mL dissolves.Magnesiumcarbonate (2.1,25mmol) and 2,2-dimethyl thiopropionamide (VI) (3.5g, 30mmol) is added in this solution, after stirring at room temperature reacts 4 hours, with water and the reaction of 1N hydrochloric acid, and stirring reaction 0.5 hour.Filter, gained solid with ethyl acetate and normal hexane (1:1) recrystallization obtain white solid N-[3-[5-ethyl formate-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide (VII) 7.25g, yield is 58.2%.
Embodiment three:
N-[3-[5-ethyl formate-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2 is added in reaction flask, 6-difluorobenzenesulfonamide (VII) (6.0g, 12mmol), sodium methylate (0.81g, 15mmol) and anhydrous ethyl acetate 50mL.Stirring at room temperature 1 hour, is warming up to 80 DEG C, back flow reaction 5 hours, cooling, and room temperature leaves standstill 12 hours.Add water 100mL, add concentrated hydrochloric acid 50mL under stirring, be warming up to backflow, react 4 hours.TLC detection reaction completes.PH to 9-10 is regulated with 2M sodium hydroxide.With chloroform extraction 3 times, merge organic phase, anhydrous sodium sulfate drying, vacuum distillation recovered solvent, obtains product N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide (VIII) 5.4g.Do not need purifying can be directly used in reaction below.
Embodiment four:
N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 is added in reaction flask; 6-difluorobenzenesulfonamide (VIII) (5.4g; 11.5mmol), N; dinethylformamide dimethylacetal (DMF-DMA) (2.74g; 23mmol) with dimethylbenzene 50mL, be warming up to 140 DEG C.Every about 4 hours, the methyl alcohol of generation is distilled out reaction system, altogether about need reaction 24 hours, TLC detection reaction terminates.Cooling, adds normal hexane 40mL, has yellow solid to produce, and filters, Guanidinium nitrate (1.36,11.5mmol), sodium hydroxide (0.46g, 11.5mmol) and propyl carbinol 50mL is added after gained solid drying, be warming up to 120 DEG C, react 12 hours, TLC detection reaction completes.Cooling, has crystal to separate out, slow crystallization 3 hours, filters.Filter cake water slurry is washed, and filtration, drying, obtain off-white color solid Da Lafeini (I) 3.58g, yield 60%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (7)

1. the preparation method of Yi Zhong Da Lafeini (I),
It is characterized in that described preparation method comprises the steps: raw material 3-(3-amino-2-fluorophenyl)-3-oxa--alkyl propionates and 2,6-difluoro chloride carries out sulfonamide reaction and obtains 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-3-oxa--alkyl propionates; Described 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-3-oxa--alkyl propionates obtains 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-2-halogen-3-oxa--alkyl propionates through halogen substiuted; Described 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-2-halogen-3-oxa--alkyl propionates and 2, the cyclization of 2-dimethyl thiopropionamide generation thiazole is obtained by reacting N-[3-[5-alkyl formate-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide; Described N-[3-[5-alkyl formate-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide obtains N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 through acetylization reaction, 6-difluorobenzenesulfonamide, described N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide and DMF dimethylacetal and the cyclization of Guanidinium nitrate generation pyrimidine are obtained by reacting Da Lafeini (I);
Alkyl in its Raw 3-(3-amino-2-fluorophenyl)-3-oxa--alkyl propionates is methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, the tertiary butyl, benzyl or phenyl; Described halogen is fluorine, chlorine, bromine or iodine.
2. the preparation method of Da Lafeini according to claim 1, it is characterized in that: described 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl]-2-halogen-3-oxa--alkyl propionates without the need to be separated directly can carry out thiazole ring-closure reaction, its reactant 3-[3-(2,6-difluorobenzenesulfonamide base)-2-fluorophenyl] molar ratio of-3-oxa--alkyl propionates, halogenating agent and 2,2-dimethyl thiopropionamide is 1:1-3:1-2.
3. the preparation method of Da Lafeini according to claim 1; it is characterized in that: described acetylization reaction is N-[3-[5-alkyl formate-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2; 6-difluorobenzenesulfonamide first adds alkali backflow in ethyl acetate solution; add concentrated hydrochloric acid backflow again; obtained N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide.
4. the preparation method of Da Lafeini according to claim 3, is characterized in that: described in the alkali added in alkali backflow be sodium hydroxide, potassium hydroxide, sodium methylate, lithium methoxide, potassium tert.-butoxide, tert-butyl alcohol magnesium, sodium tert-butoxide, salt of wormwood or sodium carbonate.
5. the preparation method of Da Lafeini according to claim 1; it is characterized in that: N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 in described pyrimidine ring-closure reaction; the molar ratio of 6-difluorobenzenesulfonamide, DMF dimethylacetal and Guanidinium nitrate is: 1:1-3:1-5.
6. the preparation method of Da Lafeini according to claim 5, is characterized in that: the solvent of described pyrimidine ring-closure reaction is methyl alcohol, ethanol, Virahol, propyl carbinol, toluene, chloroform, methyl-sulphoxide, DMF or acetonitrile.
7. the preparation method of Da Lafeini according to claim 5, is characterized in that: the temperature of described pyrimidine ring-closure reaction is 90-150 DEG C.
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