CN103588767A - Preparation method of dabrafenib - Google Patents
Preparation method of dabrafenib Download PDFInfo
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- CN103588767A CN103588767A CN201310586872.6A CN201310586872A CN103588767A CN 103588767 A CN103588767 A CN 103588767A CN 201310586872 A CN201310586872 A CN 201310586872A CN 103588767 A CN103588767 A CN 103588767A
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- fluorophenyl
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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
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Abstract
The invention discloses a preparation method of dabrafenib, which comprises the following steps of taking 3-(3-amino-2-fluorophenyl)-3-oxa-propionate (II) as a raw material, and performing sulfamidation, halogenation, thiazole cyclization, acylation, pyrimidine cyclization and the like to form the dabrafenib (I). The raw material is easy to obtain, the preparation method is concise in technology and mild in condition, is applicable to industrial production, and promotes economic and technical development of the dabrafenib.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and intermediate preparing technical field, particularly a kind of Da Lafeini preparation method.
Background technology
Silk Serineprotein kinase (BRAF) inhibitor of Da Lafeini (Dabrafenib) Shi You Britain's GlaxoSmithKline PLC (GSK) company exploitation, as a kind of single medicine oral capsule, be applicable to carry the operation irresectability melanoma of BRAF V600E 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 the Positive evaluation of the Ren Yong of European drug administration (EMA) the pharmaceutical prod council (CHMP) to Tafinlar, make this medicine be expected to become second the BRAF inhibitor that enters European market after the Wei Luofeini (Vemurafinib) under Roche.
The chemistry of Da Lafeini is by name: N-[3-[5-(2-amino-4-pyrimidyl)-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzene sulphonamide.
World patent has been reported pharmaceutical use and the synthetic method of Da Lafeini and composition thereof for No. WO2009137391, No. WO2011047238 and No. WO2012148588.According to the constructional feature of Da Lafeini and analogue thereof, such material synthetic has A, B and tri-routes of C at present.
A route is current commonplace synthetic route, first with 2,6-difluoro chloride (III), sulfonamide reaction occurs obtain intermediate (X) by 3-amino-2-fluorophenyl carbamate (IX); Under highly basic effect, there is condensation reaction with the chloro-4-methylpyrimidine of 2-(XI) and obtain intermediate (XII) in intermediate (X); Intermediate (XII) bromo obtains intermediate (XIII); Intermediate (XIII) and 2,2-dimethyl thiopropionamide (VI) cyclisation obtains intermediate (XIV); Finally, intermediate (XIV) obtains target compound Da Lafeini (I) through ammonolysis reaction.
The difference of B route is first to pass through the amido protecting of 3-amino-2-fluorophenyl carbamate (IX), and then carries out condensation, bromo and ring-closure reaction; By amino deprotection and sulfuryl amine, obtain intermediate (XIV) again; 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 such as Da Lafeini etc. with pyrimdinyl-amino structure.Reason is if the existence of two fragrant amidos can make the sulfonamide reaction of final step lose selectivity.
Investigate two synthetic routes of above-mentioned A and B, although can prepare target product, but still have that reactions steps is many, aftertreatment is difficult and the defect such as severe reaction conditions.So, seek to simplify processing step, reduce environmental pollution and the preparation method of the new Da Lafeini (I) that reduces production costs has very important realistic meaning.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of improved Da Lafeini (I), this preparation method's technique is succinct, and raw material is easy to get, quality controllable, is applicable to suitability for industrialized production.
For achieving the above object, the present invention has adopted 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, there is sulfonamide reaction and obtain intermediate 3-[3-(2,6-difluorobenzene sulfoamido)-2-fluorophenyl in 6-difluoro chloride (III)]-3-oxa--propionic acid alkyl (R
1) ester (IV); Intermediate (IV) replaces and obtains intermediate 3-[3-(2,6-difluorobenzene sulfoamido)-2-fluorophenyl through halogen (X)]-2-halogen (X)-3-oxa--propionic acid alkyl (R
1) ester (V); Intermediate (V) and 2, there is thiazole ring-closure reaction and obtains intermediate N [3-[5-formic acid alkyl (R in 2-dimethyl thiopropionamide (VI)
1) ester-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzene sulphonamide (VII); Intermediate (VII) obtains intermediate N [3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 through acetylization reaction; 6-difluorobenzene sulphonamide (VIII); intermediate (VIII) must arrive La Feini (I) with DMF dimethylacetal (DMF-DMA) and Guanidinium nitrate generation pyrimidine ring-closure reaction.
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 the phenyl of methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, the tertiary butyl, benzyl, phenyl or replacement, preferable methyl or ethyl.
Described halogen (X) is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
Described 3-[3-(2,6-difluorobenzene sulfoamido)-2-fluorophenyl]-2-halogen (X)-3-oxa--propionic acid alkyl (R
1) ester (V) can directly carry out thiazole ring-closure reaction without separation, its reactant 3-[3-(2,6-difluorobenzene sulfoamido)-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-difluorobenzene sulphonamide (VII) first adds alkali and refluxes in ethyl acetate solution; add again concentrated hydrochloric acid to reflux; make N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2,6-difluorobenzene sulphonamide (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-in described pyrimidine ring-closure reaction (the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2; 6-difluorobenzene sulphonamide (VIII), N; the molar ratio of dinethylformamide dimethylacetal (DMF-DMA) and Guanidinium nitrate is 1:1-3:1-5, preferably 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, preferably propyl carbinol or toluene.
The temperature of described pyrimidine ring-closure reaction is 90-150 ℃, preferably 120 ℃.
Than prior art; the invention has the advantages that: the preparation method of Da Lafeini provided by the present invention; by steps such as sulfuryl amine, halo, thiazole cyclization, acidylate and pyrimidine cyclizations, can obtain target compound; Atom economy, the selectivity of reaction and the controllability of operation have been improved; 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 embodiments, technical solution of the present invention is further non-limitingly described in detail.
Embodiment mono-:
In there-necked flask, add 3-(3-amino-2-fluorophenyl)-3-oxa--ethyl propionate (II) (11.3g, 50mmol), the DMAP of pyridine 10mL, catalytic amount (DMAP) and methylene dichloride 200mL, after stirring and dissolving, at 0 ℃, drip 2, the methylene dichloride 50mL solution of 6-difluoro chloride (III) (11.7g, 55mmol), drips and finishes, room temperature reaction 16 hours, TLC detection reaction finishes.Add water washing, gained organic phase is used 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-difluorobenzene sulfoamido)-2-fluorophenyl]-3-oxa--ethyl propionate (IV) 12.4g, yield is 60.5%.
Embodiment bis-:
To 3-[3-(2,6-difluorobenzene sulfoamido)-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 forming is after 30 minutes, concentrating under reduced pressure, gained resistates dissolves with dioxane 100mL.To add in this solution magnesiumcarbonate (2.1,25mmol) and 2,2-dimethyl thiopropionamide (VI) (3.5g, 30mmol), stirring at room reaction is after 4 hours, water and 1N hydrochloric acid cancellation reaction, and stirring reaction 0.5 hour.Filter, gained solid obtains white solid N-[3-[5-ethyl formate-2-(tertiary butyl)-4-thiazolyl with ethyl acetate and normal hexane (1:1) recrystallization]-2-fluorophenyl]-2,6-difluorobenzene sulphonamide (VII) 7.25g, yield is 58.2%.
Embodiment tri-:
In reaction flask, add N-[3-[5-ethyl formate-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzene sulphonamide (VII) (6.0g, 12mmol), sodium methylate (0.81g, 15mmol) and anhydrous ethyl acetate 50mL.Stirring at room 1 hour, is warming up to 80 ℃, back flow reaction 5 hours, cooling, standing 12 hours of room temperature.Add water 100mL, under stirring, add concentrated hydrochloric acid 50mL, be warming up to backflow, react 4 hours.TLC detection reaction completes.With 2M sodium hydroxide, regulate pH to 9-10.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-difluorobenzene sulphonamide (VIII) 5.4g.Do not need purifying can be directly used in reaction below.
Embodiment tetra-:
In reaction flask, add N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2; 6-difluorobenzene sulphonamide (VIII) (5.4g; 11.5mmol), N; dinethylformamide dimethylacetal (DMF-DMA) (2.74g; 23mmol), with dimethylbenzene 50mL, be warming up to 140 ℃.Every approximately 4 hours, the methyl alcohol of generation is distilled out to reaction system, altogether approximately need to react 24 hours, TLC detection reaction finishes.Cooling, adds normal hexane 40mL, has yellow solid to produce, and filters, after gained solid drying, add Guanidinium nitrate (1.36,11.5mmol), sodium hydroxide (0.46g, 11.5mmol) and propyl carbinol 50mL, be warming up to 120 ℃, react 12 hours, TLC detection reaction completes.Cooling, there is crystal to separate out, slowly crystallization is 3 hours, filters.Filter cake water is washed and starched, and filters, is dried, and obtains off-white color solid Da Lafeini (I) 3.58g, yield 60%.
It is pointed out that above-described embodiment is only explanation technical conceive of the present invention and feature, its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (9)
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--propionic acid alkyl (R
1) ester (II) and 2,6-difluoro chloride (III) carries out sulfonamide reaction and obtains intermediate 3-[3-(2,6-difluorobenzene sulfoamido)-2-fluorophenyl]-3-oxa--propionic acid alkyl (R
1) ester (IV); Intermediate (IV) replaces and obtains intermediate 3-[3-(2,6-difluorobenzene sulfoamido)-2-fluorophenyl through halogen (X)]-2-halogen (X)-3-oxa--propionic acid alkyl (R
1) ester (V); Intermediate (V) and 2, there is thiazole ring-closure reaction and obtains intermediate N [3-[5-formic acid alkyl (R in 2-dimethyl thiopropionamide (VI)
1) ester-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzene sulphonamide (VII); Intermediate (VII) obtains intermediate N [3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2 through acetylization reaction; 6-difluorobenzene sulphonamide (VIII); intermediate (VIII) must arrive La Feini (I) with DMF dimethylacetal and Guanidinium nitrate generation pyrimidine ring-closure reaction.
2. the preparation method of Da Lafeini (I) according to claim 1, is characterized in that: described raw material 3-(3-amino-2-fluorophenyl)-3-oxa--propionic acid alkyl (R
1) alkyl R in ester (II)
1phenyl for methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, the tertiary butyl, benzyl, phenyl or replacement.
3. the preparation method of Da Lafeini (I) according to claim 1, is characterized in that: described halogen (X) is fluorine, chlorine, bromine or iodine.
4. the preparation method of Da Lafeini (I) according to claim 1, is characterized in that: described 3-[3-(2,6-difluorobenzene sulfoamido)-2-fluorophenyl]-2-halogen (X)-3-oxa--propionic acid alkyl (R
1) ester (V) can directly carry out thiazole ring-closure reaction without separation, its reactant 3-[3-(2,6-difluorobenzene sulfoamido)-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.
5. the preparation method of Da Lafeini (I) according to claim 1, is characterized in that: described acetylization reaction is N-[3-[5-formic acid alkyl (R
1) ester-2-(tertiary butyl)-4-thiazolyl]-2-fluorophenyl]-2; 6-difluorobenzene sulphonamide (VII) first adds alkali and refluxes in ethyl acetate solution; add again concentrated hydrochloric acid to reflux; make N-[3-(the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2,6-difluorobenzene sulphonamide (VIII).
6. the preparation method of Da Lafeini (I) according to claim 5, is characterized in that: described in to add the alkali of alkali in refluxing 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.
7. the preparation method of Da Lafeini (I) according to claim 1; it is characterized in that: N-[3-in described pyrimidine ring-closure reaction (the 5-ethanoyl-2-tertiary butyl-4-thiazolyl)-2-fluorophenyl]-2; the molar ratio of 6-difluorobenzene sulphonamide (VIII), DMF dimethylacetal and Guanidinium nitrate is: 1:1-3:1-5.
8. the preparation method of Da Lafeini (I) according to claim 7, 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.
9. the preparation method of Da Lafeini (I) according to claim 7, is characterized in that: the temperature of described pyrimidine ring-closure reaction is 90-150 ℃.
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Non-Patent Citations (6)
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