CN104987333B - Filgotinib synthetic method - Google Patents
Filgotinib synthetic method Download PDFInfo
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- CN104987333B CN104987333B CN201510411644.4A CN201510411644A CN104987333B CN 104987333 B CN104987333 B CN 104987333B CN 201510411644 A CN201510411644 A CN 201510411644A CN 104987333 B CN104987333 B CN 104987333B
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- 0 *Nc1nc(-c2ccc(CN(CC3)CCS3(=C)=O)cc2)ccc1 Chemical compound *Nc1nc(-c2ccc(CN(CC3)CCS3(=C)=O)cc2)ccc1 0.000 description 1
- BDTDECDAHYOJRO-UHFFFAOYSA-N CCOC(N=C=S)=O Chemical compound CCOC(N=C=S)=O BDTDECDAHYOJRO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a filgotinib synthetic method and belongs to the technical field of chemical synthesis of medicines. 6-chloro-2-aminopyridine and di-tert-butyl dicarbonate ester are subjected to condensation reaction to obtain 6-chloro-2-tert-butyloxycarbonyl aminopyridine; hydrolysis reaction is performed; the obtained 6-chloro-2-tert-butyloxycarbonyl aminopyridine and trifluorinated methyl sulfonic anhydride are subjected to trifluoromethanesulfonic acid esterification reaction; the obtained 2-tert-butyloxycarbonylamino-6-pyridyltrifluoromethanesulfonate and [(1,1-dioxo-4-thiomorpholinyl)methyl]benzo-4-boronic acid pinacol ester are subjected to condensation reaction to obtain a tert-butyl ester derivative; the tert-butyl ester derivative is treated by trifluoroacetic acid and subjected to de-protection; the obtained intermediate and ethoxycarbonyl isothiocyanate are subjected to isothiocyanate reaction; the obtained intermediate and hydroxylamine hydrochloride are subjected to ring closing reaction; the obtained intermediate and cyclopropane carbonyl chloride are subjected to amidation reaction to obtain the finished product. Operation is simplified; reagents are available; the concept of environment friendliness and environment protection is embodied.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to the synthetic method of a kind of Filgotinib.
Background technology
Filgotinib is JAK1 inhibitor Filgotinib (code name GLPG0634), its chemical entitled N-[5-[4-[(1,1-dioxy
Generation-4-thio-morpholinyl) methyl] phenyl] [1,2,4] triazol [1,5-A] pyridine-2-base] cyclopropane carboxamide, its chemical structural formula is:
Filgotinib is a kind of oral JAK1 inhibitor treating rheumatic arthritis, is Belgian biomedical company
Galapagos invention grinding new drug, the most having completed the key clinical II phase studies therapeutic test, has successfully reached the research worker phase
The object of experiment hoped, curative effect is excellent.Additionally, some researchs also indicate that the Filgotinib auto-inflammatory disease such as Ke Laoen to other
Family name's disease also has good therapeutical effect.
A kind of synthetic route preparing Filgotinib disclosed in United States Patent (USP) US20100331319: respectively with 6-bromo-2-amino pyrrole
Pyridine is initiation material, obtains [1,2,4] triazol [1,5-a] pyridine parent nucleus intermediate by condensation, cyclization and amidatioon, then by two
Secondary condensation, obtains Filgotinib, and process route is as follows:
Owing to whole synthetic route step is more, and midbody product and final products are impure and by-product is more, thus pure
Changing and need to use a large amount of solvent, complex operation, yield is relatively low, relatively costly, is unfavorable for that industrialization produces and promotes, and therefore having must
Technological process to be explored is short, simple to operate, with low cost and uses the synthetic method of the Filgotinib of applicable industrialized production.
Summary of the invention
The task of the present invention is to provide the synthetic method of a kind of Filgotinib, and the method process route is reasonable, simple to operate, examination
Agent is easy to get high with total recovery and is satisfied the environmental protection effect that industrial amplification production requires and can embody excellence.
The task of the present invention is performed by, the synthetic method of a kind of Filgotinib, comprises the following steps:
A) prepare 6-hydroxyl-2-t-butoxycarbonyl amino pyridine: first by the chloro-PA of 6-in the solvent of condensation reaction with
Bis(tert-butoxycarbonyl)oxide carries out condensation reaction, obtains 6-chloro-2-t-butoxycarbonyl amino pyridine, then by chloro-for 6-2-tertbutyloxycarbonyl ammonia
Yl pyridines is put into and is hydrolyzed in the system being made up of alkali, quaternary ammonium salt phase transfer catalyst, the solvent of hydrolysis and water instead
Should, obtain 6-hydroxyl-2-t-butoxycarbonyl amino pyridine;
B) 2-t-butoxycarbonyl amino-6-pyridine radicals triflate is prepared: will be by step A) the 6-tertiary fourth of hydroxyl-2-that obtains
Oxygen carbonylamino pyridine and trifluoromethyl sulfonic acid anhydride carry out triflated reaction in acid binding agent alkali systems, obtain the tertiary fourth of 2-
Oxygen carbonylamino-6-pyridine radicals triflate;
C) intermediate (I) is prepared: will be by step B) the 2-t-butoxycarbonyl amino-6-pyridine radicals triflate that obtains and [(1,1-
Dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate forms at solvent, water, catalyst, potassium phosphate and inorganic matter
System carries out condensation reaction, obtains tert-butyl ester derivative, then this tert-butyl ester derivative trifluoroacetic acid is processed, carry out remove-insurance
Protect, obtain intermediate (I);
D) intermediate (II) is prepared: will be by step C) intermediate (I) that obtains is with ethoxycarbonyl isothiocyanate in a solvent
Carry out isothiocyanate reaction, obtain intermediate (II);
E) prepare intermediate (III): will be by step D) intermediate (II) that obtains with hydroxylamine hydrochloride at acid binding agent alkali and solvent
System in carry out ring closure reaction, obtain intermediate (III);
F) Filgotinib is prepared: will be by step E) intermediate (III) that obtains and ring the third formyl chloride be at acid binding agent alkali and solvent
System carries out amidation process, obtains Filgotinib.
In a specific embodiment of the present invention, step A) described in the solvent of condensation reaction be dichloromethane, dichloro
Ethane, chloroform, oxolane, methyl tertiary butyl ether(MTBE), 1,4-dioxane or acetonitrile;Described alkali is sodium hydroxide, hydroxide
Potassium or Cesium hydrate.;Described quaternary ammonium salt phase transfer catalyst be tetrabutylammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium iodide,
4-butyl ammonium hydrogen sulfate, benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, dodecyl three
Ammonio methacrylate or tetradecyl trimethyl ammonium chloride;The solvent of described hydrolysis is 1,4-dioxane, toluene, neighbour
Dimethylbenzene, meta-xylene, xylol, heptane, normal octane or N,N-dimethylformamide.
In another specific embodiment of the present invention, step A) described in the temperature of condensation reaction be 10~80 DEG C, reaction
Time is 0.5~8 hour;The temperature of described hydrolysis is 90~120 DEG C, and the response time is 4~8 hours.
In another specific embodiment of the present invention, step A) described in the chloro-PA of 6-, condensation reaction molten
The mol ratio of agent and Bis(tert-butoxycarbonyl)oxide three is 1.0: 5.0~30.0: 1.2~1.5, described 6-chloro-2-t-butoxycarbonyl amino
The mol ratio of pyridine, alkali, quaternary ammonium salt phase transfer catalyst, the solvent of hydrolysis and water is 1.0: 1.0~1.2:
0.01~0.10: 5.0~50.0: 20.0~50.0;Described alkali be mass percent concentration be 4.2~the sodium hydroxide solution of 33.4%,
Potassium hydroxide solution or cesium hydroxide solution.
In another specific embodiment of the present invention, step B) described in acid binding agent alkali be triethylamine, diethylamine, N, N-
Diisopropylethylamine, pyridine, piperidines, 2,6-lutidines or N-methylmorpholine;Described triflated reaction
Temperature is-10~10 DEG C, and the response time is 0.5~3 hour;Described 6-hydroxyl-2-t-butoxycarbonyl amino pyridine, trifluoromethyl
Sulphonic acid anhydride, the mol ratio of acid binding agent alkali three are 1.0: 1.2~1.5: 1.5~2.5.
Also having in a specific embodiment in the present invention, step C) described in solvent be Isosorbide-5-Nitrae-dioxane, toluene, neighbour
Dimethylbenzene, meta-xylene, xylol, heptane, normal butane or DMF;Described catalyst is two (three
Phenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium, 1,1-double (diphenylphosphine) ferrocene palladium chloride, Palladous chloride.;Described is inorganic
Thing is lithium chloride, potassium chloride or potassium iodide;The temperature of described condensation reaction is 100~130 DEG C, and the response time is 15~30 little
Time.
In more and in a specific embodiment of the present invention, step C) described in 2-t-butoxycarbonyl amino-6-pyridine radicals trifluoro
Methanesulfonates, [(1,1-dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate, solvent, water, catalyst, potassium phosphate,
Inorganic matter, the mol ratio of trifluoroacetic acid are 1.0: 1.0~1.2: 5.0~15.0: 2.0~5.0: 0.001~0.01: 0.5~1.0:
0.5~1.0: 1.0~1.5.
The present invention's and then in a specific embodiment, step D) described in solvent be dichloromethane, dichloroethanes, chlorine
Imitative, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane or acetonitrile;The temperature of described isothiocyanate reaction is 20~50
DEG C, the response time is 15~30 hours;Described intermediate (I), ethoxycarbonyl isothiocyanate, the mol ratio of solvent three
It is 1.0: 1.0~1.1: 5.0~15.0.
In the most more and in a specific embodiment of the present invention, step E) described in acid binding agent alkali be triethylamine, diethylamine,
N, N-diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, aniline, N, accelerine, N, N-diethylaniline, 2,6-
Lutidines, DMAP, tetramethyl guanidine or N-methylmorpholine;Described solvent be methanol, ethanol, isopropanol,
Normal propyl alcohol or the tert-butyl alcohol;The temperature of described ring closure reaction is 50~80 DEG C, and the response time is 12~24 hours;Described centre
The mol ratio of body (II), hydroxylamine hydrochloride, acid binding agent alkali and solvent is 1.0: 2.5~5.0: 2.0~3.0: 10.0~25.0.
In again and then in a specific embodiment of the present invention, step F) described in solvent be dichloromethane, dichloroethanes,
Chloroform, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane or acetonitrile;Described acid binding agent alkali be triethylamine, diethylamine,
DIPEA, pyridine, piperidines, tri-n-butylamine, aniline, DMA, N, N-diethylaniline,
2,6-lutidines, 4-dimethylaminopyridine, tetramethyl guanidine or N-methylmorpholine;The temperature of described amidation process is
50~80 DEG C, the response time is 2~8 hours;Described intermediate (III), ring the third formyl chloride, acid binding agent alkali and solvent
Mol ratio is 1.0: 2.5~3.0: 2.5~3.5: 10.0~25.0.
The technical scheme that the present invention provides has following technical effect that one, only makees routinely after having reacted due to each step
Post processing is without purification, and impurity is less, can directly carry out next step reaction, therefore simplify operation, and the most each step is all
Higher yield can be obtained;Its two, the process route agents useful for same of the present invention is easy to get, and technical scheme is reasonable, can produce in a large number
Meet use demand, it is adaptable to industrialized production;Its three, owing to pollutant will not be produced during making, thus permissible
Embody environmental protection effect.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme is further elaborated, it is clear that protection scope of the present invention is also
It is not limited to embodiment, other embodiments of the present invention that those skilled in the art are done, broadly fall into the scope of protection of the invention.
Embodiment 1:
A) prepare 6-hydroxyl-2-t-butoxycarbonyl amino pyridine: first by the chloro-PA of 6-in dichloromethane with two carbonic acid two
The tert-butyl ester carries out condensation reaction under stirring, and the chloro-PA of 6-, dichloromethane and Bis(tert-butoxycarbonyl)oxide three rub
Your ratio is 1: 10: 1.2, and the temperature of condensation reaction is 60 DEG C, and the time of condensation reaction is that 3h, TLC point plate determines that reaction is complete,
Reactant liquor concentrated by rotary evaporation, to dry, obtain 6-chloro-2-t-butoxycarbonyl amino pyridine, then is thrown by chloro-for 6-2-t-butoxycarbonyl amino pyridine
Enter to being made up of the sodium hydroxide solution that mass percent concentration is 9.9%, tetrabutylammonium chloride, Isosorbide-5-Nitrae-dioxane and water
Be hydrolyzed in system and under stirring reaction, and 6-chloro-2-t-butoxycarbonyl amino pyridine, mass percent concentration are
The mol ratio of sodium hydroxide solution, tetrabutylammonium chloride, Isosorbide-5-Nitrae-dioxane and the water of 9.9% is 1: 1: 0.03: 15:
20, the temperature of hydrolysis is 95 DEG C, and the time of hydrolysis is that 6h, TLC point plate determines that reaction is complete, is down to room temperature, adds
Enter dichloromethane and water, the organic facies separated, first wash with water, then wash with salt, be then dried with magnesium sulfate, concentrated by rotary evaporation is extremely
Dry, residue methanol-isopropanol mixed solvent recrystallization purifying, obtain the 6-hydroxyl-2-tertbutyloxycarbonyl in off-white color solid, shaped
Aminopyridine, yield 88%, the reaction equation of this step is as follows:
B) 2-t-butoxycarbonyl amino-6-pyridine radicals triflate is prepared: will be by step A) the 6-tertiary fourth of hydroxyl-2-that obtains
Oxygen carbonylamino pyridine and trifluoromethyl sulfonic acid anhydride carry out in triethylamine system and under stirring triflated instead
Should, the mol ratio of 6-hydroxyl-2-t-butoxycarbonyl amino pyridine, trifluoromethyl sulfonic acid anhydride and triethylamine three is 1: 1.2: 2.5,
The time of triflated reaction is 2.5h, and reaction temperature is 0 DEG C, and TCL point plate determines that reaction is complete, adds acetic acid second
Ester and water, the organic phases washed with water separated, then to wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue is used
Toluene-normal hexane mixed solvent recrystallization purifying, obtains 2-t-butoxycarbonyl amino-6-pyridine radicals triflate, and character is Huang
Color solid, yield 96.8%, the reaction equation of this step is as follows:
C) intermediate (I) is prepared: will be by step B) the 2-t-butoxycarbonyl amino-6-pyridine radicals triflate that obtains and [(1,1-
Dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate is by toluene, water, two (triphenylphosphine) palladium chloride, phosphorus
Carrying out condensation reaction in the system of acid potassium and lithium chloride composition and under stirring, the time of condensation reaction is 20h, condensation
The temperature of reaction is 110 DEG C, and TLC point plate determines that reaction is complete, obtains tert-butyl ester derivative, then is delayed by this tert-butyl ester derivative
Slowly it is added drop-wise to the trifluoroacetic acid pre-cooled to less than 10 DEG C, is then stirred at room temperature 1h, add dichloromethane and water, separate
Organic phases washed with water, then wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue is crossed silica gel column chromatography and [washed
Desolventizing: ethyl acetate/normal hexane (3:7v/v)] purification, obtain intermediate (I), character is light yellow solid, yield 89.3%,
Described 2-t-butoxycarbonyl amino-6-pyridine radicals triflate in this step, [(1,1-dioxo-4-thio-morpholinyl) methyl]
Benzene-4-pinacol borate, toluene, water, two (triphenylphosphine) palladium chloride, potassium phosphate, lithium chloride and trifluoroacetic acid
Mol ratio be 1: 1: 10: 5: 0.003: 0.7: 0.5: 1, the reaction equation of this step is as follows:
D) prepare intermediate (II): will be by step C) intermediate (I) that obtains with ethoxycarbonyl isothiocyanate at two chloroethenes
Carrying out isothiocyanate reaction in alkane and under stirring, the response time is 22h, and reaction temperature is 35 DEG C, intermediate (I),
The mol ratio of ethoxycarbonyl isothiocyanate and dichloroethanes three is 1: 1.1: 7, determines that reaction is complete through TLC point plate, adds
Enter ethyl acetate and water, the organic phases washed with water separated, then to wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is the most dry,
Residue ethyl alcohol recrystallization is purified, and obtains the intermediate (II) that character is light yellow solid, yield 83.8%, this step anti-
Answer formula as follows:
E) prepare intermediate (III): will be by step D) intermediate (II) that obtains with hydroxylamine hydrochloride by N, N-diisopropyl
Carrying out ring closure reaction in the system of ethamine and methanol composition and under stirring, the time of ring closure reaction is 18h, and cyclization is anti-
The temperature answered is 60 DEG C, and the mol ratio of intermediate (II), hydroxylamine hydrochloride, DIPEA and methanol is 1:
4: 2: 12, TLC point plate determines that reaction is complete, is cooled to room temperature, adds dichloromethane and water, the organic phases washed with water separated,
Then washing with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate
/ normal hexane (3:7v/v)] purification, obtain the intermediate (III) that character is light yellow solid, yield 80.4%, the reaction of this step
Formula is as follows:
F) prepare Filgotinib: will be by step E under stirring) intermediate (III) that obtains with ring the third formyl chloride by two
Carrying out amidation process in the system of ethamine and chloroform composition, the time of amidation process is 6h, and the temperature of amidation process is 70
DEG C, the mol ratio of intermediate (III), ring the third formyl chloride, diethylamine and chloroform is 1: 3: 3: 10, and TLC point plate determines
React complete, be cooled to room temperature, add dichloromethane and water, the organic phases washed with water separated, then wash with salt, then use sulfur
Acid magnesium is dried, and concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate/normal hexane (3:7v/v)] purification,
Obtaining character is lurid solid, i.e. obtains Filgotinib (owing to Filgotinib is a kind of new drug, thus in China the most still
Without definite Chinese, the same example of below example 2 to 4), yield 90.9%, the reaction equation of this step is as follows:
Embodiment 2:
A) prepare 6-hydroxyl-2-t-butoxycarbonyl amino pyridine: first by the chloro-PA of 6-in dichloroethanes with two carbonic acid two
The tert-butyl ester carries out condensation reaction under stirring, and the chloro-PA of 6-, dichloroethanes and Bis(tert-butoxycarbonyl)oxide three rub
Your ratio is 1: 5: 1.3, and the temperature of condensation reaction is 10 DEG C, and the time of condensation reaction is that 8h, TLC point plate determines that reaction is complete,
Reactant liquor concentrated by rotary evaporation, to dry, obtain 6-chloro-2-t-butoxycarbonyl amino pyridine, then is thrown by chloro-for 6-2-t-butoxycarbonyl amino pyridine
Enter to the body being made up of the potassium hydroxide solution that mass percent concentration is 20%, benzyl triethyl ammonium bromide, xylol and water
Be hydrolyzed in system and under stirring reaction, and 6-chloro-2-t-butoxycarbonyl amino pyridine, mass percent concentration are 20%
The mol ratio of potassium hydroxide solution, benzyl triethyl ammonium bromide, xylol and water be 1: 1.1: 0.08: 5: 30,
The temperature of hydrolysis is 100 DEG C, and the time of hydrolysis is that 5.5h, TLC point plate determines that reaction is complete, is down to room temperature, adds
Enter dichloromethane and water, the organic facies separated, first wash with water, then wash with salt, be then dried with magnesium sulfate, concentrated by rotary evaporation is extremely
Dry, residue methanol-isopropanol mixed solvent recrystallization purifying, obtain the 6-hydroxyl-2-tertbutyloxycarbonyl in off-white color solid, shaped
Aminopyridine, yield 88.3%, the reaction equation of this step is with embodiment 1;
B) 2-t-butoxycarbonyl amino-6-pyridine radicals triflate is prepared: will be by step A) the 6-tertiary fourth of hydroxyl-2-that obtains
Oxygen carbonylamino pyridine and trifluoromethyl sulfonic acid anhydride carry out in pyridine System and under stirring triflated instead
Should, the mol ratio of 6-hydroxyl-2-t-butoxycarbonyl amino pyridine, trifluoromethyl sulfonic acid anhydride and pyridine three is 1: 1.5: 1.5, three
The time of fluorine methanesulfonic acid esterification is 3h, and reaction temperature is-10 DEG C, and TCL point plate determines that reaction is complete, adds ethyl acetate
And water, the organic phases washed with water separated, then to wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is the most dry, residue first
Benzene-normal hexane mixed solvent recrystallization purifying, obtains 2-t-butoxycarbonyl amino-6-pyridine radicals triflate, and character is yellow
Solid, yield 96.9%, the reaction equation of this step is with embodiment 1;
C) intermediate (I) is prepared: will be by step B) the 2-t-butoxycarbonyl amino-6-pyridine radicals triflate that obtains and [(1,1-
Dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate is by xylol, water, Palladous chloride., potassium phosphate and potassium iodide
Carrying out condensation reaction in the system of composition and under stirring, the time of condensation reaction is 15h, and the temperature of condensation reaction is
130 DEG C, TLC point plate determines that reaction is complete, obtains tert-butyl ester derivative, then is slowly dropped to the coldest by this tert-butyl ester derivative
But to the trifluoroacetic acid of less than 10 DEG C, then it is stirred at room temperature 1h, adds dichloromethane and water, the organic phases washed with water separated,
Then washing with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate
/ normal hexane (3:7v/v)] purification, obtain intermediate (I), character is light yellow solid, yield 89.6%, described in this step
2-t-butoxycarbonyl amino-6-pyridine radicals triflate, [(1,1-dioxo-4-thio-morpholinyl) methyl] benzene-4-boric acid pinacol
The mol ratio of ester, xylol, Palladous chloride., potassium phosphate, potassium iodide and trifluoroacetic acid is 1: 1.2: 15: 2: 0.001:
0.5: 0.7: 1.2, the reaction equation of this step is with embodiment 1;
D) prepare intermediate (II): will be by step C) intermediate (I) that obtains with ethoxycarbonyl isothiocyanate at methyl-tert
Carrying out isothiocyanate reaction in butyl ether and under stirring, the response time is 15h, and reaction temperature is 50 DEG C, middle
The mol ratio of body (I), ethoxycarbonyl isothiocyanate and methyl tertiary butyl ether(MTBE) three is 1: 1: 15, determines instead through TLC point plate
Should be complete, add ethyl acetate and water, the organic phases washed with water separated, then wash with salt, then be dried with magnesium sulfate, rotation is steamed
Being concentrated to dryness, residue ethyl alcohol recrystallization is purified, and obtains the intermediate (II) that character is light yellow solid, yield 83.5%,
The reaction equation of this step is with embodiment 1;
E) prepare intermediate (III): will be by step D) intermediate (II) that obtains with hydroxylamine hydrochloride by triethylamine and isopropyl
Carrying out ring closure reaction in the system of alcohol composition and under stirring, the time of ring closure reaction is 12h, the temperature of ring closure reaction
Being 80 DEG C, the mol ratio of intermediate (II), hydroxylamine hydrochloride, triethylamine and isopropanol is 1: 2.5: 2.5: 17, TLC
Point plate determines that reaction is complete, is cooled to room temperature, adds dichloromethane and water, the organic phases washed with water separated, then washes with salt,
Being dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate/normal hexane (3:7v/v)] again
Purification, obtains the intermediate (III) that character is light yellow solid, and yield 80.6%, the reaction equation of this step is with embodiment 1;
F) prepare Filgotinib: will be by step E under stirring) intermediate (III) that obtains with ring the third formyl chloride by three
Carrying out amidation process in the system of n-butylamine and oxolane composition, the time of amidation process is 2h, the temperature of amidation process
Degree is 80 DEG C, and the mol ratio of intermediate (III), ring the third formyl chloride, tri-n-butylamine and oxolane is 1: 2.5: 3.5:
17, TLC point plates determine that reaction is complete, are cooled to room temperature, add dichloromethane and water, the organic phases washed with water separated, then
Washing with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate/just own
Alkane (3:7v/v)] purification, obtaining character is lurid solid, i.e. obtains Filgotinib, yield 91%, the reaction equation of this step
With embodiment 1.
Embodiment 3:
A) prepare 6-hydroxyl-2-t-butoxycarbonyl amino pyridine: first by the chloro-PA of 6-in Isosorbide-5-Nitrae-dioxane with two carbon
Acid di tert butyl carbonate carries out condensation reaction, the chloro-PA of 6-, Isosorbide-5-Nitrae-dioxane and Bis(tert-butoxycarbonyl)oxide under stirring
The mol ratio of three is 1: 30: 1.5, and the temperature of condensation reaction is 80 DEG C, and the time of condensation reaction is that 0.5h, TLC point plate is true
Surely reacting complete, reactant liquor concentrated by rotary evaporation, to dry, obtains 6-chloro-2-t-butoxycarbonyl amino pyridine, then by chloro-for 6-2-tertiary butyloxycarbonyl
Base aminopyridine put into by the cesium hydroxide solution that mass percent concentration is 33.4%, tetradecyl trimethyl ammonium chloride,
Be hydrolyzed in the system that N, N-2 methylformamide and water are constituted and under stirring reaction, 6-chloro-2-tertbutyloxycarbonyl ammonia
Yl pyridines, mass percent concentration be 33.4% cesium hydroxide solution, tetradecyl trimethyl ammonium chloride, N, N-2 methyl formyl
The mol ratio of amine and water is 1: 1.2: 0.1: 50: 45, and the temperature of hydrolysis is 120 DEG C, and the time of hydrolysis is
4h, TLC point plate determines that reaction is complete, is down to room temperature, adds dichloromethane and water, the organic facies separated, first washes with water, then
Washing with salt, be then dried with magnesium sulfate, concentrated by rotary evaporation is the most dry, residue methanol-isopropanol mixed solvent recrystallization purifying,
Obtaining the 6-hydroxyl-2-t-butoxycarbonyl amino pyridine in off-white color solid, shaped, yield 88.1%, the reaction equation of this step is with implementing
Example 1;
B) 2-t-butoxycarbonyl amino-6-pyridine radicals triflate is prepared: will be by step A) the 6-tertiary fourth of hydroxyl-2-that obtains
Oxygen carbonylamino pyridine and trifluoromethyl sulfonic acid anhydride carry out trifluoromethanesulfonic acid in N-methylmorpholine system and under stirring
Esterification, the mol ratio of 6-hydroxyl-2-t-butoxycarbonyl amino pyridine, trifluoromethyl sulfonic acid anhydride and N-methylmorpholine three is 1:
1.35: 2, the time of triflated reaction is 0.5h, and reaction temperature is 10 DEG C, and TCL point plate determines that reaction is complete, adds
Enter ethyl acetate and water, the organic phases washed with water separated, then to wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is the most dry,
Residue toluene-normal hexane mixed solvent recrystallization purifying, obtains 2-t-butoxycarbonyl amino-6-pyridine radicals triflate,
Character is yellow solid, yield 96.5%, and the reaction equation of this step is with embodiment 1;
C) intermediate (I) is prepared: will be by step B) the 2-t-butoxycarbonyl amino-6-pyridine radicals triflate that obtains and [(1,1-
Dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate is by normal butane, water, double (diphenylphosphine) ferrocene two of 1,1-
In the system of Palladous chloride., potassium phosphate and potassium chloride composition and carry out condensation reaction under stirring, the time of condensation reaction is
30h, the temperature of condensation reaction is 100 DEG C, and TLC point plate determines that reaction is complete, obtains tert-butyl ester derivative, then by this tert-butyl ester
Derivant is slowly dropped to the trifluoroacetic acid pre-cooled to less than 10 DEG C, is then stirred at room temperature 1h, add dichloromethane and
Water, the organic phases washed with water separated, then to wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel
Chromatographic column [eluting solvent: ethyl acetate/normal hexane (3:7v/v)] purification, obtains intermediate (I), and character is light yellow solid,
Yield 89.4%, the described 2-t-butoxycarbonyl amino-6-pyridine radicals triflate in this step, [(1,1-dioxo-4-sulfur generation
Morpholinyl) methyl] benzene-4-pinacol borate, normal butane, water, double (diphenylphosphine) the ferrocene palladium chloride of 1,1-, potassium phosphate,
The mol ratio of potassium chloride and trifluoroacetic acid is 1: 1.1: 5: 3.5: 0.01: 1: 1: 1.5, and the reaction equation of this step is with real
Execute example 1;
D) prepare intermediate (II): will be by step C) intermediate (I) that obtains with ethoxycarbonyl isothiocyanate in acetonitrile
And carrying out isothiocyanate reaction under stirring, the response time is 30h, and reaction temperature is 20 DEG C, intermediate (I),
The mol ratio of ethoxycarbonyl isothiocyanate and acetonitrile three is 1: 1.05: 5, determines that reaction is complete through TLC point plate, adds second
Acetoacetic ester and water, the organic phases washed with water separated, then to wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation, to dry, remains
Thing ethyl alcohol recrystallization is purified, and obtains the intermediate (II) that character is light yellow solid, yield 83.6%, the reaction equation of this step
With embodiment 1;
E) prepare intermediate (III): will be by step D) intermediate (II) that obtains with hydroxylamine hydrochloride by aniline and the tert-butyl alcohol
Carrying out ring closure reaction in the system of composition and under stirring, the time of ring closure reaction is 24h, and the temperature of ring closure reaction is
50 DEG C, the mol ratio of intermediate (II), hydroxylamine hydrochloride, aniline and the tert-butyl alcohol is 1: 5: 3: 25, and TLC point plate is true
Surely react complete, be cooled to room temperature, add dichloromethane and water, the organic phases washed with water separated, then wash with salt, then use
Magnesium sulfate is dried, and concentrated by rotary evaporation is to dry, and it is pure that residue crosses silica gel column chromatography [eluting solvent: ethyl acetate/normal hexane (3:7v/v)]
Changing, obtain the intermediate (III) that character is light yellow solid, yield 81%, the reaction equation of this step is with embodiment 1;
F) prepare Filgotinib: will be by step E under stirring) intermediate (III) that obtains and ring the third formyl chloride by
Carrying out amidation process in the system of N-methylmorpholine and Isosorbide-5-Nitrae-dioxane composition, the time of amidation process is 4h, amidatioon
The temperature of reaction is 50 DEG C, and the mol ratio of intermediate (III), ring the third formyl chloride, N-methylmorpholine and Isosorbide-5-Nitrae-dioxane is
1: 2.8: 2.5: 25, TLC point plate determines that reaction is complete, is cooled to room temperature, adds dichloromethane and water, the organic facies separated
Wash with water, then wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation to dry, residue cross silica gel column chromatography [eluting solvent:
Ethyl acetate/normal hexane (3:7v/v)] purification, obtaining character is lurid solid, i.e. obtains Filgotinib, yield 91.2%,
The reaction equation of this step is with embodiment 1.
Embodiment 4:
A) prepare 6-hydroxyl-2-t-butoxycarbonyl amino pyridine: first by the chloro-PA of 6-in methyl tertiary butyl ether(MTBE) with two carbon
Acid di tert butyl carbonate carries out condensation reaction, the chloro-PA of 6-, methyl tertiary butyl ether(MTBE) and Bis(tert-butoxycarbonyl)oxide under stirring
The mol ratio of three is 1: 20: 1.4, and the temperature of condensation reaction is 35 DEG C, and the time of condensation reaction is that 6h, TLC point plate determines
Reacting complete, reactant liquor concentrated by rotary evaporation, to dry, obtains 6-chloro-2-t-butoxycarbonyl amino pyridine, then by chloro-for 6-2-tertbutyloxycarbonyl
Aminopyridine is put into by the sodium hydroxide solution that mass percent concentration is 4.2%, tetrabutyl ammonium bromide, xylol and water structure
Be hydrolyzed in the system become and under stirring reaction, 6-chloro-2-t-butoxycarbonyl amino pyridine, mass percent concentration
Be the mol ratio of sodium hydroxide solution, tetrabutyl ammonium bromide, xylol and the water of 4.2% be 1: 1.05: 0.06: 25:
50, the temperature of hydrolysis is 90 DEG C, and the time of hydrolysis is that 8h, TLC point plate determines that reaction is complete, is down to room temperature, adds
Enter dichloromethane and water, the organic facies separated, first wash with water, then wash with salt, be then dried with magnesium sulfate, concentrated by rotary evaporation is extremely
Dry, residue methanol-isopropanol mixed solvent recrystallization purifying, obtain the 6-hydroxyl-2-tertbutyloxycarbonyl in off-white color solid, shaped
Aminopyridine, yield 88.7%, the reaction equation of this step is with embodiment 1;
B) 2-t-butoxycarbonyl amino-6-pyridine radicals triflate is prepared: will be by step A) the 6-tertiary fourth of hydroxyl-2-that obtains
Oxygen carbonylamino pyridine and trifluoromethyl sulfonic acid anhydride in N, N-diisopropylethylamine system and at stirring under carry out fluoroform
Sulfonic acid esterification, 6-hydroxyl-2-t-butoxycarbonyl amino pyridine, trifluoromethyl sulfonic acid anhydride and DIPEA three's
Mol ratio is 1: 1.4: 1.8, and the time of triflated reaction is 1h, and reaction temperature is 5 DEG C, and TCL point plate determines instead
Should be complete, add ethyl acetate and water, the organic phases washed with water separated, then wash with salt, then be dried with magnesium sulfate, rotation is steamed
It is concentrated to dryness, residue toluene-normal hexane mixed solvent recrystallization purifying, obtains 2-t-butoxycarbonyl amino-6-pyridine radicals trifluoro
Methanesulfonates, character is yellow solid, yield 96.7%, and the reaction equation of this step is with embodiment 1;
C) intermediate (I) is prepared: will be by step B) the 2-t-butoxycarbonyl amino-6-pyridine radicals triflate that obtains and [(1,1-
Dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate by dinethylformamide, water, tetrakis triphenylphosphine palladium,
Carrying out condensation reaction in the system of potassium phosphate and potassium chloride composition and under stirring, the time of condensation reaction is 25h, contracting
The temperature closing reaction is 120 DEG C, and TLC point plate determines that reaction is complete, obtains tert-butyl ester derivative, then by this tert-butyl ester derivative
It is slowly dropped to the trifluoroacetic acid pre-cooled to less than 10 DEG C, is then stirred at room temperature 1h, add dichloromethane and water, point
The organic phases washed with water gone out, then washes with salt, then is dried with magnesium sulfate, and concentrated by rotary evaporation is to dry, and residue is crossed silica gel column chromatography and [washed
Desolventizing: ethyl acetate/normal hexane (3:7v/v)] purification, obtain intermediate (I), character is light yellow solid, yield 89.8%,
Described 2-t-butoxycarbonyl amino-6-pyridine radicals triflate in this step, [(1,1-dioxo-4-thio-morpholinyl) methyl]
Benzene-4-pinacol borate, dinethylformamide, water, tetrakis triphenylphosphine palladium, potassium phosphate, potassium chloride and trifluoroacetic acid
The mol ratio of eight is 1: 1.15: 12.5: 4: 0.075: 0.8: 0.9: 1.4, and the reaction equation of this step is with embodiment 1;
D) prepare intermediate (II): will be by step C) intermediate (I) that obtains with ethoxycarbonyl isothiocyanate at tetrahydrochysene furan
Muttering and carry out isothiocyanate reaction under stirring, the response time is 25h, and reaction temperature is 40 DEG C, intermediate (I),
The mol ratio of ethoxycarbonyl isothiocyanate and oxolane three is 1: 1.03: 10, determines that reaction is complete through TLC point plate,
Adding ethyl acetate and water, the organic phases washed with water separated, then wash with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is the most dry,
Residue ethyl alcohol recrystallization is purified, and obtains the intermediate (II) that character is light yellow solid, yield 83.4%, this step anti-
Ying Shitong embodiment 1;
E) prepare intermediate (III): will be by step D) intermediate (II) that obtains and hydroxylamine hydrochloride by N-methylmorpholine and
Carrying out ring closure reaction in the system of ethanol composition and under stirring, the time of ring closure reaction is 21h, the temperature of ring closure reaction
Degree is 70 DEG C, and the mol ratio of intermediate (II), hydroxylamine hydrochloride, N-methylmorpholine and ethanol is 1: 3.5: 2.6: 10,
TLC point plate determines that reaction is complete, is cooled to room temperature, adds dichloromethane and water, the organic phases washed with water separated, then uses salt
Washing, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate/normal hexane (3:7
V/v)] purification, obtains the intermediate (III) that character is light yellow solid, and yield 80.8%, the reaction equation of this step is with embodiment 1;
F) prepare Filgotinib: will be by step E under stirring) intermediate (III) that obtains with ring the third formyl chloride by pyrrole
Carrying out amidation process in the system of pyridine and methyl tertiary butyl ether(MTBE) composition, the time of amidation process is 3h, the temperature of amidation process
Degree is 60 DEG C, and the mol ratio of intermediate (III), ring the third formyl chloride, pyridine and methyl tertiary butyl ether(MTBE) is 1: 2.6: 2.8:
20, TLC point plates determine that reaction is complete, are cooled to room temperature, add dichloromethane and water, the organic phases washed with water separated, then
Washing with salt, then be dried with magnesium sulfate, concentrated by rotary evaporation is to dry, and residue crosses silica gel column chromatography [eluting solvent: ethyl acetate/just own
Alkane (3:7v/v)] purification, obtaining character is lurid solid, i.e. obtains Filgotinib, yield 90.7%, the reaction of this step
Formula is with embodiment 1.
Claims (10)
1. the synthetic method of a Filgotinib, it is characterised in that comprise the following steps:
A) prepare 6-hydroxyl-2-t-butoxycarbonyl amino pyridine: first by the chloro-PA of 6-in the solvent of condensation reaction with
Bis(tert-butoxycarbonyl)oxide carries out condensation reaction, obtains 6-chloro-2-t-butoxycarbonyl amino pyridine, then by chloro-for 6-2-tertbutyloxycarbonyl ammonia
Yl pyridines is put into and is hydrolyzed in the system being made up of alkali, quaternary ammonium salt phase transfer catalyst, the solvent of hydrolysis and water instead
Should, obtain 6-hydroxyl-2-t-butoxycarbonyl amino pyridine;Wherein, the solvent of described hydrolysis be Isosorbide-5-Nitrae-dioxane,
Toluene, o-Dimethylbenzene, meta-xylene, xylol, heptane, normal octane or N,N-dimethylformamide;
B) 2-t-butoxycarbonyl amino-6-pyridine radicals triflate is prepared: will be by step A) the 6-tertiary fourth of hydroxyl-2-that obtains
Oxygen carbonylamino pyridine and trifluoromethyl sulfonic acid anhydride carry out triflated reaction in acid binding agent alkali systems, obtain the tertiary fourth of 2-
Oxygen carbonylamino-6-pyridine radicals triflate;
C) intermediate (I) is prepared: will be by step B) the 2-t-butoxycarbonyl amino-6-pyridine radicals triflate that obtains and [(1,1-
Dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate forms at solvent, water, catalyst, potassium phosphate and inorganic matter
System carries out condensation reaction, obtains tert-butyl ester derivative, then this tert-butyl ester derivative trifluoroacetic acid is processed, carry out remove-insurance
Protect, obtain intermediate (I);Wherein, described catalyst be two (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium, 1,1-
Double (diphenylphosphine) ferrocene palladium chloride, Palladous chloride.;Described inorganic matter is lithium chloride, potassium chloride or potassium iodide;Described
Solvent is Isosorbide-5-Nitrae-dioxane, toluene, o-Dimethylbenzene, meta-xylene, xylol, heptane, normal butane or N, N-diformazan
Base Methanamide;The structural formula of described intermediate (I) is:
D) intermediate (II) is prepared: will be by step C) intermediate (I) that obtains is with ethoxycarbonyl isothiocyanate in a solvent
Carry out isothiocyanate reaction, obtain intermediate (II);The structural formula of described intermediate (II) is:
E) prepare intermediate (III): will be by step D) intermediate (II) that obtains with hydroxylamine hydrochloride at acid binding agent alkali and solvent
System in carry out ring closure reaction, obtain intermediate (III);The structural formula of described intermediate (III) is:
F) Filgotinib is prepared: will be by step E) intermediate (III) that obtains and ring the third formyl chloride be at acid binding agent alkali and solvent
System carries out amidation process, obtains Filgotinib.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step A) described in condensation
The solvent of reaction is dichloromethane, dichloroethanes, chloroform, oxolane, methyl tertiary butyl ether(MTBE), 1,4-dioxane or acetonitrile;
Described alkali is sodium hydroxide, potassium hydroxide or Cesium hydrate.;Described quaternary ammonium salt phase transfer catalyst be tetrabutylammonium chloride,
Tetrabutyl ammonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride,
Tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step A) described in condensation
The temperature of reaction is 10~80 DEG C, and the response time is 0.5~8 hour;The temperature of described hydrolysis is 90~120 DEG C, reaction
Time is 4~8 hours.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step A) described in 6-
The mol ratio of chloro-PA, the solvent of condensation reaction and Bis(tert-butoxycarbonyl)oxide three is 1.0: 5.0~30.0: 1.2~1.5,
Described 6-chloro-2-t-butoxycarbonyl amino pyridine, alkali, quaternary ammonium salt phase transfer catalyst, the solvent of hydrolysis and water
Mol ratio be 1.0: 1.0~1.2: 0.01~0.10: 5.0~50.0: 20.0~50.0;Described alkali is that mass percent concentration is
4.2~the sodium hydroxide solution of 33.4%, potassium hydroxide solution or cesium hydroxide solution.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step B) described in tie up acid
Agent alkali is triethylamine, diethylamine, N, N-diisopropylethylamine, pyridine, piperidines, 2,6-lutidines or N-methylmorpholine;
The temperature of described triflated reaction is-10~10 DEG C, and the response time is 0.5~3 hour;Described 6-hydroxyl-2-uncle
Butoxy carbonyl aminopyridine, trifluoromethyl sulfonic acid anhydride, the mol ratio of acid binding agent alkali three are 1.0: 1.2~1.5: 1.5~2.5.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step C) described in condensation
The temperature of reaction is 100~130 DEG C, and the response time is 15~30 hours.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step C) described in uncle 2-
Butoxy carbonyl amino-6-pyridine radicals triflate, [(1,1-dioxo-4-thio-morpholinyl) methyl] benzene-4-pinacol borate,
Solvent, water, catalyst, potassium phosphate, inorganic matter, the mol ratio of trifluoroacetic acid are 1.0: 1.0~1.2: 5.0~15.0:
2.0~5.0: 0.001~0.01: 0.5~1.0: 0.5~1.0: 1.0~1.5.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step D) described in solvent
For dichloromethane, dichloroethanes, chloroform, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane or acetonitrile;Described is different
The temperature of sulfocyanic ester reaction is 20~50 DEG C, and the response time is 15~30 hours;Described intermediate (I), carbethoxyl group are different
Sulfocyanic ester, the mol ratio of solvent three are 1.0: 1.0~1.1: 5.0~15.0.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step E) described in tie up acid
Agent alkali is triethylamine, diethylamine, N, N-diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, aniline, N, N-dimethyl benzene
Amine, N, N-diethylaniline, 2,6-lutidines, DMAP, tetramethyl guanidine or N-methylmorpholine;Described
Solvent is methanol, ethanol, isopropanol, normal propyl alcohol or the tert-butyl alcohol;The temperature of described ring closure reaction is 50~80 DEG C, during reaction
Between be 12~24 hours;The mol ratio of described intermediate (II), hydroxylamine hydrochloride, acid binding agent alkali and solvent is 1.0:
2.5~5.0: 2.0~3.0: 10.0~25.0.
The synthetic method of a kind of Filgotinib the most according to claim 1, it is characterised in that step F) described in solvent
For dichloromethane, dichloroethanes, chloroform, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane or acetonitrile;Described ties up
Acid agent alkali is triethylamine, diethylamine, DIPEA, pyridine, piperidines, tri-n-butylamine, aniline, N, N-diformazan
Base aniline, N, N-diethylaniline, 2,6-lutidines, 4-dimethylaminopyridine, tetramethyl guanidine or N-methylmorpholine;
The temperature of described amidation process is 50~80 DEG C, and the response time is 2~8 hours;Described intermediate (III), ring the third formyl
The mol ratio of chlorine, acid binding agent alkali and solvent is 1.0: 2.5~3.0: 2.5~3.5: 10.0~25.0.
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