CN106632260B - A kind of preparation method of small molecule kinase inhibitors - Google Patents
A kind of preparation method of small molecule kinase inhibitors Download PDFInfo
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Abstract
The present invention relates to a kind of preparation methods of small molecule kinase inhibitors, specifically, the new method for preparing the small molecule kinase inhibitors of a kind of Locally Advanced for treating anaplastic lymphoma kinase (ALK) positive or metastatic non-small cell lung cancer (NSCLC) is disclosed.The method comprising the steps of: with compound (II) for starting material, by substitution reaction, reduction reaction and oxidation reaction, annulation, reduction and deprotection reaction, to form (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine shown in formula (I).This method synthetic route is environmental-friendly, safety easy to operate, and total recovery is high, good in economic efficiency, is conducive to industrialized production.
Description
Technical field
The invention belongs to chemical pharmacy fields, and in particular to a kind of small molecule targeted drug 3- for treating non-small cell lung cancer
[(1R) -1- (the chloro- 3- fluorophenyl of 2,6- bis-)-ethyoxyl] -5- [1- (4- piperidyl) -1H- pyrazoles -4- base] -2- pyridine amine
Preparation method.
Background technique
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is a kind of for treating the Locally Advanced or metastatic of anaplastic lymphoma kinase (ALK) positive
The small molecule kinase inhibitors of non-small cell lung cancer (NSCLC), the entitled Crizotinib of English, entitled 3- [(the 1R) -1- of chemistry
(2,6- bis- chloro- 3- fluorophenyl)-ethyoxyl] -5- [1- (4- piperidyl) -1H- pyrazoles -4- base] -2- pyridine amine, trade name
XALKORI (Chinese trade name Sai Ruike), is succeeded in developing by Pfizer, and ratifies to list by U.S. FDA in 2011, with
Afterwards in Japan and European Union's listing, in acquisition China SFDA approval listing in 2013.(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is with ALK, hepatocyte growth factor
Sub- receptor (c-Met, HGFR) and tyrosine kinase receptor (RON) are action target spot, by inhibiting the resistance of ALK and c-Met phosphorylation
Disconnected growth of tumour cell and survival, to reach control tumour growth, or even the effect reduced.
Its specific structural formula are as follows:
At present about the document for preparing (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine are as follows:
Sun Xueying et al. has been delivered with the chloro- 3- fluoro acetophenone of 2,6- bis- in patent CN103664896 as starting material, is led to
Reduction, chiral resolution are crossed, Mitsunobu reaction restores, and Suzuki coupling and Deprotection Boc reaction are finally synthesizing mesh
Product (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is marked, the reaction overall yield is lower, and the chiral resolution yield of second step only has 30%, generates a large amount of by-products
Object is unfavorable for environmental protection.
Hong Jian et al. has delivered 4- (halogenated -1H- pyrazol-1-yl of 4-) piperidines -1- formic acid uncle in patent CN104693184
Butyl ester is raw material, obtain more active intermediate by the Chemical Exchange of halogen, then carries out coupling and Deprotection
Reaction.The reaction route is shorter, but yield is not high, and is coupled a step using heavy metal palladium as catalyst, pollutes environment,
Or using n-BuLi as reaction reagent, increasing the risk of operation, the ee value of final products is not also high.
Wei Zhepeng et al. has been delivered in patent CN103420987 is coupled and is deprotected two steps by simple Suzuki
Suddenly, final product is synthesized.The synthetic operation is simple, and step is brief, but starting material price is more expensive, and is difficult to obtain, coupling
It is necessary that making catalyst with more serious heavy metal palladium is polluted.
The document reported at present uses heavy metal palladium mostly and makees the catalyst reacted, seriously pollutes environment, total recovery
It is not high.Therefore it provides one avoids using heavy metal as reaction reagent, environment, and gram of high income and purity is high are protected
In azoles be necessary for the synthetic route of Buddhist nun.
Summary of the invention
The object of the present invention is to provide one kind to avoid using heavy metal as reaction reagent, protects environment, and high income with
And the new synthetic method of the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of purity is high.
First aspect present invention provides a kind of preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine shown in formula (I), with compound
It (II) is starting material, by substitution reaction, reduction reaction and oxidation reaction, annulation, reduction and deprotection reaction, thus
Form (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine shown in formula (I)；Comprising steps of
(1), the preparation of compound (III):
In atent solvent, in the presence of base catalyst, compound (II) and dimethyl malenate are subjected to substitution reaction,
To form compound (III)；
(2), the preparation of compound (IV):
(2.1) in atent solvent, compound (III) and reducing catalyst are subjected to reduction reaction, to form reaction
Mixture A；
(2.2) in atent solvent, reaction mixture A and oxidation catalyst that above-mentioned steps obtain aoxidize anti-
It answers, to form compound (IV)；
(3), the preparation of compound (VI):
Under solvent-free conditions, in catalyst or in the presence of do not have catalyst, compound (IV) and compound (V) are led to
It crosses grinding and carries out annulation, to form compound (VI)；
(4), the preparation of compound (I):
In atent solvent, reducing catalyst and deprotection catalyst in the presence of, by compound (VI) carry out reduction and
Deprotection reaction, to form compound (I).
In another preferred example, in step (1), the base catalyst is selected from the group: sodium carbonate, potassium carbonate, bicarbonate
Sodium, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or combinations thereof.
In another preferred example, in step (1), the atent solvent is selected from the group: acetonitrile, methylene chloride, Isosorbide-5-Nitrae-two
Six ring of oxygen, tetrahydrofuran, toluene, dimethylbenzene etc.；Preferably 1,4- dioxane.
In another preferred example, in step (1), the base catalyst is potassium carbonate or sodium carbonate.
In another preferred example, in step (1), the reaction temperature is 60~120 DEG C, preferably 80~110 DEG C.
In another preferred example, in step (2), the reducing catalyst is selected from the group: sodium borohydride/ZnCl2, boron hydrogen
Change sodium/AlCl3, lithium aluminium hydride, sodium cyanoborohydride, palladium carbon, Raney nickel, stannous chloride, or combinations thereof.
In another preferred example, in step (2), the oxidation catalyst is selected from the group: IBX, PCC, PDC, DIB,
DMP, MnO2, or combinations thereof.
In another preferred example, in step (2), the atent solvent is selected from the group: acetonitrile, methylene chloride, Isosorbide-5-Nitrae-two
Six ring of oxygen, tetrahydrofuran, toluene, DMSO, methanol, ethyl alcohol etc., preferably tetrahydrofuran or DMSO.
In another preferred example, in step (2), the reducing catalyst is sodium borohydride/ZnCl2, sodium borohydride/
AlCl3Or lithium aluminium hydride.
In another preferred example, in step (2), the oxidation catalyst is IBX.
In another preferred example, in step (2), the reaction temperature is -15~60 DEG C, preferably -10~50 DEG C.
In another preferred example, in step (3), the catalyst is selected from the group: p-methyl benzenesulfonic acid, benzene sulfonic acid, acetic acid,
Acid Al2O3, or combinations thereof；Or without catalyst.
In another preferred example, in step (3), the catalyst is p-methyl benzenesulfonic acid.
In another preferred example, in step (4), the atent solvent is selected from the group: acetonitrile, methylene chloride, acetic acid second
Ester, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, ethyl alcohol, isopropanol, or combinations thereof.
In another preferred example, in step (4), the reducing catalyst is selected from the group: HCl/SnCl2, H2/PtO2,
Pd/C。
In another preferred example, in step (4), the deprotection catalyst is selected from the group: HCl, trifluoroacetic acid,
Me3SiI, TBSOTf/2,6- lutidines, ZnBr2/CH2Cl2, or combinations thereof.
In another preferred example, in step (4), the atent solvent is methanol.
In another preferred example, in step (4), the reducing catalyst is HCl/SnCl2。
In another preferred example, in step (4), the deprotection catalyst is hydrochloric acid (preferably concentrated hydrochloric acid), trifluoro
Acetic acid.
In another preferred example, in step (4), the reaction temperature is -20~100 DEG C, preferably -10~80 DEG C.
In another preferred example, in step (2.1), reducing catalyst is dispersed in atent solvent first, is then added
Compound (III) carries out reduction reaction, to form reaction mixture A.
In another preferred example, between step (2.1) and (2.2), the reaction for obtaining step (2.1) is further comprised the steps of:
Mixture A is quenched, is concentrated plus water, filtration treatment, collects filtrate, is further processed to obtain reaction mixture A.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
The present inventor after extensive and in-depth study, has been surprisingly found that and a kind of prepares 3- [(1R) -1- (2,6- bis- chloro- 3- fluorine
Phenyl)-ethyoxyl] -5- [1- (4- piperidyl) -1H- pyrazoles -4- base] -2- pyridine amine (i.e. (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine) new method.It should
The advantages that method has synthetic route short, and safety easy to operate is good in economic efficiency, environmental-friendly, high income, therefore it is suitble to industry
Metaplasia produces.On this basis, inventor completes the present invention.
Method of the invention may include the following steps:
(1), the preparation of compound (III)
Compound (II) and dimethyl malenate are dissolved in solvent appropriate, suitable base catalyst is then added,
Reaction is completed at temperature appropriate, obtains compound (III) through processing；
Wherein: suitable solvent is acetonitrile, methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, and dimethylbenzene etc. is excellent
Select 1,4- dioxane；Suitable catalyst is sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide,
Sodium ethoxide etc., preferably potassium carbonate, sodium carbonate；Reaction temperature is 60~120 DEG C, preferably 80~110 DEG C.
(2), the preparation of compound (IV)
At a proper temperature, reducing catalyst appropriate is dispersed in solvent appropriate, is slowly added to compound
(III), gained concentrate is diluted in solvent appropriate through processing appropriate and concentration after the reaction was completed, in temperature appropriate
Degree is lower to be added oxidation catalyst, finally obtains compound (IV)；
Wherein: suitable solvent is acetonitrile, methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, DMSO, methanol,
Ethyl alcohol etc., preferably tetrahydrofuran, DMSO；Suitable reducing catalyst is sodium borohydride/ZnCl2, sodium borohydride/AlCl3, hydrogenation
Lithium aluminium, sodium cyanoborohydride, palladium carbon, Raney nickel, stannous chloride etc., preferably sodium borohydride/ZnCl2, sodium borohydride/AlCl3, hydrogen
Change lithium aluminium；Suitable oxidation catalyst is IBX, PCC, PDC, DIB, DMP, MnO2Deng preferably IBX；Reaction temperature is -15~60
DEG C, preferably -10~50 DEG C.
(3), the preparation of compound (VI)
Compound (IV) and compound (V) are uniformly mixed, suitable catalyst is added or without catalyst, solvent-free item
Compound (VI) is obtained by grinding under part；
Wherein: suitable catalyst is p-methyl benzenesulfonic acid, benzene sulfonic acid, acetic acid, acid Al2O3, preferred p-methyl benzenesulfonic acid；Or
Person is without catalyst.
(4), the preparation of compound (I)
By compound (VI) dispersion in a suitable solution, suitable catalyst is added, at a proper temperature reduction and
Protecting group is sloughed, through processing appropriate, finally obtains compound (I)；
Wherein: suitable solvent is acetonitrile, methylene chloride, ethyl acetate, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, second
Alcohol, isopropanol etc., preferably methanol；Suitable reducing catalyst is HCl/SnCl2, H2/PtO2, Pd/C etc., preferably HCl/SnCl2；
Suitable Deprotection catalyst is HCl, trifluoroacetic acid, Me3SiI, TBSOTf/2,6- lutidines, ZnBr2/CH2Cl2
Deng, preferably HCl, trifluoroacetic acid；Preferable reaction temperature is -20~100 DEG C, preferably -10~80 DEG C.
Main advantages of the present invention include:
The new synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine provided by the invention has synthetic route short, safety easy to operate, economy effect
The advantages that benefit is good, environmental-friendly, high income, is very suitable to industrialized production.
Below with reference to specific implementation, the present invention is further explained.It should be understood that these embodiments be merely to illustrate the present invention and
It is not used in and limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition,
Or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.The present invention is implemented
Raw materials used or instrument in example, if not it illustrates, it is commercially available.
Embodiment 1.
(1), the preparation of compound (III)
Compound (II) (20g, 48.78mmol) and dimethyl malenate (6.44g, 48.78mmol) are dissolved in Isosorbide-5-Nitrae-two
In six ring of oxygen (200ml), potassium carbonate (13.48g, 97.56mmol) then is added, 100 DEG C are heated under stirring condition, reaction
6.5h, TLC detection, fully reacting.Solvent is removed in decompression rotation, residue is poured into 200ml water, with ethyl acetate (3x 100ml)
Extraction three times, merges organic phase, and then by water, salt water washing, anhydrous sodium sulfate is dry, and solvent is removed in rotation, and gained crude product is with just
Heptane mashing, filter, obtain filter cake, dry, obtain light gray solid, be compound (III) 19.4g, 86%.
1H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),
5.31 (s, 1H), 5.11 (m, 1H), 3.73 (s, 6H), 1.71 (d, J=4.8Hz, 3H) .C18H15Cl2FN2O7Calcd:
460.0240,found:460.0313。
(2), the preparation of compound (IV)
By ZnCl2(7.97g, 58.54mmol) is dispersed in anhydrous tetrahydro furan (500ml), is placed in ice-water bath, is stirred
It mixes down, is added and sodium borohydride (2.21g, 58.54mmol) is added in batches, compound (III) is slowly added at 0~5 DEG C
(18g, 39.02mmol), charging finishes reacts 4h at room temperature, and TLC detection, reaction is completed, at a temperature of being down to 0~5 DEG C slowly
Ammonium chloride saturated solution is added to be quenched, tetrahydrofuran, water supplement (300ml) are gone in rotation, and diatomite (10g) stirring 30min is added,
It filters, filtrate is extracted three times with ethyl acetate (3x 100ml), merges organic phase, then passes through water, salt water washing, anhydrous slufuric acid
Sodium is dry, and organic solvent is removed in rotation, and gained residue is diluted with DMSO (300ml), then be added IBX (11.47g,
40.97mmol), 2h, TLC detection are stirred at room temperature, and reaction is completed.Reaction system is poured into water, is saturated sodium hydroxide with 1N
Solution is adjusted to pH=8-9, then three times with ethyl acetate (3x 100ml) extraction, merges organic phase, then full by sodium bicarbonate
And solution, salt water washing, anhydrous sodium sulfate are dry, and solvent is removed in rotation, obtain compound (IV) 12.2g, 78%.
1H-NMR(400MHz,DMSO-d6):δ,9.78(s,2H),8.40(s,1H),8.05(s,1H),7.27(s,1H),
7.07 (s, 1H), 5.18 (m, 1H), 4.63 (s, 1H), 1.73 (d, J=4.8Hz, 3H) .C16H11Cl2FN2O5Calcd:
400.0029,found:400.0130。
(3), the preparation of compound (VI)
At room temperature, compound (IV) (2.0g, 3.5mmol) and compound (V) (0.75g, 3.5mmol) are placed in agate
It in mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, is passed sequentially through
Saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous sodium sulfate is dry, filters, is spin-dried for obtaining product compound (VI)
(1.48g, 73%).
(4), the preparation of compound (I)
At 0 DEG C, by SnCl2·2H2O (7.78g, 34.46mmol) is scattered in methanol (32mL) and concentrated hydrochloric acid (16mL) is mixed
It closes in liquid, then compound (VI) (10g, 17.23mmol) is added in stirring 15min, 3.5h is reacted under stirring, and TLC is detected, instead
It should complete.Water (50mL) dilution is added, at 0 DEG C, 1N sodium hydroxide solution is slowly added dropwise, until pH=8~9.Methanol is removed in rotation
Solvent, Liquid Residue are extracted three times with ethyl acetate (3x 100ml), merge organic phase, pass through water and saturated common salt water washing, nothing
Aqueous sodium persulfate is dry, is spin-dried for, and obtains product compound (I) 7.21g, and 93%
Embodiment 2.
(1), the preparation of compound (III)
Compound (II) (20g, 48.78mmol) and dimethyl malenate (6.77g, 51.22mmol) are dissolved in Isosorbide-5-Nitrae-two
In six ring of oxygen (200ml), potassium carbonate (13.48g, 97.56mmol) then is added, 100 DEG C are heated under stirring condition, reaction
6.5h, TLC detection, fully reacting.Solvent is removed in decompression rotation, residue is poured into 200ml water, with ethyl acetate (3x 200ml)
Extraction three times, merges organic phase, and then by water, salt water washing, anhydrous sodium sulfate is dry, and solvent is removed in rotation, and gained crude product is with just
Heptane mashing, filter, obtain filter cake, dry, obtain light gray solid, be compound (III) 20.02g, 89%.
1H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),
5.31 (s, 1H), 5.11 (m, 1H), 3.73 (s, 6H), 1.71 (d, J=4.8Hz, 3H) .C18H15Cl2FN2O7Calcd:
460.0240,found:460.0313。
(2), the preparation of compound (IV)
By ZnCl2(7.97g, 58.54mmol) is dispersed in anhydrous tetrahydro furan (500ml), is placed in ice-water bath, is stirred
It mixes down, is added and sodium borohydride (2.21g, 58.54mmol) is added in batches, compound (III) is slowly added at 0~5 DEG C
(18g, 39.02mmol), charging finishes reacts 4h at room temperature, and TLC detection, reaction is completed, at a temperature of being down to 0~5 DEG C slowly
Ammonium chloride saturated solution is added to be quenched, tetrahydrofuran, water supplement (300ml) are gone in rotation, and diatomite (10g) stirring 30min is added,
It filters, filtrate is extracted three times with ethyl acetate (3x 100ml), merges organic phase, then passes through water, salt water washing, anhydrous slufuric acid
Sodium is dry, and organic solvent is removed in rotation, and gained residue is diluted with DMSO (300ml), then be added IBX (11.47g,
40.97mmol), 2h, TLC detection are stirred at room temperature, and reaction is completed.Reaction system is poured into water, is saturated sodium hydroxide with 1N
Solution is adjusted to pH=8-9, then three times with ethyl acetate (3x 100ml) extraction, merges organic phase, then full by sodium bicarbonate
And solution, salt water washing, anhydrous sodium sulfate are dry, and solvent is removed in rotation, obtain compound (IV) 11.9g, 76%.
1H-NMR(400MHz,DMSO-d6):δ,9.78(s,2H),8.40(s,1H),8.05(s,1H),7.27(s,1H),
7.07 (s, 1H), 5.18 (m, 1H), 4.63 (s, 1H), 1.73 (d, J=4.8Hz, 3H) .C16H11Cl2FN2O5Calcd:
400.0029,found:400.0130。
(3), the preparation of compound (VI)
At room temperature, compound (IV) (2.0g, 3.5mmol) and compound (V) (0.75g, 3.5mmol) are placed in agate
It in mortar, mixes well, adds p-methyl benzenesulfonic acid (0.03g, 0.175mmol), grind 10min, sampling, TLC detection, reaction
It completes.Product is dissolved in ethyl acetate, saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous slufuric acid are passed sequentially through
Sodium is dry, filters, is spin-dried for obtaining product compound (VI) (1.91g, 94%).
(4), the preparation of compound (I)
At 0 DEG C, by SnCl2·2H2O (7.78g, 34.46mmol) is scattered in methanol (32mL) and concentrated hydrochloric acid (16mL) is mixed
It closes in liquid, then compound (VI) (10g, 17.23mmol) is added in stirring 15min, 3.5h is reacted under stirring, and TLC is detected, instead
It should complete.Water (50mL) dilution is added, at 0 DEG C, 1N sodium hydroxide solution is slowly added dropwise, until pH=8~9.Methanol is removed in rotation
Solvent, Liquid Residue are extracted three times with ethyl acetate (3x 100ml), merge organic phase, by saturated common salt water washing, anhydrous sulphur
Sour sodium is dry, is spin-dried for, obtains product compound (I), 7.06g, 91%.
Embodiment 3.
(1), the preparation of compound (III)
Compound (II) (20g, 48.78mmol) and dimethyl malenate (6.77g, 51.22mmol) are dissolved in Isosorbide-5-Nitrae-two
In six ring of oxygen (200ml), potassium carbonate (13.48g, 97.56mmol) then is added, 100 DEG C are heated under stirring condition, reaction
6.5h, TLC detection, fully reacting.Solvent is removed in decompression rotation, residue is poured into 200ml water, with ethyl acetate (3x 200ml)
Extraction three times, merges organic phase, and then by water, salt water washing, anhydrous sodium sulfate is dry, and solvent is removed in rotation, and gained crude product is with just
Heptane mashing, filter, obtain filter cake, dry, obtain light gray solid, be compound (III) 19.57g, 87%.
1H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),
5.31 (s, 1H), 5.11 (m, 1H), 3.73 (s, 6H), 1.71 (d, J=4.8Hz, 3H) .C18H15Cl2FN2O7Calcd:
460.0240,found:460.0313。
(2), the preparation of compound (IV)
By ZnCl2(10.64g, 78.04mmol) is dispersed in anhydrous tetrahydro furan (500ml), is placed in ice-water bath,
Under stirring, it is added and sodium borohydride (2.95g, 78.04mmol) is added in batches, compound (III) is slowly added at 0~5 DEG C
(18g, 39.02mmol), charging finishes reacts 4h at room temperature, and TLC detection, reaction is completed, at a temperature of being down to 0~5 DEG C slowly
Ammonium chloride saturated solution is added to be quenched, tetrahydrofuran, water supplement (300ml) are gone in rotation, and diatomite (10g) stirring 30min is added,
It filters, filtrate is extracted three times with ethyl acetate (3x 100ml), merges organic phase, then passes through water, salt water washing, anhydrous slufuric acid
Sodium is dry, and organic solvent is removed in rotation, and gained residue is diluted with DMSO (300ml), then be added IBX (11.47g,
40.97mmol), 2h, TLC detection are stirred at room temperature, and reaction is completed.Reaction system is poured into water, is saturated sodium hydroxide with 1N
Solution is adjusted to pH=8-9, then three times with ethyl acetate (3x 100ml) extraction, merges organic phase, then full by sodium bicarbonate
And solution, salt water washing, anhydrous sodium sulfate are dry, and solvent is removed in rotation, obtain compound (IV) 12.53g, 80%.
1H-NMR(400MHz,DMSO-d6):δ,9.78(s,2H),8.40(s,1H),8.05(s,1H),7.27(s,1H),
7.07 (s, 1H), 5.18 (m, 1H), 4.63 (s, 1H), 1.73 (d, J=4.8Hz, 3H) .C16H11Cl2FN2O5Calcd:
400.0029,found:400.0130。
(3), the preparation of compound (VI)
At room temperature, compound (IV) (2.0g, 3.5mmol) and compound (V) (0.75g, 3.5mmol) are placed in agate
It in mortar, mixes well, adds p-methyl benzenesulfonic acid (0.03g, 0.175mmol), grind 10min, sampling, TLC detection, reaction
It completes.Product is dissolved in ethyl acetate, saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous slufuric acid are passed sequentially through
Sodium is dry, filters, is spin-dried for obtaining product compound (VI) (1.85g, 91%).
(4), the preparation of compound (I)
At 0 DEG C, by SnCl2·2H2O (7.78g, 34.46mmol) is scattered in methanol (32mL) and concentrated hydrochloric acid (16mL) is mixed
It closes in liquid, then compound (VI) (10g, 17.23mmol) is added in stirring 15min, 3.5h is reacted under stirring, and TLC is detected, instead
It should complete.Water (50mL) dilution is added, at 0 DEG C, 1N sodium hydroxide solution is slowly added dropwise, until pH=8~9.Methanol is removed in rotation
Solvent, Liquid Residue are extracted three times with ethyl acetate (3x 100ml), merge organic phase, by saturated common salt water washing, anhydrous sulphur
Sour sodium is dry, is spin-dried for, obtains product compound (I), 6.98g, 90%.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (14)
1. a kind of preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine shown in formula (I), which is characterized in that with compound (II) for starting material,
By substitution reaction, reduction reaction and oxidation reaction, annulation, reduction and deprotection reaction, to be formed shown in formula (I)
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine；Comprising steps of
(1), the preparation of compound (III):
In atent solvent, in the presence of base catalyst, compound (II) and dimethyl malenate are subjected to substitution reaction, thus
It is formed compound (III)；
(2), the preparation of compound (IV):
(2.1) in atent solvent, compound (III) and reducing catalyst are subjected to reduction reaction, to form reaction mixing
Object A, wherein the reducing catalyst is selected from the group: sodium borohydride/ZnCl2, sodium borohydride/AlCl3, lithium aluminium hydride, cyano boron hydrogen
Change sodium, palladium carbon, Raney nickel, stannous chloride, or combinations thereof；
(2.2) in atent solvent, the reaction mixture A and oxidation catalyst that above-mentioned steps are obtained carry out oxidation reaction, from
And form compound (IV)；
(3), the preparation of compound (VI):
Under solvent-free conditions, in catalyst or in the presence of there is no catalyst, compound (IV) and compound (V) is passed through and ground
Mill carries out annulation, to form compound (VI)；
(4), the preparation of compound (I):
In atent solvent, in the presence of reducing catalyst and deprotection catalyst, compound (VI) is subjected to reduction and remove-insurance
Shield reaction, to form compound (I)；
Also, in step (4), the reducing catalyst is selected from the group: HCl/SnCl2, H2/PtO2, Pd/C；
The deprotection catalyst is selected from the group: HCl, trifluoroacetic acid, Me3SiI, TBSOTf/2,6- lutidines,
ZnBr2/CH2Cl2, or combinations thereof.
2. the method according to claim 1, wherein the base catalyst is selected from the group: carbon in step (1)
Sour sodium, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or combinations thereof.
3. the method as described in claim 1, which is characterized in that in step (1), the atent solvent is selected from the group: acetonitrile,
Methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene and dimethylbenzene.
4. the method according to claim 1, wherein the reducing catalyst is selected from the group in step (2):
Sodium borohydride/ZnCl2。
5. the method according to claim 1, wherein the oxidation catalyst is selected from the group in step (2):
IBX, PCC, PDC, DIB, DMP, MnO2, or combinations thereof.
6. the method as described in claim 1, which is characterized in that in step (2), the atent solvent is selected from the group: acetonitrile,
Methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, DMSO, methanol and ethyl alcohol.
7. the method according to claim 1, wherein the catalyst is selected from the group: to first in step (3)
Benzene sulfonic acid, benzene sulfonic acid, acetic acid, acid Al2O3, or combinations thereof；Or without catalyst.
8. the method according to claim 1, wherein the atent solvent is selected from the group: second in step (4)
Nitrile, methylene chloride, ethyl acetate, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, ethyl alcohol, isopropanol, or combinations thereof.
9. the method according to claim 1, wherein the reducing catalyst is selected from the group in step (4):
HCl/SnCl2。
10. the method according to claim 1, wherein the deprotection catalyst is selected from down in step (4)
Group: HCl.
11. the method according to claim 1, wherein reducing catalyst is dispersed in first in step (2.1)
In atent solvent, compound (III) then is added, reduction reaction is carried out, to form reaction mixture A.
12. the method according to claim 1, wherein between step (2.1) and (2.2), further comprise the steps of: by
The reaction mixture A that step (2.1) obtains is quenched, is concentrated plus water, filtration treatment, collects filtrate, is further processed to obtain anti-
Answer mixture A.
13. method as claimed in claim 3, which is characterized in that in step (1), the atent solvent is Isosorbide-5-Nitrae-dioxy six
Ring.
14. method as claimed in claim 6, which is characterized in that in step (2), the atent solvent is DMSO.
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