CN106632260A - Preparation method for micro-molecular kinase inhibitor - Google Patents
Preparation method for micro-molecular kinase inhibitor Download PDFInfo
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- CN106632260A CN106632260A CN201610873621.XA CN201610873621A CN106632260A CN 106632260 A CN106632260 A CN 106632260A CN 201610873621 A CN201610873621 A CN 201610873621A CN 106632260 A CN106632260 A CN 106632260A
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- 0 *c1c[n](C2CC*CC2)nc1 Chemical compound *c1c[n](C2CC*CC2)nc1 0.000 description 4
- KTEIFNKAUNYNJU-GFCCVEGCSA-N C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C3CCNCC3)nc2)c1 Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C3CCNCC3)nc2)c1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention relates to a preparation method for a micro-molecular kinase inhibitor. Specifically, the invention discloses a novel method for preparing the micro-molecular kinase inhibitor capable of treating locally-advanced or metastatic non-small cell lung cancer (NSCLC) with positive anaplastic lymphoma kinase (ALK). The method comprises the following steps: with a compound (II) as a starting material, carrying out a substitution reaction, a reduction reaction, an oxidation reaction, a cyclization reaction and a reduction and deprotection reaction so as to form crizotinib as shown in a formula (I) in the specification. The method provided by the invention has the advantages of environment-friendly synthetic route, simple and safe operation, high overall yield, good economic benefits, and facilitation industrial production.
Description
Technical field
The invention belongs to chemical pharmacy field, and in particular to a kind of small molecule targeted drug 3- for treating nonsmall-cell lung cancer
[(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-)-ethyoxyl] -5- [1- (4- piperidyls) -1H- pyrazoles -4- bases] -2- pyridine amine
Preparation method.
Background technology
(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 Locally Advanced or metastatic positive for treating anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK)
The small molecule kinase inhibitors of nonsmall-cell lung cancer (NSCLC), English entitled Crizotinib, chemical entitled 3- [(1R) -1-
(2,6- bis- chloro- 3- fluorophenyls)-ethyoxyl] -5- [1- (4- piperidyls) -1H- pyrazoles -4- bases] -2- pyridine amine, trade name
XALKORI (Chinese trade name Sai Ruike), is succeeded in developing by Pfizer, and is listed by U.S. FDA approval in 2011, with
Afterwards in Japan and European Union's listing, China SFDA approval listings were obtained 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 suppressing the resistance of ALK and c-Met phosphorylations
Disconnected growth of tumour cell and survival, so as to reach control tumour growth, or even the effect for reducing.
Its specific structural formula is：
At present the document with regard to preparing (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is：
Sun Xueying et al. has been delivered with the chloro- 3- fluoro acetophenones of 2,6- bis- as initiation material in patent CN103664896, is led to
Reduction is crossed, chiral separation, Mitsunobu reactions are restored, and Suzuki is coupled and Deprotection Boc reactions, is finally synthesizing mesh
Mark product (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, the reaction overall yield is relatively low, and the chiral separation yield of second step only has 30%, produces a large amount of by-products
Thing, is unfavorable for environmental conservation.
Hong Jian et al. has delivered 4- (4- halo -1H- pyrazol-1-yls) piperidines -1- formic acid uncles in patent CN104693184
Butyl ester is raw material, the intermediate more enlivened by the Chemical Exchange of halogen, is then coupled and Deprotection
Reaction.The reaction scheme is shorter, but yield is not high, and is coupled a step using heavy metal palladium as catalyst, pollutes environment,
Or by the use of n-BuLi as reaction reagent, increasing the danger of operation, the ee values of final products are not also high.
Wei Zhepeng et al. has been delivered in patent CN103420987 and has been coupled by simple Suzuki and two steps of deprotection
Suddenly, final product is synthesized.The synthetic operation is simple, and step is brief, but initiation material is expensive, and is difficult to obtain, and is coupled
It is necessary that making catalyst with more serious heavy metal palladium is polluted.
At present the document of report employs the catalyst that heavy metal palladium is made to react, serious environment pollution, total recovery mostly
It is not high.Therefore it provides one avoid using heavy metal as reaction reagent, environmental protection, and high income and purity it is high gram
In azoles be a need for for the synthetic route of Buddhist nun.
The content of the invention
It is an object of the invention to provide one kind avoid using heavy metal as reaction reagent, environmental protection, and high income with
And the new synthetic method of the high (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of purity.
First aspect present invention provides the preparation method of the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine shown in a kind of formula (I), and it is with compound
(II) it is initiation material, by substitution reaction, reduction reaction and oxidation reaction, annulation, reduction and deprotection reaction, so as to
Form the (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)；Including step：
(1), the preparation of compound (III)：
In atent solvent, in the presence of base catalyst, compound (II) and dimethyl malenate are carried out into substitution reaction,
So as to form compound (III)；
(2), the preparation of compound (IV)：
(2.1) in atent solvent, compound (III) and reducing catalyst are carried out into reduction reaction, so as to form reaction
Mixture A；
(2.2) in atent solvent, the reactant mixture A that above-mentioned steps are obtained and oxidation catalyst carry out aoxidizing instead
Should, so as to form compound (IV)；
(3), the preparation of compound (VI)：
It is in the presence of catalyst or no catalyst, compound (IV) and compound (V) is logical under condition of no solvent
Crossing grinding carries out annulation, so as to form compound (VI)；
(4), the preparation of compound (I)：
In atent solvent, in the presence of reducing catalyst and deprotection catalyst, by compound (VI) carry out reduction and
Deprotection reaction, so as to form compound (I).
In another preference, in step (1), described base catalyst is selected from the group：Sodium carbonate, potassium carbonate, bicarbonate
Sodium, sodium hydroxide, potassium hydroxide, Feldalat NM, Sodium ethylate, or its combination.
In another preference, in step (1), described atent solvent is selected from the group：Acetonitrile, dichloromethane, Isosorbide-5-Nitrae-two
The ring of oxygen six, tetrahydrofuran, toluene, dimethylbenzene etc.；Preferably 1,4- dioxane.
In another preference, in step (1), described base catalyst is potassium carbonate or sodium carbonate.
In another preference, in step (1), described reaction temperature is 60～120 DEG C, preferably 80～110 DEG C.
In another preference, in step (2), described reducing catalyst is selected from the group：Sodium borohydride/ZnCl2, boron hydrogen
Change sodium/AlCl3, lithium aluminium hydride, sodium cyanoborohydride, palladium carbon, Raney nickel, stannum dichloride, or its combination.
In another preference, in step (2), described oxidation catalyst is selected from the group：IBX, PCC, PDC, DIB,
DMP, MnO2, or its combination.
In another preference, in step (2), described atent solvent is selected from the group：Acetonitrile, dichloromethane, Isosorbide-5-Nitrae-two
The ring of oxygen six, tetrahydrofuran, toluene, DMSO, methanol, ethanol etc., preferably tetrahydrofuran or DMSO.
In another preference, in step (2), described reducing catalyst is sodium borohydride/ZnCl2, sodium borohydride/
AlCl3Or lithium aluminium hydride.
In another preference, in step (2), described oxidation catalyst is IBX.
In another preference, in step (2), described reaction temperature is -15～60 DEG C, preferably -10～50 DEG C.
In another preference, in step (3), described catalyst is selected from the group：P-methyl benzenesulfonic acid, benzenesulfonic acid, acetic acid,
Acid Al2O3, or its combination；Or without catalyst.
In another preference, in step (3), described catalyst is p-methyl benzenesulfonic acid.
In another preference, in step (4), described atent solvent is selected from the group：Acetonitrile, dichloromethane, acetic acid second
Ester, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, ethanol, isopropanol, or its combination.
In another preference, in step (4), described reducing catalyst is selected from the group：HCl/SnCl2, H2/PtO2,
Pd/C。
In another preference, in step (4), described deprotection catalyst is selected from the group：HCl, trifluoroacetic acid,
Me3SiI, TBSOTf/2,6- lutidines, ZnBr2/CH2Cl2, or its combination.
In another preference, in step (4), described atent solvent is methanol.
In another preference, in step (4), described reducing catalyst is HCl/SnCl2。
In another preference, in step (4), described deprotection catalyst is hydrochloric acid (preferably concentrated hydrochloric acid), trifluoro
Acetic acid.
In another preference, in step (4), described reaction temperature is -20～100 DEG C, preferably -10～80 DEG C.
In another preference, in step (2.1), reducing catalyst is dispersed in atent solvent first, is subsequently adding
Compound (III), carries out reduction reaction, so as to form reactant mixture A.
In another preference, between step (2.1) and (2.2), also including step：The reaction that step (2.1) is obtained
Mixture A Jing are quenched, concentrate, adding water, filtration treatment, collect filtrate, further process and obtain reactant mixture A.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and have in below (eg embodiment)
Can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
The present inventor has been surprisingly found that one kind prepares 3- [(1R) -1- (2,6- bis- chloro- 3- fluorine through extensively in-depth study
Phenyl)-ethyoxyl] -5- [1- (4- piperidyls) -1H- pyrazoles -4- bases] -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.Should
Method has synthetic route short, safety simple to operate, good in economic efficiency, environmental friendliness, the advantages of high income, therefore is adapted to industry
Metaplasia is produced.On this basis, inventor completes the present invention.
The method of the present invention can comprise the following steps：
(1), the preparation of compound (III)
Compound (II) and dimethyl malenate are dissolved in appropriate solvent, appropriate base catalyst is subsequently adding,
Reaction is completed at appropriate temperature, Jing process obtains compound (III)；
Wherein：Suitable solvent is acetonitrile, dichloromethane, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, dimethylbenzene etc., excellent
Select 1,4- dioxane；Suitable catalyst is sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, Feldalat NM,
Sodium ethylate etc., preferred 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, appropriate reducing catalyst is dispersed in appropriate solvent, is slowly added to compound
(III) Jing appropriate process and concentration, gained concentrate are diluted in appropriate solvent, in appropriate temperature after, reaction is completed
Degree is lower to add oxidation catalyst, finally obtains compound (IV)；
Wherein：Suitable solvent is acetonitrile, dichloromethane, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, DMSO, methanol,
Ethanol etc., preferred tetrahydrofuran, DMSO；Suitable reducing catalyst is sodium borohydride/ZnCl2, sodium borohydride/AlCl3, hydrogenation
Lithium aluminum, sodium cyanoborohydride, palladium carbon, Raney nickel, stannum dichloride etc., preferred sodium borohydride/ZnCl2, sodium borohydride/AlCl3, hydrogen
Change lithium aluminum；Suitable oxidation catalyst is IBX, PCC, PDC, DIB, DMP, MnO2Deng preferred IBX；Reaction temperature is -15～60
DEG C, preferably -10～50 DEG C.
(3), the preparation of compound (VI)
By compound (IV) and compound (V) mix homogeneously, suitable catalyst is added or without catalyst, solvent-free bar
Compound (VI) is obtained by grinding under part；
Wherein：Suitable catalyst is p-methyl benzenesulfonic acid, benzenesulfonic acid, acetic acid, acid Al2O3, preferred p-methyl benzenesulfonic acid；Or
Person is without catalyst.
(4), the preparation of compound (I)
Compound (VI) is disperseed in a suitable solution, to add appropriate catalyst, at a proper temperature reduction and
Protection group is sloughed, Jing appropriate process finally obtains compound (I)；
Wherein：Suitable solvent is acetonitrile, dichloromethane, ethyl acetate, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, second
Alcohol, isopropanol etc., preferred methanol；Suitable reducing catalyst is HCl/SnCl2, H2/PtO2, Pd/C etc., preferred HCl/SnCl2；
Suitable Deprotection catalyst is HCl, trifluoroacetic acid, Me3SiI, TBSOTf/2,6- lutidines, ZnBr2/CH2Cl2
Deng, preferred 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 the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine that the present invention is provided has synthetic route short, safety simple to operate, economy effect
The advantages of beneficial good, environmental friendliness, high income, it is especially suitable for industrialized production.
With reference to being embodied as, the present invention is expanded on further.It should be understood that these embodiments be merely to illustrate the present invention and
It is not used in restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to normal condition,
Or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.The present invention is implemented
Raw materials used or instrument in example, if not special instruction, 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 into Isosorbide-5-Nitrae-two
In the ring of oxygen six (200ml), potassium carbonate (13.48g, 97.56mmol) is subsequently adding, 100 DEG C is heated under stirring condition, reaction
6.5h, TLC detect that reaction is complete.Solvent is removed in decompression rotation, residue is poured in 200ml water, with ethyl acetate (3x 100ml)
Extraction three times, merges organic faciess, and then by water, solvent is removed in salt water washing, anhydrous sodium sulfate drying, rotation, and gained crude product is with just
Heptane is beaten, and sucking filtration obtains filter cake, dries, and obtains light gray solid, is compound (III) 19.4g, and 86%.
1H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),
(d, J=4.8Hz, the 3H) .C of 5.31 (s, 1H), 5.11 (m, 1H), 3.73 (s, 6H), 1.7118H15Cl2FN2O7Calcd:
460.0240,found:460.0313。
(2), the preparation of compound (IV)
By ZnCl2(7.97g, 58.54mmol) is dispersed in anhydrous tetrahydro furan (500ml), in being placed in ice-water bath, is stirred
Mix down, add and add in batches sodium borohydride (2.21g, 58.54mmol), compound (III) is slowly added at 0～5 DEG C
(18g, 39.02mmol), charging is finished and react at room temperature 4h, and TLC detections, reaction is completed, slow at a temperature of being down to 0～5 DEG C
Add ammonium chloride saturated solution to be quenched, tetrahydrofuran is removed in rotation, add water (300ml), and add kieselguhr (10g) to stir 30min,
Sucking filtration, filtrate is extracted three times with ethyl acetate (3x 100ml), merges organic faciess, then by water, salt water washing, and anhydrous slufuric acid
Sodium is dried, and organic solvent is removed in rotation, and gained residue is diluted with DMSO (300ml), then add IBX (11.47g,
40.97mmol), 2h is stirred under room temperature, TLC detections, reaction is completed.Reaction system is poured into water, with 1N saturation sodium hydroxide
Solution is adjusted to pH=8-9, then is extracted three times with ethyl acetate (3x 100ml), merges organic faciess, then full by sodium bicarbonate
And solution, salt water washing, anhydrous sodium sulfate drying, rotation removes solvent, obtains compound (IV) 12.2g, and 78%.
1H-NMR(400MHz,DMSO-d6):δ,9.78(s,2H),8.40(s,1H),8.05(s,1H),7.27(s,1H),
(d, J=4.8Hz, the 3H) .C of 7.07 (s, 1H), 5.18 (m, 1H), 4.63 (s, 1H), 1.7316H11Cl2FN2O5Calcd:
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 into Achatess
In mortar, fully mix, grind 10min, sampling, TLC detections, reaction is completed.Product is dissolved in ethyl acetate, is passed sequentially through
Saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous sodium sulfate drying, sucking filtration, are 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
In closing liquid, 15min is stirred, be subsequently adding compound (VI) (10g, 17.23mmol), reaction 3.5h under stirring, TLC detections, instead
Should complete.Water (50mL) dilution is added, at 0 DEG C, 1N sodium hydroxide solutions is slowly added dropwise, until pH=8～9.Methanol is removed in rotation
Solvent, debris are extracted three times with ethyl acetate (3x 100ml), merge organic faciess, by water and saturated common salt water washing, nothing
Aqueous sodium persulfate is dried, and 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 into Isosorbide-5-Nitrae-two
In the ring of oxygen six (200ml), potassium carbonate (13.48g, 97.56mmol) is subsequently adding, 100 DEG C is heated under stirring condition, reaction
6.5h, TLC detect that reaction is complete.Solvent is removed in decompression rotation, residue is poured in 200ml water, with ethyl acetate (3x 200ml)
Extraction three times, merges organic faciess, and then by water, solvent is removed in salt water washing, anhydrous sodium sulfate drying, rotation, and gained crude product is with just
Heptane is beaten, and sucking filtration obtains filter cake, dries, and obtains light gray solid, is compound (III) 20.02g, and 89%.
1H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),
(d, J=4.8Hz, the 3H) .C of 5.31 (s, 1H), 5.11 (m, 1H), 3.73 (s, 6H), 1.7118H15Cl2FN2O7Calcd:
460.0240,found:460.0313。
(2), the preparation of compound (IV)
By ZnCl2(7.97g, 58.54mmol) is dispersed in anhydrous tetrahydro furan (500ml), in being placed in ice-water bath, is stirred
Mix down, add and add in batches sodium borohydride (2.21g, 58.54mmol), compound (III) is slowly added at 0～5 DEG C
(18g, 39.02mmol), charging is finished and react at room temperature 4h, and TLC detections, reaction is completed, slow at a temperature of being down to 0～5 DEG C
Add ammonium chloride saturated solution to be quenched, tetrahydrofuran is removed in rotation, add water (300ml), and add kieselguhr (10g) to stir 30min,
Sucking filtration, filtrate is extracted three times with ethyl acetate (3x 100ml), merges organic faciess, then by water, salt water washing, and anhydrous slufuric acid
Sodium is dried, and organic solvent is removed in rotation, and gained residue is diluted with DMSO (300ml), then add IBX (11.47g,
40.97mmol), 2h is stirred under room temperature, TLC detections, reaction is completed.Reaction system is poured into water, with 1N saturation sodium hydroxide
Solution is adjusted to pH=8-9, then is extracted three times with ethyl acetate (3x 100ml), merges organic faciess, then full by sodium bicarbonate
And solution, salt water washing, anhydrous sodium sulfate drying, rotation removes solvent, obtains compound (IV) 11.9g, and 76%.
1H-NMR(400MHz,DMSO-d6):δ,9.78(s,2H),8.40(s,1H),8.05(s,1H),7.27(s,1H),
(d, J=4.8Hz, the 3H) .C of 7.07 (s, 1H), 5.18 (m, 1H), 4.63 (s, 1H), 1.7316H11Cl2FN2O5Calcd:
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 into Achatess
In mortar, fully mix, add p-methyl benzenesulfonic acid (0.03g, 0.175mmol), grind 10min, sampling, TLC detections, reaction
Complete.Product is dissolved in ethyl acetate, saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous slufuric acid is passed sequentially through
Sodium be dried, sucking filtration, be spin-dried for 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
In closing liquid, 15min is stirred, be subsequently adding compound (VI) (10g, 17.23mmol), reaction 3.5h under stirring, TLC detections, instead
Should complete.Water (50mL) dilution is added, at 0 DEG C, 1N sodium hydroxide solutions is slowly added dropwise, until pH=8～9.Methanol is removed in rotation
Solvent, debris are extracted three times with ethyl acetate (3x 100ml), merge organic faciess, by saturated common salt water washing, anhydrous sulfur
Sour sodium is dried, and is spin-dried for, and obtains product compound (I), 7.06g, and 91%.
Embodiment 3.
(1), the preparation of compound (III)
Compound (II) (20g, 48.78mmol) and dimethyl malenate (6.77g, 51.22mmol) are dissolved in into Isosorbide-5-Nitrae-two
In the ring of oxygen six (200ml), potassium carbonate (13.48g, 97.56mmol) is subsequently adding, 100 DEG C is heated under stirring condition, reaction
6.5h, TLC detect that reaction is complete.Solvent is removed in decompression rotation, residue is poured in 200ml water, with ethyl acetate (3x 200ml)
Extraction three times, merges organic faciess, and then by water, solvent is removed in salt water washing, anhydrous sodium sulfate drying, rotation, and gained crude product is with just
Heptane is beaten, and sucking filtration obtains filter cake, dries, and obtains light gray solid, is compound (III) 19.57g, and 87%.
1H-NMR(400MHz,DMSO-d6):δ8.33(s,1H),8.01(s,1H),7.29(s,1H),7.04(s,1H),
(d, J=4.8Hz, the 3H) .C of 5.31 (s, 1H), 5.11 (m, 1H), 3.73 (s, 6H), 1.7118H15Cl2FN2O7Calcd:
460.0240,found:460.0313。
(2), the preparation of compound (IV)
By ZnCl2(10.64g, 78.04mmol) is dispersed in anhydrous tetrahydro furan (500ml), in being placed in ice-water bath,
Under stirring, add and add in batches sodium borohydride (2.95g, 78.04mmol), compound (III) is slowly added at 0～5 DEG C
(18g, 39.02mmol), charging is finished and react at room temperature 4h, and TLC detections, reaction is completed, slow at a temperature of being down to 0～5 DEG C
Add ammonium chloride saturated solution to be quenched, tetrahydrofuran is removed in rotation, add water (300ml), and add kieselguhr (10g) to stir 30min,
Sucking filtration, filtrate is extracted three times with ethyl acetate (3x 100ml), merges organic faciess, then by water, salt water washing, and anhydrous slufuric acid
Sodium is dried, and organic solvent is removed in rotation, and gained residue is diluted with DMSO (300ml), then add IBX (11.47g,
40.97mmol), 2h is stirred under room temperature, TLC detections, reaction is completed.Reaction system is poured into water, with 1N saturation sodium hydroxide
Solution is adjusted to pH=8-9, then is extracted three times with ethyl acetate (3x 100ml), merges organic faciess, then full by sodium bicarbonate
And solution, salt water washing, anhydrous sodium sulfate drying, rotation removes solvent, obtains compound (IV) 12.53g, and 80%.
1H-NMR(400MHz,DMSO-d6):δ,9.78(s,2H),8.40(s,1H),8.05(s,1H),7.27(s,1H),
(d, J=4.8Hz, the 3H) .C of 7.07 (s, 1H), 5.18 (m, 1H), 4.63 (s, 1H), 1.7316H11Cl2FN2O5Calcd:
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 into Achatess
In mortar, fully mix, add p-methyl benzenesulfonic acid (0.03g, 0.175mmol), grind 10min, sampling, TLC detections, reaction
Complete.Product is dissolved in ethyl acetate, saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous slufuric acid is passed sequentially through
Sodium be dried, sucking filtration, be spin-dried for 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
In closing liquid, 15min is stirred, be subsequently adding compound (VI) (10g, 17.23mmol), reaction 3.5h under stirring, TLC detections, instead
Should complete.Water (50mL) dilution is added, at 0 DEG C, 1N sodium hydroxide solutions is slowly added dropwise, until pH=8～9.Methanol is removed in rotation
Solvent, debris are extracted three times with ethyl acetate (3x 100ml), merge organic faciess, by saturated common salt water washing, anhydrous sulfur
Sour sodium is dried, and is spin-dried for, and obtains product compound (I), 6.98g, and 90%.
The all documents referred in the present invention are all incorporated as in this application reference, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned teachings for having read the present invention, those skilled in the art can
To make various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. the preparation method of the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine shown in a kind of formula (I), it is characterised in that with compound (II) as initiation material,
By substitution reaction, reduction reaction and oxidation reaction, annulation, reduction and deprotection reaction, so as 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；Including step：
(1), the preparation of compound (III)：
In atent solvent, in the presence of base catalyst, compound (II) and dimethyl malenate are carried out into substitution reaction, so as to
Form compound (III)；
(2), the preparation of compound (IV)：
(2.1) in atent solvent, compound (III) and reducing catalyst are carried out into reduction reaction, so as to form reaction mixing
Thing A；
(2.2) in atent solvent, the reactant mixture A that above-mentioned steps are obtained and oxidation catalyst carry out oxidation reaction, from
And form compound (IV)；
(3), the preparation of compound (VI)：
Under condition of no solvent, in the presence of catalyst or no catalyst, by compound (IV) and compound (V) by grinding
Mill carries out annulation, so as 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 reduced and remove-insurance
Shield reaction, so as to form compound (I).
2. method according to claim 1, it is characterised in that in step (1), described base catalyst is selected from the group：Carbon
Sour sodium, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, Feldalat NM, Sodium ethylate, or its combination.
3. method according to claim 1, it is characterised in that in step (2), described reducing catalyst is selected from the group：
Sodium borohydride/ZnCl2, sodium borohydride/AlCl3, lithium aluminium hydride, sodium cyanoborohydride, palladium carbon, Raney nickel, stannum dichloride, or its
Combination.
4. method according to claim 1, it is characterised in that in step (2), described oxidation catalyst is selected from the group：
IBX, PCC, PDC, DIB, DMP, MnO2, or its combination.
5. method according to claim 1, it is characterised in that in step (3), described catalyst is selected from the group：To first
Benzenesulfonic acid, benzenesulfonic acid, acetic acid, acid Al2O3, or its combination；Or without catalyst.
6. method according to claim 1, it is characterised in that in step (4), described atent solvent is selected from the group：Second
Nitrile, dichloromethane, ethyl acetate, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methanol, ethanol, isopropanol, or its combination.
7. method according to claim 1, it is characterised in that in step (4), described reducing catalyst is selected from the group：
HCl/SnCl2, H2/PtO2, Pd/C.
8. method according to claim 1, it is characterised in that in step (4), described deprotection catalyst is selected from down
Group：HCl, trifluoroacetic acid, Me3SiI, TBSOTf/2,6- lutidines, ZnBr2/CH2Cl2, or its combination.
9. method according to claim 1, it is characterised in that in step (2.1), be first dispersed in reducing catalyst lazy
In property solvent, compound (III) is subsequently adding, reduction reaction is carried out, so as to form reactant mixture A.
10. method according to claim 1, it is characterised in that between step (2.1) and (2.2), also including step：Will
The reactant mixture A Jing that step (2.1) is obtained are quenched, concentrate, adding water, filtration treatment, collect filtrate, further process and obtain anti-
Answer mixture A.
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| CN108373469A (en) * | 2018-04-12 | 2018-08-07 | 大连理工大学 | Diaryl second diether compound and its pharmaceutically acceptable hydrate or salt, synthetic method and its application on antitumor |
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