CN110606842A - Process for producing pyridylamino pyrimidine derivative and intermediate thereof - Google Patents

Process for producing pyridylamino pyrimidine derivative and intermediate thereof Download PDF

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CN110606842A
CN110606842A CN201810627166.4A CN201810627166A CN110606842A CN 110606842 A CN110606842 A CN 110606842A CN 201810627166 A CN201810627166 A CN 201810627166A CN 110606842 A CN110606842 A CN 110606842A
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CN110606842B (en
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张强
罗会兵
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JIANGSU ELLIS BIO-PHARMACEUTICAL Co Ltd
Shanghai Allist Pharmaceuticals Inc
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JIANGSU ELLIS BIO-PHARMACEUTICAL Co Ltd
Shanghai Allist Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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 provides a compound of formula I2- [2- (dimethylamino ethyl) methylamino]-3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino]A process for the preparation of (E) -6- (2, 2, 2-trifluoroethoxy) pyridine, intermediates used therein and processes for the preparation of related intermediates. The method comprises the steps of carrying out condensation reaction, substitution reaction, reduction reaction, acylation reaction and elimination reaction on 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole and a compound shown in a formula VII to obtain the compound shown in the formula I. The preparation method disclosed by the invention is environment-friendly, low in cost, mild in condition, simple to operate, high in yield, high in purity of the final product and suitable for industrial production.

Description

Process for producing pyridylamino pyrimidine derivative and intermediate thereof
Technical Field
The invention relates to the technical field of organic synthesis and preparation of raw material medicines, in particular to a method for preparing an anti-tumor medicine N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide and an intermediate thereof.
Background
The compound N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide with the structure of formula I is an Epidermal Growth Factor Receptor (EGFR) inhibitor, has remarkably higher inhibitory activity on drug-resistant mutation of EGFR T790M than on wild-type EGFR (WT EGFR), has good selectivity and lower toxic and side effects, can be used for treating cancers, particularly non-small cell lung cancer, and is at the clinical stage at home at present.
The CN105315259A patent application claims the compound of formula I and discloses the preparation method thereof as follows,
in the preparation method, the iron powder/ammonium chloride is used for reducing the 6-chloro-2-trifluoroethoxy-3-nitropyridine, the post-treatment is troublesome, more waste residues are generated, and the preparation method is not beneficial to environmental protection; in the route, heavy metal is used in both coupling reaction and hydrogenation reduction reaction, the cost is high, and heavy metal residues exist in the product; the yield of the last acylation reaction is only 23 percent; the post-treatment of the multi-step reaction uses column chromatography; the preparation route has more overall steps, the total yield is only 2.3 percent, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of long route, low yield, high cost, environmental pollution and the like of the prior art, and provides a synthesis process route which has the advantages of high yield, high purity of the final product, environmental friendliness, low cost, mild conditions, simplicity in operation and suitability for industrial production.
The invention provides a preparation method of a compound 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine shown in the formula I, which comprises the following steps: in an organic solvent, the compound shown in the formula III' and the compound shown in the formula XIII are subjected to acylation reaction to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride shown in the formula II; in the presence of alkali, 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride in the formula II undergoes elimination reaction to obtain a compound in the formula I;
wherein X is Cl or Br.
In the process for the preparation of the compounds of formula I, preferably, X is Cl.
In the preparation method of the compound of the formula I, the organic solvent in the acylation reaction is preferably dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate, acetone or a mixed solvent thereof, and more preferably dichloromethane, acetonitrile, THF or a mixed solvent thereof. The obtained product, namely the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II is insoluble in an organic solvent and is separated out in a solid form, the product is directly filtered and separated for next elimination reaction, the operation is simple and convenient, impurities dissolved in the organic solvent are removed, and the final product, namely the compound of the formula I, obtained through elimination reaction has high yield and high purity.
In the preparation method of the compound of the formula I, the reaction temperature of the acylation reaction is preferably-10 ℃ to 10 ℃, and more preferably-10 ℃ to 0 ℃.
In the preparation method of the compound of formula I, the base used in the elimination reaction is preferably sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine, more preferably triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine or morpholine.
In the preparation method of the compound shown in the formula I, the molar ratio of the alkali to 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride in the elimination reaction is 4-6: 1, preferably 5-6: 1.
In the method for preparing the compound of formula I, the reaction solvent for the elimination reaction is preferably dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate, acetone or a mixed solvent thereof, more preferably dichloromethane, acetonitrile, THF or a mixed solvent thereof.
In the preparation method of the compound of the formula I, preferably, the method further comprises the step of decoloring the compound of the formula I with activated carbon in an organic solvent. The organic solvent is preferably a halogenated alkane solvent or an ester solvent, the halogenated alkane solvent is preferably dichloromethane, and the ester solvent is preferably ethyl acetate. The active carbon decoloration can remove partial impurities, so that the purity of the final product is improved.
The preparation method of the compound of formula I provided by the present invention further preferably comprises the following steps: carrying out salt-forming reaction on the compound shown in the formula III' and acid HA to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt shown in the formula III; reacting 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt of formula III with a base in an organic solvent, then carrying out acylation reaction with a compound shown in a formula XIII to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride shown in a formula II;
wherein n is 1 or 2, and X is Cl or Br.
In said step of preparing 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of formula II, preferably, X is Cl.
In said step of preparing 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of formula II, preferably n is 2.
In the preparation step of the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II, the acid HA in the salt forming reaction comprises an organic acid or an inorganic acid, and particularly, hydrochloric acid, hydrobromic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid is preferred, and hydrochloric acid is more preferred. The formula III2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indole-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt obtained by salt forming reaction is separated out in a solid form, is directly filtered and separated, eliminates impurities, HAs stable property, is storage-resistant, is not easy to deteriorate and is convenient for subsequent reaction compared with a free basic III' compound, and a final product, namely the formula I compound obtained by acylation reaction and elimination reaction HAs high purity and yield.
In the preparation step of the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II, the reaction solvent for the salt forming reaction is preferably methanol, ethanol, isopropanol, THF, 2-MeTHF or a mixed solvent thereof, more preferably ethanol, THF, 2-MeTHF or a mixed solvent thereof, and most preferably a mixed solvent of ethanol and THF.
In the preparation step of 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II, the base is preferably sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine, more preferably triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine or morpholine.
In the preparation step of the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II, the molar ratio of the base to the 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA hydrochloride of the formula III is 1-2: 1, preferably 1: 1 or 2: 1.
In the preparation step of the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II, the organic solvent is preferably dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate, acetone or a mixed solvent thereof, and more preferably dichloromethane, acetonitrile, THF or a mixed solvent thereof. The obtained product, namely the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II is insoluble in an organic solvent and is separated out in a solid form, the product is directly filtered and separated for next elimination reaction, the operation is simple and convenient, impurities dissolved in the organic solvent are removed, and the final product, namely the compound of the formula I, obtained through elimination reaction has high yield and purity.
In said step of preparing 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of formula II, preferably further comprising the step of slurrying 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt of formula III in a solvent, the solvent includes an alcohol solvent, and particularly preferably methanol, ethanol, isopropanol or a mixed solvent thereof. The purity of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt of formula III is improved by removing part of impurities through a pulping step.
The preparation method of the compound of formula I provided by the present invention further preferably comprises the following steps: reducing the compound of formula IV with a reducing agent in a solvent to obtain a compound of formula III';
in the preparation step of the compound of the formula III', the reducing agent is preferably sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen is used for reducing the compound of the formula IV in the presence of a catalyst of palladium carbon, palladium hydroxide/carbon or Raney nickel, and the hydrazine hydrate is used for reducing the compound of the formula IV in the presence of a catalyst of ferric trichloride/activated carbon; more preferably, the reducing agent is sodium hydrosulfite.
In the preparation step of the compound of formula III', the solvent is an organic solvent or a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; preferably, the solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; further preferably, the solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethylene glycol dimethyl ether, ethyl acetate, acetone, or a mixed solvent thereof.
In the preparation step of the compound of the formula III', preferably, when the reducing agent sodium hydrosulfite is used for reducing the compound of the formula IV, acid HB is further added. The added acid HB can promote the conversion of intermediate substances of the reduction reaction to products, promote the completion of the reduction reaction, improve the reaction efficiency, and have high product yield, high purity and few byproducts. The acid HB is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or acetic acid, more preferably hydrochloric acid. The molar ratio of the acid HB to the compound of the formula IV is 12-24: 1.
The preparation method of the compound of formula I provided by the present invention further preferably comprises the following steps: carrying out condensation reaction on a compound shown in a formula VI and a compound shown in a formula VII in the presence of acid to obtain a compound shown in a formula V or a salt thereof; in a polar organic solvent, carrying out substitution reaction on a compound shown in a formula V or a salt thereof and N, N, N' -trimethylethylenediamine in the presence of alkali to obtain a compound shown in a formula IV;
wherein Y is F, Cl or Br.
In the preparation step of the compound of formula IV, preferably, Y is F or Cl.
In the preparation step of the compound shown in the formula IV, in the condensation reaction, the acid is trifluoroacetic acid and TsOH2O or TsOH, the trifluoroacetic acid, TsOH2The molar ratio of O or TsOH to the compound of the formula VII is 0.5-2: 1, and a compound of the formula V or a trifluoro acetate or p-toluenesulfonate thereof is obtained through a condensation reaction; further preferably, the acid is trifluoroacetic acid, tsoh2O or TsOH, the trifluoroacetic acid, TsOH2The molar ratio of O or TsOH to the compound of the formula VII is 1.3-2: 1, preferably 1.5-1.8: 1, and the compound of the formula V is obtained through condensation reaction to obtain trifluoroacetate or p-toluenesulfonate; even more preferably, the acid is tsoh2O or TsOH, said TsOH2The molar ratio of O or TsOH to the compound of the formula VII is 1.3-2: 1, preferably 1.5-1.8: 1, and the compound of the formula V is obtained through condensation reaction. The excessive acid is added to ensure that the compound shown in the formula VII is completely converted, the product obtained by the reaction has high purity and high yield, and the obtained product is the salt shown in the formula V (such as trifluoroacetate or p-toluenesulfonate of the compound shown in the formula V), is directly precipitated in a solid form, is easy to filter and separate, and has a simple process.
In the preparation step of the compound of formula IV, the reaction solvent of the condensation reaction is preferably toluene, methanol, ethanol, isopropanol, n-butanol, 2-pentanol, isobutanol, THF, 2-MeTHF, 1, 4-dioxane, acetonitrile, ethyl acetate, acetone, 1, 2-dichloroethane or a mixed solvent thereof; more preferably toluene, n-butanol, 2-pentanol, isobutanol, 1, 4-dioxane, THF, 1, 2-dichloroethane or a mixed solvent thereof; most preferred are toluene, 1, 4-dioxane, THF, 1, 2-dichloroethane or a mixed solvent thereof.
In the preparation step of the compound of formula IV, the base in the substitution reaction is preferably potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine, and more preferably potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium carbonate.
In the preparation step of the compound of formula IV, the polar organic solvent in the substitution reaction is preferably DMF, dimethyl sulfoxide, acetonitrile, THF, 2-MeTHF, N-methyl-2-pyrrolidone, N-dimethylacetamide, hexamethylphosphoric triamide, N' -trimethylethylenediamine or a mixed solvent thereof, and more preferably DMF, dimethyl sulfoxide, N-dimethylacetamide or a mixed solvent thereof.
In said step of preparing the compound of formula IV, preferably, a step of further slurrying the compound of formula V or a salt thereof is included. The solvent used for the beating includes a cyclic ether solvent, and THF or 2-MeTHF is particularly preferable.
In the preparation step of the compound of formula IV, preferably, a step of further slurrying the compound of formula IV is included. The solvent used for beating comprises a nitrile solvent or a cyclic ether solvent, the nitrile solvent is preferably acetonitrile, and the cyclic ether solvent is preferably THF.
The preparation method of the compound of the formula I preferably adopts the following synthetic route:
wherein, X is Cl or Br, and Y is F, Cl or Br. Wherein each reaction condition is the same as that described above.
The process for the preparation of the compounds of the formula I further preferably employs the following synthetic route:
wherein n is 1 or 2, X is Cl or Br, and Y is F, Cl or Br. Wherein each reaction condition is the same as that described above.
The preparation method of the compound of formula I provided by the present invention further preferably comprises the following steps: in the presence of alkali a, carrying out etherification reaction on a compound shown in the formula XII and trifluoroethanol to obtain a compound shown in the formula XI; reducing a compound of formula XI with a reducing agent in a solvent to obtain a compound of formula X; in the presence of alkali b, carrying out acylation reaction on the compound of the formula X and an acylating agent to obtain a compound of a formula IX; carrying out nitration reaction on the compound of the formula IX and a nitration reagent to obtain a compound of a formula VIII; in the presence of acid, carrying out hydrolysis reaction on the compound shown in the formula VIII to obtain a compound shown in the formula VII;
wherein Y is F, Cl or Br.
In said step of preparing the compound of formula VII, said base a in the etherification reaction is preferably NaH, LiHMDS, NaHMDS or KHMDS, more preferably NaH.
In the preparation step of the compound of formula VII, the reaction solvent of the etherification reaction is preferably toluene, methanol, ethanol, isopropanol, n-butanol, 2-pentanol, isobutanol, acetonitrile, THF, 2-MeTHF, 1, 4-dioxane, ethyl acetate, acetone or a mixed solvent thereof, and more preferably toluene, methanol, 2-pentanol, isobutanol, acetonitrile, THF, 1, 4-dioxane or a mixed solvent thereof.
In the preparation step of the compound of the formula VII, the reducing agent in the reaction of reducing the compound of the formula XI is preferably sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen reduction of the compound of the formula XI is carried out in the presence of palladium carbon, palladium hydroxide/carbon or Raney nickel as a catalyst, and the hydrazine hydrate reduction of the compound of the formula XI is carried out in the presence of iron trichloride/activated carbon as a catalyst; more preferably, the reducing agent is sodium hydrosulfite.
In said preparation step of the compound of formula VII, preferably, when the compound of formula XI is reduced with the reducing agent sodium hydrosulfite, the acid HB is further added. The added acid HB can promote the conversion of intermediate substances of the reduction reaction to products, promote the completion of the reduction reaction, improve the reaction efficiency, and have high product yield, high purity and few byproducts. The acid HB is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or acetic acid, more preferably hydrochloric acid. The molar ratio of the acid HB to the compound of the formula XI is 8-12: 1, and preferably 10: 1.
In the preparation step of the compound of formula VII, the solvent in the reaction of reducing the compound of formula XI is an organic solvent or a mixed solvent of water and the organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; preferably, the solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; further preferably, the solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethylene glycol dimethyl ether, ethyl acetate, acetone, or a mixed solvent thereof.
In the preparation step of the compound of formula VII, the base b in the acylation reaction is preferably triethylamine, N-diisopropylethylamine, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide, more preferably triethylamine or N, N-diisopropylethylamine.
In the preparation step of the compound of formula VII, the acylating agent in the acylation reaction is TFAA or trifluoroacetyl chloride, preferably TFAA.
In the preparation step of the compound of formula VII, the reaction solvent of the acylation reaction is preferably dichloromethane, acetonitrile, THF, 2-MeTHF, 1, 4-dioxane, ethyl acetate, acetone or a mixed solvent thereof, more preferably dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate or a mixed solvent thereof, and most preferably dichloromethane, acetonitrile, THF or a mixed solvent thereof.
In the preparation step of the compound of the formula VII, the nitrating reagent in the nitration reaction is HNO3/H2SO4、KNO3/H2SO4Or fuming nitric acid; preferably HNO3/H2SO4Or KNO3/H2SO4。
In the preparation step of the compound of formula VII, the acid in the hydrolysis reaction is preferably hydrochloric acid, sulfuric acid, TsOH2O, TsOH methanesulfonic acid or benzenesulfonic acid, more preferably TsOH2O or TsOH.
In the preparation step of the compound of formula VII, the reaction solvent of the hydrolysis reaction is preferably methanol, ethanol, isopropanol, acetonitrile, THF, 2-MeTHF, 1, 4-dioxane, ethyl acetate, acetone or a mixed solvent thereof, more preferably methanol, ethanol, acetonitrile, THF, ethyl acetate, acetone or a mixed solvent thereof, and most preferably methanol, ethanol, acetonitrile, THF or a mixed solvent thereof.
The invention provides a preparation method of the compound of the formula I, and further preferably comprises a purification method of the compound of the formula I,
the method comprises the following steps: mixing the crude product of the compound of the formula I with a benign solvent, heating for dissolving, dripping a poor solvent, cooling, and carrying out suction filtration to obtain a purified compound of the formula I;
the second method comprises the following steps: mixing the crude product of the compound of the formula I with an organic solvent, heating to dissolve the crude product clearly, cooling, and carrying out suction filtration to obtain the purified compound of the formula I.
In the first method or the second method of the method for purifying the compound of the formula I, the temperature of the heated solvent is 40-82 ℃.
In the first method or the second method of the method for purifying the compound of the formula I, the cooling temperature is 15-25 ℃.
In the first method of the process for purifying the compound of formula I, the benign solvent is preferably acetone, acetonitrile, methanol, ethanol, isopropanol, dichloromethane, THF, 2-MeTHF, ethyl acetate, DMF or a mixed solvent thereof, more preferably acetone, ethyl acetate, acetonitrile, THF, methanol, ethanol, isopropanol, dichloromethane, DMF or a mixed solvent thereof.
In process one of the processes for purifying the compound of formula I, the weight g of the crude compound of formula I and benign solvent: the volume ml ratio is 1: 4-35.
In the first method of the method for purifying a compound of formula I, the poor solvent is preferably water, n-heptane, n-hexane, n-pentane, cyclohexane, toluene, benzene, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixed solvent thereof, and more preferably water, n-heptane, methyl tert-butyl ether or a mixed solvent thereof.
In the first method of the purification method of the compound of formula I, the volume ratio of the benign solvent to the poor solvent is preferably 0.5-5: 1, and more preferably 0.5-3.6: 1.
In the second method of the purification method of the compound of formula I, the organic solvent is preferably acetone, acetonitrile, methanol, ethanol, isopropanol, dichloromethane, THF, 2-MeTHF, ethyl acetate, toluene, xylene, methyl tert-butyl ether or a mixed solvent thereof, more preferably acetone, acetonitrile, methanol, ethanol, isopropanol, THF, ethyl acetate, toluene, xylene or a mixed solvent thereof.
In process two of the processes for purifying the compound of formula I, the weight g of the crude compound of formula I and the organic solvent: the volume ml ratio is preferably 1: 5-35, and more preferably 1: 6-25.
In the first or second method of the method for purifying the compound of formula I, preferably, after heating and dissolving, stirring is continued for 0.5 to 1 hour, preferably 0.5 hour, under heat preservation.
In the purification method of the compound of the formula I, preferably, the method I or the method II is carried out under the protection of nitrogen or argon.
The invention also provides intermediate compounds or salts of the formula,
wherein n is 1 or 2; x is Cl or Br; y is F, Cl or Br; HA is an acid selected from hydrochloric acid, hydrobromic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, preferably hydrochloric acid.
The invention also provides intermediate compounds or salts of the formula,
the invention also provides the use of the above intermediate compound or salt for the preparation of a compound of formula I or a salt thereof.
The invention also provides a preparation method of the mesylate of the compound shown in the formula I, which comprises the step of reacting the compound shown in the formula I prepared by the preparation method of the compound shown in the formula I with methanesulfonic acid.
The present invention also provides a process for the preparation of a compound of formula VII, comprising: in the presence of alkali a, carrying out etherification reaction on a compound shown in the formula XII and trifluoroethanol to obtain a compound shown in the formula XI; reducing a compound of formula XI with a reducing agent in a solvent to obtain a compound of formula X; in the presence of alkali b, carrying out acylation reaction on the compound of the formula X and an acylating agent to obtain a compound of a formula IX; carrying out nitration reaction on the compound of the formula IX and a nitration reagent to obtain a compound of a formula VIII; in the presence of acid, carrying out hydrolysis reaction on the compound shown in the formula VIII to obtain a compound shown in the formula VII;
wherein Y is F, Cl or Br; wherein the reaction conditions in each step are the same as those described above.
The invention also provides a preparation method of the compound of the formula V or the salt thereof, which comprises the steps of carrying out condensation reaction on the compound of the formula VI and the compound of the formula VII in the presence of acid to obtain the compound of the formula V or the salt thereof,
wherein Y is F, Cl or Br; wherein each reaction condition is the same as that described above.
The present invention also provides a process for preparing a compound of formula IV, comprising: carrying out condensation reaction on a compound shown in a formula VI and a compound shown in a formula VII in the presence of acid to obtain a compound shown in a formula V or a salt thereof; in a polar organic solvent, carrying out substitution reaction on a compound shown in a formula V or a salt thereof and N, N, N' -trimethylethylenediamine in the presence of alkali to obtain a compound shown in a formula IV;
wherein Y is F, Cl or Br; wherein each reaction condition is the same as that described above.
The invention also provides a preparation method of the compound of the formula III ', which comprises the steps of reducing the compound of the formula IV by a reducing agent to obtain the compound of the formula III',
wherein the reducing agent is preferably sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen is used for reducing the compound shown in the formula IV in the presence of palladium carbon, palladium hydroxide/carbon or Raney nickel serving as catalysts, and the hydrazine hydrate is used for reducing the compound shown in the formula IV in the presence of iron trichloride/activated carbon serving as a catalyst.
In the preparation method of the compound of the formula III', more preferably, the reducing agent is sodium hydrosulfite.
In the preparation method of the compound of the formula III', preferably, when the reducing agent sodium hydrosulfite is used for reducing the compound of the formula IV, acid HB is further added. The added acid HB can promote the conversion of intermediate state substances of the reduction reaction to products, promote the completion of the reduction reaction, improve the reaction efficiency, and have high product purity, high yield and few byproducts. The acid HB is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or acetic acid, more preferably hydrochloric acid. The molar ratio of the acid HB to the compound of the formula IV is 12-24: 1.
In the preparation step of the compound of formula III', the reaction solvent used in the reaction of reducing the compound of formula IV with the reducing agent is an organic solvent or a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; preferably, the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; further preferably, the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethylene glycol dimethyl ether, ethyl acetate, acetone, or a mixed solvent thereof.
The invention also provides a process for preparing 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of formula II comprising: in an organic solvent, the compound shown in the formula III' and the compound shown in the formula XIII are subjected to acylation reaction to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride shown in the formula II;
wherein X is Cl or Br; wherein each reaction condition is the same as that described above.
The present invention still further provides a process for the preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of formula II comprising: carrying out salt-forming reaction on the compound shown in the formula III' and acid HA to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt shown in the formula III; reacting 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt of formula III with a base in an organic solvent, then carrying out acylation reaction with a compound shown in a formula XIII to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride shown in a formula II;
wherein n is 1 or 2, and X is Cl or Br; wherein each reaction condition is the same as that described above.
The invention also provides a method for purifying the compound of the formula I, which comprises the following steps,
the method comprises the following steps: mixing the crude product of the compound of the formula I with a benign solvent, heating for dissolving, dripping a poor solvent, cooling, and carrying out suction filtration to obtain a purified compound of the formula I;
the second method comprises the following steps: mixing the crude product of the compound of the formula I with an organic solvent, heating to dissolve the crude product clearly, cooling, and carrying out suction filtration to obtain the purified compound of the formula I. Wherein each purification condition is the same as that described above.
The invention also provides a preparation method of the compound shown in the formula I, which comprises the steps of reducing the compound shown in the formula IV by using a reducing agent,
the reducing agent is preferably sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen is used for reducing the compound shown in the formula IV in the presence of palladium carbon, palladium hydroxide/carbon or Raney nickel serving as a catalyst, and the hydrazine hydrate is used for reducing the compound shown in the formula IV in the presence of iron trichloride/activated carbon serving as a catalyst; more preferably, the reducing agent is sodium hydrosulfite.
In the preparation method of the compound of the formula I, preferably, when the reducing agent sodium hydrosulfite is used for reducing the compound of the formula IV, an acid HB is further added. The added acid HB can promote the conversion of intermediate state substances of the reduction reaction to products, promote the completion of the reduction reaction, improve the reaction efficiency, and have high product purity, high yield and few byproducts. The acid HB is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or acetic acid, more preferably hydrochloric acid. The molar ratio of the acid HB to the compound of the formula IV is 12-24: 1.
In the preparation method of the compound of the formula I, a reaction solvent used in a reaction of reducing the compound of the formula IV by a reducing agent is an organic solvent or a mixed solvent of water and the organic solvent, wherein the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; preferably, the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof; further preferably, the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethylene glycol dimethyl ether, ethyl acetate, acetone, or a mixed solvent thereof.
The abbreviations of the reagents used in the present invention are as follows:
THF tetrahydrofuran
2-MeTHF 2-methyltetrahydrofuran
TFAA trifluoroacetic anhydride
DCM dichloromethane
TsOH.H2O-p-toluenesulfonic acid monohydrate
TsOH p-toluenesulfonic acid
NaH sodium hydrogen
LiHMDS lithium hexamethyldisilazide
NaHMDS sodium bis (trimethylsilyl) amide
KHMDS potassium hexamethyldisilazide
DMF N, N-dimethylformamide
The preparation method has the advantages that:
(1) the compound of formula VI and the compound of formula VII are subjected to condensation reaction without using heavy metal catalyst, so that the cost is low and no heavy metal residue is generated.
(2) In the condensation reaction of the compound of the formula VI and the compound of the formula VII, the compound of the formula VII can be completely converted by using excessive acid, the product obtained by the reaction has high purity and high yield, and the obtained product is the salt of the compound of the formula V, is directly precipitated in a solid form, is easy to filter and separate and has simple process.
(3) Salifying the compound shown in the formula III 'in an organic solvent to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt shown in the formula III', separating out the salt in a solid form, directly filtering and separating the salt, and removing impurities; compared with the free alkali type III' compound, the salt of the compound is stable in property, not easy to deteriorate, storage-resistant and convenient for subsequent reaction, and the final product, namely the compound in the formula I, obtained through acylation reaction and elimination reaction has high purity and high yield.
(4) When the reducing agent sodium hydrosulfite is used for reducing the compounds shown in the formula IV and the formula XI, acid HB is further added, the added acid HB can promote the intermediate substances of the reduction reaction to be converted into products, the reduction reaction is promoted to be complete, the reaction efficiency is improved, the purity of the reaction products is high, the yield is high, and the byproducts are few.
(5) The nitro is reduced by using the reducer sodium hydrosulfite, the method is environment-friendly, the product has no heavy metal residue, the obtained product has high purity, high yield, low cost, mild reaction conditions and low requirements on reaction equipment, and the operation is safe.
(6) Compared with the prior art, the acylation reaction of the hydrochloride of the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine of the formula II is carried out in an organic solvent system with 3-chloropropionyl chloride to directly precipitate out a solid product which is insoluble in an organic solvent, namely the 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, the 2, 2-trifluoroethoxy) pyridine hydrochloride is filtered and separated for next elimination reaction, the reaction condition of the acylation reaction is mild, the operation is simple and convenient, impurities dissolved in an organic solvent are removed, and the final product, namely the compound shown in the formula I, obtained through elimination reaction has high purity and high yield.
(7) The compound of the formula I is purified and has high purity.
(8) The method has the advantages of high total yield of the route, high product purity, environmental friendliness, low cost, mild conditions and simple operation, and is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the present invention is not limited to the following examples. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The melting point of the substance is measured by using WRR melting point apparatus J009 of Shanghainegaceae, and the temperature rise rate is controlled to be 1.5 deg.C/min when measuring the melting point.
The purity of the substance is detected by an Agilent1260 type High Performance Liquid Chromatography (HPLC) instrument, and the detection wavelength is 332 nm.
Example 1: preparation of 6-chloro-3-nitro-2- (2, 2, 2-trifluoroethoxy) pyridine (XI-1)
Toluene (24.0L) was added to the reaction vessel, 2, 6-dichloro-3-nitropyridine (3000g, 15.54mol) was added thereto, the internal temperature was adjusted to a range of-20 ℃ to-10 ℃, and sodium hydrogen (933g, 23.33mol) was added in portions. A solution of 2, 2, 2-trifluoroethanol (1586g, 16.00mol) in toluene (6.0L) was added dropwise. The reaction was carried out for 2h, and the end of the reaction was monitored by TLC and HPLC. After the reaction was complete, 10% ammonium chloride solution (6.0L) was added dropwise. Standing and layering. The organic phase was washed with water (6.0L) and concentrated under reduced pressure. Adding ethyl acetate (0.3L), heating to 40-50 ℃, dropwise adding n-heptane (2.7L), cooling to-15 to-5 ℃ after dropwise adding, continuing to crystallize for 3 hours, and filtering. The product was obtained as a solid 3017g with a yield of 75.65%.
1H NMR(500MHz，DMSO-d6)δ8.60(d，J＝8.0Hz，1H)，7.50(d，J＝8.5Hz，lH)，5.13(q，J＝9.0Hz，2H)；
13C NMR(126MHz，DMSO-d6)δ153.20，151.09，139.34，132.67，123.38(q，J＝277.2Hz)，119.14，63.34(q，J＝36Hz)；
MS m/z：256.99[M+1]。
Example 2: preparation of 6-chloro-3-amino-2- (2, 2, 2-trifluoroethoxy) pyridine (X-1)
Acetonitrile (21.0L) and water (21.0L) were added to the reactor at room temperature, stirring was turned on, 6-chloro-3-nitro-2- (2, 2, 2-trifluoroethoxy) pyridine (3017.0g, 11.76mol) obtained in example 1 was added, and sodium hydrosulfite (15.1Kg, 70.54mol) was added. Controlling the temperature to be 27-33 ℃ and reacting for 2 hours. 36% concentrated hydrochloric acid (11.9Kg, 117.60mol) was added dropwise and the reaction was continued for 1.5 hours. Sodium bicarbonate solid (12.8Kg, 12.96mol) was added. The resulting mixture was filtered, the mother liquor was separated into layers, and the organic phase was washed with saturated brine (21.0L), and concentrated under reduced pressure to obtain an oily substance.
1H NMR(500MHz，DMSO-d6)δ7.03(d，J＝8.0Hz，1H)，6.90(d，J＝8.0Hz，1H)，5.21(s，2H)，4.93(q，J＝9.0Hz，2H)；
13C NMR(126MHz，DMSO-d6)δ148.16，131.72，130.55，123.93(q，J＝278.5Hz)，121.02，118.42，61.72(q，J＝34.0Hz)；
MS m/z：227.01[M+1]。
Example 3: preparation of 6-chloro-3- (2, 2, 2-trifluoroacetamido) -2- (2, 2, 2-trifluoroethoxy) pyridine (IX-1)
At room temperature, dichloromethane (10.4L) was added to the reaction vessel, stirring was turned on, 6-chloro-3-amino-2- (2, 2, 2-trifluoroethoxy) pyridine (2664g, 11.76mol) obtained in example 2 was added, diisopropylethylamine (2279g, 17.64mol) was added, the temperature was controlled at-15 to-10 ℃, a solution of trifluoroacetic anhydride (2963g, 14.11mol) in dichloromethane (5.2L) was added dropwise, and stirring was continued for 20 minutes after dropping. Water (13.0L) was added dropwise, the layers were separated, the organic phase was concentrated under reduced pressure, and the reaction was carried out in the next step in theoretical calculation.
1H NMR(400MHz，DMSO-d6)δ11.23(s，7H)，7.95(d，J＝8.0Hz，1H)，7.34(d，J＝8.0Hz，1H)，5.03(q，J＝8.9Hz，2H)；
13C NMR(101MHz，DMSO-d6)δ155.74(q，J＝46.6Hz)，155.60，145.37，140.24，124.01(q，J＝278.8Hz)，119.07，118.30，116.19(q，J＝289.9Hz)，62.99(q，J＝35.4Hz)；
MS m/z.322.99[M+1]。
Example 4: preparation of 6-chloro-5-nitro-3- (2, 2, 2-trifluoroacetylamino) -2- (2, 2, 2-trifluoroethoxy) pyridine (VIII-1)
At room temperature, concentrated sulfuric acid (11.7L) is added into a reaction kettle, stirring is started, 6-chloro-3- (2, 2, 2-trifluoroacetamido) -2- (2, 2, 2-trifluoroethoxy) pyridine (3.9Kg, 11.76mol) obtained in example 3 is added, potassium nitrate solid (1783.4g, 17.64mol) is added in batches, stirring is continued for about 40 minutes after the addition is finished, the temperature is reduced after the reaction is monitored, the internal temperature is controlled to be 10-25 ℃, dichloromethane (27.3L) is started to be added dropwise, stirring is carried out for 45 minutes, layering is carried out, an organic phase is taken, and the organic phase is washed once by water (11.7L). Concentrating the organic phase under reduced pressure, and theoretically calculating to put the next reaction.
1H NMR(500MHz，DMSO-d6)δ11.58(s，1H)，8.78(s，1H)，5.17(q，J＝8.7Hz，2H)；
13C NMR(126MHz，DMSO-d6)δ155.89，155.43(q，J＝37.8Hz)，138.84，138.57，135.05，123.22(q，J＝273.4Hz)，118.47，115.51(q，J＝278.5Hz)，63.65(q，J＝35.3Hz)；
MS m/z：367.98[M+1]。
Example 5: preparation of 6-chloro-5-nitro-3-amino-2- (2, 2, 2-trifluoroethoxy) pyridine (VII-1)
Methanol (13.0L) was added to a reaction vessel at room temperature, 6-chloro-5-nitro-3- (2, 2, 2-trifluoroacetamido) -2- (2, 2, 2-trifluoroethoxy) pyridine (4322g, 11.76mol) obtained in example 4 was added, p-toluenesulfonic acid monohydrate (3355g, 17.64mol) was added, the reaction was carried out at 60 to 65 ℃ for 15 hours, and methanol was removed under reduced pressure. Methyl t-butyl ether (13.0L) and water (6.5L) were added and the pH was adjusted to 7-8 with potassium carbonate. The layers were separated and the organic phase was washed once with water (8.6L), separated and concentrated under reduced pressure. Adding n-heptane (21.5L), controlling the temperature to be 60-65 ℃, stirring for 1 hour, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on a filter cake at 50 ℃ for 18 hours to obtain 1475g of the product.
The total yield of the five reactions of example 1 to example 5 was 34.9%.
1H NMR(500 MHz，DMSO-d6)δ7.62(s，1H)，5.92(s，2H)，5.05(q，J＝8.9Hz，2H).
13C NMR(126MHz，DMSO-d6)δ149.30，139.53，132.84，123.46，123.44(q，J＝278.5Hz)，116.25，62.52(q，J＝35.3Hz)；
MS m/z：272.00[M+1]。
Example 6: preparation of 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (V-1)
Toluene (50mL) was charged to a 100mL reaction flask, followed by the addition of 6-chloro-5-nitro-3-amino-2- (2, 2, 2-trifluoroethoxy) pyridine (5.0g, 18.4mmol), the compound of formula VII-1, 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (5.8g, 23.8mmol), p-toluenesulfonic acid monohydrate (1.8g, 9.2mmol), stirring, and the reaction mixture was heated to 110 ℃ and 115 ℃ for 24 hours. The temperature is reduced to 22 ℃, the mixture is filtered, and filter cakes are dried by blowing at 50 ℃ for 20 hours to obtain the compound 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (10.4g, 74.7 HPLC area% purity) of the formula V-1. The next reaction was carried out according to HPLC purity.
1H NMR(400MHz，DMSO-d6)δ9.43(s，1H)，8.76(s，1H)，8.46-8.45(d，J＝5.4Hz，1H)，8.39(s，1H)，8.38-8.36(d，J＝7.8Hz，1H)，7.57-7.55(d，J＝8.2Hz，1H)，7.41-7.40(d，J＝5.4Hz，1H)，7.31-7.27(t，J＝7.5Hz，1H)，7.20-7.16(t，J＝7.5Hz，1H)，5.23-5.16(q，J＝8.8Hz，2H)，3.90(s，3H)；
MS m/z：479.08[M+1]。
Example 7: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (IV)
Adding N, N-dimethylformamide (30mL) into a 250mL reaction bottle, adding the compound of the formula V-1 obtained in example 6, namely 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (10.4g, 16.22mmol), stirring, sequentially adding potassium carbonate (4.48g, 32.44mol) and N, N, N' -trimethylethylenediamine (2.48g, 24.33mol), heating the reaction mixture to 77-82 ℃, and carrying out heat preservation reaction for 1-1.5 hours. Water (60mL) was added and the temperature was lowered to room temperature. Suction was applied, the filter cake was transferred to a 50L reactor, acetonitrile (40mL) was added, and heating and refluxing were carried out for 2 hours. The temperature is reduced to room temperature, the mixture is filtered, and filter cakes are dried by air blowing at 50 ℃ for 18 hours to obtain a compound of the formula IV, namely 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (6.7g), and the total yield of the two steps of the reaction is 66.8 percent compared with the total yield of the two steps of the reaction in the example 6.
1H NMR(500MHz，DMSO-d6)δ8.62(s，1H)，8.41(s，1H)，8.26(s，2H)，8.24(s，1H)，7.48(d，J＝8.2Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16(d，J＝5.3Hz，1H)，7.05(t，J＝7.3Hz，1H)，5.04(q，J＝8.9Hz，2H)，3.84(s，3H)，3.69(t，J＝6.9Hz，2H)，2.89(s，3H)，2.55(t，J＝6.9Hz，2H)，2.17(s，6H)；
13C NMR(126MHz，DMSO-d6)δ162.15，160.55，156.99，154.98，148.42，137.53，132.83，132.68，125.50，123.58(q，J＝279.7Hz)，124.38，122.11，122.06，120.67，113.38，112.27，110.30，107.11，62.14(q，J＝35.3Hz)，56.10，49.51，45.34，45.33，39.35，32.98。
MS m/z.：545.22[M+1]。
Example 8: preparation of 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine p-toluenesulfonate (V-1')
Toluene (7.43L) was charged into a 20L reactor, followed by the addition of 6-chloro-5-nitro-3-amino-2- (2, 2, 2-trifluoroethoxy) pyridine (743.0g, 2.74mol), the compound of formula VII-1, 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (866.7g, 3.56mol), p-toluenesulfonic acid monohydrate (780.7g, 4.10mol), stirring, and the reaction mixture was heated to 110 ℃ and 115 ℃ for 36 hours. Controlling the temperature to be 15-30 ℃, adding tetrahydrofuran (3.72L) and stirring for 30 minutes. Suction filtration was performed, and the filter cake was transferred to a 50L reactor, and tetrahydrofuran (4.46L) was added thereto, followed by heating and refluxing for 3 hours. Reducing the temperature to 15-25 ℃, carrying out suction filtration, and carrying out forced air drying on a filter cake at 50 ℃ for 17 hours to obtain 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine p-toluenesulfonate (1719g, 85.96 HPLC area% purity). The next reaction was carried out according to HPLC purity.
Melting point: 216.0-218.3 deg.C
1H NMR(500MHz，DMSO-d6)δ9.70(s，1H)，9.21(s，1H)，8.62(s，1H)，8.40(d，J＝6.2Hz，1H)，8.24(d，J＝7.8Hz，1H)，7.59(d，J＝8.3Hz，1H)，7.50(d，J＝6.5Hz，1H)，7.49(d，J＝8.3Hz，2H)，7.32(t，J＝7.6Hz，1H)，7.18(t，J＝7.5Hz，1H)，7.12(d，J＝7.9Hz，2H)，5.17(q，J＝8.8Hz，2H)，3.91(s，3H)，2.29(d，J＝5.2Hz，3H)；
13C NMR(126MHz，DMSO-d6)δ166.66，157.35，155.72，147.40，140.87，139.90，139.72，138.59，135.83，130.09，129.99，129.98，129.97，127.39，127.38，127.37，127.15，125.22(q，J＝278.5Hz)，124.97，123.85，123.69，113.63，112.97，110.27，63.58(q，J＝35.3Hz)，35.57，22.81。
Example 9: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (IV)
Adding N, N-dimethylformamide (5.14L) into a 50L reaction kettle, adding 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine p-toluenesulfonate (1714.0g, 2.261mol) obtained in example 8, stirring, sequentially adding potassium carbonate (624.7g, 4.52mol) and N, N, N' -trimethylethylenediamine (346.2g, 3.39mol), heating the reaction mixture to 77-82 ℃, and carrying out heat preservation reaction for 1-1.5 hours. Water (10.28L) was added and the temperature was reduced to room temperature. Suction filtration was performed, and the filter cake was transferred to a 50L reactor, acetonitrile (6.86L) was added, and heating and refluxing were performed for 2 hours. Reducing the temperature to 15-25 ℃, carrying out suction filtration, and carrying out forced air drying on a filter cake at 50 ℃ for 18 hours to obtain a compound 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (1142g) in the formula IV, wherein the total yield of the two steps of the reaction is 76.54% in the example 8.
1H NMR(500MHz，DMSO-d6)δ8.62(s，1H)，8.41(s，1H)，8.26(s，2H)，8.24(s，1H)，7.48(d，J＝8.2Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16(d，J＝5.3Hz，1H)，7.05(t，J＝7.3Hz，1H)，5.04(q，J＝8.9Hz，2H)，3.84(s，3H)，3.69(t，J＝6.9Hz，2H)，2.89(s，3H)，2.55(t，J＝6.9Hz，2H)，2.17(s，6H)；
13C NMR(126MHz，DMSO-d6)δ162.15，160.55，156.99，154.98，148.42，137.53，132.83，132.68，125.50，123.58(q，J＝279.7Hz)，124.38，122.11，122.06，120.67，113.38，112.27，110.30，107.11，62.14(q，J＝35.3Hz)，56.10，49.51，45.34，45.33，39.35，32.98。
MS m/z：545.22[M+1]。
Example 10: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (IV)
Acetonitrile (10mL) is added into a 50L reaction kettle, 2-chloro-3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine p-toluenesulfonate (1.0g, 1.5mmol) obtained in example 8 is added, stirring is carried out, potassium carbonate (577mg, 3mmol) and N, N, N' -trimethylethylenediamine (320mg, 2.25mmol) are sequentially added, the reaction mixture is heated to 77-82 ℃, and the temperature is kept for reaction for 1-2 hours. Water (10mL) was added and the temperature was lowered to room temperature. Suction filtration is carried out, thus obtaining the compound 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (629mg) with the purity of 95.94 percent, which is 77 percent of the total yield of the two steps of the reaction with the embodiment 8.
Example 11: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (III')
The compound of formula IV, 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.0g, 7.34mmol) was added to a 100mL reaction flask at room temperature, tetrahydrofuran (27mL) and water (13mL) were added, and the mixture was stirred for 10-20 minutes. Sodium hydrosulfite (9.6g, 44.1mmol) was added to the reaction kettle in portions. And after the addition is finished, continuously stirring for 10-20 minutes. And controlling the temperature of the reaction kettle to be 30-35 ℃ for reaction. And (3) sampling a liquid phase after 2 hours of reaction, detecting that the purity of the product, namely the compound shown in the formula III' is 64.68%, continuing the reaction, adding 40mL of water into the reaction liquid after 17 hours of reaction, standing and layering, taking a tetrahydrofuran phase, extracting the water phase twice by 100mL of dichloromethane, combining organic phases, washing with saturated saline, standing and layering, and concentrating under reduced pressure to obtain 3.2g of a solid with the purity of 62.32%.
1H NMR(500MHz，DMSO)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，2H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；
MS m/z：515.24[M+1]。
Example 12: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (III')
In a 100mL single vial of 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (2.0g, 3.67mmol), palladium on carbon (200mg), ethanol (20mL), hydrogen balloon replacement 2 times, hydrogen gas introduction, magnetic stirring, and reaction at room temperature overnight (17 hours). After the detection reaction is finished, suction filtration is carried out, filtrate is taken, and the filtrate is decompressed and concentrated to be dry, so that 2.1g of product with the purity of 56.93 percent is obtained.
Example 13: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (III')
Adding 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (1317.0g, 2.42mol) serving as a compound shown in the formula IV into a 50L reaction kettle at room temperature, adding tetrahydrofuran (8.8L) and water (4.3L), and stirring for 10-20 minutes. Sodium hydrosulfite (2970.0g, 14.52mol) is added into the reaction kettle in batches. And after the addition is finished, continuously stirring for 10-20 minutes. Controlling the temperature of the reaction kettle to 40-45 ℃ and reacting for 2 hours. Concentrated hydrochloric acid (5882.2g, 58.08mol) was added dropwise to the reaction kettle. After the dropwise addition, heating to 42-47 ℃ and reacting for 15 hours. 30% sodium hydroxide (2323.2g, 58.08mol) aqueous solution is added dropwise, and solid sodium bicarbonate (1219.7g, 14.52mol) is added in batches to adjust the pH value to 6-8. Stirring for 20 min, vacuum filtering, standing the filtrate, and layering. The organic phase is decompressed and concentrated to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indole-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine, the purity is 97.1 percent, the theoretical yield is 100 percent, and the pyridine is directly used for the next reaction.
1H NMR(500MHz，DMSO)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，2H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；
MS m/z：515.24[M+1]。
Example 14: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine dihydrochloride (III-1)
To 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine obtained in example 13, THF (5.3L) and ethanol (4.0L) were added, the temperature was raised to 50 to 70 ℃ and concentrated hydrochloric acid (617.8g, 6.1mol) was added dropwise. After the dropwise addition, the mixture was cooled to room temperature and stirred for 12 hours. Suction filtration was carried out, and the filter cake was air-dried at 50 ℃ to obtain 1507.4g of crude product. Adding methanol (6.0L) and ethanol (4.5L) into a 20L reaction bottle, adding the crude product, heating to 55-60 ℃, carrying out hot beating for 1-2 hours, cooling to room temperature, and carrying out suction filtration to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine dihydrochloride (1335.6g), wherein the liquid phase purity is 99.80 percent, and the yield is 94.0 percent in the two steps of the reaction with the example 13. Melting point: 236.6-240.8 ℃.
1H NMR(500MHz，DMSO-d6)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，1H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；
13C NMR(126MHz，DMSO-d6)δ166.81，153.27，152.17，150.76，138.61，138.16，138.15，125.46，124.94，123.83(q.J＝278.5Hz)，123.42，123.41，122.60，122.59，120.52，111.34，111.17，106.29，62.14(q，J＝35.3Hz)，53.53，46.28，42.27，42.26，40.92，33.67。
Example 15: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine dihydrochloride (III-1)
Adding 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (1136.0g, 2.09mol) serving as a compound shown in the formula IV into a 50L reaction kettle at room temperature, adding acetonitrile (7.95L) and water (7.95L), and stirring for 10-20 minutes. Sodium hydrosulfite (2563.9g, 12.50mol) was added in portions to the reaction kettle. And after the addition is finished, continuously stirring for 10-20 minutes. And controlling the temperature of the reaction kettle to 35-40 ℃ and reacting for 3 hours. Concentrated hydrochloric acid (2505.3g, 25.08mol) was added dropwise to the reaction kettle. After the dropwise addition, heating to 35-45 ℃ and reacting for 18 hours. And (3) dropwise adding 30% sodium hydroxide (1003.2g, 25.08mol) aqueous solution to adjust the pH value to 6-8. Solid sodium bicarbonate (1053.5g, 12.54mol) was added to adjust the pH to 7-8. Stirring for 40 min, suction filtering, standing the filtrate, layering, and concentrating the organic phase under reduced pressure. The purity of the detected liquid phase is 97.60%.
Adding ethanol (5.68L) into the product obtained in the previous step, heating to 50-70 ℃, and dropwise adding concentrated hydrochloric acid (522g, 5.23 mol). After the dropwise addition, the mixture was cooled to room temperature and stirred for 15 hours. Suction filtration is carried out, filter cake is dried by blowing at 50 ℃ to obtain 2- [2- (dimethylamino ethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indole-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine dihydrochloride (780g), and the purity of liquid phase is 98.74 percent.
Example 16: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride (II-1)
2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine dihydrochloride (1543.5g, 2.63mol) is added into a 50L reaction kettle, dichloromethane (13.1L) and triethylamine (532.2g, 5.26mol) are added, stirring is carried out, the temperature is reduced to-10 to-5 ℃, and a dichloromethane (10.0L) solution of 3-chloropropionyl chloride (501.5g, 3.95mol) is added dropwise. After the dropwise addition, stirring for 10-20 minutes under a heat preservation condition, carrying out suction filtration, wherein a filter cake is a wet product (2683.5g) of the hydrochloride of the formula II-12- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine, and the wet product is directly used for the next reaction according to the theoretical yield of 100%.
Melting point: 233.2-238.7 DEG C
1H NMR(500MHz，DMSO-d6)δ10.18(s，1H)，8.57(s，1H)，8.42(s，1H)，8.27(t，J＝6.6Hz，2H)，8.17(s，1H)，7.51(d，J＝8.1Hz，1H)，7.26-7.22(m，1H)，7.22-7.17(m，2H)，4.99(q，J＝9.1Hz，2H)，3.91(d，J＝6.3Hz，2H)，3.89(s，3H)，3.55(s，2H)，3.13(s，2H)，3.02(t，J＝6.1Hz，2H)，2.85(s，3H)，2.64(s，6H)；
13C NMR(126MHz，DMSO-d6)δ168.41，161.88，160.22，157.34，148.05，146.73，137.62，133.25，130.86，125.43，124.09(q，J＝279.2Hz)，122.04，121.74，120.88，118.51，116.60，112.33，110.40，107.09，61.65(q，J＝35.3Hz)，54.90，40.96，40.95，40.60，38.71，32.96，32.95，32.94。
Example 17: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I, crude)
The wet product of 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride of the formula II obtained in example 16 (2683.5g) was charged into a 20L reactor, acetonitrile (16.8L) and triethylamine (1329.3g, 13.15mol) were added, stirred and heated under reflux for 4 hours. Cooling to room temperature, adding purified water (4.20L), stirring for 3-4 hours at room temperature, and performing suction filtration. Transferring the filter cake to a 50L reaction kettle, adding dichloromethane (17L), and adjusting the pH value to 7-8 by using a saturated sodium bicarbonate water solution (17L). Separating the liquid, transferring the organic phase to a 20L reaction kettle, adding activated carbon (84.3g), refluxing for 1 hour, cooling to 20-30 ℃, and performing suction filtration. The filtrate was concentrated to dryness under reduced pressure to give 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine of formula I (1390g), which was reacted in the two steps of example 16 in a total yield of 92.9% and a purity of 99.21%.
1H NMR(500MHz，DMSO-d6)δ9.96(s，1H)，8.71(s，1H)，8.44(s，1H)，8.29(d，J＝5.3Hz，1H)，8.26(d，J＝7.7Hz，1H)，8.13(s，1H)，7.51(d，J＝8.2Hz，1H)，7.24(t，J＝7.2Hz，1H)，7.20(d，J＝5.3Hz，1H)，7.15(t，J＝7.2Hz，1H)，6.51(dd，J＝17.0，10.2Hz，1H)，6.28(dd，J＝17.0，1.8Hz，1H)，5.78(dd，J＝10.2，1.8Hz，1H)，5.00(q，J＝9.1Hz，2H)，3.89(s，3H)，3.18(t，J＝6.5Hz，2H)，2.87(s，3H)，2.48(t，J＝6.5Hz，2H)，2.22(s，6H)；
13C NMR(126MHz，DMSO-d6)δ163.40，161.84，160.26，157.35，148.07，147.15，137.60，133.23，131.61，130.07，126.67，125.41，124.03(q，J＝278.5Hz)，122.00，121.68，120.80，118.39，116.13，112.36，110.37，107.02，61.29(q，J＝35.3Hz)，56.57，52.44，45.60，45.59，38.54，32.93；
MS m/z：569.25[M+1]。
Example 18: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (III')
The compound 2- [2- (dimethylaminoethyl) methylamino ] -3-nitro-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (20.0g, 36.73mmol) of the formula IV is added to a 1L reaction flask at room temperature, tetrahydrofuran (134mL) and water (66mL) are added, and the mixture is stirred for 10-20 minutes. Sodium hydrosulfite (47.9g, 220.38mmol) was added portionwise to the reaction flask. And after the addition is finished, continuously stirring for 10-20 minutes. The internal temperature was controlled to 35-40 ℃ and the reaction was carried out for 3 hours. Concentrated hydrochloric acid (89.3g, 881.52mmol) was added dropwise to the reaction flask. After the dropwise addition, heating to 42-47 ℃ and reacting for 17 hours. 30% aqueous sodium hydroxide (35.26g, 881.52mmol) was added dropwise, and solid sodium bicarbonate (18.5g, 220.38mmol) was added in portions to adjust the pH to 6-8. After stirring for 30 minutes, the mixture was filtered, and the filtrate was allowed to stand and separate into layers. The organic phase was concentrated to dryness under reduced pressure to give 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (19.2g) in 95.8% purity in 97.12% yield.
Example 19: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride (II-1)
Adding 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (5g, 9.72mmol) into a 250mL reaction bottle, adding dichloromethane (42mL), stirring, reducing the temperature to-5-0 ℃ under the protection of argon, and dropwise adding 3-chloropropionyl chloride (1.851g) and dichloromethane (33 mL). After the dropwise addition, stirring is carried out for 10-20 minutes under the condition of heat preservation, after the detection reaction is finished, the reaction product is concentrated under reduced pressure to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride (7.0g) with the purity of 85.67 percent. Melting point: 233.5-238.9 ℃.
1H NMR(500MHz，DMSO-d6)δ10.18(s，1H)，8.57(s，1H)，8.42(s，1H)，8.27(t，J＝6.6Hz，2H)，8.17(s，1H)，7.51(d，J＝8.1Hz，1H)，7.26-7.22(m，1H)，7.22-7.17(m，2H)，4.99(q，J＝9.1Hz，2H)，3.91(d，J＝6.3Hz，2H)，3.89(s，3H)，3.55(s，2H)，3.13(s，2H)，3.02(t，J＝6.1Hz，2H)，2.85(s，3H)，2.64(s，6H)；
13C NMR(126MHz，DMSO-d6)δ168.41，161.88，160.22，157.34，148.05，146.73，137.62，133.25，130.86，125.43，124.09(q，J＝279.2Hz)，122.04，121.74，120.88，118.51，116.60，112.33，110.40，107.09，61.65(q，J＝35.3Hz)，54.90，40.96，40.95，40.60，38.71，32.96，32.95，32.94。
Example 20: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I, crude)
The 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride obtained in example 19 is added into a 250mL reaction bottle, acetonitrile (45mL) and triethylamine (4.9g) are added, magnetic stirring is carried out, argon protection is carried out, the oil bath is heated to reflux, reaction is carried out for 6H, water (23mL) is added dropwise, the temperature in the oil bath is naturally reduced to room temperature, suction filtration is carried out, a filter cake is transferred into a 500mL reaction bottle, dichloromethane (100mL) is added, and a saturated sodium bicarbonate solution (100mL) is added to adjust the pH value to 7-8. The resulting solid was dried in an oven at 50 ℃ to give 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.1g) having a purity of 97.7% and a total yield of 74.17% by two-step reaction of example 19.
Comparative example 1: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I, crude)
Adding 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (1g, 1.94mmol) into a 50mL multi-neck flask, replacing 3 times with argon by taking tetrahydrofuran (10mL) as a solvent, stirring at 0-5 ℃ under the protection of argon, slowly dropwise adding 3-chloropropionyl chloride (0.37g, 2.92mmol), stirring for 15min, keeping the temperature of 0-5 ℃ for 1 hour, adding sodium hydroxide (0.31g, 7.77mmol) and water (1mL) into the reaction solution, heating to 65 ℃ and stirring for 15 hours, adding a saturated ammonium chloride solution (10mL), separating, washing the organic phase with a saturated sodium bicarbonate solution (10mL), the organic phase was concentrated to dryness to give 1.04g of a yellow solid, 94.9% yield and 87.35% purity.
Comparative example 2: preparation of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I, crude)
2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (5.0g) was added to a 250mL reaction flask, acetone (50mL) and potassium carbonate (940mg) were added, stirred, argon-protected, cooled to-50 deg.C, and 3-chloropropionyl chloride (1.481g) was added dropwise. After the dropwise addition, the temperature is raised to-20 ℃, the mixture is kept warm and stirred for 30 minutes, a solution of sodium hydroxide (350mg) and water (60ml) is dropwise added in the 10min, the mixture is continuously stirred for 3 to 4 hours at the room temperature, the filtration is carried out, and a filter cake is dried in an oven at the temperature of 50 ℃ to obtain the compound 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.28g) with the purity of 64.18 percent, which is a compound shown in the formula II-1'.
1H NMR(400MHz，DMSO-d6)δ10.32(s，1H)，10.21(s，1H)，8.54(s，1H)，8.43(s，1H)8.29-8.28(d，J＝5.1Hz，1H)，8.28-8.26(d，J＝6.2Hz，1H)，8.19(s，1H)，7.54-7.52(d，J＝8.0Hz，1H)，7.27-7.18(m，3H)，5.77(s，2H)，5.00(q，J＝9.1Hz，1H)，3.92(t，J＝6.2Hz，1H)，3.63(t，J＝5.7Hz，2H)，3.28(t，J＝5.7Hz，2H)，3.06-3.03(t，J＝6.2Hz，2H)，2.85(s，3H)，2.74(s，6H).
MS m/z：605.23[M+1]。
Adding 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.28g) into a 250mL reaction bottle, adding acetonitrile (45mL) and triethylamine (3.606g), magnetically stirring, carrying out argon protection, heating the oil bath until the temperature is raised to reflux, reacting for 6H, dropwise adding water (23mL), naturally cooling the oil bath and continuously stirring overnight (16H), carrying out suction filtration and solid drying to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-chloro-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) Pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (3.3g) in 95.13% purity in 59.42% yield over two steps.
Example 21: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Transferring a 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine crude product (1390g) to a 50L reaction kettle, adding acetone (25.0L), replacing for 3 times by argon, heating to 45-50 ℃, completely dissolving the solid, and dropwise adding purified water (6.95L). After the dropwise addition, cooling to 20-25 ℃, and stirring for 2 hours. Suction filtration is carried out, and the filter cake is vacuum-dried for 24 hours at 50 ℃ to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (895 g). The reaction yield is 66.7%, and the purity is 99.89%.
Example 22: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 100mL of ethyl acetate, heating the oil bath to 70-75 ℃ to completely dissolve the solid, naturally cooling the oil bath to 25 ℃, performing suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2), 2, 2-Trifluoroethoxy) pyridine (3.1g), purity 99.73%, yield 62.0%.
Example 23: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 100mL of ethyl acetate, heating the oil bath to 70-75 ℃ to completely dissolve the solid, continuing to stir for 30min at the constant temperature, and dropwise adding 150mL of n-heptane. After the dripping, the temperature is naturally reduced to 25 ℃ in an oil bath, and the 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.0g) is obtained through suction filtration and drying, wherein the purity is 99.32 percent, and the yield is 80 percent.
Example 24: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 75mL acetonitrile, heating to 77-82 ℃ in an oil bath, completely dissolving the solid, and dropwise adding 25mL water. After the solution is dripped into an oil bath, the temperature is naturally reduced to 25 ℃, and the solution is filtered and dried to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.3g), the purity is 99.64 percent, and the yield is 86 percent.
Example 25: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 75mL acetonitrile, heating to 77-82 ℃ in an oil bath, completely dissolving the solid, and continuing to keep the temperature and stir for 30 min. And naturally cooling to 25 ℃ in an oil bath, carrying out suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.0g), wherein the purity is 99.45 percent, and the yield is 80 percent.
Example 26: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine crude product (5.0g) into a 250mL three-necked bottle, adding 20mL tetrahydrofuran, heating to 45-50 ℃ in an oil bath, completely dissolving the solid, continuing to keep the temperature and stir for 30min, and dropwise adding 40mL n-heptane. After the dripping, the temperature is naturally reduced to 25 ℃ in an oil bath, and the 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.23g) is obtained through suction filtration and drying, wherein the purity is 99.51 percent, and the yield is 84.6 percent.
Example 27: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 100mL of isopropanol, heating to 50 ℃ in an oil bath, completely dissolving the solid, and continuing to keep the temperature and stir for 30 min. And naturally cooling to 22 ℃ in an oil bath, carrying out suction filtration and drying to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (4.25g), wherein the purity is 99.51% and the yield is 85%.
Example 28: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 75mL of methanol, heating to 55-60 ℃ in an oil bath, and completely dissolving the solid. And naturally cooling to 17 ℃ in an oil bath, stirring overnight, performing suction filtration and drying to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (3.55g), wherein the purity is 99.63 percent, and the yield is 71 percent.
Example 29: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
A250 mL three-necked bottle is added with a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine, 50mL of dichloromethane is added, the temperature of an oil bath is raised to 40 ℃, the solid is completely dissolved, the heat preservation and the stirring are continued for 30min, and 100mL of n-heptane is added dropwise. And naturally cooling to 15 ℃ in an oil bath, stirring overnight, performing suction filtration and drying to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (3.78g), wherein the purity is 99.56 percent, and the yield is 75.6 percent.
Example 30: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding 100mL of toluene, heating to 65 ℃ in an oil bath, completely dissolving the solid, and continuing to keep the temperature and stir for 30 min. And naturally cooling to 20 ℃ in an oil bath, carrying out suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (3.27g), wherein the purity is 99.57 percent, and the yield is 65.4 percent.
Example 31: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (5.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 250mL three-necked bottle, adding DMF50mL, heating to 80 ℃ in an oil bath, completely dissolving the solid, continuing to preserve heat and stir for 30min, and dropwise adding 25mL of water. And naturally cooling to 20 ℃ in an oil bath, carrying out suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (3.84g), wherein the purity is 99.77 percent, and the yield is 76.8 percent.
Example 32: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine crude product (1.0g) into a 25mL single-neck bottle, adding tetrahydrofuran (6mL), carrying out argon protection, heating in an oil bath to 40-45 ℃ for complete dissolution, continuing to keep the temperature and stir for 30min, naturally cooling to 22 ℃ in the oil bath, and carrying out suction filtration to obtain a solid. The solid was transferred to a crystallizing dish and dried to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (622mg) with a purity of 99.83% and a yield of 62.2%.
Example 33: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (1.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 50mL single-neck bottle, adding acetone (15mL), carrying out argon protection, heating in an oil bath to 45-50 ℃ for complete dissolution, continuing to keep the temperature and stir for 30min, naturally cooling to 22 ℃ in the oil bath, carrying out suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (537mg), purity 99.83%, yield 53.7%.
Example 34: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (1.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 50mL single-neck bottle, adding tetrahydrofuran (8mL), carrying out argon protection, heating the oil bath to 40-45 ℃ for complete dissolution, continuing to keep the temperature and stir for 30min, dropwise adding water (16mL), naturally cooling the oil bath to 21 ℃, carrying out suction filtration and drying to obtain a purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (880mg), purity 99.68%, yield 88.0%.
Example 35: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (1.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 100mL single-neck bottle, adding ethanol (35mL), argon protecting, heating the oil bath to 75-80 ℃ for complete dissolution, dropwise adding water (10mL) for 10min, naturally cooling the oil bath to 20 ℃, performing suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (915mg) in 91.5% yield and 99.49% purity.
Example 36: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding a crude product (1.0g) of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine into a 50mL single-neck bottle, adding dimethylbenzene (20mL), protecting with argon, heating in an oil bath to 80 ℃ for complete dissolution, naturally cooling to 20 ℃ in the oil bath, carrying out suction filtration and drying to obtain the purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2), 2, 2-Trifluoroethoxy) pyridine (798mg), yield 79.8%, purity 99.48%.
Example 37: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine crude product (5.0g) into a 250mL three-necked bottle, adding 125mL of ethanol, heating to 75-80 ℃ in an oil bath, completely dissolving the solid, continuing to preserve heat and stir for 30min, naturally cooling to 25 ℃, performing suction filtration and drying to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2), 2, 2-Trifluoroethoxy) pyridine (3.7g), purity 99.66%, yield 74%.
Example 38: purification of 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (I)
Adding crude 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine (1.0g) into a 100mL single-neck bottle, adding methanol (35mL), carrying out argon protection, heating the oil bath to 80 ℃ for complete dissolution, dropwise adding water (10mL) for 10min, naturally cooling the oil bath to 20 ℃, carrying out suction filtration and drying to obtain purified 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamide-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2), 2, 2-trifluoroethoxy) pyridine (912mg), yield 91.2%, purity 99.53%.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (30)

1. A process for the preparation of the compound 2- [2- (dimethylaminoethyl) methylamino ] -3-acrylamido-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino ] -6- (2, 2, 2-trifluoroethoxy) pyridine of formula I, comprising the steps of: in an organic solvent, the compound shown in the formula III' and the compound shown in the formula XIII are subjected to acylation reaction to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride shown in the formula II; in the presence of alkali, 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride in the formula II undergoes elimination reaction to obtain a compound in the formula I;
wherein X is Cl or Br.
2. The method according to claim 1, wherein the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate, acetone, or a mixed solvent thereof;
and/or the base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine;
and/or the molar ratio of the base to 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride in the formula II is 4-6: 1;
and/or the reaction solvent for the elimination reaction is dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate, acetone or a mixed solvent thereof.
3. The method according to claim 2, wherein the organic solvent is dichloromethane, acetonitrile, THF or a mixed solvent thereof;
and/or the base is triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine or morpholine;
and/or the molar ratio of the base to 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride in the formula II is 5-6: 1;
and/or the reaction solvent for the elimination reaction is dichloromethane, acetonitrile, THF or a mixed solvent thereof.
4. The method of claim 1, further comprising the steps of: carrying out salt-forming reaction on the compound shown in the formula III' and acid HA to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt shown in the formula III; reacting 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt of formula III with a base in an organic solvent, then carrying out acylation reaction with a compound shown in a formula XIII to obtain 2- [2- (dimethylaminoethyl) methylamino ] -3- (3-X-propionamido) -5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine hydrochloride shown in a formula II;
wherein n is 1 or 2, and X is Cl or Br.
5. The method according to claim 4, wherein the acid HA is hydrochloric acid, hydrobromic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid;
and/or the reaction solvent of the salt-forming reaction is methanol, ethanol, isopropanol, THF, 2-MeTHF or a mixed solvent thereof;
and/or the base is sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine;
and/or the molar ratio of the base to the 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA acid salt in the formula III is 1-2: 1;
and/or the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethyl acetate, acetone or a mixed solvent thereof.
6. The method of claim 5, wherein the acid HA is hydrochloric acid;
and/or the reaction solvent of the salt-forming reaction is ethanol, THF, 2-MeTHF or a mixed solvent thereof;
and/or the base is triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine or morpholine;
and/or the molar ratio of the base to the salt of 2- [2- (dimethylaminoethyl) methylamino ] -3-amino-5- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amino ] -6- (2, 2, 2-trifluoroethoxy) pyridine HA of formula III is 1: 1 or 2: 1;
and/or the organic solvent is dichloromethane, acetonitrile, THF or a mixed solvent thereof.
7. The method of claim 1 or 4, further comprising the step of decolorizing the compound of formula I with activated carbon in an organic solvent, which is dichloromethane or ethyl acetate.
8. The process according to any one of claims 1 to 7, wherein the process for the preparation of the compound of formula I further comprises the steps of: reducing the compound of formula IV with a reducing agent in a solvent to obtain a compound of formula III';
9. the preparation method according to claim 8, wherein the reducing agent is sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen reduction of the compound of formula IV is carried out in the presence of palladium carbon, palladium hydroxide/carbon or Raney nickel as a catalyst, and the hydrazine hydrate reduction of the compound of formula IV is carried out in the presence of iron trichloride/activated carbon as a catalyst;
and/or the solvent is an organic solvent or a mixed solvent of water and the organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof.
10. The method of claim 9, wherein the reducing agent is sodium hydrosulfite;
and/or the solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof.
11. The method according to claim 9 or 10, wherein an acid HB is further added when the reducing agent sodium hydrosulfite reduces the compound of formula IV.
12. The method according to claim 11, wherein the acid HB is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or acetic acid;
and/or the molar ratio of the acid HB to the compound of the formula IV is 12-24: 1.
13. The method of claim 8, wherein the method of preparing the compound of formula I further comprises the steps of: carrying out condensation reaction on a compound shown in a formula VI and a compound shown in a formula VII in the presence of acid to obtain a compound shown in a formula V or a salt thereof; in a polar organic solvent, carrying out substitution reaction on a compound shown in a formula V or a salt thereof and N, N, N' -trimethylethylenediamine in the presence of alkali to obtain a compound shown in a formula IV;
wherein Y is F, Cl or Br.
14. The method of claim 13, wherein the acid is trifluoroacetic acid, tsoh2O or TsOH, the trifluoroacetic acid, TsOH2The molar ratio of O or TsOH to the compound of the formula VII is 0.5-2: 1, and a compound of the formula V or a trifluoro acetate or p-toluenesulfonate thereof is obtained through a condensation reaction;
and/or the reaction solvent of the condensation reaction is toluene, methanol, ethanol, isopropanol, n-butanol, 2-pentanol, isobutanol, THF, 2-MeTHF, 1, 4-dioxane, acetonitrile, ethyl acetate, acetone, 1, 2-dichloroethane or a mixed solvent thereof;
and/or the base is potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine;
and/or the polar organic solvent is DMF, dimethyl sulfoxide, acetonitrile, THF, 2-MeTHF, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, hexamethylphosphoric triamide, N, N, N' -trimethylethylenediamine or a mixed solvent thereof.
15. The method of claim 14, wherein the acid is trifluoroacetic acid, tsoh2O or TsOH, the trifluoroacetic acid, TsOH2The molar ratio of O or TsOH to the compound of the formula VII is 1.3-2: 1, and the compound of the formula V is obtained through condensation reaction to obtain trifluoroacetate or p-toluenesulfonate;
and/or the reaction solvent of the condensation reaction is toluene, n-butanol, 2-pentanol, isobutanol, 1, 4-dioxane, THF, 1, 2-dichloroethane or a mixed solvent thereof;
and/or the alkali is potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium carbonate;
and/or the polar organic solvent is DMF, dimethyl sulfoxide, N-dimethylacetamide or a mixed solvent thereof.
16. The method of claim 15, wherein the acid is tsoh2O or TsOH, said TsOH2The molar ratio of O or TsOH to the compound of the formula VII is 1.3-2: 1, preferably 1.5-1.8: 1, and the compound of the formula V is obtained through condensation reaction.
17. The process of claim 13, wherein the process for preparing the compound of formula I further comprises the steps of: in the presence of alkali a, carrying out etherification reaction on a compound shown in the formula XII and trifluoroethanol to obtain a compound shown in the formula XI; reducing a compound of formula XI with a reducing agent in a solvent to obtain a compound of formula X; in the presence of alkali b, carrying out acylation reaction on the compound of the formula X and an acylating agent to obtain a compound of a formula IX; carrying out nitration reaction on the compound of the formula IX and a nitration reagent to obtain a compound of a formula VIII; in the presence of acid, carrying out hydrolysis reaction on the compound shown in the formula VIII to obtain a compound shown in the formula VII;
wherein Y is F, Cl or Br.
18. The method of claim 17, wherein the base a is NaH, LiHMDS, NaHMDS or KHMDS;
and/or the reducing agent is sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen is used for reducing the compound in the formula XI in the presence of palladium carbon, palladium hydroxide/carbon or Raney nickel serving as a catalyst, and the hydrazine hydrate is used for reducing the compound in the formula XI in the presence of iron trichloride/activated carbon serving as a catalyst;
and/or the solvent is an organic solvent or a mixed solvent of water and the organic solvent, and the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, isopropanol, THF, 2-MeTHF, 1, 4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof;
and/or the base b is triethylamine, N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide;
and/or, the acylating agent is TFAA or trifluoroacetyl chloride;
and/or the nitrating agent is HNO3/H2SO4、KNO3/H2SO4Or fuming nitric acid;
and/or the acid is hydrochloric acid, sulfuric acid, TsOH2O, TsOH, methanesulfonic acid or benzenesulfonic acid.
19. The method of claim 18, wherein the base a is NaH;
and/or the reducing agent is sodium hydrosulfite;
and/or the solvent is a mixed solvent of water and an organic solvent, and the organic solvent is dichloromethane, acetonitrile, THF, 2-MeTHF, ethylene glycol dimethyl ether, ethyl acetate, acetone or a mixed solvent thereof;
and/or the base b is triethylamine or N, N-diisopropylethylamine;
and/or, the acylating agent is TFAA;
and/or the nitrating agent is HNO3/H2SO4Or KNO3/H2SO4；
And/or the acid is TsOH2O or TsOH.
20. The process according to claim 18 or 19, wherein an acid HB, which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or acetic acid, preferably hydrochloric acid, is further added when the reducing agent sodium hydrosulfite reduces the compound of formula XI.
21. The method of claim 1 or 7, further comprising a purification process of the compound of formula I:
the method comprises the following steps: mixing the crude product of the compound of the formula I with a benign solvent, heating for dissolving, dripping a poor solvent, cooling, and carrying out suction filtration to obtain a purified compound of the formula I;
the second method comprises the following steps: mixing the crude product of the compound of the formula I with an organic solvent, heating to dissolve the crude product clearly, cooling, and carrying out suction filtration to obtain the purified compound of the formula I.
22. The method according to claim 21, wherein in the first or second method, the temperature of the heated supernatant is 40 to 82 ℃;
and/or, in the first method or the second method, the cooling temperature is 15-25 ℃.
23. The method according to claim 21 or 22, wherein the benign solvent in the first method is acetone, acetonitrile, methanol, ethanol, isopropanol, dichloromethane, THF, 2-MeTHF, ethyl acetate, DMF or a mixed solvent thereof;
and/or the weight g to volume ml ratio of the crude compound of the formula I to the benign solvent in the first method is 1: 4-35;
and/or, in the first method, the poor solvent is water, n-heptane, n-hexane, n-pentane, cyclohexane, toluene, benzene, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixed solvent thereof;
and/or the volume ratio of the benign solvent to the poor solvent in the first method is 0.5-5: 1;
and/or, in the second method, the organic solvent is acetone, acetonitrile, methanol, ethanol, isopropanol, dichloromethane, THF, 2-MeTHF, ethyl acetate, toluene, xylene, methyl tert-butyl ether or a mixed solvent thereof;
and/or the weight g to volume ml ratio of the crude compound of the formula I to the organic solvent in the second method is 1: 5-35.
24. The method of claim 21, wherein one or the other of the methods is performed under a nitrogen or argon atmosphere.
25. An intermediate compound or salt of the formula,
wherein n is 1 or 2; x is Cl or Br; y is F, Cl or Br; HA is an acid selected from hydrochloric acid, hydrobromic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.
26. An intermediate compound or salt of the formula,
27. an intermediate compound or salt as claimed in claim 25 or 26 for use in the preparation of a compound of formula I or a salt thereof.
28. A process for the preparation of a compound of formula III 'comprising reducing a compound of formula IV with a reducing agent to give a compound of formula III',
the reducing agent is sodium hydrosulfite, hydrogen or hydrazine hydrate, wherein the hydrogen is used for reducing the compound shown in the formula IV in the presence of palladium carbon, palladium hydroxide/carbon or Raney nickel as a catalyst, and the hydrazine hydrate is used for reducing the compound shown in the formula IV in the presence of iron trichloride/activated carbon as a catalyst.
29. The preparation method of claim 28, wherein when the reducing agent sodium hydrosulfite is used for reducing the compound of formula IV, an acid HB which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or acetic acid is further added.
30. The method of claim 29, wherein the molar ratio of acid HB to the compound of formula IV is 12-24: 1.
CN201810627166.4A 2018-06-15 2018-06-15 Process for producing pyridylamino pyrimidine derivative and intermediate thereof Active CN110606842B (en)

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