CN106957336B - Preparation method of fluzetinib - Google Patents

Preparation method of fluzetinib Download PDF

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CN106957336B
CN106957336B CN201610018460.6A CN201610018460A CN106957336B CN 106957336 B CN106957336 B CN 106957336B CN 201610018460 A CN201610018460 A CN 201610018460A CN 106957336 B CN106957336 B CN 106957336B
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CN106957336A (en
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余俊
于海洲
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Abstract

The invention relates to a preparation method of flupirtine, which can be used for treating non-small cell lung cancer. The method comprises the steps of taking (R) -5-bromo-3- [1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -2-nitropyridine as a starting material, carrying out coupling reaction with a hydroxyphenylboronic acid pinacol ester compound III under the action of a suitable catalyst and alkali to obtain a compound VII, carrying out esterification under the action of alkali to obtain a compound VI, carrying out coupling reaction with a dimethylphosphonic oxide compound IV under the action of a suitable catalyst and alkali to obtain a compound V, and finally carrying out nitro reduction to obtain a compound I. The method has the advantages of reasonable process design, high reaction yield, simple and convenient operation, no harsh reaction conditions and capability of realizing industrial production with high efficiency and high quality.

Description

Preparation method of fluzetinib
Technical Field
The invention relates to the technical field of medicine manufacturing, in particular to a preparation method of a compound of flupirtine for treating non-small cell lung cancer, namely a preparation method of (R) -3- [1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [ 3-fluorophenyl-1-dimethylphosphonyloxy-4-yl ] pyridine-2-amine.
Background
Fluzetinib, chemical name: (R) -3- [1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [ 3-fluorophenyl-1-dimethylphosphamido-4-yl ] pyridin-2-amine, structure:
Figure BDA0000904927100000011
fluoritinib is a drug useful for the treatment of non-small cell lung cancer, a leading cause of cancer death worldwide, by modulating the activity of Anaplastic Lymphoma Kinase (ALK) and cMet kinase. Approximately 85% of lung cancers are non-small cell lung cancers (NSCLC). An ALK gene rearrangement involving a small inversion within chromosome 2p to form a fusion gene comprising portions of the echinoderm microtubule binding protein-like 4(EML4) gene and the ALK gene was identified in a small subset (6-7%) of NSCLC patients. The tumorigenic potential of EML4-ALK has been confirmed in transgenic mice with hundreds of adenocarcinoma nodules in both lungs, and inhibition of ALK in lung cancer by oral administration of an effective ALK inhibitor resulted in tumor shrinkage or stable disease in most patients, and effectively reduced tumor burden by administration of an effective ALK inhibitor.
cMet is a high affinity hepatocyte growth factor receptor (HGF). The cMet/HGF/SF signal is essential for normal cell proliferation, migration, angiogenesis, embryogenesis, organ formation and tissue regeneration. Aberrant cMet/HGF/SF signaling (caused by mutations or overexpression of the c-Met protooncogene and HGF) plays a major role in tumor formation, invasion and metastasis in many human tumors. cMet is highly expressed in many cancers, and this expression correlates with poor prognosis in patients. cMet, which activates point mutations in the kinase domain, is implicated in the cause of hereditary papillary renal cancers and has also been detected in sporadic papillary renal cancers, lung cancers, head and neck cancers, childhood hepatocellular carcinomas, and gastric cancers. Furthermore, amplification of the cMet locus was detected in patients with gastric, metastatic colorectal cancer and esophageal adenocarcinoma. cMet is an attractive therapeutic target for cancer therapy.
Thus, the identification of small molecules that specifically modulate kinase activity, particularly ALK and/or cMet kinase activity, provides therapeutic approaches for the treatment of cancer, inflammation, cardiovascular and metabolic diseases, psychological and neurological disorders.
At present, the preparation method of the international literature publication I is mainly limited to the compound patent reports: WO2004058267, which can be summarized as the following route:
Figure BDA0000904927100000021
although the reaction steps of the route are short, in the step one reaction, the reaction time is too long, the yield is extremely low (50%), and a preparation column is required for purification, so that the industrial scale-up cannot be carried out. In step two, industrial scale-up cannot be performed due to the very large amount of palladium catalyst used (40%), low yield (60%), and poor product purity (85.3%).
Disclosure of Invention
The present invention aims to solve the above problems and provide a process for producing a compound (i) with high purity and high yield, which comprises:
Figure BDA0000904927100000031
the method comprises the steps of taking a compound II as an initial raw material, firstly carrying out Suzuki coupling reaction on the compound II and a hydroxyphenylboronic acid pinacol ester compound III to obtain a compound VII, then carrying out phenolic hydroxyl trifluoromethanesulfonic acid esterification to obtain a compound VI, then carrying out coupling reaction on the compound VI and a dimethylphosphonic acid oxy compound IV to obtain a compound V, and finally carrying out nitro reduction to obtain I. The method comprises the following specific steps:
(1) the 4-bromo-3-fluorophenol and bis (pinacolborate) are subjected to coupling reaction under the action of a proper catalyst and alkali to obtain a compound III:
Figure BDA0000904927100000032
adding 4-bromo-3-fluorophenol and bis (pinacolato) borate into an organic solvent, adding a proper catalyst and alkali, and heating and stirring until the 4-bromo-3-fluorophenol completely reacts. Cooling the reaction liquid, filtering, adding purified water, extracting, washing, drying, filtering, concentrating, and pulping the residue with organic solvent. Filtering to obtain brown powdery solid III;
the catalyst is selected from palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, palladium acetate or tris (dibenzylideneacetone) dipalladium, preferably tetrakis (triphenylphosphine) palladium;
the alkali is selected from potassium carbonate, sodium hydroxide, potassium acetate or sodium acetate, preferably potassium acetate;
the 4-bromo-3-fluorophenol: bis-pinacol boronate ester: catalyst: the molar ratio of the base is about 1:1.0-1.5:0.05:2.0-3, preferably 1:1.3:0.05: 2.5;
the organic solvent is selected from tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, toluene, xylene, 1, 4-dioxane or N, N-dimethylformamide, and preferably 1, 4-dioxane;
the coupling reaction is carried out at a reflux temperature, and the reaction time is 3-5 hours.
(2) The raw material (R) -5-bromine-3- [1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -2-nitropyridine and a compound III are subjected to coupling reaction under the action of a proper catalyst and alkali to obtain a compound VII:
Figure BDA0000904927100000041
adding the raw materials and the compound III into a water-miscible organic solvent, adding a proper catalyst and alkali, and carrying out reflux reaction until the raw materials are basically reacted completely. Cooling, adding purified water and benign solvent, extracting, washing, drying, filtering, concentrating, dissolving the residue with benign organic solvent, slowly adding poor solvent while stirring, and pouring out supernatant (1); dissolving the residual dark brown viscous substance with benign organic solvent, adding poor solvent under stirring, and pouring out supernatant liquid 2; and combining the clear liquids 1 and 2, and concentrating under reduced pressure to obtain a gray yellow solid VII.
The catalyst is selected from palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, palladium acetate or tris (dibenzylideneacetone) dipalladium, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex;
the alkali is selected from potassium carbonate, sodium hydroxide, potassium acetate or sodium acetate, and preferably sodium carbonate;
the compound II: compound iii: catalyst: the molar ratio of the base is about 1:1.0-1.5:0.01:2.0-3.0, preferably 1:1.4:0.01: 2.5;
the solvent in the coupling reaction stage is selected from ethylene glycol dimethyl ether, isopropyl ether, methanol, ethanol, water, 1, 4-dioxane or N, N-dimethylformamide, and preferably a mixed solvent of ethylene glycol dimethyl ether, methanol and water;
the benign solvent is selected from dichloromethane, methyl tert-butyl ether or ethyl acetate, preferably ethyl acetate;
the poor solvent is selected from water, n-heptane, n-hexane or cyclohexane, preferably n-hexane;
the coupling reaction is carried out at a reflux temperature for 2-5 hours.
(3) And VII, esterifying the obtained product by using phenolic hydroxyl trifluoromethanesulfonic acid under the action of alkali to obtain a compound VI:
Figure BDA0000904927100000051
and (3) adding VII and alkali into an organic solvent, slowly dropwise adding trifluoromethanesulfonic anhydride into the reaction mixed liquid under the heat preservation condition, and after dropwise adding, preserving heat to react the VII completely. Washing the reaction solution with purified water, back-extracting the water layer with benign solvent, combining the organic layers, washing, drying, filtering, concentrating, and purifying the residue by column chromatography. Collecting qualified components, concentrating under reduced pressure, pulping residues by using a poor solvent, and filtering to obtain a light yellow solid VI.
The base is selected from triethylamine, pyridine, N-diisopropylethylamine or N-methylmorpholine, and pyridine is preferred;
the organic solvent is selected from dichloromethane, toluene, xylene, tetrahydrofuran or diethyl ether, preferably dichloromethane;
the VII: alkali: the molar ratio of trifluoromethanesulfonic anhydride is about 1:3.5-4.5:2.0-3.0, preferably 1:4: 2.8;
the benign solvent is selected from dichloromethane, toluene, xylene, tetrahydrofuran or diethyl ether, preferably dichloromethane;
the poor solvent is selected from water, n-heptane, n-hexane or cyclohexane, preferably n-hexane;
the reaction temperature is 20-30 ℃, and the reaction lasts 17-19 hours.
(4) And VI, carrying out coupling reaction with IV under the action of a proper catalyst and alkali to obtain a compound V:
Figure BDA0000904927100000052
VI, IV and alkali are added into the organic solvent, stirred and heated to reflux. Adding catalyst, refluxing and reacting until VI reaction is completed. And directly adding the reaction solution into purified water under stirring, extracting, washing, drying, filtering, and concentrating under reduced pressure to obtain brown oily matter V.
The base is selected from triethylamine, pyridine, N-diisopropylethylamine or N-methylmorpholine, preferably triethylamine;
the organic solvent is selected from tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, toluene, xylene, acetonitrile, 1, 4-dioxane or N, N-dimethylformamide, preferably acetonitrile;
VI: IV: catalyst: the molar ratio of the base is about 1:2.0-2.5:0.1:3.5-4.5, preferably 1:2.3:0.1: 4;
the coupling reaction is carried out at a reflux temperature for 1-2 hours.
(5) V, reducing through a nitro group to obtain a compound I:
Figure BDA0000904927100000061
and V, dissolving in an organic solvent, adding a catalyst and a hydrogen source, and carrying out reflux reaction until the reaction is complete. Concentrating under reduced pressure to remove solvent, adding organic solvent and alkaline water into the residue, stirring, filtering, washing, layering, extracting alkaline solution with organic solvent, and mixing organic layers. Adding purified water into the organic layer, and adding hydrochloric acid into the organic layer to form salt under stirring; separating out an organic layer, washing with a hydrochloric acid aqueous solution, combining acid aqueous layers, sequentially washing, dissociating, extracting, washing, drying, filtering, concentrating, carrying out column chromatography, collecting qualified components, carrying out reduced pressure concentration to remove a solvent, pulping residues with the organic solvent, filtering, and recrystallizing to obtain a white solid I.
The organic solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, ethanol or methanol, preferably ethanol;
the catalyst is selected from metal catalysts, such as Fe powder, Pd and Ni based catalysts, preferably Fe powder;
when the metal-based catalyst is Pd, the hydrogen source is selected from hydrogen or ammonium formate;
when the metal-based catalyst is Fe, the hydrogen source is selected from hydrochloric acid or acetic acid;
when the metal-based catalyst is Ni, the hydrogen source is selected from hydrogen or hydrazine hydrate;
the reduction reaction is carried out at a reflux temperature for 2-3 hours;
the recrystallization solvent is selected from ethanol, acetone, dichloromethane, ethyl acetate, tetrahydrofuran or methanol, and acetone is preferred;
further preferably, the preparation method of the present invention specifically comprises:
and adding acetone (8V) into the crude product of the compound I, heating and refluxing to be clear, filtering, concentrating under reduced pressure until 2.4V-2.6V is remained in the total volume, naturally cooling to 20-30 ℃, and stirring for crystallization for 15-17 hours. Filtration gave pure compound i.
The preparation process is simple to operate, and the obtained product is high in yield, good in purity and suitable for industrial production.
Detailed Description
The following provides a specific implementation method of the preparation method of the compound flupirtine for treating non-small cell lung cancer.
Examples
(1) Preparation of Compound III
Figure BDA0000904927100000071
4-bromo-3-fluorophenol (4.82g, 25.24mmol), bis (pinacolato) borate (8.25g, 32.47m mol), potassium acetate (6.16g, 62.84mmol) and tetrakis (triphenylphosphine) palladium (1.46g, 1.28mmol) were put into a reaction flask, 1, 4-dioxane (56ml) was added thereto, and the mixture was heated under stirring and refluxed for 4 hours, with the temperature outside of T95 ℃ and the 4-bromo-3-fluorophenol was almost completely reacted by TLC detection. After the reaction solution was cooled, the reaction solution was filtered through Celite and washed with ethyl acetate (10 ml. times.2). The filtrates were combined, and water (25ml) was added to the mixture, followed by extraction with ethyl acetate (40 ml. times.3). The organic layers were combined, washed successively with water (40ml) and sodium chloride solution (40 ml. times.2), and dried over anhydrous sodium sulfate. Concentrated by filtration, and the residue was slurried with n-hexane (30ml) for 20 hours. Filtering, washing a filter cake by using normal hexane, and drying by blowing air at 45 ℃ to obtain 4.70g of brown powder solid with the mass yield: 97.5%, purity: 93.9 percent.
(2) Preparation of Compound VII
Figure BDA0000904927100000072
Mixing compound II (700.0g, 1.707mol), compound III (569.0g, 2.390mol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (PdCl)2(dppf)2·CH2Cl213.9g, 17.070mmol), anhydrous sodium carbonate (452.4g, 4.268mol), 1, 2-dimethoxyethane (3.0L), methanol (1.5L) and purified water (1.5L) are added into a reaction bottle, heated and stirred, reflux reaction is carried out for 3-4 hours, and TLC detection is carried out until the compound II is basically reacted completely. Cooling to 20-30 deg.C, adding purified water (7.0L) and ethyl acetate (9.5L), stirring, standing to separate out water layer, and extracting with ethyl acetate (7.0L); the organic layers were combined, washed successively with 2N hydrochloric acid solution (10.0L) and saturated sodium chloride solution (10.0L. times.2), and dried over anhydrous sodium sulfate (2.0 kg). The mixture was filtered and concentrated, and the residue was dissolved in ethyl acetate (3.0L), and n-hexane (6.0L) was slowly added with stirring, followed by stirring for 15 to 17 hours. Separating out a supernatant liquid 1, dissolving the dark brown viscous substance with ethyl acetate (0.7L), adding n-hexane (1.4L) under stirring, stirring for 2-3 hours after the addition is finished, and separating out a supernatant liquid 2; and (3) combining the supernatant liquid 1 and the supernatant liquid 2, concentrating under reduced pressure, and drying the residue for 16-18 hours in vacuum at 40 +/-5 ℃ to obtain a compound VII (688.8g, a gray yellow solid) with the mass yield: 98.4 percent.
TLC conditions: n-hexane-ethyl acetate (3:1), GF254 silica gel plate, ultraviolet development;
(3) preparation of Compound VI
Figure BDA0000904927100000081
Dissolving a compound VII (688.8g, 1.561mol) with dichloromethane (7.0L), putting into a reaction bottle, adding pyridine (502ml, 6.244mol), dropwise adding trifluoromethanesulfonic anhydride (735ml, 4.371mol) while stirring, controlling the reaction temperature to be 20-30 ℃, reacting for 2-3 hours, keeping the temperature to be 20-30 ℃ for 17-19 hours, and basically completely reacting by TLC detection. The reaction solution was washed with purified water (7.0L. times.2), the aqueous layer was back-extracted with methylene chloride (7.0L), and the organic layers were combined, washed with a saturated sodium chloride solution (10.0L), and dried over anhydrous sodium sulfate (2.0 kg). Filtration and concentration, column chromatography purification of the residue, eluent: n-hexane/ethyl acetate 15: 1. Collecting qualified components, concentrating under reduced pressure, pulping residues for 2-3 hours by using n-hexane, filtering, and drying filter cakes for 16-18 hours in vacuum at the temperature of 40 +/-5 ℃ to obtain a compound VI (624.0g, light yellow solid). The quality yield is as follows: 90.6%, purity: 97.96 percent.
TLC conditions: n-hexane-ethyl acetate (7:1), GF254 silica gel plate, ultraviolet development;
(4) preparation of Compound V
Figure BDA0000904927100000082
Adding a compound VI (624.0g, 1.088mol), a compound IV (195.3g, 2.502mol), triethylamine (606ml, 4.352mol) and acetonitrile (6.0L) into a reaction bottle, stirring and heating until reflux is realized, adding a catalyst [1,1' -bis (diphenylphosphino) ferrocene ] after the reflux is kept stable, and then adding a catalyst]Palladium dichloride dichloromethane complex (PdCl)2(dppf)2CH2Cl298.0g, 0.120mol), refluxing and reacting for 1-1.5 hours, and detecting by TLC to ensure that the reaction is almost complete. Adding the reaction solution into purified water (20.0L) under stirring, and extracting with ethyl acetate (25.0L); the aqueous layer was separated and back-extracted with ethyl acetate (10.0L). The organic layers were combined, washed with saturated sodium chloride solution (15.0L) and dried over anhydrous sodium sulfate (3.5 kg). Filtration and concentration under reduced pressure gave compound V (689.5g, brown oil). The quality yield is as follows: 110.5 percent.
TLC conditions: n-hexane-ethyl acetate (10:1), GF254 silica gel plate, ultraviolet development;
(5) preparation of Compound I
Figure BDA0000904927100000091
Dissolving the compound V (689.5g, 1.376mol) in ethanol (6.0L), putting into a reaction bottle, adding hydrochloric acid (303ml, 3.027mol), stirring, adding iron powder (462.3g, 8.256mol), refluxing for 2-2.5 hours, and basically completing the reaction by TLC detection. Cooled to 50. + -. 5 ℃ and concentrated under reduced pressure to remove the solvent, ethyl acetate (10.0L) and 2.5N sodium hydroxide solution (10.0L) were added to the residue, stirred, allowed to stand, filtered over celite, and the filter cake was washed with ethyl acetate/methanol mixed solution (4:1, 1.0L. times.4). The aqueous alkaline layer was separated, extracted with ethyl acetate (4.0L) and the organic layers combined. Adding purified water (15.0L) into the organic layer, and adding hydrochloric acid (1.2L) into the organic layer under stirring to form salt; the organic layer was separated, washed with 2N hydrochloric acid (2.5L), and the aqueous acid layers were combined and washed with ethyl acetate (2.5L). The acid aqueous layer was added with 7.5N sodium hydroxide (2.5L), extracted with ethyl acetate (4.0L. times.3), and the organic layers were combined, washed successively with 2N sodium hydroxide (10.0L), purified water (10.0L. times.2), and a saturated sodium chloride solution (10.0L. times.2), and dried over anhydrous sodium sulfate (1.5 kg). Filtration, concentration under reduced pressure, column chromatography purification of the residue, eluent: collecting qualified components, concentrating under reduced pressure to remove the solvent, pulping the residue with acetone (300ml) for 16-18 hours, filtering, washing with acetone (80ml), and drying with air blowing at 45 +/-5 ℃ for 17-18 hours to obtain a crude compound I (308.7g, yellow solid). The quality yield is as follows: 44.7%, purity: 96.8 percent.
TLC conditions: dichloromethane-methanol (15:1), GF254 silica gel plate, ultraviolet development;
adding acetone (2.5L) into the crude product (308.5g, 0.654mol) of the compound I, heating and refluxing to be clear, filtering, concentrating under reduced pressure until 750-800 ml of the total volume remains, naturally cooling to 25 +/-5 ℃, stirring and crystallizing for 15-17 hours. Filtering, washing with acetone (80ml), and vacuum drying the filter cake at 80 +/-5 ℃ for 20-22 hours to obtain the compound I (209.8g, white-like solid). The quality yield is as follows: 68.0%, purity: 99.98 percent.
Spectral data:
1H NMR(500MHz,CDCl3)δ(ppm)1.75(s,3H),1.77(s,3H),1.85-1.87(d,J＝6.5，3H),5.12(br,2H),6.06-6.10(q,J＝6.5Hz,1H),6.99(s,1H),7.04-7.07(m,1H),7.28-7.31(m,1H),7.40-7.43(m,1H),7.44-7.53(m,2H),7.85(s,1H).
13C NMR(100MHz):δ＝17.7,18.2,18.8,72.5,116.5(d,J＝92.5Hz),117.3(d,J＝17.5Hz),117.6(dd,J＝455,41.5Hz),120.3,121.9(d,J＝76Hz),125.5(dd,J＝350,145Hz),128.8(d,J＝145Hz),129.5(dd,J＝515,85Hz),130(dd,J＝525,135Hz),134.9(d,J＝230Hz),135.7(d,J＝230Hz),136.7,139.1,150.4,156.4,158.5(d,J＝640Hz),160.5(d,J＝610Hz).
IR(KBr):3478,3268,3081,2982,1627,1514,1483,1551,1455,1427,1397,1189,1274,1096,860,819,775cm-1；
MS(m/z)：471.06031[M+H]+。
the foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and decorations can be made without departing from the concept of the present invention, and these modifications and decorations should also be regarded as being within the protection scope of the present invention.

Claims (26)

1. A process for the preparation of compound i, comprising the steps of:
1) the compound A4-bromine-3-fluorophenol reacts with the compound B bis pinacol borate under the action of a catalyst I and an alkali I to obtain a compound III,
Figure FDA0002555363040000011
2) the compound II (R) -5-bromo-3- [1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -2-nitropyridine reacts with a compound III under the action of a catalyst II and a base II to obtain a compound VII,
Figure FDA0002555363040000012
3) the compound VII is esterified by trifluoromethanesulfonic anhydride under the action of organic base to obtain a compound VI,
Figure FDA0002555363040000013
4) the compound VI reacts with a compound IV under the action of a catalyst III and an alkali III to obtain a compound V,
Figure FDA0002555363040000014
5) the compound V is reduced to obtain a compound I,
Figure FDA0002555363040000015
2. the process for preparing compound i according to claim 1, wherein in step 1), the catalyst is selected from palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, palladium acetate or tris (dibenzylideneacetone) dipalladium.
3. The process for preparing compound i according to claim 1, wherein in step 1), the base is selected from potassium carbonate, sodium hydroxide, potassium acetate or sodium acetate.
4. The process for preparing compound i according to claim 1, wherein in step 2), the catalyst ii is selected from palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, palladium acetate or tris (dibenzylideneacetone) dipalladium.
5. The process for preparing compound i according to claim 1, wherein in step 2), the base ii is selected from potassium carbonate, sodium hydroxide, potassium acetate or sodium acetate.
6. The process for preparing compound i according to claim 1, wherein in step 3), the organic base is selected from triethylamine, pyridine, N-diisopropylethylamine or N-methylmorpholine.
7. The process for preparing compound i according to claim 1, wherein in step 4), the catalyst is selected from palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, palladium acetate or tris (dibenzylideneacetone) dipalladium.
8. The process for preparing compound i according to claim 1, wherein in step 4), the base is selected from triethylamine, pyridine, N-diisopropylethylamine or N-methylmorpholine.
9. The process for the preparation of compound i according to claim 1, wherein the compound i is purified by recrystallization from an organic solvent.
10. The process for the preparation of compound i according to claim 9, wherein the organic solvent is selected from ethanol, acetone, dichloromethane, ethyl acetate, tetrahydrofuran or methanol.
11. The process for the preparation of compound i according to claim 9, wherein the organic solvent is acetone.
12. The process according to claim 1 for the preparation of compound I, wherein the 4-bromo-3-fluorophenol: bis-pinacol boronate ester: a first catalyst: the molar ratio of the first alkali is 1:1.0-1.5:0.05: 2.0-3.
13. The process according to claim 1 for the preparation of compound I, wherein the 4-bromo-3-fluorophenol: bis-pinacol boronate ester: a first catalyst: the molar ratio of base one is 1:1.3:0.05: 2.5.
14. A process for the preparation of compound I according to claim 1, wherein said compound ii: compound iii: and (2) catalyst II: the molar ratio of the second alkali is 1:1.0-1.5:0.01: 2.0-3.0.
15. A process for the preparation of compound I according to claim 1, wherein said compound ii: compound iii: and (2) catalyst II: the molar ratio of the second base is 1:1.4:0.01: 2.5.
16. The process for the preparation of compound I according to claim 1, wherein said compound vii: organic base: the molar ratio of the trifluoromethanesulfonic anhydride is 1:3.5-4.5: 2.0-3.0.
17. The process for the preparation of compound I according to claim 1, wherein said compound vii: organic base: the molar ratio of trifluoromethanesulfonic anhydride was 1:4: 2.8.
18. A process for the preparation of compound I according to claim 1, wherein compound vi: a compound IV: catalyst three: the molar ratio of the alkali III is 1:2.0-2.5:0.1: 3.5-4.5.
19. A process for the preparation of compound I according to claim 1, wherein compound vi: a compound IV: catalyst three: the molar ratio of the alkali III is 1:2.3:0.1: 4.
20. A compound shown in a formula VII,
Figure FDA0002555363040000041
21. the preparation method of the compound VII is characterized by comprising the following steps:
1) the compound A4-bromo-3-fluorophenol reacts with the compound B bis pinacol borate under the action of a catalyst I and an alkali I to obtain a compound III,
Figure FDA0002555363040000042
2) the compound II (R) -5-bromo-3- [1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -2-nitropyridine reacts with a compound III under the action of a catalyst II and a base II to obtain a compound VII,
Figure FDA0002555363040000043
22. the process for preparing compound vii as claimed in claim 21 wherein the 4-bromo-3-fluorophenol: bis-pinacol boronate ester: a first catalyst: the molar ratio of the first alkali is 1:1.0-1.5:0.05: 2.0-3.
23. The process for preparing compound vii as claimed in claim 21 wherein the 4-bromo-3-fluorophenol: bis-pinacol boronate ester: a first catalyst: the molar ratio of base one is 1:1.3:0.05: 2.5.
24. A process for the preparation of compound vii as claimed in claim 21 wherein compound ii: compound iii: and (2) catalyst II: the molar ratio of the second alkali is 1:1.0-1.5:0.01: 2.0-3.0.
25. A process for the preparation of compound vii as claimed in claim 21 wherein compound ii: compound iii: and (2) catalyst II: the molar ratio of the second base is 1:1.4:0.01: 2.5.
26. A compound of the formula V,
Figure FDA0002555363040000051
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Publication number Priority date Publication date Assignee Title
WO2004058267A1 (en) * 2002-12-23 2004-07-15 Ariad Pharmaceuticals, Inc. Heterocycles and uses thereof
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Publication number Priority date Publication date Assignee Title
WO2004058267A1 (en) * 2002-12-23 2004-07-15 Ariad Pharmaceuticals, Inc. Heterocycles and uses thereof
CN103826641A (en) * 2011-02-24 2014-05-28 江苏豪森药业股份有限公司 Phosphorus containing compounds as protein kinase inhibitors

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