CN108658851B - 2-chloro-3-methyl-6-acylaminopyridine and preparation method and application thereof - Google Patents
2-chloro-3-methyl-6-acylaminopyridine and preparation method and application thereof Download PDFInfo
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- 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
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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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the fields of pharmaceutical chemistry and chemical synthesis, and particularly relates to 2-chloro-3-methyl-6-acylaminopyridine, a preparation method and application thereof. The invention provides 2-chloro-3-methyl-6-acylaminopyridine represented by the following general formula II or pharmaceutically acceptable salts, esters, prodrugs or solvates thereof, which are important intermediates for anti-cystic fibrosis active ingredients. The compound represented by the general formula IA or IB, which is obtained by the compound represented by the general formula II, can be directly used for preparing an anti-cystic fibrosis drug. The synthesis method of the compound represented by the general formula IA or IB provided by the invention has the following advantages: safe, simple and convenient method, high yield and suitability for industrial production.
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and chemical synthesis, and in particular relates to 2-chloro-3-methyl-6-acylaminopyridine, and a preparation method and application thereof.
Background
In 2015, the us FDA approved a compound drug Orkambi for the treatment of cystic fibrosis, lu Maka torr (lumacaftor) and ivakaftor (ivacaftor), both oral cystic fibrosis transmembrane conductance regulator (cystic fibrosis transmemebrane conductance regulator, CFTR). Lu Maka Torr can improve the conformational stability of F508del CFTR, thereby enhancing processing and transport of the mature protein to the cell surface. Ivacizumab as a CFTR enhancer helps to enhance chloride transport by enhancing the opening of the channel.
2-chloro-3-methyl-6-aminopyridine (IA) and 2-chloro-3-methyl-6-aminopyridine (IB) are important intermediates for the preparation of Lu Maka Torr, and the related document WO2007056341 reports a synthetic method of Lu Maka Torr.
According to literature reports, the synthesis method of the two intermediates is as follows:
the patent documents WO2007056341, WO2008141119 and WO20080019915 report the synthesis of IA, wherein 2-amino-5-methylpyridine is used as a starting material, pivaloyl is adopted as a starting material, oxidation reaction is carried out between the starting material and peroxide to obtain pyridine nitrogen oxide, then chlorination reaction is carried out under the existence of phosphorus oxychloride, and pivaloyl is finally hydrolyzed to obtain the product IA.
Literature Tetrahedron,2011,67 (47), 9063-9066 reports a process for preparing IA and IB, but a mixture of the two is obtained in a 1:1 ratio.
Patent document WO2008100867 reports a process for the preparation of IB, using 2-bromo-3-methylpyridine as starting material, by oxidation to give nitrogen oxides, then reacting with 4-chloro-2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazine, and finally hydrolysis to give the product IB.
These reports have low yields, use peroxides for oxidation reactions to obtain key nitrogen oxides, and all require strongly acidic hydrolysis to obtain the product. The industrial use of peroxides brings great potential safety hazards, and the strongly acidic conditions can severely corrode production equipment. Therefore, the above method is poor in safety and is not suitable for industrial production.
Therefore, the method for preparing the 2-chloro-3-methyl-6-aminopyridine (IA) and the 2-chloro-3-methyl-6-aminopyridine (IB) which have good safety and high yield and are suitable for industrial production is urgent to find.
Disclosure of Invention
Object of the Invention
In order to solve the deficiencies in the prior art, it is an object of the present invention to provide a 2-chloro-3-methyl-6-acylaminopyridine or a pharmaceutically acceptable salt or solvate thereof, which is an important intermediate for a variety of anti-cystic fibrosis active ingredients.
It is another object of the present invention to provide a method for synthesizing 2-chloro-3-methyl-6-acylaminopyridine by reacting an organoboron reagent with a bromo compound.
It is a further object of the present invention to provide the use of 2-chloro-3-methyl-6-acylaminopyridine.
Technical proposal
In order to achieve the above object, the present invention provides 2-chloro-3-methyl-6-acylaminopyridine represented by the following general formula II:
wherein R is selected from hydrogen, C 1 -C 10 Straight-chain or branched alkyl, C 3 -C 10 Cycloalkyl, substituted or unsubstituted phenyl.
Preferably, R is selected from C 1 -C 4 Straight or branched alkyl, substituted or unsubstituted phenyl. "substituted" in the substituted phenyl refers to being substituted with one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy acyl, halogenated C1-C6 alkoxy, nitro, cyano, C1-C6 alkanoyl orHalogenated C1-C6 alkanoyl.
Another aspect of the present invention provides a method for preparing 2-chloro-3-methyl-6-acylaminopyridine by reacting 2-chloro-3-bromo-6-aminopyridine with carboxylic acid or a derivative thereof to obtain SUZUKI reaction between 2-chloro-3-bromo-6-acylaminopyridine and 2-chloro-3-bromo-6-acylaminopyridine, the method being realized by the following reaction formula:
wherein R is as defined in formula II;
the method comprises the following steps:
1) Acylating a compound represented by the formula IV with acyl chloride in the presence of alkali or condensing a compound represented by the formula III with carboxylic acid in the presence of condensing agent;
2) Reacting a compound represented by formula III with methyl boric acid in the presence of a catalyst and a base to obtain a compound represented by formula II.
In the above process, the base used in step 1) is an organic or inorganic base, preferably selected from triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-dimethyl-4-aminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide; the solvent used in step 1) is selected from the group consisting of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, ethyl acetate and ethylene glycol dimethyl ether; the reaction temperature in step 1) may vary within a wide range, typically from-20℃to 100℃and preferably from-10℃to 60 ℃. The condensing agent is selected from N, N '-Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), N, N' -Diisopropylcarbodiimide (DIC), O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), O- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyBOP).
In the above method, the catalyst used in step 2) is a catalyst used for the coupling reaction, preferably selected from palladium acetate, palladium chloride, tetra-triphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, 1 '-bis-diphenylphosphino ferrocene palladium dichloride, 1' -bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex; the alkali used in the step 2) is organic alkali or inorganic alkali and is selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide; the solvent used in the step 2) is one or more selected from dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether and water. The reaction temperature in step 2) may vary within a wide range, typically from 0℃to 200℃and preferably from 50℃to 160 ℃.
The invention further provides an application of the 2-chloro-3-methyl-6-acylaminopyridine shown in the general formula II, wherein the 2-chloro-3-methyl-6-acylaminopyridine shown in the general formula II is subjected to deprotection reaction in an acidic environment to obtain a compound shown in the general formula IA, and the compound IB is obtained by bromination reaction of the IA.
Wherein R is as defined in formula II.
In the above process, the acidic system in step 3) is an acid-water mixture or an acid-alcohol mixture, in particular a mixture of hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid with, for example, water, methanol, ethanol, propanol or isopropanol, the reaction temperature can vary within a wide range, generally from 0 ℃ to 200 ℃, preferably from 20 ℃ to 160 ℃;
in the above process, the brominating reagent described in step 4) is selected from phosphorus tribromide, phosphorus tribromide and phosphorus pentabromide, the solvent used is selected from one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether and chlorobenzene, and the reaction temperature can vary within a wide range, typically from 0 ℃ to 200 ℃, preferably from 20 ℃ to 180 ℃.
Advantageous effects
The 2-chloro-3-methyl-6-acylaminopyridine represented by the general formula II or the pharmaceutically acceptable salt or solvate thereof is an important intermediate of an active ingredient for resisting cystic fibrosis. In addition, the compound shown in the formula IA, which is obtained through hydrolysis or alcoholysis reaction of the compound shown in the formula II, can be directly used for preparing medicines for treating cystic fibrosis. In addition, the compound of formula IB obtained by bromination of the compound of formula IA can be directly used for preparing medicines for treating cystic fibrosis.
The method for synthesizing the 2-chloro-3-methyl-6-aminopyridine through the SUZUKI reaction provided by the invention utilizes the cheap and simple chemical raw material 2-chloro-3-bromo-6-aminopyridine as a raw material, prepares the compound shown in the general formula II through an acylation reaction and a SUZUKI coupling reaction, prepares the compound shown in the general formula IA through a simple hydrolysis reaction or an alcoholysis reaction, prepares the compound shown in the general formula IB through a simple bromination reaction, does not need peroxide, does not need a nitrogen oxide intermediate, and has the advantages of high safety, high yield, mild reaction conditions, simplicity and convenience in operation, suitability for industrialization and the like.
Detailed Description
Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details set forth in the following examples, as other variations will be known and apparent to those of ordinary skill in the art in light of the present disclosure.
Example 1:
6-amino-3-bromo-2-chloroPyridine (2.07 g,10 mmol) was dissolved in 50ml dichloromethane, triethylamine (2.0 eq) was added, pivaloyl chloride (1.2 eq) was slowly added dropwise, the temperature was slowly raised to 40 ℃ after the addition, stirring was carried out for 24 hours, TLC showed complete reaction of the starting materials, and concentration under reduced pressure gave a residue. To the residue was added a mixture of 30ml of water and 1ml of concentrated hydrochloric acid, stirred and filtered to give 2.65g of a white solid in 90% yield. 1 H NMR(400MHz,CDCl3)δ8.11(d,J=8.6Hz,1H),7.97(br s,1H),7.88(d,J=8.6Hz,1H),1.31(s,9H).
Example 2:
6-amino-3-bromo-2-chloropyridine (2.07 g,10 mmol) was dissolved in 50ml dichloromethane, triethylamine (2.0 eq) was added, acetyl chloride (1.2 eq) was slowly added dropwise, and stirring was completed for 24 hours, TLC showed complete reaction of the starting materials, and concentration under reduced pressure was performed to give a residue. To the residue was added a mixture of 30ml of water and 1ml of concentrated hydrochloric acid, stirred and filtered to give 2.34g of a white solid in 94.7% yield. 1 H NMR(400MHz,CDCl3)δ8.05(d,J=8.6Hz,1H),7.91(br s,1H),7.88(d,J=8.6Hz,1H),2.20(s,3H).
Example 3:
6-amino-3-bromo-2-chloropyridine (2.07 g,10 mmol) was dissolved in 50ml dichloromethane, triethylamine (2.0 eq) was added, benzoyl chloride (1.2 eq) was added, the temperature was raised to 50℃and stirred for 24 hours, TLC showed complete reaction of starting materials, and concentrated under reduced pressure to give a residue. To the residue was added a mixture of 30ml of water and 1ml of concentrated hydrochloric acid, stirred and filtered to give 2.52g of a white solid, yield 80.7%.
1 H NMR(400MHz,CDCl3)δ8.05(d,J=8.6Hz,1H),7.5-8.0(m,7H).
Example 4:
compound III-1 (2.91 g,10 mmol), methylboronic acid (1.25 eq), naHCO3 (4 eq), pd (dppf) Cl2 (0.01 eq) were added to a 250ml flask, water (30 ml), 1, 4-dioxane (30 ml) were added in sequence, protected with N2, heated to reflux and reacted for 24 hours. The mixture was allowed to stand for delamination, the aqueous layer was removed, the organic layer was concentrated to dryness, 50ml of ethyl acetate and 20ml of water were added, stirred for 0.5 hour, the mixture was allowed to stand for delamination, the organic phase was concentrated, and the residue was recrystallized from isopropyl alcohol to give 1.7g of II-1 in 75% yield. 1 H NMR(400MHz,CDCl3)δ8.07(d,J=8.2Hz,1H),7.93(br s,1H),7.53(d,J=8.2Hz,1H),2.31(s,3H),1.29(s,9H).MS-ESI:m/z 225(M-1).
Example 5:
compound III-2 (2.5 g,10 mmol), methylboronic acid (1.25 eq), naHCO3 (4 eq), pd (dppf) Cl2 (0.01 eq) were added to a 250ml flask, water (30 ml), 1, 4-dioxane (30 ml) were added in sequence, protected with N2, heated to reflux and reacted for 24 hours. The mixture was allowed to stand for delamination, the aqueous layer was removed, the organic layer was concentrated to dryness, 50ml of ethyl acetate and 20ml of water were added, stirred for 0.5 hour, the mixture was allowed to stand for delamination, the organic phase was concentrated, and the residue was recrystallized from isopropyl alcohol to give 1.38g of II-3 in 75% yield. 1 H NMR(400MHz,CDCl3)δ8.02(d,J=8.2Hz,1H),7.89(br s,1H),7.55(d,J=8.2Hz,1H),2.33(s,3H),2.18(s,3H).MS-ESI:m/z 183(M-1).
Example 6:
compound III-2 (3.1 g,10 mmol), methylboronic acid (1.25 eq), naHCO3 (4 eq), pd (dppf) Cl2 (0.01 eq) were added to a 250ml flask, water (30 ml), 1, 4-dioxane (30 ml) were added in sequence, protected with N2, heated to reflux and reacted for 24 hours. The mixture was allowed to stand for delamination, the aqueous layer was removed, the organic layer was concentrated to dryness, 50ml of ethyl acetate and 20ml of water were added, stirred for 0.5 hour, the mixture was allowed to stand for delamination, the organic phase was concentrated, and the residue was recrystallized from isopropyl alcohol to give 2g of II-3 in 80% yield.
1 H NMR(400MHz,CDCl3)δ8.02(d,J=8.2Hz,1H),7.6-7.85(m,6H),7.56(d,J=8.2Hz,1H),2.23(s,3H).MS-ESI:m/z 245(M-1).
Example 7:
II-1 (2.26 g,10 mmol), methanol (20 ml) and concentrated hydrochloric acid (1 eq) were placed in a 50ml reaction flask, heated to 70℃and stirred for 1 hour, concentrated, 10ml of water was added, the pH of the system was adjusted to neutral with sodium hydroxide, and filtered to give 1.2g of the product in 85% yield.
1 H NMR(400MHz,CDCl3)δ7.28(d,J=8.0Hz,1H),6.35(d,J=8.0Hz,1H),4.39(br s,2H),2.22(s,3H).MS(ESI)m/z:143(M+1)
Example 8:
II-2 (1.84 g,10 mmol), methanol (20 ml) and concentrated hydrochloric acid (1 eq) were placed in a 50ml reaction flask, heated to 70℃and stirred for 1 hour, concentrated, 10ml of water was added, the pH of the system was adjusted to neutrality with sodium hydroxide, and filtered to give 1.0g of the product in 71% yield.
Example 9:
II-1 (2.46 g,10 mmol), methanol (20 ml) and concentrated hydrochloric acid (1 eq) were placed in a 50ml reaction flask, heated to 70℃and stirred for 1 hour, concentrated, 10ml of water was added, the pH of the system was adjusted to neutral with sodium hydroxide, and filtered to give 1.3g of the product in 92% yield.
Example 10:
3.4g of chloride IA is added into 10ml of phosphorus tribromide, heated to 140 ℃, TLC reaction is completed after 6 hours of reaction, the temperature is reduced to ambient temperature, the mixture is slowly added into crushed ice, 40% sodium hydroxide is added to adjust the pH value to 10, a large amount of solid is separated out, the mixture is filtered, and a filter cake is washed with 20ml of water, so that 4g of a product IB is obtained, and the yield is 91%. 1 H NMR(400MHz,CDCl3)δ7.25(d,J=8.0Hz,1H),6.38(d,J=8.0Hz,1H),4.48(brs,2H),2.24(s,3H).
The foregoing examples are for illustrative purposes only, and the scope of the present invention is not limited thereto. Modifications will be obvious to those skilled in the art and the present invention is limited only by the scope of the appended claims.
Claims (8)
1. 2-chloro-3-methyl-6-acylaminopyridine represented by the following general formula II or a pharmaceutically acceptable salt thereof:
wherein R is a substituted or unsubstituted phenyl group;
the substitution means substitution with one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy acyl, halogenated C1-C6 alkoxy, nitro, cyano, C1-C6 alkanoyl or halogenated C1-C6 alkanoyl.
2. A method for synthesizing 2-chloro-3-methyl-6-acylaminopyridine represented by the general formula II, which is achieved by the following reaction scheme:
wherein R is selected from hydrogen, C 1 -C 10 Straight-chain or branched alkyl, C 3 -C 10 Cycloalkyl, substituted or unsubstituted phenyl; the substitution means substitution with one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy acyl, halogenated C1-C6 alkoxy, nitro, cyano, C1-C6 alkanoyl or halogenated C1-C6 alkanoyl;
the method comprises the following steps:
1) Acylating a compound represented by the formula IV with acyl chloride in the presence of alkali or condensing a compound represented by the formula III with carboxylic acid in the presence of condensing agent;
2) Reacting a compound represented by formula III with methyl boric acid in the presence of a catalyst and a base to obtain a compound represented by formula II.
3. The process according to claim 2, wherein the base used in step 1) is an organic or inorganic base;
the catalyst used in the step 2) is a catalyst used in a coupling reaction, and the used alkali is an organic alkali or an inorganic alkali;
the solvent used in step 1) is selected from the group consisting of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, ethyl acetate and ethylene glycol dimethyl ether;
the solvent used in the step 2) is one or more selected from dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, ethyl acetate, ethylene glycol dimethyl ether and water.
4. A process according to claim 3, wherein the base used in step 1) is selected from triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-dimethyl-4-aminopyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide.
5. A process according to claim 3 wherein the catalyst used in step 2) is selected from palladium acetate, palladium chloride, tetra-triphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, 1 '-bis-diphenylphosphine ferrocene palladium dichloride, 1' -bis-diphenylphosphine ferrocene palladium dichloride dichloromethane complex.
6. A process according to claim 3, wherein the base used in step 2) is selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide.
7. The application of the 2-chloro-3-methyl-6-acylaminopyridine shown in the general formula II is characterized in that the 2-chloro-3-methyl-6-acylaminopyridine shown in the general formula II is subjected to hydrolysis or alcoholysis reaction in an acidic environment to obtain a compound shown in the general formula IA, and the compound shown in the general formula IA is subjected to bromination reaction to obtain a compound shown in the general formula IB;
wherein R is a substituted or unsubstituted phenyl group;
the substitution means substitution with one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy acyl, halogenated C1-C6 alkoxy, nitro, cyano, C1-C6 alkanoyl or halogenated C1-C6 alkanoyl;
the reaction comprises the following steps:
3) Hydrolyzing or alcoholysis reaction is carried out on the compound shown in the formula II under an acidic system to obtain a compound shown in the formula IA;
4) The compound represented by formula IA is subjected to bromination reaction in the presence of a brominating reagent to obtain a compound represented by formula IB.
8. The use according to claim 7, wherein,
the acid system in the step 3) is an acid-water mixture or an acid-alcohol mixture, the acid is hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid, and the alcohol is methanol, ethanol, propanol or isopropanol;
the brominating reagent in the step 4) is selected from one or more of phosphorus tribromide, phosphorus tribromide and phosphorus pentabromide.
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CN101356170A (en) * | 2005-11-08 | 2009-01-28 | 沃泰克斯药物股份有限公司 | Heterocyclic modulators of ATP-binding cassette transporters |
CN101687842A (en) * | 2007-05-09 | 2010-03-31 | 沃泰克斯药物股份有限公司 | The CFTR conditioning agent |
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CN101356170A (en) * | 2005-11-08 | 2009-01-28 | 沃泰克斯药物股份有限公司 | Heterocyclic modulators of ATP-binding cassette transporters |
CN101687842A (en) * | 2007-05-09 | 2010-03-31 | 沃泰克斯药物股份有限公司 | The CFTR conditioning agent |
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