CN117024354B - Preparation method of Rui Mi Buti Ni - Google Patents

Preparation method of Rui Mi Buti Ni Download PDF

Info

Publication number
CN117024354B
CN117024354B CN202311290768.2A CN202311290768A CN117024354B CN 117024354 B CN117024354 B CN 117024354B CN 202311290768 A CN202311290768 A CN 202311290768A CN 117024354 B CN117024354 B CN 117024354B
Authority
CN
China
Prior art keywords
compound
reaction
chloride
ligand
bipyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202311290768.2A
Other languages
Chinese (zh)
Other versions
CN117024354A (en
Inventor
洪浩
肖毅
林汉
吴淼
李校根
魏源
井蕾
陈鸿标
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Asymchem Pharmaceutical Co Ltd
Original Assignee
Tianjin Asymchem Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin Asymchem Pharmaceutical Co Ltd filed Critical Tianjin Asymchem Pharmaceutical Co Ltd
Priority to CN202311290768.2A priority Critical patent/CN117024354B/en
Publication of CN117024354A publication Critical patent/CN117024354A/en
Application granted granted Critical
Publication of CN117024354B publication Critical patent/CN117024354B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Abstract

The invention provides a preparation method of Rui Mi Buti Ni. The preparation method comprises the following steps: step S1, carrying out reduction coupling reaction on raw materials comprising a compound 1, a compound 2, a reducing agent and a nickel-containing catalyst to obtain a compound 3; and step S2, carrying out condensation reaction on the raw materials comprising the compound 3 and acrylic acid to obtain the Rayleigh Mi Buti Ni. The invention provides a new route for synthesizing the Rui Mi Buti Ni, does not use any Pd metal catalyst and expensive bisboronic acid pinacol ester and cyclopropylboric acid in the whole route, effectively reduces the synthesis cost, has simple and convenient operation, and is suitable for industrialized amplified production.

Description

Preparation method of Rui Mi Buti Ni
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of Rayleigh Mi Buti Ni.
Background
Remibrutinib (rui Mi Buti ni) is a medicine developed by nowa corporation for treating Chronic Spontaneous Urticaria (CSU), and phase II clinical trials show that the medicine has good safety and tolerance, and phase III clinical trials are currently being conducted. At present, only one synthetic route for Remibrutinib has been reported, wherein four steps involve the use of a noble metal catalyst Pd, and expensive pinacol diboronate and cyclopropylboronic acid are used, resulting in high synthesis costs. The invention provides a new synthesis method, avoids the use of noble metal catalysts, effectively reduces the cost, is simple and convenient to operate, and is suitable for industrialized amplified production.
The synthetic route of Remibrutinib has been reported in 2015 by Angst, D., gessier, F., vulpetti, A (U.S. Pat. No. 5, 2015152068A1, 2015) and the like, and is shown below:
the method comprises the steps of respectively carrying out Pd-catalyzed coupling reaction, pd/C reduction, substitution and other conversions to obtain a borate intermediate, carrying out ammoniation, methyl cutting and Mitsunobu reaction to obtain a chloro intermediate, carrying out Pd-catalyzed suzuki coupling reaction on the borate intermediate and the chloro intermediate, and finally removing Boc protecting groups and acrylic acid to obtain Remibrutinib. It can be seen that the 9 steps of the route include 3 Pd catalyzed coupling reactions and 1 Pd/C reduction reactions, and that the synthesis cost is high using pinacol diboronate and cyclopropylboronic acid.
Disclosure of Invention
The invention mainly aims to provide a preparation method of the rayleigh Mi Buti Ni, which aims to solve the problem of high cost in the method for preparing the rayleigh Mi Buti Ni in the prior art.
In order to achieve the above object, according to one aspect of the present invention, there is provided a method for preparing rayleigh Mi Buti ni, comprising: step S1, carrying out reduction coupling reaction on raw materials comprising a compound 1, a compound 2, a reducing agent and a nickel-containing catalyst to obtain a compound 3; step S2, carrying out condensation reaction on a raw material comprising the compound 3 and acrylic acid to obtain the Rayleigh Mi Buti Ni; wherein, the structural formulas of the compound 1, the compound 2 and the compound 3 are as follows in sequence:
/>。
Further, in the step S1, the molar ratio of the compound 1, the compound 2 to the reducing agent is 1: 1-1.2: 3-4; and/or the reducing agent is selected from any one or more of zinc powder, manganese powder and magnesium powder; and/or the temperature of the reductive coupling reaction is 25-100 ℃, and/or the time of the reductive coupling reaction is 6-16 h.
Further, in the step S1, the raw materials further include a first ligand and a first solvent, and the molar ratio of the reducing agent, the first ligand, and the nickel-containing catalyst is 1 to 1.1: 1-1.2: 4, a step of; and/or the first ligand is selected from any one or more of a monophosphine ligand, a diphosphine ligand and a nitrogen ligand; the monophosphine ligand is selected from triphenylphosphine, tris (o-methylphenyl) phosphine, tris (m-methylphenyl) phosphine, tris (p-methylphenyl) phosphine, tris (3, 5-xylyl) phosphine, tris (mesityl) phosphine, tris (1-naphthyl) phosphine, [ (4- (N, N-dimethylamino) phenyl)]Any one or more of di-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-tert-butylphosphine, tricyclohexylphosphine tetrafluoroborate, tricyclohexylphosphine, n-butyldi (1-adamantyl) phosphine, 2- (di-tert-butylphosphine) biphenyl; the biphosphine ligand is selected from any one or more of DPPE, 1, 2-bis (diphenylphosphine) benzene, 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene, 1' -bis (diphenylphosphine) ferrocene, N-dimethyl-1- ((S) -2-diphenylphosphine) ferrocene) ethylamine and 1,1' -binaphthyl-2, 2' -bis (diphenylphosphine); the nitrogen ligand is selected from N, N, N ', N' -tetramethyl ethylenediamine, N, N '-dimethyl-1, 2-cyclohexanediamine, 1, 2-diaminocyclohexane, 4-dimethylaminopyridine, terpyridine, 2' -isopropylidenebis [ 4-tert-butyl-2-oxazoline ]2- (4-benzyl-4, 5-dihydro-oxazol-2-yl) -pyridine, 2- [2- (diphenylphosphine) phenyl]-4-isopropyl-2-oxazoline, 1' -binaphthyl-2, 2' -diamine, 2' -bipyridine, 2, 6-bis [1- (2-tert-butylphenylimino) ethyl]Pyridine, 4' -di-tert-butyl-2, 2' -bipyridine, 6' -dimethyl-2, 2' -bipyridine, 4' -dimethoxy-2, 2' -bipyridine 2,2' -bipyridine-5, 5' -dicarboxylic acid, 2' -bipyridine-4, 4' -dicarboxylic acid, 4' -dichloro-2, 2' -bipyridine, 4' -diamino-2, 2' -bipyridine any one or more of 4,4' -biphenyl-2, 2-bipyridine, 4' -dimethylamino-2, 2' -bipyridine, 1, 10-phenanthroline, 5, 6-dimethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 3, 8-dibromophenanthroline, 1, 10-phenanthroline-2, 9-dicarboxylic acid; and/or the nickel-containing catalyst is selected from NiCl 2 、NiBr 2 、NiI 2 、Ni(acac) 2 、Ni(COD) 2 、Ni(DME)Cl 2 、Ni(PPh 3 ) 2 Cl 2 、Ni(PCy) 2 Cl 2 、Ni(dppe)Cl 2 、Ni(dppp)Cl 2 、Ni(dppb)Cl 2 、Ni(dppf)Cl 2 Any one or more of the following; and/or the first solvent is selected from any one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, methylene dichloride, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol and toluene.
Further, in the step S1, the raw materials further include an additive, where the additive is selected from any one or more of lithium chloride, magnesium chloride, zinc chloride, ferric chloride, ferrous chloride, zirconium chloride, cobalt chloride, nickel chloride, chromium chloride, calcium chloride, lithium bromide, lithium iodide, lithium triflate, ketone triflate, ferrous triflate, ferric triflate, scandium triflate, ytterbium triflate, manganese bis (triflate), lithium tetrafluoroborate, magnesium bromide, magnesium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium acetate, tetraethylammonium bromide, and tetramethylammonium chloride.
Further, in the step S1, the preparation method of the compound 1 includes: in an inert gas atmosphere, carrying out substitution reaction on raw materials comprising a compound 4, a compound 5 and a base to obtain a compound 1, wherein the structural formulas of the compound 4 and the compound 5 are as follows:
/>
and/or the molar ratio of compound 4, compound 5 to base is 1: 1-1.2: 1-2; and/or the alkali is selected from any one or more of lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium hydroxide and lithium hydroxide; and/or the temperature of the substitution reaction is 20-30 ℃, and/or the time of the substitution reaction is 6-16 h.
Further, the preparation method of the compound 4 comprises the following steps: under the illumination condition, performing nitroreduction reaction on the compound 6 under the action of a first catalyst to obtain a compound 4, wherein the structural formula of the compound 6 is as follows:
and/or the wavelength of illumination is 365-400 nm, and/or the temperature of the nitroreduction reaction is 20-40 ℃, and/or the time of the nitroreduction reaction is 1-3 h; and/or the mass ratio of the first catalyst to the compound 6 is 2-3: 1.
further, the preparation method of the compound 5 comprises the following steps: carrying out a Kumada reaction on a raw material comprising a compound 7, a cyclopropylating Grignard reagent, a second catalyst and a second ligand to obtain a compound 5, wherein the compound 7 has the following structural formula:
the molar ratio of compound 7, cyclopropylated grignard reagent, second catalyst to second ligand is 1: 1.5-2.5: 0.05-0.1: 2-6; and/or the cyclopropylating grignard reagent is cyclopropyl magnesium bromide and/or cyclopropyl magnesium chloride; and/or the second catalyst is selected from any one or more of ferric triacetylacetonate, ferric sulfate, ferric acetate and ferric chloride; and/or the second ligand is selected from any one or more of N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone and 1, 3-tetramethylurea; and/or the temperature of the Kumada reaction is 15-25 ℃, and/or the time of the Kumada reaction is 3-5 h.
Further, in the step S1, the preparation method of the compound 2 includes: carrying out demethylation reaction on a raw material comprising the compound 8 and an acid catalyst to obtain a compound 9; will include compound 9,Triphenylphosphine, a,Carrying out Mitsunobu reaction on the raw material of diisopropyl azodicarboxylate to obtain a compound 10; carrying out ammonolysis reaction on raw materials comprising the compound 10 and ammonia gas to obtain a compound 2; wherein, the structural formulas of the compound 8, the compound 9 and the compound 10 are as follows:
/> />
the molar ratio of the compound 8 to the acid catalyst is 1: 1.5-2; and/or the acidic catalyst is aluminum chloride and/or ammonium chloride; and/or the temperature of the demethylation reaction is 25-50 ℃, and/or the time of the demethylation reaction is 6-16 h; and/or compound 9,The molar ratio of triphenylphosphine to diisopropyl azodicarboxylate is 1: 1-1.5: 1-1.5: 1-1.5; and/or the temperature of the Mitsunobu reaction is 20-30 ℃, and/or the time of the Mitsunobu reaction is 2-6 h; and/or the temperature of the ammonolysis reaction is 20-30 ℃, and/or the ammonolysis reaction time is 16-40 h.
Further, the preparation method of the compound 1 further comprises the following steps: carrying out ammonification reaction on the raw materials comprising the compound 5, ammonia and third catalysis to obtain a compound 11; carrying out coupling reaction on raw materials comprising a compound 11, a compound 12, an alkaline substance, a copper metal catalyst, a third ligand and a second solvent, wherein the structural formulas of the compound 11 and the compound 12 are as follows:
/>
The molar ratio of compound 5 to the third catalyst is 1: 1-1.5, and/or the third catalysis is selected from any one or more of calcium chloride, ferric chloride, magnesium chloride, cobalt chloride, zinc chloride, nickel chloride and magnesium sulfate; and/or the temperature of the ammonification reaction is 20-30 ℃, and/or the time of the ammonification reaction is 24-48 h; and/or the temperature of the coupling reaction is 50-120 ℃, and/or the time of the coupling reaction is 8-16 h; and/or the molar ratio of compound 11, compound 12, alkaline substance, copper metal catalyst, third ligand is 1: 1-1.2: 1.5-2: 0.2 to 0.4: 0.4-0.8; and/or the alkaline substance is inorganic base or organic base, wherein the inorganic base is selected from any one or more of carbonate, phosphate, hydroxide and alkoxide; the carbonate is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; the phosphate is selected from one or more of lithium phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and cesium phosphate; the hydroxide is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide; the alkoxide is selected from one or more of potassium tert-butoxide, sodium ethoxide and sodium methoxide; the organic base is selected from any one or more of potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, triethylamine, N-diisopropylethylamine, pyridine and 2-methylpyridine; and/or copper metal catalyst is selected from any one or more of cuprous iodide, cuprous bromide, cuprous chloride, cupric acetate, copper 3-methyl salicylate, copper (II) trifluoromethane sulfonate, copper sulfate, tetraethyl cyanogen hexafluorophosphate and copper (I) chloride [1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-subunit ]; and/or the third ligand is selected from any one or more of a monophosphine ligand, a diphosphine ligand and a nitrogen ligand; the monophosphine ligand is selected from any one or more of triphenylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-tert-butylphosphine and 2- (di-tert-butylphosphine) biphenyl; the biphosphine ligand is selected from any one or more of DPPE, 1' -bis (diphenylphosphine) ferrocene, N-dimethyl-1- ((S) -2-diphenylphosphine) ferrocene) ethylamine and 1,1' -binaphthyl-2, 2' -bisdiphenylphosphine; the nitrogen ligand is selected from N, N, N ', N' -tetramethyl ethylenediamine and N, N '-dimethyl-1, 2-cyclohexanediamine, 1, 2-diaminocyclohexane, 4-dimethylaminopyridine, terpyridine, 2' -isopropylidenebis [ 4-tert-butyl-2-oxazoline ], 2- (4-benzyl-4, 5-dihydro-oxazol-2-yl) -pyridine, 2- [2- (diphenylphosphine) phenyl ] -4-isopropyl-2-oxazoline, 1 '-binaphthyl-2, 2' -diamine, 2 '-bipyridine, 2, 6-bis [1- (2-tert-butylphenylimino) ethyl ] pyridine, 4' -di-tert-butyl-2, 2 '-bipyridine, 6' -dimethyl-2, 2 '-bipyridine 4,4' -dimethoxy-2, 2 '-bipyridine, 2' -bipyridine-5, 5 '-dicarboxylic acid, 2' -bipyridine-4, 4 '-dicarboxylic acid, 4' -dichloro-2, 2 '-bipyridine, 4' -diamino-2, 2 '-bipyridine, 4' -biphenyl-2, 2-bipyridine 4,4 '-dimethylamino-2, 2' -bipyridine, 1, 10-phenanthroline, 5, 6-dimethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 3, 8-dibromophenanthroline, 1, 10-phenanthroline-2, 9-dicarboxylic acid, any one or more of N1, N2-di (furan-2-ylmethyl) oxamide, N '-bis (2, 4, 6-trimethoxyphenyl) oxamide, N' -dibenzyl oxalyl diamine; and/or the second solvent is selected from any one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, methylene dichloride, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol and toluene.
In the step S2, the raw materials further comprise trifluoroacetic acid, N-diisopropylethylamine and 1-propyl phosphoric acid cyclic anhydride.
By applying the technical scheme of the application, the application provides a new route for synthesizing the Rui Mi Buti Ni, and no Pd metal catalyst, expensive bisboronic acid pinacol ester and cyclopropyl boric acid are used in the whole route, so that the synthesis cost is effectively reduced, and the method is simple and convenient to operate and suitable for industrial scale-up production.
Detailed Description
It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other. The present application will be described in detail with reference to examples.
As analyzed in the background of the application, the method for preparing the rayleigh Mi Buti ni in the prior art has the problem of higher cost, and in order to solve the problem, the application provides a preparation method of the rayleigh Mi Buti ni.
In one exemplary embodiment, a method of preparing rayleigh Mi Buti ni is provided, the method comprising: step S1, carrying out reduction coupling reaction on raw materials comprising a compound 1, a compound 2, a reducing agent and a nickel-containing catalyst to obtain a compound 3; step S2, carrying out condensation reaction on a raw material comprising the compound 3 and acrylic acid to obtain the Rayleigh Mi Buti Ni; wherein, the structural formulas of the compound 1, the compound 2 and the compound 3 are as follows in sequence:
/>。
The application provides a new route for synthesizing the Rui Mi Buti Ni, does not use any Pd metal catalyst and expensive bisboronic acid pinacol ester and cyclopropylboric acid in the whole route, effectively reduces the synthesis cost, has simple and convenient operation, and is suitable for industrialized amplified production.
In one embodiment of the present application, in the step S1, the molar ratio of the compound 1, the compound 2 to the reducing agent is 1: 1-1.2: 3-4; and/or the reducing agent is selected from any one or more of zinc powder, manganese powder and magnesium powder; and/or the temperature of the reductive coupling reaction is 25-100 ℃, and/or the time of the reductive coupling reaction is 6-16 h.
The reducing agent plays a role in promoting the formation of the active catalyst, and the molar ratio of the compound 1, the compound 2 and the reducing agent is preferably within the above range, so that the reaction substrates are favored to cooperatively form the compound 3 as much as possible, and the above control of the temperature and time of the reductive coupling reaction is favored to improve the reaction efficiency and effect thereof.
In one embodiment of the present application, in the step S1, the raw materials further include a first ligand and a first solvent, a reducing agent, the first ligand, and nickelThe molar ratio of the catalyst is 1-1.1: 1-1.2: 4, a step of; and/or the first ligand is selected from any one or more of a monophosphine ligand, a diphosphine ligand and a nitrogen ligand; and/or the monophosphine ligand is selected from triphenylphosphine, tris (o-methylphenyl) phosphine, tris (m-methylphenyl) phosphine, tris (p-methylphenyl) phosphine, tris (3, 5-xylyl) phosphine, tris (mesityl) phosphine, tris (1-naphthyl) phosphine, [ (4- (N, N-dimethylamino) phenyl) ]Any one or more of di-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-tert-butylphosphine, tricyclohexylphosphine tetrafluoroborate, tricyclohexylphosphine, n-butyldi (1-adamantyl) phosphine, 2- (di-tert-butylphosphine) biphenyl; and/or the biphosphine ligand is selected from any one or more of DPPE, 1, 2-bis (diphenylphosphine) benzene, 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene, 1' -bis (diphenylphosphine) ferrocene, N-dimethyl-1- ((S) -2-diphenylphosphine) ferrocene) ethylamine, 1' -binaphthyl-2, 2' -bis-diphenylphosphine; and/or the nitrogen ligand is selected from N, N, N ', N' -tetramethyl ethylenediamine, N, N '-dimethyl-1, 2-cyclohexanediamine, 1, 2-diaminocyclohexane, 4-dimethylaminopyridine, terpyridine, 2' -isopropylidenedio [ 4-tert-butyl-2-oxazoline]2- (4-benzyl-4, 5-dihydro-oxazol-2-yl) -pyridine, 2- [2- (diphenylphosphine) phenyl]-4-isopropyl-2-oxazoline, 1' -binaphthyl-2, 2' -diamine, 2' -bipyridine, 2, 6-bis [1- (2-tert-butylphenylimino) ethyl]Pyridine, 4' -di-tert-butyl-2, 2' -bipyridine, 6' -dimethyl-2, 2' -bipyridine, 4' -dimethoxy-2, 2' -bipyridine 2,2' -bipyridine-5, 5' -dicarboxylic acid, 2' -bipyridine-4, 4' -dicarboxylic acid, 4' -dichloro-2, 2' -bipyridine, 4' -diamino-2, 2' -bipyridine any one or more of 4,4' -biphenyl-2, 2-bipyridine, 4' -dimethylamino-2, 2' -bipyridine, 1, 10-phenanthroline, 5, 6-dimethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 3, 8-dibromophenanthroline, 1, 10-phenanthroline-2, 9-dicarboxylic acid; preferably the nickel containing catalyst is selected from NiCl 2 、NiBr 2 、NiI 2 、Ni(acac) 2 、Ni(COD) 2 、Ni(DME)Cl 2 、Ni(PPh 3 ) 2 Cl 2 、Ni(PCy) 2 Cl 2 、Ni(dppe)Cl 2 、Ni(dppp)Cl 2 、Ni(dppb)Cl 2 、Ni(dppf)Cl 2 Any one or more of the following; and/or the first solvent is selected from any one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, methylene dichloride, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol and toluene.
The addition of the first ligand, the nickel-containing catalyst and the above preferable species to the above raw material system for the reductive coupling reaction is preferable to contribute to an improvement in the efficiency of the reductive coupling reaction, thereby improving the yield and purity of the Rayleigh Mi Buti Ni.
In order to further improve the efficiency of the reductive coupling reaction, in some embodiments of the present application, in the step S1, the preferred raw material further includes an additive, preferably the additive helps to promote the reductive coupling reaction, further preferably the additive is selected from any one or more of lithium chloride, magnesium chloride, zinc chloride, ferric chloride, ferrous chloride, zirconium chloride, cobalt chloride, nickel chloride, chromium chloride, calcium chloride, lithium bromide, lithium iodide, lithium triflate, ketone triflate, ferrous triflate, ferric triflate, scandium triflate, ytterbium triflate, manganese bis (triflate), lithium tetrafluoroborate, magnesium bromide, magnesium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium acetate, tetraethylammonium bromide, and tetramethylammonium chloride.
In one embodiment of the present application, in the step S1, the preparation method of the compound 1 includes: in an inert gas atmosphere, carrying out substitution reaction on raw materials comprising a compound 4, a compound 5 and a base to obtain a compound 1, wherein the structural formulas of the compound 4 and the compound 5 are as follows:
/>
the molar ratio of the compound 4, the compound 5 and the alkali is 1: 1-1.2: 1-2; and/or the alkali is selected from any one or more of lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium hydroxide and lithium hydroxide; and/or the temperature of the substitution reaction is 20-30 ℃, and/or the time of the substitution reaction is 6-16 h.
The inert gas atmosphere helps to avoid interference of oxygen and the like with the reaction, and the preferred base helps to promote the substitution reaction between compound 4 and compound 5, and the preferred temperature and time of the substitution reaction helps to improve the efficiency and effect thereof.
In one embodiment of the present application, the preparation method of the compound 4 includes: under the illumination condition, performing nitroreduction reaction on the compound 6 under the action of a first catalyst to obtain a compound 4, wherein the structural formula of the compound 6 is as follows:
the wavelength of illumination is 365-400 nm, and/or the temperature of the nitroreduction reaction is 20-40 ℃, and/or the time of the nitroreduction reaction is 1-3 h; and/or the mass ratio of the first catalyst to the compound 6 is 2-3: 1.
The above photo-catalyzed nitroreduction reaction is preferred to help control the continuous progress of the nitroreduction reaction. The preferred mass ratio of the first catalyst to the compound 6 helps to increase the limits of the nitroreduction reaction, preferably the temperature and time of the nitroreduction reaction helps to increase the efficiency and effectiveness of the nitroreduction reaction.
In one embodiment of the present application, the preparation method of the compound 5 includes: carrying out a Kumada reaction on a raw material comprising a compound 7, a cyclopropylating Grignard reagent, a second catalyst and a second ligand to obtain a compound 5, wherein the compound 7 has the following structural formula:
the molar ratio of compound 7, cyclopropylated grignard reagent, second catalyst to second ligand is 1: 1.5-2.5: 0.05-0.1: 2-6; the cyclopropylating Grignard reagent is cyclopropyl magnesium bromide and/or cyclopropyl magnesium chloride; and/or the second catalyst is selected from any one or more of ferric triacetylacetonate, ferric sulfate, ferric acetate and ferric chloride; and/or the second ligand is selected from any one or more of N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone and 1, 3-tetramethylurea; and/or the temperature of the Kumada reaction is 15-25 ℃, and/or the time of the Kumada reaction is 3-5 h.
The preferred types of the above second catalyst and the second ligand help promote the occurrence of the Kumada reaction, the preferred molar ratio of the compound 7, the cyclopropylating grignard reagent, the second catalyst and the second ligand help to increase the conversion of the compound, and the preferred temperature and time of the Kumada reaction help to increase the efficiency and effectiveness of the Kumada reaction.
In one embodiment of the present application, in the step S1, the preparation method of the compound 2 includes: carrying out demethylation reaction on a raw material comprising the compound 8 and an acid catalyst to obtain a compound 9; will include compound 9,Carrying out Mitsunobu reaction on raw materials of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound 10; carrying out ammonolysis reaction on raw materials comprising the compound 10 and ammonia gas to obtain a compound 2; wherein, the structural formulas of the compound 8, the compound 9 and the compound 10 are as follows:
/> />
preferably, the molar ratio of compound 8 to the acidic catalyst is 1: 1.5-2; preferably the acidic catalyst is aluminum chloride and/or ammonium chloride; and/or the temperature of the demethylation reaction is 25-50 ℃, and/or the time of the demethylation reaction is 6-16 h;and/or compound 9,The molar ratio of triphenylphosphine to diisopropyl azodicarboxylate is 1: 1-1.5: 1-1.5: 1-1.5; and/or the temperature of the Mitsunobu reaction is 20-30 ℃, and/or the time of the Mitsunobu reaction is 2-6 h; preferably, the ammonolysis reaction temperature is 20-30 ℃, and preferably, the ammonolysis reaction time is 16-40 h.
Preferably the molar ratio of compound 8, the acidic catalyst, compound 9,The molar ratios of triphenylphosphine to diisopropyl azodicarboxylate are each in the above range, contributing to an increase in the conversion of compound 8 and compound 9, respectively. The acidic catalyst helps to promote the demethylation reaction, preferably the temperature and time of the demethylation reaction helps to increase the efficiency and effectiveness of the demethylation reaction. Triphenylphosphine and diisopropyl azodicarboxylate help to promote the occurrence of the Mitsunobu reaction, preferably the temperature and time of the Mitsunobu reaction help to increase its efficiency and effectiveness. Preferably the temperature and time of the ammonolysis reaction help to increase its efficiency and effectiveness.
In an embodiment of the present application, the preparation method of the compound 1 further includes: carrying out ammonification reaction on the raw materials comprising the compound 5, ammonia and third catalysis to obtain a compound 11; carrying out coupling reaction on raw materials comprising a compound 11, a compound 12, an alkaline substance, a copper metal catalyst, a third ligand and a second solvent, wherein the structural formulas of the compound 11 and the compound 12 are as follows:
/>
the above method provides another route for the synthesis of compound 1, thereby further expanding the class of substrates of the present application.
To further increase the efficiency and effectiveness of the ammonification reaction and the coupling reaction, it is preferred that the molar ratio of compound 5 to the third catalyst is 1: 1-1.5, and/or the third catalysis is selected from any one or more of calcium chloride, ferric chloride, magnesium chloride, cobalt chloride, zinc chloride, nickel chloride and magnesium sulfate; and/or the temperature of the ammonification reaction is 20-30 ℃, and/or the time of the ammonification reaction is 24-48 h; preferably, the temperature of the coupling reaction is 50-120 ℃, and/or the time of the coupling reaction is 8-16 h; and/or the molar ratio of compound 11, compound 12, alkaline substance, copper metal catalyst, third ligand is 1: 1-1.2: 1.5-2: 0.2 to 0.4: 0.4-0.8; and/or the alkaline substance is an inorganic base or an organic base, preferably the inorganic base is selected from any one or more of carbonate, phosphate, hydroxide and alkoxide, further, and/or the carbonate is selected from any one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; preferably, the phosphate is selected from any one or more of lithium phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and cesium phosphate; preferably, the hydroxide is selected from any one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide; preferably, the alkoxide is selected from any one or more of potassium tert-butoxide, sodium ethoxide and sodium methoxide; preferably, the organic base is selected from any one or more of potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, triethylamine, N-diisopropylethylamine, pyridine and 2-methylpyridine; preferably, the copper metal catalyst is selected from any one or more of cuprous iodide, cuprous bromide, cuprous chloride, cupric acetate, copper 3-methyl salicylate, copper (II) trifluoromethane sulfonate, copper sulfate, tetraethyl cyanogen hexafluorophosphate and copper (I) chloride [1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-subunit ]; preferably, the third ligand is selected from any one or more of a monophosphine ligand, a biphosphine ligand and a nitrogen ligand; preferably, the monophosphine ligand is selected from any one or more of triphenylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-tert-butylphosphine and 2- (di-tert-butylphosphine) biphenyl; preferably, the biphosphine ligand is selected from any one or more of DPPE, 1' -bis (diphenylphosphine) ferrocene, N-dimethyl-1- ((S) -2-diphenylphosphine) ferrocene) ethylamine, 1' -binaphthyl-2, 2' -bisdiphenylphosphine; preferably the nitrogen ligand is selected from the group consisting of N, N, N ', N' -tetramethyl ethylenediamine, N, N '-dimethyl-1, 2-cyclohexanediamine, 1, 2-diaminocyclohexane, 4-dimethylaminopyridine, terpyridine, 2' -isopropylidenebis [ 4-tert-butyl-2-oxazoline ], 2- (4-benzyl-4, 5-dihydro-oxazol-2-yl) -pyridine, 2- [2- (diphenylphosphine) phenyl ] -4-isopropyl-2-oxazoline, 1 '-binaphthyl-2, 2' -diamine, 2 '-bipyridine, 2, 6-bis [1- (2-tert-butylphenylimino) ethyl ] pyridine, 4' -di-tert-butyl-2, 2 '-bipyridine, 6' -dimethyl-2, 2 '-bipyridine 4,4' -dimethoxy-2, 2 '-bipyridine, 2' -bipyridine-5, 5 '-dicarboxylic acid, 2' -bipyridine-4, 4 '-dicarboxylic acid, 4' -dichloro-2, 2 '-bipyridine, 4' -diamino-2, 2 '-bipyridine, 4' -biphenyl-2, 2-bipyridine 4,4 '-dimethylamino-2, 2' -bipyridine, 1, 10-phenanthroline, 5, 6-dimethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 3, 8-dibromophenanthroline, 1, 10-phenanthroline-2, 9-dicarboxylic acid, any one or more of N1, N2-di (furan-2-ylmethyl) oxamide, N '-bis (2, 4, 6-trimethoxyphenyl) oxamide, N' -dibenzyl oxalyl diamine; preferably, the second solvent is selected from any one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, methylene chloride, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, toluene.
In one embodiment of the present application, in the step S2, the raw material further includes trifluoroacetic acid, N-diisopropylethylamine, and 1-propylphosphoric acid cyclic anhydride.
The conversion conditions of the above compound 3 to remineralization Mi Buti by the catalytic effect of the above materials can be referred to the prior art and will not be described in detail herein.
The application is described in further detail below in connection with specific examples which are not to be construed as limiting the scope of the application as claimed.
Example 1
Step1：
1-bromo-5-fluoro-2-methyl-3-nitrobenzene (compound 6,1 eq,2.0 g), 6 g titanium dioxide were added to a dry clean 250 mL reaction flask, methanol (40 vol,80 mL) and purified water (10 vol,20 mL) were added, then 8 mL triethanolamine was added and stirred well, the system was pumped by peristaltic pump and the reaction was carried out under light at 365 nm (300W) at room temperature for 3 h (light fraction volume 50 mL). After completion of the reaction, celite was added for filtration, the filtrate was concentrated, purified water (10 vol,20 mL) was added, extraction was performed three times with ethyl acetate (30 vol,60 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 4 as a brown solid in 92% yield.
Step2：
Under the protection of nitrogen, 4-chloro-2-fluorobenzoic acid methyl ester (compound 7,1 eq,80.0 g), ferric triacetylacetonate (0.05 eq,7.5 g) are added into a dry and clean 5L reaction bottle, anhydrous THF (10 vol.,800 mL) is added, anhydrous N-methylpyrrolidone (6 eq,252.3 g) is added after stirring until the anhydrous THF is dissolved, the mixture is uniformly stirred, the temperature is reduced to 0 ℃, then, cyclopropyl magnesium bromide (2 eq,165.5 g) with the concentration of 1M is added by controlling the temperature, and the temperature is raised to 15-25 ℃ after the addition is finished, and the reaction is continued. After the reaction, the temperature is controlled to be 10-30 ℃, 1M dilute hydrochloric acid (1.5 eq,159 mL) is added for quenching reaction, ethyl acetate (10 vol,800 mL) is extracted three times, the organic phases are combined, the organic phases are washed by saturated sodium chloride aqueous solution (10 vol,800 mL) and water (10 vol,800 mL) in sequence, and the organic phases dried by anhydrous sodium sulfate are concentrated under reduced pressure to obtain black liquid 72 g with the yield of 87%.
Step3：
Under the protection of nitrogen, adding 2-bromo-4-fluoro-6-aminomethyl into a dry and clean 500 mL reaction bottle in sequenceBenzene (compound 4,1 eq,10 g), methyl 4-cyclopropyl-2-fluorobenzoate (compound 5,1 eq,9.5 g) and anhydrous dry toluene (10 vol.,100 mL), after stirring to dissolve, cooling to 0 ℃, controlling Wen Dijia M NaHMDS in THF (1.5 eq,36.8 mL), after completion of the dropwise addition, slowly warming to room temperature for reaction 16 h. After the reaction, toluene (10 vol., 100. 100 mL) was added to the system, followed by cooling to 0℃and dropwise addition of saturated NH 4 The Cl aqueous solution is brought to pH to 8, a large amount of solids are separated out, the solid is filtered, a filter cake is pulped by purified water (10 vol.,100, mL) for 2 h and then filtered again, the filter cake is soaked and washed twice by the purified water (2 vol.,20, mL), and the solid 17.2 g is obtained after drying, and the yield is 90%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.54 – 7.42 (m, 2H), 7.12 – 7.03 (m, 2H), 2.29 (d, J = 1.0 Hz, 3H), 2.08 – 1.97 (m, 1H), 1.09 – 1.01 (m, 2H), 0.85 – 0.76 (m, 2H)。
Step4：
N- (3-bromo-5-fluoro-2-methylphenyl) -4-cyclopropyl-2-fluorobenzamide (compound 1,1 eq,2 g), (2- ((4-amino-6-chloropyrimidin-5-yl) oxy) ethyl) (methyl) carbamate (compound 2,1 eq,1.6 g), zinc powder (4 eq,1.4 g), nickel chloride (0.3 eq,0.2 g), magnesium iodide (1 eq,1.5 g) triphenylphosphine (0.6 eq,0.9 g) were added sequentially to a reaction flask of 100 mL under nitrogen, dried, deoxygenated N, N dimethylacetamide (10 vol.,20 mL) was added, and the temperature was raised to 40℃for reaction 16 h. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate: n-heptane=1:3) to give a white solid 2.7. 2.7 g in 88% yield.
Step5：
Under the protection of nitrogen, 4, 6-dichloro-5-methylThe oxypyrimidine (compound 8,1 eq,25 g) was added to a dry clean 500 mL reactor flask, dichloroethane (16 vol.,400 mL) was added, stirred until dissolved, cooled to 0 ℃, and AlCl was added in portions at controlled temperature 3 (1.5 eq,27.9 g) and then the reaction was continued by heating the system to 50℃for reaction 6 h. After the reaction was completed, the temperature of the system was lowered to 0 ℃, 1. 1M diluted hydrochloric acid (1.4 eq,196 mL) was added to the system by controlling the temperature, then methanol (2 vol.,50 mL) was slowly added, the system was vigorously stirred for 10 minutes, and then purified water (40 vol.,1000 mL) was added to dilute the system, and stirred for 10 minutes. Extraction 2 times with a DCM/MeOH (10:1) mixture (20 vol.,500 mL), once with ethyl acetate (20 vol.,500 mL) combined organic phases and concentration under reduced pressure gave a solid 20.9 g in 90% yield.
Step6：
4, 6-dichloropyrimidin-5-ol (compound 9,1 eq,30 g) was added to a dry clean 1000 mL reaction flask under nitrogen protection, tetrahydrofuran (10 vol.,300 mL), triphenylphosphine (1.3 eq,62 g) was added, after the starting materials dissolved, the system was cooled to 0 ℃, wen Dijia diisopropyl azodicarboxylate (2 eq,73.5 g) and tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate (1.2 eq,38.28 g) were controlled, and after the addition was completed, the reaction was continued at room temperature. After the reaction is finished, concentrating under reduced pressure to remove the solvent, then adding n-heptane (20 vol.,600, mL) for pulping, precipitating a large amount of triphenylphosphine oxide solid, carrying out suction filtration, concentrating the filtrate, and repeating the operation until the content of triphenylphosphine oxide solid in the product is less than 10%, thereby finally obtaining the product 57.9 g with a yield of 92%.
Step7:
Tert-butyl N- [2- (4, 6-dichloropyrimidin-5-yl) oxyethyl ] -N-methylcarbamate (compound 10,1eq,15.6 g) was added to a dry and clean 1000 mL reaction flask at room temperature, isopropanol (5 vol.,78 mL) was added, the system was cooled to 0 ℃ after the starting materials had been dissolved, ammonia (35 eq,59.5 g) was added to the system at room temperature, and the reaction was continued after restoring to room temperature, 16 h. After the reaction was completed, purified water (10 vol,156 mL) was added to the system to precipitate a large amount of solids, which were filtered, and the cake was rinsed with purified water (5 vol,78 mL) and dried to give a white solid, 14.3 g, in 95% yield.
Step8&9：
Tert-butyl (2- ((4-amino-6- (3- (4-cyclopropyl-2-fluorobenzamido) -5-fluoro-2-methylphenyl) pyrimidin-5-yl) oxy) ethyl) (methyl) carbamate (compound 3, 1eq, 335 mg) was added to a dry clean 20 mL reaction flask, dichloromethane (15 vol.,5 mL) was added and mixed well, then trifluoroacetic acid (10 eq,0.47 mL) was added and the reaction was continued at room temperature for 15 h. After the completion of the reaction, the system was concentrated under reduced pressure to give a brown oily liquid, which was diluted with N, N-dimethylformamide (4 mL) and transferred to a reaction flask.
To N, N-dimethylformamide (65 vol.,4 mL) were added acrylic acid (1 eq,62 mg), N-diisopropylethylamine (2 eq,0.30 mL) and 1-propylphosphoric acid cyclic anhydride (50% N, N-dimethylformamide solution, 0.86eq,0.44 mL) in this order, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then added dropwise to the above reaction flask at 0℃and stirring was continued at 0℃for 1 h. After the reaction was completed, purified water was added and extracted with ethyl acetate, and the organic phase was washed with purified water and saturated aqueous sodium chloride solution in this order, and the organic phase was concentrated under reduced pressure and purified by column chromatography (DCM/meoh=50:1) to give a white solid.
Example 2
The difference from example 1 is that in Step1, the ratio of titanium dioxide to compound 6 to mass is 2:1, single step yield was 85% to finally yield remineral Mi Buti.
Example 3
The difference from example 1 is that in Step1, the ratio of titanium dioxide to compound 6 to mass is 1:1, the single Step yield is 50%, and as a result, the yield of the product is Mi Buti Ni.
Example 4
The difference from example 1 is that in Step2, the molar ratio of compound 7, cyclopropylmagnesium bromide, ferric triacetylacetonate to N-methylpyrrolidone is 1:1.5:0.05:6, a single step yield of 82% yielded as final result, reminiscent Mi Buti.
Example 5
The difference from example 1 is that in Step2, the molar ratio of compound 7, cyclopropylmagnesium bromide, ferric triacetylacetonate to N-methylpyrrolidone is 1:1:0.05:6, a single step yield of 65% was obtained to give as a final result, as Mi Buti Ni.
Example 6
The difference from example 1 is that in Step2, the second catalyst is ferric chloride, the single Step yield is 35%, and as a result, rayleigh Mi Buti ni is obtained.
Example 7
The difference from example 1 is that in Step2, the second ligand was 1, 3-dimethyl-2-imidazolidinone, and the single Step yield was 50%, resulting in the final yield of remineral Mi Buti.
Example 8
The difference from example 1 is that in Step3, the molar ratio of compound 4, compound 5 to basic catalyst is 1:1:1.2, single step yield 80% to yield as final result of rev Mi Buti ni.
Example 9
The difference from example 1 is that in Step3, the molar ratio of compound 4, compound 5 to base is 1:1:0.5, single step yield of 45% to yield as final result of rev Mi Buti.
Example 10
The difference from example 1 is that in Step3, the base is NaOH and the single Step yield is 50% to finally obtain the rayleigh Mi Buti ni.
Example 11
The difference from example 1 is that in Step4, the molar ratio of compound 1, compound 2 to zinc powder is 1:1:3, single step yield was 78% to finally yield remineral Mi Buti.
Example 12
The difference from example 1 is that in Step4, the molar ratio of compound 1, compound 2 to zinc powder is 1:1:1, single step yield was 42% to finally yield remineral Mi Buti.
Example 13
The difference from example 1 is that in Step4, the temperature of the reductive coupling reaction was 100℃and the time was 6 hours, the single Step yield was 75%, and thus, the result was that the Rayleigh Mi Buti Ni was obtained.
Example 14
The difference from example 1 is that in Step4, the molar ratio of zinc powder, triphenylphosphine, nickel chloride is 4:0.5:1, single step yield was 79% to finally yield remineral Mi Buti.
Example 15
The difference from example 1 is that in Step4, the molar ratio of zinc powder, triphenylphosphine, nickel chloride is 4:0.2:1, single step yield was 46% to finally yield remineral Mi Buti.
Example 16
The difference from example 1 is that in Step4, the first ligand is a bisphosphine ligand: 1, 2-bis (diphenylphosphine) benzene was obtained in a single step in a yield of 51% to yield as a final product, as r Mi Buti ni.
Example 17
The difference from example 1 is that in Step4, the first ligand is a nitrogen ligand: n, N, N ', N' -tetramethyl ethylenediamine biphosphine ligand was obtained in a single step yield of 56% to yield as a final product of Rayleigh Mi Buti Ni.
Example 18
The difference from example 1 is that in Step4, the nickel-containing catalyst is Ni (dppp) Cl 2 The single step yield was 62% to finally yield Rayleigh Mi Buti Ni.
Example 19
The difference from example 1 is that in Step4, the first solvent is tetrahydrofuran, the additive is ferrous chloride, and the single Step yield is 21%, and thus, the final product is as high as Mi Buti ni.
Example 20
The difference from example 1 is that in Step5, compound 8 is compared with AlCl 3 The molar ratio of (2) is 1:0.5, single step harvestThe rate was 43%, and thus, rayleigh Mi Buti Ni was obtained.
Example 21
The difference from example 1 is that in Step5, the demethylation reaction was carried out at 30℃for 6 hours, with a single Step yield of 32% and finally obtaining the final product of Rayleigh Mi Buti Ni.
Example 22
The difference from example 1 is that in Step6, compound 9,The molar ratio of triphenylphosphine to diisopropyl azodicarboxylate is 1:1:1:1, single step yield 58% to yield as final result of remineralization Mi Buti.
Example 23
The difference from example 1 is that Step3 comprises Step3A and Step3B, wherein Step3A and Step3B are specifically as follows:
Step3A：
methyl 4-cyclopropyl-2-fluorobenzoate (compound 5,1 eq,3 g) was added to a dry clean 250 mL reaction flask at room temperature, dissolved in methanol (10 vol.,30 mL), calcium chloride (1.2 eq,2.1 g) was added and stirred well, cooled to 0deg.C, 7M methanolic ammonia solution (48 eq,106 mL) was slowly added dropwise, and then the reaction was continued at room temperature to continue 24 h. After the completion of the reaction, the filtrate was filtered, concentrated under reduced pressure to precipitate a solid, and filtered to obtain a white solid (compound 11) 2.7. 2.7 g in 91% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.61 – 7.47 (m, 3H), 7.02 – 6.93 (m, 2H), 1.98 (ddd, J = 13.3, 8.6, 5.0 Hz, 1H), 1.06 – 0.96 (m, 2H), 0.79 – 0.69 (m, 2H)。
Step3B：
4-cyclopropyl-2-fluorobenzamide (11, 1 eq,2 g), 2, 6-dibromo-4-fluoroboluene (12, 1 eq,2.99 g), copper sulfate (0.2 eq,0.84 g), 1, 2-diaminocyclohexane (0.4 eq,0.18 g), cesium carbonate (2 eq,2.6 g) were added to a reaction flask of 50 ml in this order under nitrogen, isopropanol (10 vol.,20 mL) was added, and the system was warmed to 80 ℃ to react 16 h. After the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (n-heptane: ethyl acetate=5:1) to give product 3.56. 3.56 g in 87% yield.
And finally obtaining the Rayleigh Mi Buti Ni.
Example 24
The difference from example 23 is that in Step3B, the coupling reaction temperature was 120 ℃ and the time was 6h, the single Step yield was 80%, and finally, the yield was Mi Buti ni.
Example 25
The difference from example 23 is that in Step3A, the molar ratio of compound 5 to calcium chloride is 1:1, single step yield was 85% to finally yield remineral Mi Buti.
Example 26
The difference from example 23 is that in Step3A, the third catalyst was magnesium chloride, the single Step reaction yield was 83% and thus, as a result, rayleigh Mi Buti ni was obtained.
Example 27
The difference from example 23 is that in Step3B, the molar ratio of compound 11, compound 12, cesium carbonate, copper sulfate, 1, 2-diaminocyclohexane is 1:1:2:0.4:0.8, single step yield 89% to yield as final result, as Mi Buti ni.
Example 28
The difference from example 23 is that in Step3B, the basic material is sodium tert-butoxide, the single Step yield is 75%, and thus, the final product is as high as Mi Buti ni.
Example 29
The difference from example 23 is that in Step3B, the copper metal catalyst was tetraethylcopper hexafluorophosphate with a single Step yield of 65% and finally obtained as remineralization Mi Buti.
Example 30
The difference from example 23 is that in Step3B, the third ligand is tri-tert-butylphosphine, the single Step yield is 45%, and as a result, the yield of the product is as high as Mi Buti.
The yields and purities of each Step of Steps 1 to Step6 of examples 1 to 22 and the final obtained yield and purity of Rayleigh Mi Buti Ni are shown in Table 1.
The yields and purities of each Step of Steps 1 to Step6 of examples 23 to 30 and the final obtained yield and purity of Rayleigh Mi Buti Ni are shown in Table 2.
TABLE 1
TABLE 2
From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:
the invention provides a new route for synthesizing the Rui Mi Buti Ni, does not use any Pd metal catalyst and expensive bisboronic acid pinacol ester and cyclopropylboric acid in the whole route, effectively reduces the synthesis cost, has simple and convenient operation, and is suitable for industrialized amplified production.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A method for preparing rayleigh Mi Buti ni, comprising:
step S1, carrying out reduction coupling reaction on raw materials comprising a compound 1, a compound 2, a reducing agent and a nickel-containing catalyst to obtain a compound 3;
step S2, carrying out condensation reaction on a raw material comprising the compound 3 and acrylic acid to obtain the Rayleigh Mi Buti Ni;
wherein the structural formulas of the compound 1, the compound 2 and the compound 3 are as follows in sequence:
。
2. the method according to claim 1, wherein in the step S1, the molar ratio of the compound 1, the compound 2 and the reducing agent is 1: 1-1.2: 3-4; and/or the reducing agent is selected from any one or more of zinc powder, manganese powder and magnesium powder; and/or the temperature of the reductive coupling reaction is 25-100 ℃, and/or the time of the reductive coupling reaction is 6-16 h.
3. The preparation method according to claim 1 or 2, wherein in the step S1, the raw materials further comprise a first ligand and a first solvent, and the molar ratio of the reducing agent, the first ligand and the nickel-containing catalyst is 1 to 1.1: 1-1.2: 4, a step of;
and/or the first ligand is selected from any one or more of a monophosphine ligand, a diphosphine ligand and a nitrogen ligand; the ligand of the mono phosphine is selected from any one or more of triphenylphosphine, tri (o-methylphenyl) phosphine, tri (m-methylphenyl) phosphine, tri (p-methylphenyl) phosphine, tri (3, 5-xylyl) phosphine, tri (mesityl) phosphine, tri (1-naphthyl) phosphine, [ (4- (N, N-dimethylamino) phenyl ] di-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tricyclohexylphosphine, N-butylbis (1-adamantyl) phosphine, 2- (di-tert-butylphosphine) biphenyl, and the ligand of the bi-phosphine is selected from any one or more of DPPE, 1, 2-bis (diphenylphosphine) benzene, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 1' -bis (diphenylphosphine) ferrocene, N-dimethyl-1- ((S) -2-diphenylphosphine) ferrocene, and 1,1' -binaphthyl-2, 2' -bis-diphenylphosphine; the nitrogen ligand is selected from N, N, N ', N' -tetramethyl ethylenediamine and N, N '-dimethyl-1, 2-cyclohexanediamine, 1, 2-diaminocyclohexane, 4-dimethylaminopyridine, terpyridine, 2' -isopropylidenebis [ 4-tert-butyl-2-oxazoline ], 2- (4-benzyl-4, 5-dihydro-oxazol-2-yl) -pyridine, 2- [2- (diphenylphosphine) phenyl ] -4-isopropyl-2-oxazoline, 1 '-binaphthyl-2, 2' -diamine, 2 '-bipyridine, 2, 6-bis [1- (2-tert-butylphenylimino) ethyl ] pyridine, 4' -di-tert-butyl-2, 2 '-bipyridine 6,6' -dimethyl-2, 2 '-bipyridine, 4' -dimethoxy-2, 2 '-bipyridine, 2' -bipyridine-5, 5 '-dicarboxylic acid, 2' -bipyridine-4, 4 '-dicarboxylic acid, 4' -dichloro-2, 2 '-bipyridine, 4' -diamino-2, 2 '-bipyridine 4,4' -biphenyl-2, 2-bipyridine, 4 '-dimethylamino-2, 2' -bipyridine, 1, 10-phenanthroline, 5, 6-dimethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 3, 8-dibromophenanthroline, any one or more of 1, 10-phenanthroline-2, 9-dicarboxylic acid;
And/or the nickel-containing catalyst is selected from NiCl 2 、NiBr 2 、NiI 2 、Ni(acac) 2 、Ni(COD) 2 、Ni(DME)Cl 2 、Ni(PPh 3 ) 2 Cl 2 、Ni(PCy) 2 Cl 2 、Ni(dppe)Cl 2 、Ni(dppp)Cl 2 、Ni(dppb)Cl 2 、Ni(dppf)Cl 2 Any one or more of the following;
and/or the first solvent is selected from any one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, methylene dichloride, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol and toluene.
4. The preparation method according to claim 1 or 2, wherein in the step S1, the raw material further comprises an additive selected from any one or more of lithium chloride, magnesium chloride, zinc chloride, ferric chloride, ferrous chloride, zirconium chloride, cobalt chloride, nickel chloride, chromium chloride, calcium chloride, lithium bromide, lithium iodide, lithium trifluoromethane sulfonate, ketone trifluoromethane sulfonate, ferrous trifluoromethane sulfonate, ferric trifluoromethane sulfonate, scandium trifluoromethane sulfonate, ytterbium trifluoromethane sulfonate, manganese bis (trifluoromethane sulfonate), lithium tetrafluoroborate, magnesium bromide, magnesium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium acetate, tetraethylammonium bromide, and tetramethylammonium chloride.
5. The preparation method according to claim 1 or 2, wherein in the step S1, the preparation method of the compound 1 comprises:
and carrying out substitution reaction on raw materials comprising a compound 4, a compound 5 and a base in an inert gas atmosphere to obtain the compound 1, wherein the compound 4 and the compound 5 have the following structural formulas:
，
the molar ratio of the compound 4, the compound 5 and the base is 1: 1-1.2: 1-2; and/or the alkali is selected from any one or more of lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium hydroxide and lithium hydroxide; and/or the temperature of the substitution reaction is 20-30 ℃, and/or the time of the substitution reaction is 6-16 h.
6. The process according to claim 5, wherein the process for producing the compound 4 comprises:
under the illumination condition, performing nitroreduction reaction on the compound 6 under the action of a first catalyst to obtain the compound 4, wherein the structural formula of the compound 6 is as follows:
，
the wavelength of the illumination is 365-400 nm, and/or the temperature of the nitroreduction reaction is 20-40 ℃, and/or the time of the nitroreduction reaction is 1-3 h;
And/or the mass ratio of the first catalyst to the compound 6 is 2-3: 1.
7. the method of preparation of claim 5, wherein the method of preparation of compound 5 comprises:
carrying out a Kumada reaction on a raw material comprising a compound 7, a cyclopropylating Grignard reagent, a second catalyst and a second ligand to obtain the compound 5, wherein the compound 7 has the following structural formula:
，
the molar ratio of the compound 7, the cyclopropylating grignard reagent, the second catalyst and the second ligand is 1: 1.5-2.5: 0.05-0.1: 2-6;
the cyclopropylating Grignard reagent is cyclopropyl magnesium bromide and/or cyclopropyl magnesium chloride; and/or the second catalyst is selected from any one or more of ferric triacetylacetonate, ferric sulfate, ferric acetate and ferric chloride; and/or the second ligand is selected from any one or more of N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone and 1, 3-tetramethylurea;
and/or the temperature of the Kumada reaction is 15-25 ℃, and/or the time of the Kumada reaction is 3-5 h.
8. The preparation method according to claim 1 or 2, wherein in the step S1, the preparation method of the compound 2 comprises:
Carrying out demethylation reaction on a raw material comprising the compound 8 and an acid catalyst to obtain a compound 9;
will include the compound 9,Carrying out Mitsunobu reaction on raw materials of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound 10;
carrying out ammonolysis reaction on raw materials comprising the compound 10 and ammonia gas to obtain a compound 2; wherein the structural formulas of the compound 8, the compound 9 and the compound 10 are as follows:
，
the molar ratio of the compound 8 to the acid catalyst is 1: 1.5-2; and/or the acidic catalyst is aluminum chloride and/or ammonium chloride; and/or the temperature of the demethylation reaction is 25-50 ℃, and/or the time of the demethylation reaction is 6-16 h;
and/or the compound 9, theThe molar ratio of the triphenylphosphine to the diisopropyl azodicarboxylate is 1: 1-1.5: 1-1.5: 1-1.5; and/or the temperature of the Mitsunobu reaction is 20-30 ℃, and/or the time of the Mitsunobu reaction is 2-6 h;
and/or the ammonolysis reaction temperature is 20-30 ℃, and/or the ammonolysis reaction time is 16-40 h.
9. The production method according to claim 1 or 2, characterized in that the production method of the compound 1 further comprises:
Carrying out ammonification reaction on the raw materials comprising the compound 5, ammonia and third catalysis to obtain a compound 11;
carrying out a coupling reaction on a raw material comprising a compound 11, a compound 12, an alkaline substance, a copper metal catalyst, a third ligand and a second solvent, wherein the structural formulas of the compound 11 and the compound 12 are as follows:
，
the molar ratio of the compound 5 to the third catalyst is 1: 1-1.5, and/or the third catalyst is selected from any one or more of calcium chloride, ferric chloride, magnesium chloride, cobalt chloride, zinc chloride, nickel chloride and magnesium sulfate; and/or the temperature of the ammonification reaction is 20-30 ℃, and/or the time of the ammonification reaction is 24-48 h;
and/or the temperature of the coupling reaction is 50-120 ℃, and/or the time of the coupling reaction is 8-16 h;
and/or the molar ratio of the compound 11, the compound 12, the basic substance, the copper metal catalyst, the third ligand is 1: 1-1.2: 1.5-2: 0.2 to 0.4: 0.4-0.8;
and/or the alkaline substance is an inorganic base or an organic base, wherein the inorganic base is selected from any one or more of carbonate, phosphate, hydroxide and alkoxide; the carbonate is selected from any one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; the phosphate is selected from any one or more of lithium phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and cesium phosphate; the hydroxide is selected from any one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide; the alkoxide is selected from any one or more of potassium tert-butoxide, sodium ethoxide and sodium methoxide; the organic base is selected from any one or more of potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, triethylamine, N-diisopropylethylamine, pyridine and 2-methylpyridine;
And/or the copper metal catalyst is selected from any one or more of cuprous iodide, cuprous bromide, cuprous chloride, cupric acetate, copper 3-methyl salicylate, copper (II) trifluoromethane sulfonate, copper sulfate, tetraethyl cyanohexafluorophosphate and chlorine [1, 3-bis (2, 6-diisopropyl phenyl) imidazole-2-subunit ] copper (I);
and/or the third ligand is selected from any one or more of a monophosphine ligand, a diphosphine ligand and a nitrogen ligand; the monophosphine ligand is selected from any one or more of triphenylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-tert-butylphosphine and 2- (di-tert-butylphosphine) biphenyl; the biphosphine ligand is selected from any one or more of DPPE, 1' -bis (diphenylphosphine) ferrocene, N-dimethyl-1- ((S) -2-diphenylphosphine) ferrocene) ethylamine and 1,1' -binaphthyl-2, 2' -bisdiphenylphosphine; the nitrogen ligand is selected from N, N, N ', N' -tetramethyl ethylenediamine and N, N '-dimethyl-1, 2-cyclohexanediamine, 1, 2-diaminocyclohexane, 4-dimethylaminopyridine, terpyridine, 2' -isopropylidenebis [ 4-tert-butyl-2-oxazoline ], 2- (4-benzyl-4, 5-dihydro-oxazol-2-yl) -pyridine, 2- [2- (diphenylphosphine) phenyl ] -4-isopropyl-2-oxazoline, 1 '-binaphthyl-2, 2' -diamine, 2 '-bipyridine, 2, 6-bis [1- (2-tert-butylphenylimino) ethyl ] pyridine, 4' -di-tert-butyl-2, 2 '-bipyridine, 6' -dimethyl-2, 2 '-bipyridine 4,4' -dimethoxy-2, 2 '-bipyridine, 2' -bipyridine-5, 5 '-dicarboxylic acid, 2' -bipyridine-4, 4 '-dicarboxylic acid, 4' -dichloro-2, 2 '-bipyridine, 4' -diamino-2, 2 '-bipyridine, 4' -biphenyl-2, 2-bipyridine 4,4 '-dimethylamino-2, 2' -bipyridine, 1, 10-phenanthroline, 5, 6-dimethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 3, 8-dibromophenanthroline, 1, 10-phenanthroline-2, 9-dicarboxylic acid, any one or more of N1, N2-di (furan-2-ylmethyl) oxamide, N '-bis (2, 4, 6-trimethoxyphenyl) oxamide, N' -dibenzyl oxalyl diamine;
And/or the second solvent is selected from any one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, ethylene glycol dimethyl ether, methylene dichloride, chloroform, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol and toluene.
10. The process according to claim 1 or 2, wherein in step S2, the starting material further comprises trifluoroacetic acid, N-diisopropylethylamine, 1-propylphosphoric acid cyclic anhydride.
CN202311290768.2A 2023-10-08 2023-10-08 Preparation method of Rui Mi Buti Ni Active CN117024354B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311290768.2A CN117024354B (en) 2023-10-08 2023-10-08 Preparation method of Rui Mi Buti Ni

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311290768.2A CN117024354B (en) 2023-10-08 2023-10-08 Preparation method of Rui Mi Buti Ni

Publications (2)

Publication Number Publication Date
CN117024354A CN117024354A (en) 2023-11-10
CN117024354B true CN117024354B (en) 2023-12-08

Family

ID=88632223

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311290768.2A Active CN117024354B (en) 2023-10-08 2023-10-08 Preparation method of Rui Mi Buti Ni

Country Status (1)

Country Link
CN (1) CN117024354B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101898999A (en) * 2009-11-19 2010-12-01 华东理工大学 Method for synthesizing pyridinecarbaldehydes compound with direct oxidization method
WO2015079417A1 (en) * 2013-11-29 2015-06-04 Novartis Ag Novel amino pyrimidine derivatives
WO2016164580A1 (en) * 2015-04-07 2016-10-13 Novartis Ag Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
WO2020234779A1 (en) * 2019-05-23 2020-11-26 Novartis Ag Crystalline forms of a btk inhibitor
CN113004248A (en) * 2021-03-16 2021-06-22 绍兴文理学院 Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101898999A (en) * 2009-11-19 2010-12-01 华东理工大学 Method for synthesizing pyridinecarbaldehydes compound with direct oxidization method
WO2015079417A1 (en) * 2013-11-29 2015-06-04 Novartis Ag Novel amino pyrimidine derivatives
CN105683181A (en) * 2013-11-29 2016-06-15 诺华股份有限公司 Novel amino pyrimidine derivatives
CN110172056A (en) * 2013-11-29 2019-08-27 诺华股份有限公司 New aminopyridine derivative
WO2016164580A1 (en) * 2015-04-07 2016-10-13 Novartis Ag Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
WO2020234779A1 (en) * 2019-05-23 2020-11-26 Novartis Ag Crystalline forms of a btk inhibitor
CN113004248A (en) * 2021-03-16 2021-06-22 绍兴文理学院 Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Daniela Angst et al,.."Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase".《American Chemical Society》.2020,第5102−5118页. *

Also Published As

Publication number Publication date
CN117024354A (en) 2023-11-10

Similar Documents

Publication Publication Date Title
CA2732947A1 (en) Process for preparing amines from alcohols and ammonia
US9096626B2 (en) Monophosphorus ligands and their use in cross-coupling reactions
CN112441875B (en) Method for copper photocatalytic synthesis of 9-trifluoromethyl-9, 10-dihydrophenanthrene compound
CN113713856A (en) Photosensitive COFs catalyst and method for catalytically synthesizing thiophosphate derivatives
CN117024354B (en) Preparation method of Rui Mi Buti Ni
CN113563231A (en) Para C-H alkylated arylamine and preparation method thereof
CN109824579B (en) Preparation method of (S) -phenyl (pyridine-2-yl) methanol derivative
CN114685475B (en) Planar chiral oxazolopyridine ligand compound based on cycloaralkyl skeleton, and synthetic method and application thereof
Huo et al. Highly Efficient Bulky α‐Diimine Palladium Complexes for Suzuki‐Miyaura Cross‐Coupling Reaction
CN112694489B (en) Preparation method of N-heterocyclic carbene copper catalyst
CN105209435A (en) Pyridine- or pyrazine-containing compounds
WO2017193288A1 (en) Synthesis of phosphine ligands bearing tunable linkage: methods of their use in catalysis
CN112321639A (en) Preparation method of aryl diphenylphosphine derivative
CN113004248A (en) Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt
CN112675920A (en) Mono-chiral center catalyst, preparation thereof and method for catalytically synthesizing chiral alcohol compound and chiral alpha-allyl alcohol
CN110627831A (en) Bibiaryl acetal phosphines, their preparation and use in coupling reactions
CN116003360B (en) Preparation method for synthesizing orange compounds from carbon dioxide and alkyne
CN112759616B (en) Tri-discoene carbene palladium compound and application thereof
CN114805435B (en) Process for preparing biaryl phosphine compounds
CN109053556A (en) Pyridyl group bridging-phenyl-amino pyridine compounds and their, complex and its synthesis and application
CN113861238B (en) Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis
CN111909100B (en) Method for preparing uracil and thymine derivatives
CN113200812B (en) 1,3,5-trisubstituted aryl compound synthesis method
CN108997431B (en) Synthesis method and application of p-xylene glycol derived bidentate phosphite ligand
CN111808041B (en) Difluoroalkyl aryl oxazolidinone compound and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant