CN110041334B - Preparation method of aminophenol compound - Google Patents
Preparation method of aminophenol compound Download PDFInfo
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- CN110041334B CN110041334B CN201910030672.XA CN201910030672A CN110041334B CN 110041334 B CN110041334 B CN 110041334B CN 201910030672 A CN201910030672 A CN 201910030672A CN 110041334 B CN110041334 B CN 110041334B
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a preparation method of an aminophenol compound. Specifically, the amino compound and cyclohexanedione are used for preparing the aminophenol compound under the action of an oxidant TEMPO, so that the preparation method is high in reaction yield, high in product purity, easy to purify and beneficial to industrial production.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a preparation method of an aminophenol compound.
Background
Aminophenol compounds are an important class of chemical substances and can be used as intermediates for the preparation of pharmaceutically active substances and the like.
In the prior art, a plurality of methods for preparing aminophenol compounds exist, but most of the methods are not suitable for industrial production due to low reaction yield, complex treatment after reaction, difficult separation and purification and the like. For example, CN1938261A discloses a method for preparing aminophenol compounds, comprising reacting a cyclohexanedione compound with an amine compound under neutral or basic conditions, and in the presence or absence of a dehydrogenation reagent.
The aminophenol compounds can be used for preparing various active substances, such as antitumor drugs. Wherein the IDO (Indoleamine-pyrrole-2, 3-dioxygenase, indolamine-pyrorol-2, 3-dioxygenase) inhibitor is an antitumor drug with wide application prospect. A large number of studies at present show that IDO is highly expressed in leukemia cells, so that local T cell proliferation is inhibited, T-cell mediated immune reaction is inhibited, T-cell activation signal transduction is inhibited, and the attack of tumor cells escaping from an immune system is mediated. WO2016169421 discloses a novel IDO inhibitor having a compound structure represented by formula (I) which exhibits excellent IDO inhibitory effect. The existing preparation method of the compound I has low yield, and the product of multi-step reaction needs to be purified by column chromatography, so that the cost is high, the operation is complex, the amplification is difficult, and the industrial production is severely limited.
PCT/CN2018/095371 (application No. 2018.07.12) describes a novel process for the preparation of compounds of formula I,
in the reaction route, the imidazoisoindolylaminophenol A is an important intermediate, and the quality of the intermediate directly influences the preparation and purification difficulty of subsequent products. The preparation method mainly comprises the step of reacting an amino compound with cyclohexanedione in the presence of oxygen, and has the disadvantages of incomplete reaction, low yield, poor product purity and great difficulty in purifying subsequent products.
2,2,6, 6-tetramethyl piperidine oxide (hereinafter referred to as TEMPO) is a stable nitroxide radical and has wide application in the fields of chemistry, biology, food industry, agriculture and the like. It can be used as reversible end-capping agent for free radical polymerization, and can also be used as heterogeneous catalyst for oxidation reaction of various alcohols and polyols. TEMPO is also an important oxidation catalyst, used in some specific chemical reactions, such as the oxidation of primary alcohols to aldehydes, with high selectivity, without further oxidation of the reaction to organic acids; oxidizing the secondary alcohol to a ketone; can also be used for preparing optically active alpha-amino aldehyde.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel preparation method of an aminophenol compound.
The invention provides a preparation method of a compound shown as a formula II, which comprises the step of reacting a compound shown as a formula III with a compound shown as a formula IV in the presence of TEMPO,
wherein R is1And R2The same or different, each of which is independently selected from the group consisting of hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally substituted with one or more substituents selected from the group consisting of alkyl group, halogen group, hydroxy group, amino group, nitro group, cyano group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; alternatively, the first and second electrodes may be,
R1and R2Together with the adjacent nitrogen atom form a 5-or 6-membered heterocyclic ring, preferably pyrrolidinyl, piperidinyl, or piperazinyl, optionally substituted with 1-3R3Substituted;
R3the same or different, and each is independently selected from the group consisting of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, and fused ring groups, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and fused ring groups are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, amino, nitro, cyano, and alkoxy,
wherein the condensed ring group is formed by condensing a group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl with 1-2 groups independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl. For example, the compound may be a fused product of a 5-or 6-membered heteroaryl group, a 5-or 6-membered heterocyclic group and 1 to 2 members independently selected from a phenyl group, a 5-or 6-membered heteroaryl group, and a 5-or 6-membered heterocyclic group, and the 5-or 6-membered heteroaryl group and the heterocyclic group are preferably nitrogen-containing heteroaryl groups and heterocyclic groups.
In certain embodiments, the compound of formula II is
The compound of formula III is
The compound of formula IV is
Wherein n is an integer of 0, 1,2 or 3.
In certain embodiments, the compound of formula II is
The compound of formula III is
The compound of formula IV is
Wherein R is4The same or different and each is independently selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
m is an integer of 0, 1,2, 3 or 4.
In certain embodiments, the compound of formula II is
The compound of formula III is
The compound of formula IV is
In certain preferred embodiments, the compound of formula II is
The compound of formula III is
The molar ratio of the compound shown in the formula III to TEMPO can be 1: 0.1-1: 7, and preferably 1: 1.2-1: 3.
The molar ratio of the compound shown in the formula III to the compound shown in the formula IV can be 1: 0.7-1: 100, and preferably 1: 2-1: 4.
The solvent for the reaction may be a conventional solvent, and for example, may be one or more of dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropanol, propanol, ethanol, methanol, and water.
The reaction temperature may be from 0 ℃ to 200 ℃, preferably from 20 ℃ to 100 ℃.
In certain embodiments, other oxidizing agents besides TEMPO may also be present in the reaction to facilitate the reaction. The other oxidant may be, for example, oxygen, NaOCl, t-BuOCl, CuCl, or the like.
In certain embodiments, TEMPO can be added to the reaction system all at once, or in multiple portions, such as two, three, or four portions.
In another aspect, the present invention provides a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound represented by formula II by the method of the present invention.
Further, the preparation method of the compound shown in the formula I or the pharmaceutically acceptable salt thereof further comprises the step of preparing the compound shown in the formula V by using the compound shown in the formula II as a reactant.
Wherein X is a leaving group selected from the group consisting of-Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methylsulfonyloxy, p-toluenesulfonyloxy, phenylsulfonyloxy, acetoxy or phosphate, -SR, -SO2R, R are C1～C6An alkyl group; x is preferably-Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy or benzenesulfonyloxy.
Further, the method also comprises the step of carrying out coupling reaction on the compound shown in the formula V and the compound shown in the formula VI in the presence of a catalyst to prepare the compound shown in the formula VII.
Wherein X may be selected from the group consisting of-Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, -SR, -SO2R, R are C1～C6An alkyl group; x is preferably-Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy or benzenesulfonyloxy;
y may be selected from-BF3K、-BRaRb、-Sn(Rc)qor-Zn-X';
Raand RbIndependently selected from-OH, alkyl, alkoxy or optionally substituted C1～C6Monohydric and dihydric alcohols, or RaAnd RbForm a ring together, RcIndependently selected from C1～C6Alkyl, X' is selected from-Cl、-Br、-I；
q is an integer of 0, 1,2, 3 or 4;
R5selected from hydrogen or hydroxyl protecting groups.
In certain preferred embodiments, Y is selected from BF3K and BRaRbThe BRaRbIn RaAnd RbIndependently selected from-OH, alkyl, alkoxy, or BRaRbIs pinacol boronate, i.e.
The catalyst may comprise PdLp、PdCl2Lp、Pd(OAc)2Lp、Pd2(dba)3Lp、Pd(II)Lp、Pd(0)、NiCl2Lp、Ni(COD)2Lp、NiCl2(NEt3)2Or NiCl2(bipy) wherein L is a phosphine-containing ligand, which may be PPh, or an N-heterocyclic carbene ligand3、dppf、PCy3、tBu3P、P(OMe)3Dppe or dppb, p is independently an integer selected from 0, 1,2, 3 or 4.
For example, the catalyst may be Pd (PPh)3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2Pd/C, Pd (OAc)2、PCy3/Pd2(dba)3、NiCl2(dppf)、NiCl2(PPh3)2、Ni{P(OMe)3}2Cl2、NiCl2(PCy3)2、NiCl2(dppe)，NiCl2(dppb)，NiCl2(NEt3)2、NiCl2(bipy)、NiCl2·6H2O、NiCl2Or Ni (COD)2Pd (PPh) is preferred3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2Pd/C, Pd (OAc)2、PCy3/Pd2(dba)3More preferably Pd (PPh)3)2Cl2。
In certain embodiments, the reaction is carried out in the presence of an alkaline substance, preferably Na2CO3,Ba(OH)2、K3PO4、Cs2CO3、K2CO3、TlOH、KF、CsF、Bu4F. One or more of NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR and TlOR, wherein R is independently selected from C1～C6An alkyl group. Wherein NaOR, KOR or TlOR may be NaOMe, NaOEt, KOtBu or TlOEt, for example. The alkaline substance is more preferably Na2CO3Or K2CO3One or more of (a).
The solvent for the reaction may be a conventional solvent, and for example, may be one or more of dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethylsulfoxide, acetonitrile, propionitrile, isopropanol, ethanol, water, preferably one or more of dimethylformamide, dioxane, water, more preferably a combination of dioxane and water.
In certain embodiments, R5Is a hydroxyl protecting group. The preparation method also comprises the step of removing the hydroxyl protecting group of the compound shown in the formula VII.
According to the invention, the amino compound and cyclohexanedione are used for preparing the aminophenol compound under the action of the oxidizing agent TEMPO, the reaction is complete, the reaction yield is high, the reaction conditions are mild, the prepared aminophenol compound has excellent purity, and the purification operation is greatly simplified.
When the method disclosed by the invention is applied to the preparation of the compound intermediate shown in the formula I, the prepared aminophenol intermediate is high in yield and purity, so that the subsequent reaction does not need complicated and time-consuming purification steps such as column passing and the like, the post-treatment process is simplified, the production efficiency is greatly improved, and the method is more suitable for industrial production.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl.
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate, preferably phenyl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "fused ring group" means a group formed by fusing a group selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl with 1 to 2 groups independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and non-limiting examples thereof include:
the term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "carboxy" refers to-C (O) OH.
The term "aldehyde" refers to — CHO.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "acyl halide" refers to a compound containing a group that is-C (O) -halogen.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
The compounds of the inventionIn the chemical structure of the substance, bond
No configuration is specified, i.e. if configurational isomerism is present in the chemical structure, the bond
Can be that
Or
Or at the same time contain
And
two configurations.
Detailed Description
The present invention will be explained in detail with reference to specific examples below, so that those skilled in the art can more fully understand the specific examples of the present invention to illustrate the technical solutions of the present invention, and not to limit the present invention in any way.
Example 1
Compound a (177g, 0.495mol, prepared according to the disclosure of WO 2016169421) was dissolved in 1.5L dichloromethane, 300mL 1, 4-dioxane was added, concentrated hydrochloric acid (412mL, 4.95mol) was added dropwise with cooling in an ice water bath, warmed to room temperature, and the reaction was stirred for 2 hours. After completion of the reaction, 600mL of water was added to the reaction mixture, and the aqueous phase was separated by extraction. Dissolving sodium hydroxide (215g, 5.38mol) in 215mL of water, slowly dropping the water phase into the water phase, adjusting the pH value to 8-9, extracting the water phase with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 144.8g of a compound b, wherein the product is directly subjected to the next reaction without purification.
Example 2
128.6g of compound b were subjected to chiral preparation (separation conditions: chiral preparation column Superchiral S-AY (Chiralway),2cm I.D.. times.25 cm Length,5 um; mobile phase: CO2EtOH/DEA 60/40/0.05(v/v/v), flow rate: 50g/min), collecting target components, in the process, preparing a column without blockage, and concentrating under reduced pressure to obtain a compound b' 55g, wherein the optical purity is as follows: 99.4%, chemical purity: 99.2 percent.
Example 3
Dissolving compounds b' (77.3g, 300mmol) and c (100.9g, 900mmol) in 1150mL of ethanol, heating to 60 ℃, adding TEMPO (93.75g, 600mmol) in batches into the reaction system, stirring for reaction for 12 hours, cooling the reaction liquid to 0-10 ℃, stirring for 1 hour, filtering, leaching the filter cake with methyl tert-butyl ether, collecting the filter cake, and drying in vacuum to obtain compound d (141.6g, off-white solid), yield: 67.5% and 97% chemical purity.
Example 4
Compound d (141.6g, 405mol) was dissolved in 2.8L of dichloromethane. The temperature is reduced to 0 ℃, pyridine (160.2g, 2025mmol) is added, and Tf is added dropwise2O (148.5g, 526mmol), and the reaction was stirred for 1 hour with heat preservation. After the reaction is finished, adding 2L of water into the reaction solution, adjusting the pH value to 2-3 by using 1M hydrochloric acid, standing for layering, separating an organic phase, extracting a water phase by using dichloromethane, combining the organic phase, drying over anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a compound e (195g, brown foamy solid) with chemical purity: 97.99 percent, and the product is directly subjected to the next reaction without purification.
Example 5
Compound e (65g, 135mmol) and compound f (64.3g, 270mmol, prepared as disclosed in CN 105189461A) were dissolved in 1300mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 5:1), and sodium carbonate (42.9g, 405mmol) and Pd (dppf) Cl were added in that order2(9.9g, 13.5mmol), heated to reflux under argon and stirred for 3 hours. After the reaction, the reaction solution was cooled to room temperature, 325mL of water was added, the mixture was stirred at room temperature for 30min, filtered, the filter cake was rinsed with water, the filter cake was collected, dispersed with 1.2L of methanol, concentrated hydrochloric acid (34mL) was added, stirred for 30min, concentrated to remove methanol, 1.8L of water was added, stirred for 30min, filtered, the solid was rinsed with water, the aqueous phases were combined, back-extracted with ethyl acetate (600 mL. times.2), the aqueous phase was collected, saturated NaHCO was used for the extraction, and the resulting mixture was concentrated in vacuo3Adjusting the pH value of the solution to be alkaline, separating out a solid, filtering to obtain a solid, washing with water, and drying in vacuum to obtain 41g of a compound I, wherein the yield is 68.5%, and the chemical purity is as follows: 98.6%, optical purity: 99.8 percent.
Comparative example
First step of
Compound b' (75g, 292mmol) prepared according to example 2 was dissolved in 2L ethanol, compound C (49.1g, 438mmol) and 10% Pd/C7.5 g were added sequentially, the temperature was raised to 75 deg.C, air was introduced, and the reaction was stirred for 28 hours. After the reaction is finished, filtering to remove Pd/C, leaching a filter cake with methanol, concentrating the filtrate under reduced pressure, adding 500mL of ethanol into the residue to dissolve, adding 2.5L of methyl tert-butyl ether, stirring to separate out a solid, filtering, collecting the filter cake, and drying to obtain 54.1g of a compound d, yield: 53%, chemical purity: 89.8 percent.
Second step of
Compound d (54.1g, 0.155mol) was dissolved in 700mL of dichloromethane. Cooling to 0 deg.C, adding pyridine (61.3g, 0.775mol), and adding Tf dropwise2O (56.8g, 0.201 mol). The reaction mixture was warmed to room temperature and stirred for 1 hour. After the reaction is finished, adding 60mL of water into the reaction solution, adjusting the pH value to 2 by using 1M hydrochloric acid, standing for layering, separating an organic phase, extracting a water phase by using dichloromethane, and combining the organic phaseThe phases were dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (eluent: DCM: MeOH ═ 10:1) to give compound e 41g, yield: 55%, chemical purity: 92.76 percent.
The third step
Compound e (41g, 85mmol) and compound f (40.5g, 170mmol) were dissolved in 820mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 5:1), and sodium carbonate (27g, 255mmol) and pd (dppf) Cl were added in this order2(6.2g, 8.5mmol), heated to reflux under argon, and stirred for reaction for 3 hours. After the reaction is finished, cooling the reaction liquid to room temperature, adding 200mL of water, stirring at room temperature for 30min, filtering, leaching the filter cake with water, collecting the filter cake, dispersing with 750mL of methanol, adding concentrated hydrochloric acid (22mL), stirring for 30min, concentrating to remove methanol, adding 1.2L of water, stirring for 30min, filtering, leaching the solid with water, combining the water phases, back extracting with ethyl acetate (400mL multiplied by 2), collecting the water phase, and using saturated NaHCO to perform back extraction on the water phase and the solid phase3Adjusting the pH value of the solution to be alkaline, separating out a solid, filtering to obtain a solid, washing with water, and drying in vacuum to obtain 29.3g of a compound I, wherein the yield is 66%, and the chemical purity is as follows: 95.1%, optical purity: 99.7 percent.
Since the invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (10)
1. A process for the preparation of a compound of formula II comprising the step of reacting a compound of formula III with a compound of formula IV in the presence of TEMPO,
the compound of formula II is
The compound of formula III is
The compound of formula IV is
Wherein R is4Are the same or different and are each independently selected from the group consisting of lower alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, halogen, amino, nitro, hydroxy, cyano;
m is an integer of 0, 1,2, 3 or 4;
the molar ratio of the compound shown in the formula III to TEMPO is 1: 0.1-1: 7;
the molar ratio of the compound shown in the formula III to the compound shown in the formula IV is 1: 0.7-1: 100;
the solvent for the reaction is selected from one or more of dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropanol, propanol, ethanol, methanol and water.
2. The process according to claim 1, wherein the compound of formula II is
The compound of formula III is
The compound of formula IV is
3. The process according to claim 2, wherein the compound of formula II is
The compound of formula III is
4. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula III to TEMPO is 1: 1.2-1: 3.
5. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula III to the compound represented by the formula IV is 1:2 to 1: 4.
6. The method of claim 1, wherein an additional oxidizing agent is present in the reaction.
7. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula II according to the process of any one of claims 1 to 6,
the method also comprises the step of preparing the compound shown in the formula V by taking the compound shown in the formula II as a reactant;
the method also comprises the step of carrying out coupling reaction on the compound shown as the formula V and the compound shown as the formula VI in the presence of a catalyst to prepare the compound shown as the formula I,
wherein X is selected from-Cl and-Br-I, -F, trifluoromethanesulfonyloxy, methylsulfonyloxy, p-toluenesulfonyloxy, phenylsulfonyloxy, acetoxy or phosphate, -SR, -SO2R, R are C1～C6An alkyl group;
y is pinacol borate;
R5is hydrogen;
the catalyst is selected from Pd (PPh)3)2Cl2；
The reaction is carried out in the presence of a basic substance.
8. The process according to claim 7, wherein X is selected from the group consisting of-Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy.
9. The method according to claim 8, wherein the alkaline substance is Na2CO3、Ba(OH)2、K3PO4、Cs2CO3、K2CO3、TlOH、KF、CsF、Bu4F. One or more of NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR and TlOR, wherein R is independently selected from C1～C6An alkyl group.
10. The method according to claim 9, wherein the alkaline substance is selected from Na2CO3Or K2CO3One or more of (a).
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| CN1938261A (en) * | 2004-03-25 | 2007-03-28 | 大塚制药株式会社 | Preparation method for aminophenol compound |
| WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
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| CN1938261A (en) * | 2004-03-25 | 2007-03-28 | 大塚制药株式会社 | Preparation method for aminophenol compound |
| WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
| CN106715440A (en) * | 2015-04-21 | 2017-05-24 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
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