CN109983019A - A kind of preparation method of imidazo isoindoles derivative - Google Patents

A kind of preparation method of imidazo isoindoles derivative Download PDF

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CN109983019A
CN109983019A CN201880004428.XA CN201880004428A CN109983019A CN 109983019 A CN109983019 A CN 109983019A CN 201880004428 A CN201880004428 A CN 201880004428A CN 109983019 A CN109983019 A CN 109983019A
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preparation
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resolution
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CN109983019B (en
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黄建
尤凌峰
姜威
罗扬
王军政
冯君
贺峰
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Chengdu Suncadia Pharmaceuticals Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

A kind of preparation method of imidazo isoindoles derivative.In particular to the preparation method of one kind imidazo isoindoles derivative as shown in formula (I), compound shown in the formula (III) of high-optical-purity is obtained including splitting compound shown in formula (II).It is reacted again using compound shown in formula (III) as raw material, obtained finished product optical purity is high, at low cost, more economical, is also more suitable industrialized production.

Description

A kind of preparation method of imidazo isoindoles derivative Technical field
The invention belongs to field of medicaments, are related to a kind of preparation method of imidazo isoindoles derivative.
Background technique
Indoles amine-pyrroles -2,3- dioxygenase (Indoleamine-pyrrole-2,3-dioxygenase, it IDO) is a kind of iron content ferroheme monomeric protein, at present a large number of studies show that IDO higher expression in leukaemia cell, keeps local T cell proliferation suppressed, the immune response for inhibiting T- cell-mediated, the transduction of T- cell activation signal is set to be obstructed, thus the attack of mediate tumor cell escape immune system.It has been found that most of mankind's tumor groups express IDO with becoming second nature.Therefore, IDO is the target of the cancer immunotherapy of a tool potentiality.
IDO inhibitor has a good application prospect as drug in pharmaceuticals industry.WO2016169421 discloses a kind of new IDO inhibitor, shown in compound structure such as formula (I),
The compound shows excellent IDO inhibiting effect.The synthetic method of such compound is mainly reacted by halogenophenyl pyrazoles with piperidyl imidazo iso-indoles at present, is then made by chiral resolution.
During the preparation process it was found that the chiral resolution yield of final step is very low, when being split especially with chiral column, since raceme and product solubility in eluant, eluent is not high, it is easy to be precipitated during the preparation process that chiral column is caused to block, seriously affects fractionation efficiency.
Summary of the invention
For overcome the deficiencies in the prior art, the purpose of the present invention is to provide a kind of preparation methods of new imidazo isoindoles derivative.
One aspect of the present invention provides new reaction intermediate, the compound as shown in formula III,
Compound shown in formula IV,
Wherein, X is selected from-Cl ,-Br ,-I ,-F, trifluoro-methanesulfonyl oxy, mesyloxy, phenylsulfonyloxy, acetoxyl group or phosphate-based ,-SR ,-SO 2R, R C 1~C 6Alkyl；It is preferred that-Cl ,-Br ,-I, trifluoro-methanesulfonyl oxy, mesyloxy or phenylsulfonyloxy.
Compound shown in Formula VII,
Wherein, R2 is selected from hydroxyl protection base；
And compound shown in formula d,
Another aspect of the present invention provides the preparation method such as formula III compound represented, includes the steps that compound shown in chiral resolution Formula II,
The method of the chiral resolution can be chemical resolution, film fractionation, Chromatographic resolution, Capillary Electrophoresis fractionation and biological resolution etc..
In some embodiments, the method for the chiral resolution is Chromatographic resolution.
In some embodiments, the method for the chiral resolution is chemical resolution.The resolving agent used can be organic acid etc., such as L-TARTARIC ACID, D- tartaric acid, dibenzoyl-L-tartaric acid (L-DBTA), dibenzoyl-D-tartaric acid (D-DBTA), two pairs of toluoyl-L-tartaric acids (L-DTTA) or two pairs of toluoyl-D-tartaric acids (D-DTTA), R- camphorsulfonic acid, S- camphorsulfonic acid, D- mandelic acid, L- mandelic acid, Pidolidone, D-Glu, ASPARTIC ACID, D-ASP etc., it is preferred that L-DTTA, D-DTTA, Pidolidone, D-Glu, ASPARTIC ACID, D-ASP, more preferable D-DTTA.
The molar ratio of compound shown in the resolving agent and Formula II can be 1:1~4:1.
The process of resolving agent split-type II compound represented can carry out in conventional solvent, and preferred solvent includes water or hydrophilic organic solvent (such as C 1~C 6Alcohols, such as methanol and ethyl alcohol；Ketone, such as acetone and methyl ethyl ketone；Ethers, such as tetrahydrofuran and dioxanes；Acetonitrile；N,N-Dimethylformamide；And N, N- dimethyl sulfoxide)；Or its mixed solvent, more preferable methanol or ethyl alcohol.
Free intermediate split salt process be it is conventional, alkali can be used to dissociate, the alkali used that dissociates is preferably the hydroxide aqueous solution of alkali metal, preferably sodium hydrate aqueous solution；Solvent can be conventional solvent, such as methylene chloride, tetrahydrofuran, chloroform etc..
In order to improve the optical purity for splitting obtained compound III, can be recrystallized to obtained intermediate fractionation salt is split.The process that salt is split into the present invention can generally carry out at normal temperature, it can also carry out under heating conditions when necessary, and the step of recrystallizing, can generally carry out under heating conditions, first heating dissolves fractionation salt in the solvent, then slowly completes the process of recrystallization at room temperature.
Present aspect additionally provides a kind of compound shown in formula I or the preparation method of its pharmaceutically acceptable salt, includes the steps that being prepared according to the method for the present invention such as formula III compound represented.
Further, the preparation method of compound or its pharmaceutically acceptable salt shown in formula I of the present invention further includes the steps that compound shown in formula IV is prepared by reactant of compound shown in formula III.
Wherein, X is leaving group, selected from-Cl ,-Br ,-I ,-F, trifluoro-methanesulfonyl oxy, mesyloxy, phenylsulfonyloxy, acetoxyl group or phosphate-based ,-SR ,-SO 2R, R C 1~C 6Alkyl；X preferably-Cl ,-Br ,-I, trifluoro-methanesulfonyl oxy, mesyloxy or phenylsulfonyloxy.
The method can be single step reaction (such as Buckwald coupling), be also possible to multistep reaction (such as first react with cyclohexanedione and generate piperidyl phenol intermediate, then synthesize compound IV).
Further, the method also includes by compound shown in compound shown in formula IV and Formula V existing for the catalyst the step of carrying out compound shown in coupling reaction preparation formula VI under the conditions of.
Wherein, Y is selected from-BF 3K、-BR aR b、-Sn(R c) mOr-Zn-X '；
R aAnd R bIndependently selected from-OH, alkyl, alkoxy or the arbitrarily C that replaces 1~C 6Unitary and dihydric alcohol or R aAnd R bIt is together cyclic, R cIndependently selected from C 1~C 6Alkyl, X ' are selected from-Cl ,-Br ,-I；
The integer that m is 0,1,2,3 or 4；
R 1Selected from hydrogen or hydroxyl protection base.
In some preferred embodiments, Y is selected from BF 3K and BR aR b, the BR aR bMiddle R aAnd R bIndependently selected from-OH, alkyl, alkoxy or BR aR bFor pinacol borate, i.e.,
The catalyst may include PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2Or NiCl 2(bipy), wherein L is containing Phosphine ligands or N- heterocyclic carbene ligand, and the Phosphine ligands that contain can be PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3, dppe or dppb, p it is independent be selected from 0,1,2,3 or 4 integer.
For example, the catalyst can be Pd (PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2, palladium carbon, Pd (OAc) 2、PCy 3/Pd 2(dba) 3、NiCl 2(dppf)、NiCl 2(PPh 3) 2、Ni{P(OMe) 3} 2Cl 2、NiCl 2(PCy 3) 2、NiCl 2(dppe), NiCl 2(dppb), NiCl 2(NEt 3) 2、NiCl 2(bipy)、NiCl 2·6H 2O、NiCl 2Or Ni (COD) 2, preferably Pd (PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2, palladium carbon, Pd (OAc) 2、PCy 3/Pd 2(dba) 3, more preferable Pd (PPh 3) 2Cl 2。
In some embodiments, the reaction is reacted in the presence of a basic, wherein the preferred Li of alkaline matter 2CO 3、Na 2CO 3、Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4One of NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR or a variety of, wherein R is independently selected from C 1~C 6Alkyl.Wherein NaOR, KOR or TlOR for example can be NaOMe, NaOEt, KOtBu or TlOEt.The more preferable Na of alkaline matter 2CO 3Or K 2CO 3One of or it is a variety of.
The solvent of the reaction can be Conventional solvents, such as one of can be dimethylformamide, 1-Methyl-2-Pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, dimethyl ether, isopropanol, ethyl alcohol, water or a variety of, preferably one of dimethylformamide, dimethyl ether, dioxane, water or a variety of.Reaction temperature can be 60 DEG C~150 DEG C.
In some embodiments, R 1For hydroxyl protection base, the method also includes being prepared compound shown in Formulas I for the deprotection of compound shown in Formula IV.
The compound III that the present invention obtains high-optical-purity by splitting compound II reacts again, obtained subsequent products remain high optical purity, product not racemization in the coupling reaction in later period, obtained finished product optical purity is high, last chiral the problem of preparing stifled pillar is avoided, process stabilizing easily reproduces.In addition, split at compound II it is at low cost, it is more economical, be also more suitable industrialized production.
When splitting compound II, compound III can be efficiently separated out using Chromatographic resolution and chemical resolution.It when being split using resolving agent, is swift in response, post-processing is easy, and byproduct is recyclable to be recycled, and obtained compound III optical purity is high, is very suitable to industry's enlarging production.
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 20 carbon atom.Preferably comprise alkyl of 1 to 10 carbon atom, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tert-butyl or amyl etc..Low alkyl group more preferably containing 1 to 6 carbon atom, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group or tert-butyl, amyl, heptyl etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from alkoxy, halogen, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, carbonyl.
" aryl " refers to 6 to the 14 yuan of full carbon monocycles or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, preferably 6 to 10 yuan of aryl, more preferable phenyl and naphthalene of the pi-electron system with conjugation, most preferably phenyl.Aryl can be substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" heteroaryl " refers to that wherein hetero atom includes oxygen, sulphur and nitrogen comprising 1 to 4 hetero atom, the heteroaromatic system of 5 to 14 annular atoms.Preferably 6 to 10 yuan.Heteroaryl is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together.Heteroaryl can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carbonyl ,-carboxylic acid or carboxylate.
" heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, it includes 3 to 20 annular atoms, wherein one or more annular atoms are selected from the hetero atom of nitrogen, oxygen or S (O) n (wherein n is integer 0 to 2), it but does not include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom, more preferable cycloalkyl ring includes 3 to 10 annular atoms.The non-limiting embodiment of monocyclic cycloalkyl includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc..Polycyclic naphthene base includes the heterocycle of loop coil, condensed ring and bridged ring.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), and wherein alkyl is as defined above.Non-limiting embodiment includes methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Alkoxy can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from for alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carbonyl, carboxylic acid or carboxylate." hydroxyl " refers to-OH group.
" hydroxyl protection base " is the group appropriate for hydroxyl protection known in the art, referring to document (" Protective Groups in Organic Synthesis ", 5 ThEd.T.W.Greene&P.G.M.Wuts the hydroxy-protective group in).As an example, preferably, the hydroxyl protection base can be (C 1-10Alkyl or aryl) 3Silylation, such as: triethyl group silicon substrate, triisopropylsilyl, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate etc.；It can be C 1-10Alkyl replaces alkyl, preferably alkoxy or the alkyl of aryl substitution, more preferable C 1-6The C that alkoxy replaces 1-6The C that alkyl or phenyl replaces 1-6Alkyl, most preferably C 1-4The C that alkoxy replaces 1-4Alkyl, such as: methyl, tert-butyl, allyl, benzyl, methoxy (MOM), ethoxyethyl group, 2- THP trtrahydropyranyl (THP) etc.；It can be (C 1-10Alkyl or aromatic radical) acyl group, such as: formoxyl, acetyl group, benzoyl etc.；It can be (C 1-6Alkyl or C 6-10Aryl) sulfonyl；It is also possible to (C 1-6Alkoxy or C 6-10Aryloxy) carbonyl.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes the event or environment occurs or not spot occasion.For example, mean " optionally by alkyl-substituted heterocyclic group " alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
Specific embodiment
The present invention is explained in detail below with reference to specific example, so that those skilled in the art is more fully understood specific example of the present invention and is only used to illustrate the technical scheme of the present invention, does not limit the present invention in any way.
Embodiment 1
Compound a (177g, 0.495mol are prepared according to WO2016169421 published method) is dissolved in 1.5L methylene chloride, 300mL 1 is added, under ice-water bath is cooling, concentrated hydrochloric acid (412mL is added dropwise in 4- dioxane, 4.95mol), it is warmed to room temperature, is stirred to react 2 hours.After reaction, 600mL water, extraction and separation water phase are added into reaction solution.By sodium hydroxide (215g, it 5.38mol) is dissolved in 215mL water, it is slowly dropped into above-mentioned water phase, is adjusted to pH value 8~9, water phase is extracted with dichloromethane, merge organic phase, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, compound II 144.8g is obtained, product directly carries out next step reaction without further purification.
Embodiment 2
Compound II 128.6g progress chirality is prepared into (separation condition: chiral preparatory column Superchiral S-AY (Chiralway), 2cm I.D.*25cm Length, 5um；Mobile phase: CO 2/ EtOH/DEA=60/40/0.05 (v/v/v), flow velocity: 50g/min), target components are collected, column is prepared in the process and occurs without stopping state, be concentrated under reduced pressure, obtain compound III 63.6g, optical purity: 99.4%, chemical purity: 99.2%.
Embodiment 3
At 25-30 DEG C, compound II (35.1g) is dissolved in ethyl alcohol 600mL, the ethanol solution 600ml of D-DTTA 142g is added, is stirred 16 hours at 25-30 DEG C, there are a large amount of light yellow solids, filter cake is added in ethyl alcohol 600mL, is cooled to 25-30 DEG C after being heated to reflux by filtering, filtering, filter cake dries to obtain 51.5g white solid, methylene chloride 750mL and water 500mL is added in solid, stirring is lower to adjust pH value to 10-11 with the sodium hydroxide solution of 2N.Liquid separation, water layer are extracted with methylene chloride (400mL*3).Merge organic phase, anhydrous sodium sulfate dries, filters, and revolving removes solvent and obtains light yellow solid Compound III 12.85g, optical purity: 99.2%, chemical purity: 99.5%, yield 36.6%, effective isomers yield 73.2%.
Embodiment 4
The first step
Compound III (75g, 292mmol) is dissolved in 2L ethyl alcohol, compound c (49.1g, 438mmol) and 10%Pd/C 7.5g is sequentially added, is warming up to 75 DEG C, blowing air is stirred to react 28 hours.After reaction, it is filtered to remove Pd/C, filter cake is eluted with methanol, and filtrate decompression is concentrated, and is dried in vacuo, is obtained compound d 54.1g, yield: 53%.
Second step
Compound d (54.1g, 0.155mol) is dissolved in 700mL methylene chloride.It is cooled to 0 DEG C, is added pyridine (61.3g, 0.775mol), then Tf is added dropwise 2O (56.8g, 0.201mol).It is warming up to room temperature, is stirred to react 1 hour.After reaction, 60mL water is added in reaction solution, with 1M salt acid for adjusting pH value to 2, stratification, organic phase is separated, water phase is extracted with dichloromethane, and merges organic phase, anhydrous magnesium sulfate is dry, filtering, filtrate decompression concentration, gained residue column chromatograph (eluant, eluent: DCM:MeOH=10:1), obtain compound e 41g, yield: 55%.
Embodiment 5
By compound e (41g, 85mmol) and compound f (40.5g, 170mmol, prepared according to method disclosed in CN105189461A) it is dissolved in 800mL 1, the in the mixed solvent of 4- dioxane and water (V:V=5:1), sequentially add sodium carbonate (27g, 255mmol) and Pd (dppf) Cl 2(6.2g, 8.5mmol) is warming up to reflux under argon gas protection, is stirred to react 3 hours.After reaction, reaction solution is cooled to room temperature, and 200mL water is added, 30min is stirred at room temperature, filtering, filter cake are eluted with water, collect filter cake, dispersed with 750mL methanol, be added concentrated hydrochloric acid (22mL), stirs 30min, concentration removes methanol, and 1.2L water is added, and stirs 30min, filtering, solid are eluted with water, merge water phase, (400mL × 2) are stripped with ethyl acetate, collect water phase, with saturation NaHCO 3To alkalinity solid is precipitated, the solid was filtered, washes, and vacuum drying obtains compound I 23.9g, yield 63.5%, optical purity: 99.7% in solution tune pH.
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are obvious for those skilled in this art and are included within the scope of the invention.

Claims (14)

  1. Compound shown in formula III,
  2. Compound shown in formula IV,
    Wherein, X is selected from-Cl ,-Br ,-I ,-F, trifluoro-methanesulfonyl oxy, mesyloxy, phenylsulfonyloxy, acetoxyl group or phosphate-based ,-SR ,-SO 2R, R C 1~C 6Alkyl；X preferably-Cl ,-Br ,-I, trifluoro-methanesulfonyl oxy, mesyloxy or phenylsulfonyloxy.
  3. Compound shown in Formula VII,
    Wherein, R 2Selected from hydroxyl protection base.
  4. Compound shown in formula d,
  5. A kind of preparation method of such as formula III compound represented, includes the steps that compound shown in chiral resolution Formula II,
  6. Preparation method according to claim 5, which is characterized in that the method for the chiral resolution is selected from chemical resolution, film fractionation, Chromatographic resolution, Capillary Electrophoresis fractionation and biological resolution, preferably chemical resolution and Chromatographic resolution.
  7. Preparation method according to claim 6, it is characterized in that, resolving agent used in the chemical resolution is selected from L-TARTARIC ACID, D- tartaric acid, L-DBTA, D-DBTA, L-DTTA or D-DTTA, R- camphorsulfonic acid, S- camphorsulfonic acid, D- mandelic acid, L- mandelic acid, Pidolidone, D-Glu, ASPARTIC ACID, D-ASP, it is preferred that L-DTTA, D-DTTA, Pidolidone, D-Glu, ASPARTIC ACID, D-ASP, more preferable D-DTTA.
  8. Preparation method according to claim 6, which is characterized in that the molar ratio of compound shown in resolving agent used in the chemical resolution and Formula II is 1:1~4:1.
  9. Preparation method according to claim 6, which is characterized in that the reaction dissolvent of the chemical resolution is selected from water, C 1~C 6Alcohols, acetone, methyl ethyl ketone, tetrahydrofuran, dioxanes, acetonitrile, n,N-Dimethylformamide, N, one of N- dimethyl sulfoxide or a variety of, preferably methanol or ethyl alcohol.
  10. The preparation method of a kind of compound shown in formula I or its pharmaceutically acceptable salt includes the steps that preparing such as formula III compound represented according to the method for claim 5 to 9 any one.
  11. Preparation method according to claim 10, which is characterized in that the method also includes the step of using compound shown in formula III as compound shown in reactant preparation formula IV,
    Wherein, X is selected from-Cl ,-Br ,-I ,-F, trifluoro-methanesulfonyl oxy, mesyloxy, phenylsulfonyloxy, acetoxyl group or phosphate-based ,-SR ,-SO 2R, R C 1~C 6Alkyl；X preferably-Cl ,-Br ,-I, trifluoro-methanesulfonyl oxy, mesyloxy or phenylsulfonyloxy.
  12. Preparation method according to claim 10, which is characterized in that the step of carrying out compound shown in coupling reaction preparation formula VI under the conditions of the method also includes by compound shown in compound shown in formula IV and Formula V existing for the catalyst,
    Wherein, X is selected from-Cl ,-Br ,-I ,-F, trifluoro-methanesulfonyl oxy, mesyloxy, phenylsulfonyloxy, acetoxyl group or phosphate-based ,-SR ,-SO 2R, R C 1~C 6Alkyl；X preferably-Cl ,-Br ,-I, trifluoro-methanesulfonyl oxy, mesyloxy or phenylsulfonyloxy；
    Y is selected from-BF 3K、-BR aR b、-Sn(R c) mOr-Zn-X '；
    R aAnd R bIndependently selected from-OH, alkyl, alkoxy or the arbitrarily C that replaces 1~C 6Unitary and dihydric alcohol or R aAnd R bIt is together cyclic, R cIndependently selected from C 1~C 6Alkyl, X ' are selected from-Cl ,-Br ,-I；
    The integer that m is 0,1,2,3 or 4；
    R 1Selected from hydrogen or hydroxyl protection base；
    The Y preferably is selected from BF 3K and BR aR b, wherein the BR aR bMiddle R aAnd R bPreferably independently it is selected from-OH, alkyl, alkoxy or BR aR bFor pinacol borate.
  13. Preparation method according to claim 12, which is characterized in that the catalyst is selected from PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2Or NiCl 2(bipy),
    Wherein L is containing Phosphine ligands or N- heterocyclic carbene ligand, and the Phosphine ligands that contain are selected from PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3, dppe or dppb, p it is independent be selected from 0,1,2,3 or 4 integer,
    Preferred Pd (the PPh of the catalyst 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2, palladium carbon, Pd (OAc) 2、PCy 3/Pd 2(dba) 3, more preferable Pd (PPh 3) 2Cl 2。
  14. Preparation method according to claim 12, which is characterized in that the reaction is reacted in the presence of a basic, wherein the preferred Li of alkaline matter 2CO 3、Na 2CO 3、Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4One of NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR or a variety of, wherein R is independently selected from C 1~C 6Alkyl, the more preferable Na of alkaline matter 2CO 3Or K 2CO 3One of or it is a variety of.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142237A1 (en) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors
CN105189461A (en) * 2013-03-14 2015-12-23 葛兰素史克知识产权第二有限公司 2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142237A1 (en) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors
CN105189461A (en) * 2013-03-14 2015-12-23 葛兰素史克知识产权第二有限公司 2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors
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

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
伍平华: "盐酸达泊西汀的合成", 《中国现代应用药学》 *
何仁: "《金属有机化学》", 30 September 2007, 华东理工大学出版社 *
夏百根、黄乾明主编: "《有机化学》", 30 June 2002, 中国农业出版社 *
赵娟: "罗通定的合成工艺改进", 《中国药物化学杂志》 *
郭宏垚: "γ-分泌酶抑制剂（LY411575）的合成工艺研究", 《高等学校化学学报》 *
黄俊: "盐酸维那卡兰的合成", 《中国医药工业杂志》 *

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