CN106928117A - A kind of preparation method of deuterated aromatics organic compound - Google Patents

A kind of preparation method of deuterated aromatics organic compound Download PDF

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CN106928117A
CN106928117A CN201710093515.4A CN201710093515A CN106928117A CN 106928117 A CN106928117 A CN 106928117A CN 201710093515 A CN201710093515 A CN 201710093515A CN 106928117 A CN106928117 A CN 106928117A
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alkyl
substitution
aryl
deuterated
group
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CN106928117B (en
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刘文博
王欣
钟大猷
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Wuhan University WHU
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Wuhan University WHU
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Abstract

The invention provides a kind of preparation method of deuterated aromatic compound.First be dissolved in the mixed solvent of deuterated solvent or deuterated solvent with Conventional solvents together for halogenated aromatic compound and alkali metal salt MA by the present invention, then organosilicon reagent is added dropwise, the stirring reaction at -40 DEG C to 150 DEG C, separating-purifying after reaction obtains deuterated aromatic compound；The method does not need the participation of transition metal or metal tin reagent, can efficiently, it is economical, green prepare deuterated aromatic compound, deuterated rate is more than 95% in prepared deuterated product.The method mild condition, substrate universality is good, and yield is high, and prepared deuterated compound is widely used in pharmaceutical chemistry and organic chemistry filed.

Description

A kind of preparation method of deuterated aromatics organic compound
Technical field
The present invention relates to a kind of preparation method of deuterated aromatics organic compound, belong to organic synthesis field.
Background technology
Deuterated compound due to its mass spectrum (MS), nuclear magnetic resoance spectrum (2H NMR) and electron spin resonance spectroscopy (ESR) in Show uniqueness signal, and be widely used in reaction intermediate mark, biological metabolism analysis, natural products source of students synthesis test Aspect [a) Pieniaszek, H.J. such as card, residue of pesticide detection and pollution sources tracking；Mayersohn,M.；Adams,M.P.； Reinhart,R.J.；Barrett,J.S.J.Clin.Pharmacol.1999,39,817.b)Yen,K.C.；Stone,J.A.； Carides,A.D.；Rolan,P.；Woolf,E.；Ju,W.D.J.Pharm.Sci.1999,88,568.c)Gani,D.； Young,D.W.J.Chem.Soc.,Chem.Commun.1983,576.d)Gani,D.；Hitchcock,P.B.；Young, D.W.J.Chem.Soc.,Chem.Commun.1983,898.].Especially in imitation medicine research and development, all of imitated medicine is all Need to do Conformance Assessment with deuterated compound.Further, since the difference of C-D keys and C-H key bond energys, is frequently utilized for research Kinetic isotope effect (KIE) in organic reaction, for the prediction of reaction mechanism provides information.[Wiberg, K.B.Chem.Rev.1955,55,713.] otherness of this bond energy is also employed among pharmaceutical chemistry, and scientist is had found medicine After specific hydrogen is substituted for deuterium in thing molecule, it is possible to delay drug metabolism and extend half-life period.Recently, deuterated medicine (heavy Drugs the focus of research) is increasingly becoming, deutetrabenazine (SD-809) was have approved if FDA such as 2015 in treatment Application in terms of tardive dyskinesia.Additionally, deuterated venlafaxine and other several deuterated medicines also into Clinical research.[a)Elison,C.；Rapoport,H.；Laursen,R.；Elliott,H.W.Science 1961,134, 1078.b)Shao,L.；Abolin,C.；Hewitt,M.C.；Koch,P.；Varney, M.Bioorg.Med.Chem.Lett.2006,16,691.c)Sharma,R.；Strelevitz,T.J.；Gao,H.；Clark, A.J.；Schildknegt,K.；Obach,R.S.；Ripp,S.L.；Spracklin,D.K.；Tremaine,L.M.；Vaz, A.D.N.Drug Metabolism and Disposition 2012,40,625.d)Gant,T.G.J.Med.Chem.2014, 57,3595.e)Gant,T.G.；Sarshar,S.Methods of Reduction of Interpatient Variability.US 2010/0076087 A1,2010.f)Thomas,G.G.；Sarshar,S.；Hyung,S.W.WO 2008/140859A1,2008.g)Braman,V.；Graham,P.；Cheng,C.；Turnquist,D.；Harnett,M.； Sabounjian,L.；Shipley,J.Clin.Pharmacol.Drug Dev.2013,2,53.h)Schneider,F.； Hillgenberg,M.；Koytchev,R.；Alken,R.-G.Arzneim.Forsch.Drug.Res.2006,56,295.]
At present, the method for synthesizing deuterated aromatic compound mainly has following three kinds：A) metal-halogen is exchanged/is quenched；B) mistake Cross metal Pd, Ni etc. and participate in dehalogenation；C) free radical dehalogenation hydrogenolysis [a) Alonso, F.；Beletskaya,I.P.；Yus, M.Chem.Rev.2002,102,4009.b)Wiberg,K.B.Chem.Rev.1955,55,713.c)Pinder, A.R.Synthesis,1980,425.d)Koketsu,K.；Oguri,H.；Watanabe,K.；Oikawa, H.Org.Lett.2006,8,4719.e)Kim,S.-U.；Song,K.-S.；Jung,D.-S.；Chae,Y.-A.；Lee, H.J.Planta Med.1996,62,54.f)Maruyama,K.；Furuta,H.；Otsuki,T.Chem.Lett.1981, 1025.g)Tashiro,M.；Iwasaki,A.；Fukata,G.J.Org.Chem.1978,43,196.h)Mutsumi,T.； Iwata,H.；Maruhashi,K.；Monguchi,Y.；Sajiki,H.Tetrahedron.2011,67,1158.i) Mutsumi,T.；Maruhashi,K.；Monguchi,Y.；Sajiki,H.Synlett.2008,2811.j)Miura,Y.； Oka,H.；Yamano,E.；Morita,M.J.Org.Chem.1997,62,1188.].Although these known methods can be always The extensive halogenated aromatic compound in source sets out and is effectively synthesized corresponding deuterated aromatic compound, but all exist it is clearly disadvantageous, Such as generally require and use transition metal (Pd, Ni, Rh etc.), deuterated solvent (the such as THF- of poisonous tin hydrogen reagent or costliness d5, 10g/ $ 375, Aldrich or other deuterated reagents that need to separately prepare such as Bu3SnD、NaBD4Deng), severe reaction conditions (ratio As used inflammable metal reagent at -78 DEG C), and high selectivity, deuterated rate high synthesising target compound still have it is larger Challenge, especially the reaction of transition metal-catalyzed class is to the compatible poor of the unsaturated functional groups such as double bond.In order to solve with Upper problem, this seminar carries out dehalogenation reaction and prepares deuterated fragrance with silane, alkali metal salt as medium, with deuterated solvent as deuterium source Class compound.The reaction can not only efficiently synthesize target product, and substrate applicability is strong, and using the method to lead drug Molecule carries out later stage modification and can quickly prepare its deuterated analogs.Additionally, cheap (the potassium methoxide of raw material that the method is used 50g/$167, Alfa；Deuterated solvent such as CD3CN, 10g/ $ 140, Aldrich), and whole process do not need transition metal or The participation of metal tin reagent, effectively saved cost, it is to avoid the heavy metal in environmental pollution and product is remaining, in medicine point The later stage modification aspect of son has larger advantage.
The content of the invention
In order to solve problems of the prior art, the present invention provides one kind and effectively prepares deuterated aromatics organic compound The method of thing, the method does not need the participation of transition metal or metal tin reagent.
The technical scheme that the present invention is provided is specific as follows：
A kind of preparation method of deuterated aromatic compound, comprises the following steps：By halogenated aromatic compound D, alkali metal salt MA and organosilicon reagent C in stirring reaction, separating-purifying after reaction at -40 DEG C to 150 DEG C, that is, obtains deuterated virtue in solvent B Aroma compounds.
Described halogenated aromatic compound D is halo aromatic compound or halo heteroaromatic ring compounds；
In described alkali metal salt MA, M=Na+、K+、Rb+Or Cs+, A is selected from the one kind in following anion：[OR1]-–、 [SR1]–、[NR1 2]–、[SiR1 3]–、[OSiR1 3]–、[SSiR1 3]–、[N(SiR1)2]–, wherein, R1It is hydrogen, C1-12Alkyl or contain Heteroatomic alkyl, C6-30Alkyl-substituted aryl or containing the one kind in heteroatomic alkyl-substituted aryl；
Described solvent B is the mixed solvent of deuterated reagent or deuterated reagent and conventional reagent；Described deuterated reagent is D2O、CD3OD、CD3COCD3、CD3Cl、CD2Cl2、C6D6、C6D5CD3、CD3SOCD3、DCON(CD3)2、CD3One kind or several in CN The mixing planted；Described conventional reagent is methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofurans, second Ether, dimethyl second diether, methyl tertiary butyl ether(MTBE), the alkane of 1,4- epoxies six, the alkane of 1,3- epoxies six, dichloromethane, 1,2- dichloroethanes, Chloroform, carbon tetrachloride, C4-12Saturated alkane, C3-12Fluoro or chloralkane, benzene,toluene,xylene, trimethylbenzene, diformazan Sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetone, 1-METHYLPYRROLIDONE, acetonitrile, C3-12Saturation alkane One or more in base nitrile；
Described organosilicon reagent C, with the structure shown in formula (I), formula (II) or formula (III)：
Wherein m is 0,1,2 or 3；X is 2 to 100 integer；Wherein, R is identical or different group, is selected from：
I) C of base is replaced containing R '1-12Alkyl, its carbon chain backbone can be inserted into one or more-O- ,-S- and/or-NR2 2-, R2It is hydrogen or short-chain alkyl；
Ii the C of base) is replaced containing R '6-30Alkyl-substituted aryl, its carbon chain backbone can be inserted into one or more-O- ,-S- And/or-NR22-, R2It is hydrogen or short-chain alkyl；
Iii the C of base) is replaced containing R '6-30Aryl substitution alkyl, its carbon chain backbone can be inserted into one or more-O- ,- S- and/or-NR22-, R2It is hydrogen or short-chain alkyl；
Iv-the O-C of base) is replaced containing R '1-12Alkyl or-S-C1-12Alkyl, its carbon chain backbone can be inserted into one or more- O- ,-S- and/or-NR22-, R2It is hydrogen or short-chain alkyl；
V)-the O-C of base is replaced containing R '5-20Or-S-C5-20Aryl or fragrant heterocyclic radical；
Vi-the O-C of base) is replaced containing R '6-30Alkyl or-S-C6-30Alkyl-substituted aryl or fragrant heterocyclic radical, its carbochain bone Frame can be inserted into one or more-O- ,-S- and/or-NR2 2-, R2It is hydrogen or short-chain alkyl；
Or vii)-the O-C containing R ' substitution bases6-30Or-S-C6-30Aryl substitution alkyl or aryl substitution containing heteroatomic Alkyl；Wherein, R ' is selected from the one kind in following group：Hydrogen, phosphate, phosphite ester, alkylphosphines, aryl phosphine, C1-20Alkyl Thioether, mercaptan, sulfoxide, sulfone, ammonia, acid amides, imines, enamine, nitro, nitroso, ether, alcohol, epoxy, aldehyde, ketone, ester, silane, silicon Ether, borine, boric acid, borate, halogen, the substitution base containing metallic tin or germanium, C5-20Aryl thioethers, mercaptan, sulfoxide, sulfone, Ammonia, acid amides, imines, enamine, nitro, nitroso, ether, alcohol, epoxy, aldehyde, ketone, ester, carbonate group, silane, silicon ether, borine, boron Acid, borate, halogen, the substitution base containing metallic tin or germanium.
Preferably：
Described solvent B is CD3SOCD3、DCON(CD3)2、CD3One or more mixtures in CN；Described conventional examination Agent be tetrahydrofuran, dichloromethane, 2- methyltetrahydrofurans, dimethyl second diether, methyl tertiary butyl ether(MTBE), toluene in one kind or Several mixture of person.
Described organosilicon reagent C is Me3SiSiMe3Or Et3SiSiEt3；Described alkali metal salt MA be KOMe or KOEt；Described solvent B is CD3CN or CD3The mixture of CN and tetrahydrofuran.
Described R1It is C1-4Alkyl or C6-10Aryl.
Described R group is the C for replacing base containing R '1-4Alkyl or the C containing R ' substitution bases6-10Aryl.
Deuterated aromatic compound prepared by the present invention is to be with halo aromatic compound or halo heteroaromatic ring compounds Raw material, in the mixed solvent (solvents) of deuterated reagent or deuterated reagent and other solvents, be with silane (silane) Medium, reacts in the presence of alkali metal salt (MA) and is obtained, and can be represented with following equation：
Or
WhereinIt refer to halo aromatic compound.Described halo aromatic compound is F, Br or I substitution Benzene, naphthalene or anthracene, wherein b are 1 to 6 arbitrary integers, and a is 0 to 5 integer.Any one X is independent, optionally from halogen Atom bromine or iodine.Any one R3Substitution base is also independent, can be selected from following arbitrary structures：Halogen；Hydroxyl；Sulfydryl； Alkoxy；Phenol epoxide；Alkylthio group；Phenol sulfenyl；Alkyl-substituted acyl group；The acyl group of aryl substitution；The acyl group of alkoxy substitution；Phenol The acyl group of epoxide substitution；Alkyl-substituted thiocarbonyl [- C (S) -]；The thiocarbonyl [- C (S) -] of aryl substitution；Alkoxy takes The thiocarbonyl [- C (S) -] in generation；The thiocarbonyl [- C (S) -] of phenol epoxide substitution；Alkyl or the amide groups of aryl substitution；Alkane Base or the ester group of aryl substitution；Alkyl or the thioester substrate of aryl substitution；Alkyl or the carbonate group of aryl substitution；Alkyl Or the thiocarbonic acid ester group of aryl substitution；Cyano group；Isocyano group；Nitro；Nitroso；Alkyl or the azo of aryl substitution；Weight Nitrogen；Nitrine；Alkyl or the amine of aryl substitution；Alkyl or the imines of aryl substitution；Alkyl or the enamine of aryl substitution；Alkane Base or the phosphine of aryl substitution；Alkyl or the phosphite ester of aryl substitution；Alkyl or the phosphoramidite of aryl substitution；Alkyl Or the phosphate of aryl substitution；Alkyl or the phosphamide of aryl substitution；Borine；Alkyl or the borine of aryl substitution；Boron Acid；Borate [- B (OR4)2, wherein R4It is alkyl or carbonyl]；Borate；Silane；Alkyl-substituted silane；Alkoxy replaces Silane；The silane of phenol epoxide substitution；The silane of halogen substitution；Or substitution chain or ring-type alkane, containing fluothane Hydrocarbon, alkene, aromatic hydrocarbons, heteroaromatic construction unit；Or the C of oxygen-containing, nitrogen, sulphur, phosphine3-C12Heterocycle.
WhereinRefer to halo heteroaromatic ring compounds, described halo heteroaromatic ring compounds are F, Br or I Substituted furans, benzofuran, pyrroles, indoles, thiophene, benzothiophene, imidazoles, pyrazoles, oxazole, isoxazoles, thiazole, different thiophene Azoles, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinolin, carbazole or indolizine compound.The virtue of described halogen atom substitution Fragrant heterocycle compound is optionally from following structure：
Wherein：Q optionally from 0 to 5 integer, r optionally from 0 to 6 integer, s optionally from 0 to 8 integer, n optionally from 1 to Arbitrary integer between 8.Wherein each X is independent, and optionally from halogen atom bromine or iodine, its position of substitution is place The optional position in addition to hetero atom on aromatic rings.Wherein Y is optionally from O, S or N (R ")；Wherein R " is nitrogen-protecting group, is appointed Meaning is selected from acetyl group (Ac), benzoyl (Bz), benzyl (Bn), methoxvethoxvmethvl (MEM), dimethoxytrityl Free radical (DMT), methoxyl methyl (MOM), to Methoxytrityl (MMT), to methoxy-benzyl (PMB), pivaloyl Base (Piv), THP trtrahydropyranyl (THP), tetrahydrofuran base (THF), trityl (triphenylmethyl, Tr), silicon ether [bag Include most widely used trimethylsilyl ethers (TMS), t-Butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) etc.], uncle Butoxy carbonyl (Boc), benzyloxycarbonyl group (Cbz), to methoxybenzyl carbonyl (p-methoxylbenzyl carbonyl, Moz), tablet held before the breast by officials It is methoxycarbonyl group (Fmoc), 3,4- dimethoxy-benzyls (3,4-dimethoxybenzyl, DMPM), p-methoxyphenyl (PMP), right Tosyl (Ts), p-nitrophenyl sulfonyl (sulfonamide, Nosyl) or substitution sulfonyl, substitution silicon substrate, Substituted carbonyl, the ester group of substitution, or any C selected from substitution1-12Alkyl, containing fluoroalkyl, aryl, fragrant heterocyclic radical Group.Wherein any one R5All it is independent, optionally from following group：Halogen；Hydroxyl；Sulfydryl；Alkoxy；Phenol epoxide；Alkyl Substituted acyl group；The acyl group of aryl substitution；The acyl group of alkoxy substitution；The acyl group of phenol epoxide substitution；Alkyl-substituted thio carbonyl Base [- C (S) -]；The thiocarbonyl [- C (S) -] of aryl substitution；The thiocarbonyl [- C (S) -] of alkoxy substitution；Phenol epoxide replaces Thiocarbonyl [- C (S) -]；Alkyl or the amide groups of aryl substitution；Alkyl or the ester group of aryl substitution；Alkyl or virtue The thioester substrate of base substitution；Alkyl or the carbonate group of aryl substitution；Alkyl or the thiocarbonic acid ester group of aryl substitution；Cyanogen Base；Isocyano group；Nitro；Nitroso；Alkyl or the azo of aryl substitution；Diazonium；Nitrine；Alkyl or the amine of aryl substitution； Alkyl or the imines of aryl substitution；Alkyl or the enamine of aryl substitution；Alkyl or the phosphine of aryl substitution；Alkyl or virtue The phosphite ester of base substitution；Alkyl or the phosphoramidite of aryl substitution；Alkyl or the phosphate of aryl substitution；Alkyl or The phosphamide of aryl substitution；Borine；Alkyl or the borine of aryl substitution；Boric acid；Borate [- B (OR4)2, wherein R4It is alkyl Or carbonyl]；Borate；Silane；Alkyl-substituted silane；The silane of alkoxy substitution；The silane of phenol epoxide substitution；Halogen takes The silane in generation；Or the chain or alkane, fluorine-containing alkane, alkene, aromatic hydrocarbons, the aromatic heterocycle construction unit of ring-type of substitution； Or the heterocycle of the C3-C12 of oxygen-containing, nitrogen, sulphur, phosphine.
WhenOrWhen the X group that intramolecular contains is same element, by dehalogenation After reaction, these elements are all replaced by deuterium element；When the X group that its intramolecular contains is different halogens, the work of dehalogenation reaction Property order be I>Br, can regulate and control selective deuterated by controlling the use equivalent of alkali metal salt and organo-silicon compound Reaction.In described alkali metal salt MA, M=Na+、K+、Rb+Or Cs+, A is selected from the one kind in following anion：[OR1]–、 [SR1]-–、[NR1 2]–、[SiR1 3]–、[OSiR1 3]–、[SSiR1 3]–、[N(SiR1)2]–, wherein, R1It is hydrogen, C1-12Alkyl or contain Heteroatomic alkyl, C6-30Alkyl-substituted aryl or containing the one kind in heteroatomic alkyl-substituted aryl, prioritizing selection C1-4Alkyl or C6-10Aryl.
In raw material dosage, halogenated aromatic compound, alkali metal salt MA, the mol ratio of organosilicon reagent are 1：1：1 to 1： 5：5, preferably 1：2：2；Mol ratio >=1 of the deuterated reagent and halogenated aromatic compound:1, preferably 5:1.
The invention provides a kind of effectively with silane, alkali metal salt as medium, deuterated solvent replaces for the halogen in deuterium source Aromatics organic compound method that deuterated aromatic compounds are prepared by dehalogenation reaction；It is various containing difference there is provided preparing The method of the deuterated compound of aromatic ring structure；Additionally providing carries out later stage modification to lead drug molecule and then quickly synthesizes it The method of deuterated analogs.This method is applicable to the aromatics of the halogen substitution of various different substituents of structure containing different kinds of aromatic ring Compound, reaction condition is gentle, easy to operate, need not add any additive in reaction in addition to alkali.And reaction yield also compared with Good (generally 56%-98%), deuterated conversion ratio is higher (general>95%).In addition, this method do not need transition metal or The participation of metal tin reagent, the heavy metal that effectively prevent in environmental pollution and product is remaining.
This method is related to the aromatic compounds that halogen replaces in siliceous organic compound, alkali metal salt and at least one By dehalogenation reaction system under conditions of the organic reagent of kind deuterium element substitution or the mixture of the reagent and other Conventional solvents Standby deuterated aromatics organic compound.This method does not need the participation of transition metal or metal tin reagent, can efficiently, pass through Ji, green prepare deuterated aromatic compounds, in prepared deuterated product deuterated rate be more than 95%.
The method of the present invention is that a kind of effective, green, cheap aromatic compounds replaced by halogen prepare deuterated virtue The method of fragrant class compound.
The method of the present invention is a kind of by dehalogenation reaction, with the side of halogen atom in deuterium substituted aroma class organic compound Method.The deuterated rate of product is more than 95%.
The present invention has advantages below and beneficial effect：
1. the present invention does not need the participation of transition metal or metal tin reagent, can efficiently, economy, greenly prepare deuterium For aromatic compound, deuterated rate is more than 95% in prepared deuterated product.
2. raw material of the present invention is cheap and easy to get, the cost of the deuterated aromatic compound of industrial production is effectively reduced, with good Application prospect.
Specific embodiment
Will be helpful to understand the present invention by following embodiments, but be not intended to limit present disclosure.
Embodiment 1：It is the alkali metal salt of standard substrate dehalogenation reaction and grinding for deuterated solvent with the bromo- N- methyl indols of 5- Study carefully：
Wherein, MA represents alkali metal salt, [CH3(H)SiO]nPolymethyl hydrogen siloxane is represented, equiv refers to equivalent, deuterium The mixture of deuterated reagent or deuterated reagent and Conventional solvents is represented for solvent, volume is 1mL.Wherein, CD3CN is deuterated second Nitrile, THF is tetrahydrofuran, Et2O is ether, and DME is dimethyl second diether, and MTBE is methyl tertiary butyl ether(MTBE), DMSO-d6It is deuterated Dimethyl sulfoxide.When using mixed solvent, mol ratio >=1 of deuterated reagent and raw material:1, most preferably 5:1.
Embodiment 2:The preparation of 5- deuterium-N- methyl indols and its gram order reaction
The bromo- N- methyl indols (0.5mmol) of 105mg 5- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL In, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL Water quenching is gone out, and with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is stone Oily ether：Ethyl acetate=20：1 (v/v), obtains 5- deuterium-N- methyl indols 57mg (weak yellow liquid, yield 87%).1H NMR (400MHz, CDCl3) δ=7.72 (s, 1H), 7.43-7.36 (m, 1H), 7.32 (s, 1H), 7.14-7.08 (m, 1H), 6.57 (d, J=2.9Hz, 1H), 3.83 (s, 3H).GC-MS(EI+):132.1.
By the bromo- N- methyl indols (10mmol) of 2.1g 5- and 1.403g potassium methoxides (20mmol) be dissolved in the deuterated acetonitriles of 5mL and In the mixed solution of 15mL tetrahydrofurans, to 4mL hexamethyldisilanes (20mmol), at room temperature stirring reaction are added dropwise in mixture 6h.After reaction completely, plus 100mL water quenchings are gone out, and with 3 extractions of 300mL ether point, collect organic phase, removal of solvent under reduced pressure.Post layer Analysis separating-purifying, eluant, eluent is petroleum ether：Ethyl acetate=20：1 (v/v), obtains 5- deuterium-N- methyl indols 1.08mg (yellowish Color liquid, yield 83%).
Embodiment 3:The preparation of 5- deuteriums-N- methyl indols under mixed solvent
The bromo- N- methyl indols (0.5mmol) of 105mg 5- and 70.15mg potassium methoxides (1mmol) are dissolved in the 130 deuterated second of μ L In the mixed liquor of nitrile (2.5mmol) and 870 μ L tetrahydrofurans, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, Stirring reaction 3h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, decompression Remove solvent.Column chromatography for separation is purified, and eluant, eluent is petroleum ether：Ethyl acetate=20：1 (v/v), obtains 5- deuterium-N- methyl Yin Diindyl 48mg (weak yellow liquid, yield 73%).1H NMR (400MHz, CDCl3) δ=7.72 (s, 1H), 7.43-7.36 (m, 1H), 7.32 (s, 1H), 7.14-7.08 (m, 1H), 6.57 (d, J=2.9Hz, 1H), 3.83 (s, 3H).GC-MS(EI+): 132.1。
Embodiment 4：The synthesis of 4- deuterium-N- methyl indols
The bromo- N- methyl indols (0.5mmol) of 105mg 4- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL In, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL Water quenching is gone out, and with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is stone Oily ether：Ethyl acetate=20：1 (v/v), obtains 4- deuterium-N- methyl indols 57mg (weak yellow liquid, yield 87%).1H NMR (400MHz, CDCl3) δ=7.40 (dd, J=8.2,1.2Hz, 1H), 7.36-7.28 (m, 1H), 7.23-7.17 (m, 1H), 7.13-7.08 (m, 1H), 6.58 (d, J=2.8Hz, 1H), 3.83 (d, J=0.8Hz, 3H).GC-MS(EI+):132.1.
Embodiment 5:The synthesis of 7- deuterium-N- methyl indols
The bromo- N- methyl indols (0.5mmol) of 105mg 7- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL In, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL Water quenching is gone out, and with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is stone Oily ether：Ethyl acetate=20：1 (v/v), obtains 7- deuterium-N- methyl indols 57mg (weak yellow liquid, yield 87%).1H NMR (400MHz, CDCl3) δ=7.70 (dd, J=7.9,1.1Hz, 1H), 7.33-7.24 (m, 1H), 7.22-7.14 (m, 1H), 7.11 (d, J=3.1Hz, 1H), 6.55 (d, J=3.1Hz, 1H), 3.84 (s, 3H).GC-MS(EI+):132.1.
Embodiment 6:The synthesis of 5- deuterium benzothiophenes
106.5mg 5- bromobenzothiophenes (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL In, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL Water quenching is gone out, and with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is stone Oily ether：Ethyl acetate=20：1 (v/v), obtains 5- deuterium benzothiophenes 53mg (weak yellow liquid, yield 78%).1H NMR (400MHz, CDCl3) δ=8.02-7.91 (m, 1H), 7.88 (s, 1H), 7.55-7.23 (m, 3H).GC-MS(EI+):135.0.
Embodiment 7:The synthesis of 5- deuterium-N- benzylindoles
The bromo- N- benzylindoles (0.5mmol) of 143mg 5- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL In, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 4h at room temperature.After reaction completely, plus 10mL Water quenching is gone out, and with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is stone Oily ether：Ethyl acetate=10：1 (v/v), obtains 5- deuterium-N- benzylindoles 91mg (weak yellow liquid, yield 87%).1H NMR (400MHz, CDCl3) δ=7.71 (s, 1H), 7.32 (ddd, J=10.6,6.4,3.1Hz, 4H), 7.22 (d, J=6.1Hz, 1H), 7.19-7.10 (m, 3H), 6.61 (d, J=2.1Hz, 1H), 5.36 (s, 2H).GC-MS(EI+):208.1.
Embodiment 8:The synthesis of 5- deuterium-N-Mom indoles
The bromo- N-Mom indoles (0.5mmol) of 120mg 5- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL In, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 4h at room temperature.After reaction completely, plus 10mL Water quenching is gone out, and with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is stone Oily ether：Ethyl acetate=10：1 (v/v), obtains 5- deuterium-N-Mom indoles 56mg (weak yellow liquid, yield 69%).1H NMR (400MHz, CDCl3) δ=7.70 (s, 1H), 7.55 (dd, J=8.3,0.4Hz, 1H), 7.36-7.27 (m, 1H), 7.23 (d, J =3.2Hz, 1H), 6.61 (d, J=3.2Hz, 1H), 5.50 (s, 2H), 3.29 (s, 3H).GC-MS(EI+):162.1.
Embodiment 9:The synthesis of 1- deuterium -2- methoxynaphthalenes
The bromo- 2- methoxynaphthalenes (0.5mmol) of 118.6mg 1- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated second of 1mL In nitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 5h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 1- deuterium -2- methoxynaphthalenes 71mg (weak yellow liquid, yield 89%).1H NMR (400MHz, CDCl3) δ=7.96-7.69 (m, 3H), 7.56-7.43 (m, 1H), 7.42-7.33 (m, 1H), 7.18 (d, J =8.8Hz, 1H), 3.96 (s, 3H).GC-MS(EI+):159.1.
Embodiment 10:The synthesis of 2- deuterium -6- methoxynaphthalenes
The bromo- 6- methoxynaphthalenes (0.5mmol) of 118.6mg 2- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated second of 1mL In nitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 5h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 2- deuterium -6- methoxynaphthalenes 61mg (weak yellow liquid, yield 76%).1H NMR (400MHz, CDCl3) δ=7.87-7.72 (m, 3H), 7.47 (d, J=8.2Hz, 1H), 7.18 (d, J=6.6Hz, 2H), 3.96(s,3H)。GC-MS(EI+):159.1。
Embodiment 11:The synthesis of 4- deuterium -3- Nitroanisoles
The iodo- 3- Nitroanisoles (0.5mmol) of 139.5mg 4- and 70.15mg potassium methoxides (1mmol) are dissolved in 1mL deuterated In acetonitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 4- deuterium -3- Nitroanisoles 65mg (yellow liquid, yield 84%).1H NMR (400MHz, CDCl3) δ=7.84-7.64 (m, 1H), 7.44-7.35 (m, 1H), 7.26-7.15 (m, 1H), 3.86 (s, 3H)。GC-MS(EI+):154.1。
Embodiment 12:The synthesis of 1- deuterium -4- benzyloxy benzene
The bromo- 4- benzyloxies benzene (0.5mmol) of 131.5mg 1- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated second of 1mL In nitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 1- deuteriums -4- benzyloxy benzene 91mg (yellow liquid, yield 98%).1H NMR (400MHz, CDCl3) δ=7.53-7.48 (m, 2H), 7.48-7.41 (m, 2H), 7.37 (dd, J=14.6,7.8Hz, 3H),7.08–7.02(m,2H),5.12(s,2H)。GC-MS(EI+):185.1。
Embodiment 13:The synthesis of 3- deuterium quinoline
104mg 3- bromoquinolines (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL, to mixed 200 μ L hexamethyldisilanes (1mmol) are added dropwise in compound, at room temperature stirring reaction 3h.After reaction completely, plus 10mL water quenchings are gone out, With 3 extractions of 30mL ether point, organic phase, removal of solvent under reduced pressure are collected.Column chromatography for separation is purified, and eluant, eluent is petroleum ether：Second Acetoacetic ester=10：1 (v/v), obtains 3- deuterium quinoline 38mg (yellow liquid, yield 58%).1H NMR (400MHz, CDCl3) δ= 8.91 (d, J=1.1Hz, 1H), 8.32 (s, 1H), 8.14-8.05 (m, 1H), 7.74 (dd, J=7.8,1.0Hz, 2H), 7.59 (dd, J=8.0,1.1Hz, 1H).GC-MS(EI+):130.1.
Embodiment 14:The synthesis of 5- deuterium quinoline
104mg 5- bromoquinolines (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL, to mixed 200 μ L hexamethyldisilanes (1mmol) are added dropwise in compound, at room temperature stirring reaction 3h.After reaction completely, plus 10mL water quenchings are gone out, With 3 extractions of 30mL ether point, organic phase, removal of solvent under reduced pressure are collected.Column chromatography for separation is purified, and eluant, eluent is petroleum ether：Second Acetoacetic ester=10：1 (v/v), obtains 5- deuterium quinoline 57mg (yellow liquid, yield 87%).1H NMR(400MHz,CDCl3) δ= 8.91 (dd, J=4.1,1.5Hz, 1H), 8.13 (dd, J=11.8,8.5Hz, 2H), 7.71 (dd, J=8.4,7.0Hz, 1H), 7.54 (d, J=6.8Hz, 1H), 7.43-7.33 (m, 1H).GC-MS(EI+):130.1.
Embodiment 15:The synthesis of 4- (4- deuteriums phenyl) morpholine
121mg 4- (4- bromophenyls) morpholine (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated second of 1mL In nitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 4h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=20：1 (v/v), obtains 4- (4- deuteriums phenyl) morpholine 71mg (white solid, yield 87%).1H NMR(400MHz,CDCl3) δ=7.23 (d, J=8.1Hz, 2H), 6.94 (dd, J=27.6,12.4Hz, 2H), 3.82 (s, 4H),3.11(s,4H)。GC-MS(EI+):164.1。
Embodiment 16:The synthesis of 2- deuterium -9,9- dimethyl fluorenes
The bromo- 9,9- dimethyl fluorenes (0.5mmol) of 136.5mg 2- and 70.15mg potassium methoxides (1mmol) are dissolved in 1mL deuterated In acetonitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 12h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 2- deuterium -9,9- dimethyl fluorenes 81mg (white solid, yield 83%).1H NMR(400MHz,CDCl3) δ 7.78 (d, J=7.5Hz, 2H), 7.48 (d, J=3.2Hz, 2H), 7.43-7.32 (m, 6H), 1.54(s,6H)。GC-MS(EI+):195.1。
Embodiment 17:The synthesis of the deuterium -9- methyl carbazoles of 3,6- bis-
The bromo- 9- methyl carbazoles (0.5mmol) of 169.5mg 3,6- bis- and 70.15mg potassium methoxides (1mmol) are dissolved in 1mL deuteriums In for acetonitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 12h at room temperature.After reaction completely, Plus 10mL water quenchings are gone out, with 3 extractions of 30mL ether point, organic phase, removal of solvent under reduced pressure are collected.Column chromatography for separation is purified, wash-out Agent is petroleum ether：Ethyl acetate=5：1 (v/v), obtains deuterium -9- methyl carbazoles 70mg (white solid, yield 77%) of 3,6- bis- 。1H NMR(400MHz,CDCl3) δ 8.11=(s, 2H), 7.49 (d, J=8.2Hz, 2H), 7.41 (d, J=8.2Hz, 2H), 3.87(s,3H)。GC-MS(EI+):183.1。
Embodiment 18:The synthesis of 6- deuterium -1,2,3,4- tetrahydrochysene -9- methyl carbazoles
The bromo- 1,2,3,4- tetrahydrochysenes -9- methyl carbazoles (0.5mmol) of 132mg 6- and 70.15mg potassium methoxides (1mmol) is molten In the deuterated acetonitriles of 1mL, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 12h at room temperature.Reaction After completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is carried Pure, eluant, eluent is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 6- deuterium -1, and 2,3,4- tetrahydrochysene -9- methyl carbazoles 57mg are (light Yellow liquid, yield 61%).1H NMR(400MHz,CDCl3) δ=7.53 (s, 1H), 7.33-7.28 (m, 1H), 7.24-7.16 (m, 1H), 3.65 (d, J=1.4Hz, 3H), 2.77 (ddt, J=7.7,6.4,3.8Hz, 4H), 2.07-1.82 (m, 4H).GC- MS(EI+):186.1。
Embodiment 19:2- (N- methyl-N-benzyls) amino -3- deuterium pyridines
By 162mg 2- (N- methyl-N-benzyls) amino -3- iodine pyridines (0.5mmol) and 70.15mg potassium methoxides (1mmol) It is dissolved in the deuterated acetonitriles of 1mL, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 12h at room temperature.Instead After answering completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation Purification, eluant, eluent is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 2- (N- methyl-N-benzyls) amino -3- deuterium pyridines 90mg (weak yellow liquid, yield 90%).1H NMR(400MHz,CDCl3) δ=8.19-8.09 (m, 1H), 7.38 (dd, J= 7.0,1.7Hz, 1H), 7.26 (t, J=7.2Hz, 2H), 7.19 (dd, J=10.3,4.8Hz, 3H), 6.51 (dd, J=7.1, 5.0Hz,1H),4.75(s,2H),3.02(s,3H)。GC-MS(EI+):199.1。
Embodiment 20:The synthesis of 5- deuterium-N- pi-allyl indoles
The bromo- N- pi-allyls indoles (0.5mmol) of 118mg 5- and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated second of 1mL In nitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 3h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=100：1 (v/v), obtains 5- deuteriums-N- pi-allyl indoles 52mg (weak yellow liquid, yield 66%) 。1H NMR(400MHz,CDCl3) δ=7.78 (d, J=2.3Hz, 1H), 7.50-7.40 (m, 1H), 7.33 (dd, J=7.8, 2.5Hz, 1H), 7.24-7.16 (m, 1H), 6.65 (d, J=2.3Hz, 1H), 6.19-6.01 (m, 1H), 5.36-5.26 (m, 1H),5.23–5.14(m,1H),4.86–4.74(m,2H)。GC-MS(EI+):158.1。
Embodiment 21:The synthesis of 2- (2- deuteriums phenyl) pyridine
117.5mg 2- (2- bromophenyls) pyridine (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in 1mL deuterated In acetonitrile, to 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 12h at room temperature.After reaction completely, plus 10mL water quenchings are gone out, and with 3 extractions of 30mL ether point, collect organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, eluant, eluent It is petroleum ether：Ethyl acetate=10：1 (v/v), obtains 2- (2- deuteriums phenyl) pyridine 68mg (weak yellow liquid, yield 87%).1H NMR(400MHz,CDCl3) δ=8.74-8.67 (m, 1H), 8.05-7.95 (m, 1H), 7.80-7.68 (m, 2H), 7.54-7.45 (m, 2H), 7.45-7.38 (m, 1H), 7.23 (ddd, J=5.4,4.9,2.3Hz, 1H).GC-MS(EI+):156.1.
Embodiment 22:The synthesis of deuterated estrone
181.5mg bromos estrone (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL, To 200 μ L hexamethyldisilanes (1mmol) are added dropwise in mixture, stirring reaction 12h at room temperature.After reaction completely, plus 10mL water It is quenched, with 3 extractions of 30mL ether point, collects organic phase, removal of solvent under reduced pressure.Column chromatography for separation is purified, and eluant, eluent is oil Ether：Ethyl acetate=5：1 (v/v), obtains deuterated estrone 110mg (white solid, yield 77%).1H NMR(400MHz, CDCl3) δ 7.21 (s, 1H), 6.64 (d, J=8.8Hz, 1H), 3.78 (s, 3H), 3.02-2.80 (m, 2H), 2.53-2.36 (m, 1H),2.32–2.20(m,1H),2.10–1.90(m,3H),1.71–1.17(m,8H),1.03–0.80(m,3H)。GC-MS(EI +):285.1。
Embodiment 23~63
Bromo aromatic compound (0.5mmol) and 70.15mg potassium methoxides (1mmol) are dissolved in the deuterated acetonitriles of 1mL, to mixed 200 μ L hexamethyldisilanes (1mmol) are added dropwise in compound, at room temperature stirring reaction 12h.After reaction completely, plus 10mL water quenchings are gone out, With 3 extractions of 30mL ether point, organic phase, removal of solvent under reduced pressure are collected.Column chromatography for separation is purified, and obtains corresponding deuterated fragrance Compound.Result is as shown in the table：
Above-described embodiment is the present invention preferably implementation method, but embodiments of the present invention are not by above-described embodiment Limitation, it is other it is any without departing from Spirit Essence of the invention and the change, modification, replacement made under principle, combine, simplification, Equivalent substitute mode is should be, is included within protection scope of the present invention.

Claims (9)

1. a kind of preparation method of deuterated aromatic compound, comprises the following steps：By halogenated aromatic compound, alkali metal salt and have Machine silica reagent in the mixed solvent of deuterated solvent or deuterated solvent with Conventional solvents in stirring reaction at -40 DEG C to 150 DEG C, Separating-purifying after reaction, that is, obtain deuterated aromatic compound.
2. a kind of preparation method of deuterated aromatic compound as claimed in claim 1, comprises the following steps：By halogenated aromatic Compound D, alkali metal salt MA and organosilicon reagent C are separated in stirring reaction at -40 DEG C to 150 DEG C, after reaction in solvent B and carried It is pure, that is, obtain deuterated aromatic compound；
Described halogenated aromatic compound D is halo aromatic compound or halo heteroaromatic ring compounds；
In described alkali metal salt MA, M=Na+、K+、Rb+Or Cs+, A is selected from the one kind in following anion：[OR1]-–、 [SR1]–、[NR1 2]–、[SiR1 3]–、[OSiR1 3]–、[SSiR1 3]–、[N(SiR1)2]–, wherein, R1It is hydrogen, C1-12Alkyl or contain Heteroatomic alkyl, C6-30Alkyl-substituted aryl or containing the one kind in heteroatomic alkyl-substituted aryl；
Described solvent B is the mixed solvent of deuterated reagent or deuterated reagent and conventional reagent；Described deuterated reagent is D2O、 CD3OD、CD3COCD3、CD3Cl、CD2Cl2、C6D6、C6D5CD3、CD3SOCD3、DCON(CD3)2、CD3In CN one or more Mixing；Described conventional reagent is methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofurans, ether, two Methyl second diether, methyl tertiary butyl ether(MTBE), the alkane of 1,4- epoxies six, the alkane of 1,3- epoxies six, dichloromethane, 1,2- dichloroethanes, chloroform, Carbon tetrachloride, C4-12Saturated alkane, C3-12Fluoro or chloralkane, benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetone, 1-METHYLPYRROLIDONE, acetonitrile, C3-12Saturated alkyl nitrile in One or more；
Described organosilicon reagent C, with the structure shown in formula (I), formula (II) or formula (III)：
Wherein m is 0,1,2 or 3；X is 2 to 100 integer；Wherein, R is identical or different group, is selected from：
I) C of base is replaced containing R '1-12Alkyl, its carbon chain backbone can be inserted into one or more-O- ,-S- and/or-NR2 2-, R2For Hydrogen or short-chain alkyl；
Ii the C of base) is replaced containing R '6-30Alkyl-substituted aryl, its carbon chain backbone can be inserted into one or more-O- ,-S- and/ Or-NR2 2-, R2It is hydrogen or short-chain alkyl；
Iii the C of base) is replaced containing R '6-30Aryl substitution alkyl, its carbon chain backbone can be inserted into one or more-O- ,-S- and/ Or-NR2 2-, R2It is hydrogen or short-chain alkyl；
Iv-the O-C of base) is replaced containing R '1-12Alkyl or-S-C1-12Alkyl, its carbon chain backbone can be inserted into one or more-O- ,- S- and/or-NR2 2-, R2It is hydrogen or short-chain alkyl；
V)-the O-C of base is replaced containing R '5-20Or-S-C5-20Aryl or fragrant heterocyclic radical；
Vi-the O-C of base) is replaced containing R '6-30Alkyl or-S-C6-30Alkyl-substituted aryl or fragrant heterocyclic radical, its carbon chain backbone can It is inserted into one or more-O- ,-S- and/or-NR2 2-, R2It is hydrogen or short-chain alkyl；
Or vii)-the O-C containing R ' substitution bases6-30Or-S-C6-30Aryl substitution alkyl or aryl substitution containing heteroatomic alkane Base；Wherein, R ' is selected from the one kind in following group：Hydrogen, phosphate, phosphite ester, alkylphosphines, aryl phosphine, C1-20Alkyl sulfide Ether, mercaptan, sulfoxide, sulfone, ammonia, acid amides, imines, enamine, nitro, nitroso, ether, alcohol, epoxy, aldehyde, ketone, ester, silane, silicon ether, Borine, boric acid, borate, halogen, the substitution base containing metallic tin or germanium, C5-20Aryl thioethers, mercaptan, sulfoxide, sulfone, ammonia, Acid amides, imines, enamine, nitro, nitroso, ether, alcohol, epoxy, aldehyde, ketone, ester, carbonate group, silane, silicon ether, borine, boric acid, Borate, halogen, the substitution base containing metallic tin or germanium.
3. the preparation method of deuterated aromatic compound according to claim 2, it is characterised in that：Described solvent B is CD3SOCD3、DCON(CD3)2、CD3One or more mixtures in CN；Described conventional reagent is tetrahydrofuran, dichloromethane One or several mixture in alkane, 2- methyltetrahydrofurans, dimethyl second diether, methyl tertiary butyl ether(MTBE), toluene.
4. the preparation method of deuterated aromatic compound according to claim 2, it is characterised in that：Described organosilicon reagent It is Me3SiSiMe3Or Et3SiSiEt3；Described alkali metal salt MA is KOMe or KOEt；Described solvent B is CD3CN or CD3The mixture of CN and tetrahydrofuran.
5. the preparation method of deuterated aromatic compound according to claim 2, it is characterised in that：Described halo is aromatic ring Compound is benzene, naphthalene or the anthracene of F, Br or I substitution, and described halo heteroaromatic ring compounds are furans, the benzo furan of F, Br or I substitution Mutter, pyrroles, indoles, thiophene, benzothiophene, imidazoles, pyrazoles, oxazole, isoxazoles, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, Pyrazine, quinoline, isoquinolin, carbazole or indolizine compound.
6. the preparation method of deuterated aromatic compound according to claim 5, it is characterised in that：Described halo is aromatic ring Compound has following structure：
Wherein b is 1 to 6 arbitrary integer；
Wherein any one X is independent, selected from bromine or iodine；
Wherein a is 0 to 5 integer；
Wherein any one R3Substitution base is all independent, optionally from following structure：Halogen；Hydroxyl；Sulfydryl；Alkoxy；Phenol oxygen Base；Alkylthio group；Phenol sulfenyl；Alkyl-substituted acyl group；The acyl group of aryl substitution；The acyl group of alkoxy substitution；The substitution of phenol epoxide Acyl group；Alkyl-substituted thiocarbonyl；The thiocarbonyl of aryl substitution；The thiocarbonyl of alkoxy substitution；The substitution of phenol epoxide Thiocarbonyl；Alkyl or the amide groups of aryl substitution；Alkyl or the ester group of aryl substitution；Alkyl or the sulphur of aryl substitution Ester group；Alkyl or the carbonate group of aryl substitution；Alkyl or the thiocarbonic acid ester group of aryl substitution；Cyano group；Isocyano group；Nitre Base；Nitroso；Alkyl or the azo of aryl substitution；Diazonium；Nitrine；Alkyl or the amine of aryl substitution；Alkyl or aryl Substituted imines；Alkyl or the enamine of aryl substitution；Alkyl or the phosphine of aryl substitution；Alkyl or the phosphorous of aryl substitution Acid esters；Alkyl or the phosphoramidite of aryl substitution；Alkyl or the phosphate of aryl substitution；Alkyl or the phosphorus of aryl substitution Acid amides；Borine；Alkyl or the borine of aryl substitution；Boric acid；Borate；Borate；Silane；Alkyl-substituted silane；Alcoxyl The silane of base substitution；The silane of phenol epoxide substitution；The silane of halogen substitution；Or substitution chain or ring-type alkane, Fluorine-containing alkane, alkene, aromatic hydrocarbons, aromatic heterocycle construction unit；Or the C of oxygen-containing, nitrogen, sulphur, phosphine3-C12Heterocycle；
Described halo heteroaromatic ring compounds are optionally from following structure：
Wherein：Q optionally from 0 to 5 integer, r optionally from 0 to 6 integer, s optionally from 0 to 8 integer, n optionally from 1 to 8 it Between arbitrary integer；
Wherein each X is independent, and optionally from halogen atom fluorine, chlorine, bromine or iodine, its position of substitution is to be removed on the aromatic rings of place Optional position outside hetero atom；
Wherein Y is optionally from O, S or N (R ")；Wherein R " is nitrogen-protecting group, arbitrarily selected from one or more in following group： Acetyl group, benzoyl, benzyl, methoxvethoxvmethvl, dimethoxytrityl free radical, methoxyl methyl, to methoxy Base trityl, to methoxy-benzyl, pivaloyl group, THP trtrahydropyranyl, tetrahydrofuran base, trityl, silicon ether, tertiary fourth Oxygen carbonyl, benzyloxycarbonyl group, to methoxybenzyl carbonyl, tablet held before the breast by officials methoxycarbonyl group, 3,4- dimethoxy-benzyls, p-methoxyphenyl, to toluene Sulfonyl, p-nitrophenyl sulfonyl, the sulfonyl of substitution, the silicon substrate of substitution, the carbonyl of substitution, the ester group of substitution, or arbitrarily Selected from the C of substitution1-12Alkyl, containing fluoroalkyl, aryl, aromatic heterocycle group；
Each of which R5All be it is independent, optionally from following group one or more：Halogen；Hydroxyl；Sulfydryl；Alkoxy； Phenol epoxide；Alkylthio group；Phenol sulfenyl；Alkyl-substituted acyl group；The acyl group of aryl substitution；The acyl group of alkoxy substitution；Phenol epoxide takes The acyl group in generation；Alkyl-substituted thiocarbonyl；The thiocarbonyl of aryl substitution；The thiocarbonyl of alkoxy substitution；Phenol epoxide takes The thiocarbonyl in generation；Alkyl or the amide groups of aryl substitution；Alkyl or the ester group of aryl substitution；Alkyl or aryl replace Thioester substrate；Alkyl or the carbonate group of aryl substitution；Alkyl or the thiocarbonic acid ester group of aryl substitution；Cyano group；Isocyanide Base；Nitro；Nitroso；Alkyl or the azo of aryl substitution；Diazonium；Nitrine；Alkyl or the amine of aryl substitution；Alkyl or The imines of aryl substitution；Alkyl or the enamine of aryl substitution；Alkyl or the phosphine of aryl substitution；What alkyl or aryl replaced Phosphite ester；Alkyl or the phosphoramidite of aryl substitution；Alkyl or the phosphate of aryl substitution；Alkyl or aryl replace Phosphamide；Borine；Alkyl or the borine of aryl substitution；Boric acid；Borate；Borate；Silane；Alkyl-substituted silane； The silane of alkoxy substitution；The silane of phenol epoxide substitution；The silane of halogen substitution；Substituted chain or the alkane of ring-type, contain Fluothane hydrocarbon, alkene, aromatic hydrocarbons, aromatic heterocycle construction unit；Oxygen-containing, nitrogen, sulphur, the C of phosphine3-C12Heterocycle.
7. the preparation method of deuterated aromatic compound according to claim 2, it is characterised in that：Described halogenated aromatic Compound, alkali metal salt MA, the mol ratio of organosilicon reagent are 1：1：1 to 1：5：5；The deuterated reagent and halogenated aromatic compound Mol ratio >=1:1.
8. the preparation method of deuterated aromatic compound according to claim 2, it is characterised in that：Described R1It is C1-4Alkyl Or C6-10Aryl.
9. the preparation method of deuterated aromatic compound according to claim 2, it is characterised in that：Described R group is C1-4 Alkyl or C6-10Aryl.
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Publication number Priority date Publication date Assignee Title
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009269853A (en) * 2008-05-07 2009-11-19 Taiho Yakuhin Kogyo Kk Method for deuterating heterocyclic ring-bearing compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009269853A (en) * 2008-05-07 2009-11-19 Taiho Yakuhin Kogyo Kk Method for deuterating heterocyclic ring-bearing compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TOMONOBU MUTSUMI ET AL: "Halogen-deuterium exchange reaction mediated by tributyltin hydride using THF-d8 as the deuterium source", 《TETRAHEDRON》 *
YOZO MIURA ET AL: "Convenient Deuteration of Bromo Aromatic Compounds by Reductive Debromination with Sodium Amalgam in CH3OD", 《J. ORG. CHEM.》 *

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