CN107098835A - A kind of synthetic method of medicine intermediate sulfide compound - Google Patents

A kind of synthetic method of medicine intermediate sulfide compound Download PDF

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CN107098835A
CN107098835A CN201710215205.5A CN201710215205A CN107098835A CN 107098835 A CN107098835 A CN 107098835A CN 201710215205 A CN201710215205 A CN 201710215205A CN 107098835 A CN107098835 A CN 107098835A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B45/00—Formation or introduction of functional groups containing sulfur
    • C07B45/06—Formation or introduction of functional groups containing sulfur of mercapto or sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B01J2231/4294—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using S nucleophiles, e.g. thiols
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0213—Complexes without C-metal linkages
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/16—Copper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/847—Nickel

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  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a kind of synthetic method of medicine intermediate sulfide compound, methods described includes：Under nitrogen atmosphere, in organic solvent, in the presence of catalyst, organic ligand, activator and alkali, lower formula (I) compound and following formula formula (II) compound reacts, and reacts after terminating through post processing, obtains the formula (III) compound, whereinEach R1It is each independently C1‑C6Alkyl；R2For C1‑C6Alkyl, C1‑C6Alkoxy, halogen or nitro；X is halogen.In summary, the invention provides a kind of synthetic method of carbonyl substituted aryl sulfide compound, the process employs new recombination reaction system, pass through the comprehensive selection of catalyst, organic ligand, activator and alkali and organic solvent, purpose product is obtained so as to high yield, and reaction process is gentle, meets chemical industry, the demand of medicine and other fields, wide market.

Description

A kind of synthetic method of medicine intermediate sulfide compound
Technical field
The present invention relates to a kind of synthetic method of sulfide compound, more particularly, to a kind of carbonyl that can be used as medicine intermediate The synthetic method of base substituted aryl sulfide compound, belongs to organic chemistry especially medicine intermediate synthesis field.
Background technology
In organic chemistry especially medicinal chemistry art, thioether is a kind of very important sulfur-containing compound, due to it Potential bioactivity and received much concern in fields such as organic synthesis, pharmaceutical synthesis.Wherein, carbonyl substituted thioethers are jeterocyclic chemistries The intermediate commonly used in the synthesis of compound, it is widely applied in pharmaceutical compound, thus exploitation carbonyl substituted thioethers chemical combination The novel method for synthesizing of thing is the research interest place of numerous researchers all the time.
In recent years, in the prior art it has been reported that the synthesis technique of some carbonyl substituted thioethers class compounds, for example：
(" the Ionic Liquid as Catalyst and Reaction Medium such as Brindaban C. Ranu:A Simple,Convenient and Green Procedure for the Synthesis of Thioethers, Thioesters and Dithianes using an Inexpensive Ionic Liquid,[pmIm] Br”, Adv.Synth.Catal., 2005,347,1811-1818) one kind is reported by alkyl halide class compound and sulfur alcohol compound The method to prepare thioether is reacted, its reaction equation is as follows：
R-X+R1SH→RSR1
(" Titanium (IV)-Catalyzed Enantioselective Sulfenylation of such as Marjan Jereb β-Ketoesters ", Organic Letters, 2005,7,4041-4043) report a kind of 'beta '-ketoester of titanium complex catalysis Sulfation reaction method, its reaction equation is as follows：
(" Direct, organocatalytic a-sulfenylation of the aldehydes and such as Wang Wei Ketones ", Tetrahedron Letters, 2004,45,8229-8231) report a kind of the direct of aldehydes or ketones class compound Sulfation reaction method, its reaction equation is as follows：
As described above, the synthetic method of a variety of sulfide compounds is disclosed in the prior art, however, these methods still can not expire Sufficient chemical industry, the common requirements in medical synthesis field, still suffer from that reaction yield is relatively low, reaction process has many defects such as to be optimized.
Considering based on these problems, the present inventor by substantial amounts of Experimental Research, and then propose one kind can be used as doctor The synthetic method of the carbonyl substituted aryl sulfide compound of medicine intermediate, the process employs efficient catalyst system and catalyzing, by right The screening of plurality of reagents species promotes being smoothed out for reaction, and reaction condition is gentle, before extensive commercial Application Scape.
The content of the invention
In order to overcome the new synthesis of many defects and searching carbonyl substituted aryl sulfide compound as indicated above Method, present inventor has performed in-depth study and exploration, after enough creative works have been paid, so as to complete this hair It is bright.
Specifically, technical scheme and content are related to carbonyl substituted aryl thioether shown in a kind of lower formula (III) The synthetic method of compound, methods described includes：Under nitrogen atmosphere, in organic solvent, in catalyst, organic ligand, work In the presence of agent and alkali, lower formula (I) compound and following formula formula (II) compound reacts, and reacts after terminating through post processing, obtains To the formula (III) compound,
Wherein, each R1It is each independently C1-C6Alkyl；
R2For C1-C6Alkyl, C1-C6Alkoxy, halogen or nitro；
X is halogen.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxy refers to the C with implication1-C6Alkyl The group obtained after being connected with O atom.
In the synthetic method of the present invention, the halogen for example can be F, Cl, Br or I.
In the synthetic method of the present invention, X is most preferably Br.
In the synthetic method of the present invention, the catalyst is the mixing of organocopper compound and organo-nickel compounds The mol ratio of thing, wherein organocopper compound and organo-nickel compounds is 2:0.5-1, for example, can be 2:0.5、2:0.7、2:0.9 Or 2:1.
Wherein, the organocopper compound is Cu (TFA)2(trifluoroacetic acid copper), Cu (acac)2(acetylacetone copper), [(CH3CN)4Cu]PF6(the acetonitrile copper of hexafluorophosphoric acid four), Cu (PPh3) Br (triphenylphosphine cuprous bromide) or Cu (PPh3)2NO3It is (double (triphenylphosphine) cuprous nitrate) in any one, most preferably Cu (PPh3)2NO3。
Wherein described organo-nickel compounds are double (1,5- cyclo-octadiene) nickel (Ni (COD)2), nickel acetylacetonate (Ni (acac)2) or nickel carbonyl in any one, most preferably Ni (acac)2。
In the synthetic method of the present invention, the organic ligand is any one in following formula L1-L3,
Most preferably L1.
In the synthetic method of the present invention, the activator is p-methoxyphenyl tellurium oxide.
The present invention the synthetic method in, the alkali be NaOH, sodium carbonate, cesium carbonate, potassium acetate, potassium tert-butoxide, It is any in caustic alcohol, diethanol amine, 1,4- diazabicylos [2.2.2] octane (DABCO) or lithium diisopropylamine (LDA) One kind, most preferably cesium carbonate.
In the synthetic method of the present invention, the organic solvent is the mixing of chlorobenzene and DMSO (dimethyl sulfoxide (DMSO)) The volume ratio of thing, wherein chlorobenzene and DMSO is 1:2.
Wherein, the consumption of the organic solvent does not have strict restriction, and those skilled in the art can be according to actual conditions Suitable selection is carried out with determining, such as its consumption size no longer carries out detailed to facilitate reaction to carry out and post-process, herein Thin description.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and formula (II) compound is 1: 1.4-2, for example, can be 1:1.4、1:1.6、1:1.8 or 1:2.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and catalyst is 1:0.1-0.16, The mole dosage of i.e. described formula (II) compound with constitute the catalyst organocopper compound and organo-nickel compounds it is total The ratio of mole dosage is 1:0.1-0.16, for example, can be 1:0.1、1:0.13 or 1:0.16.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and organic ligand is 1:0.05- 0.1, for example can be 1:0.05、1:0.07、1:0.09 or 1:0.1.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and activator is 1:0.1-0.2, For example can be 1:0.1、1:1.5 or 1:0.2.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and alkali is 1:2-3, for example can be 1:2、1:2.5 or 1:3.
In the synthetic method of the present invention, reaction temperature is 60-90 DEG C, for example, can be 60 DEG C, 70 DEG C, 80 DEG C or 90 ℃。
In the synthetic method of the present invention, the reaction time is 5-8 hours, for example, can be 5 hours, 6 hours, 7 hours Or 8 hours.
In the synthetic method of the present invention, the post processing after reaction terminates is specific as follows：After completion of the reaction, it will react System naturally cools to room temperature, filtering, and the aqueous hydrochloric acid solution that mass percent concentration is 5-10% is added into filtrate, is fully shaken Swing, then add ethyl acetate and extract 2-3 times, merge organic phase, through vacuum distillation, residue crosses the silica gel of 300-400 mesh Column chromatography, with volume ratio 1:2 acetone is rinsed with petroleum ether, so as to obtain the formula (III) compound.
In summary, the invention provides a kind of synthetic method of carbonyl substituted aryl sulfide compound, this method is used New recombination reaction system, by the comprehensive selection of catalyst, organic ligand, activator and alkali and organic solvent, from And purpose product can be obtained with high yield, and reaction process is gentle, meets chemical industry, the demand of medicine and other fields, market prospects It is wide.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and Purpose only be used for enumerate the present invention, not to the present invention real protection scope constitute it is any type of it is any limit, it is more non-will
Protection scope of the present invention is confined to this.
Embodiment 1
Under room temperature and nitrogen atmosphere, to appropriate organic solvent, (volume ratio is 1:2 chlorobenzene and DMSO mixture) in, add The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 140mmol, 10mmol catalyst (are 8mmolCu (PPh3)2NO3With 2mmolNi(acac)2Mixture), 5mmol organic ligand L1,10mmol activator p-methoxyphenyl tellurium oxides and 200mmol Alkali cesium carbonate, then heats to 60 DEG C, and stirring reaction 8 hours at such a temperature；
After completion of the reaction, reaction system is naturally cooled into room temperature, filtered, it is 5% that mass percent concentration is added into filtrate Aqueous hydrochloric acid solution, then fully vibration add ethyl acetate and extract 2-3 time, merge organic phase, through vacuum distillation, remain Thing crosses the silica gel column chromatography of 300-400 mesh, with volume ratio 1:2 acetone is rinsed with petroleum ether, so as to obtain above formula
(III) compound, yield is 97.1%.
1HNMR(CDCl3,400MHz):δ 17.22 (s, 1H), 7.06 (d, J=8.0Hz, 2H), 6.97 (d, J=8.2Hz, 2H),2.34(s,6H),2.29(s,3H)。
Embodiment 2
Under room temperature and nitrogen atmosphere, to appropriate organic solvent, (volume ratio is 1:2 chlorobenzene and DMSO mixture) in, add The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 170mmol, 12mmol catalyst (are 8mmolCu (PPh3)2NO3With 4mmolNi(acac)2Mixture), 8mmol organic ligand L1,15mmol activator p-methoxyphenyl tellurium oxides and 250mmol Alkali cesium carbonate, then heats to 75 DEG C, and stirring reaction 6 hours at such a temperature；
After completion of the reaction, reaction system is naturally cooled into room temperature, filtered, it is 7% that mass percent concentration is added into filtrate Aqueous hydrochloric acid solution, then fully vibration add ethyl acetate and extract 2-3 time, merge organic phase, through vacuum distillation, remain Thing crosses the silica gel column chromatography of 300-400 mesh, with volume ratio 1:2 acetone is rinsed with petroleum ether, so as to obtain formula (III) chemical combination Thing, yield is 97.4%.
1HNMR(CDCl3,400MHz):δ 17.42 (s, 1H), 8.12 (d, J=8.8Hz, 2H), 7.23 (d, J=9.1Hz, 2H),2.31(s,6H)。
Embodiment 3
Under room temperature and nitrogen atmosphere, to appropriate organic solvent, (volume ratio is 1:2 chlorobenzene and DMSO mixture) in, add The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 200mmol, 16mmol catalyst (are 12mmolCu (PPh3)2NO3With 4mmolNi(acac)2Mixture), 10mmol organic ligand L1,20mmol activator p-methoxyphenyl tellurium oxides and 300mmol alkali cesium carbonates, then heat to 90 DEG C, and stirring reaction 5 hours at such a temperature；
After completion of the reaction, reaction system is naturally cooled into room temperature, filtered, it is 10% that mass percent concentration is added into filtrate Aqueous hydrochloric acid solution, then fully vibration add ethyl acetate and extract 2-3 time, merge organic phase, through vacuum distillation, remain Thing crosses the silica gel column chromatography of 300-400 mesh, with volume ratio 1:2 acetone is rinsed with petroleum ether, so as to obtain formula (III) chemical combination Thing, yield is 97.5%.
1HNMR(CDCl3,400MHz):δ 17.34 (s, 1H), 7.22 (t, J=8.0Hz, 1H), 6.67 (m, 1H), 6.64(m,1H), 6.61(m,1H),3.78(s,3H),2.35(s,6H)。
Embodiment 4
Under room temperature and nitrogen atmosphere, to appropriate organic solvent, (volume ratio is 1:2 chlorobenzene and DMSO mixture) in, add The upper formula (I) compounds of 100mmol, the upper formula (II) compounds of 160mmol, 14mmol catalyst (are 10mmolCu (PPh3)2NO3With 4mmolNi(acac)2Mixture), 6mmol organic ligand L1,18mmol activator p-methoxyphenyl tellurium oxides and 220mmol Alkali cesium carbonate, then heats to 70 DEG C, and stirring reaction 7 hours at such a temperature；
After completion of the reaction, reaction system is naturally cooled into room temperature, filtered, it is 5% that mass percent concentration is added into filtrate Aqueous hydrochloric acid solution, then fully vibration add ethyl acetate and extract 2-3 time, merge organic phase, through vacuum distillation, remain Thing crosses the silica gel column chromatography of 300-400 mesh, with volume ratio 1:2 acetone is rinsed with petroleum ether, so as to obtain formula (III) chemical combination Thing, yield is 97.2%.
1HNMR(CDCl3,400MHz):δ 17.44 (s, 1H), 7.23 (d, J=8.8Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 2.71 (s, 4H), 1.13 (t, J=7.8Hz, 6H).
Embodiment 5-36：The influence of catalytic component
Embodiment 5-8：Except by the Cu (PPh in catalyst3)2NO3Replace with Cu (TFA)2Outside, other operations are constant, so that weight A 1-4 is carried out again, obtains embodiment 5-8.
Embodiment 9-12：Except by the Cu (PPh in catalyst3)2NO3Replace with Cu (acac)2Outside, other operations are constant, So as to which embodiment 1-4 is repeated, embodiment 9-12 is obtained.
Embodiment 13-16：Except by the Cu (PPh in catalyst3)2NO3Replace with [(CH3CN)4Cu]PF6Outside, other operations It is constant, so that embodiment 1-4 is repeated, obtain embodiment 13-16.
Embodiment 17-20：Except by the Cu (PPh in catalyst3)2NO3Replace with Cu (PPh3) outside Br, other operations are not Become, so that embodiment 1-4 is repeated, obtain embodiment 17-20.
Embodiment 21-24：Except by the Ni (acac) in catalyst2Replace with Ni (COD)2Outside, other operations are constant, from And embodiment 1-4 is repeated, obtain embodiment and obtain embodiment 21-24.
Embodiment 25-28：Except by the Ni (acac) in catalyst2Replace with outside nickel carbonyl, other operations are constant, from And embodiment 1-4 is repeated, obtain embodiment and obtain embodiment 25-28.
Embodiment 29-32：Except by catalyst replace with consumption be the original total consumption sum of two kinds of components one-component Cu (PPh3)2NO3Outside, other operations are constant, so that embodiment 1-4 is repeated, obtains embodiment and obtain embodiment 29-32.
Embodiment 33-36：Except by catalyst replace with consumption be the original total consumption sum of two kinds of components one-component Ni (acac)2Outside, other operations are constant, so that embodiment 1-4 is repeated, obtains embodiment and obtain embodiment 33-36.
As a result it see the table below 1.
Table 1
" -- " represents to be not present.
As can be seen here, respectively in organocopper compound and organo-nickel compounds, Cu (PPh3)2NO3With Ni (acac)2Tool There is best catalytic effect, other copper compounds or nickel compound cause yield to have substantially reduction (even with Cu (PPh3)2NO3Very similar Cu (PPh3) Br is also such).In addition, when any one-component is used alone, yield is reduced more To be obvious, Ni (acac) is especially single use2When, yield is drastically reduced.This proves Cu (PPh3)2NO3With Ni (acac)2Can Obtain unexpected concerted catalysis effect.
Embodiment 37-48：The influence of organic ligand
Embodiment 37-40：In addition to organic ligand L1 is replaced with into L2, other operations are constant, so that embodiment is repeated 1-4, obtains embodiment and obtains embodiment 37-40.
Embodiment 41-44：In addition to organic ligand L1 is replaced with into L3, other operations are constant, so that reality is repeated A 1-4 is applied, embodiment is obtained and obtains embodiment 41-44.
Embodiment 45-48：In addition to organic ligand L1 is omitted, other operations are constant, so that reality is repeated A 1-4 is applied, embodiment is obtained and obtains embodiment 45-48.
As a result 2 be see the table below.
Table 2
As can be seen here, in organic ligand, L1 effect is best, and when without using organic ligand, yield, which has, significantly to drop It is low.
Embodiment 49-52：The influence of activator
In addition to activator is omitted, other operations are constant, so that embodiment 1-4 is repeated, obtains embodiment and obtain To embodiment 49-52, it is 88.4-89.8% to find its yield product.
As can be seen here, the presence of activator, can significantly improve yield, serve activation, facilitation.
Embodiment 53-60：The influence of alkali
In addition to the following Different Alkali of use, other operations are constant, so as to correspond to different embodiments and be carried out a 53- 60, institute see the table below 3 using alkali, correspondence embodiment and products collection efficiency.
Table 3
As can be seen here, in all alkali, cesium carbonate has a best effect, even with its very similar sodium carbonate, production Rate is also reduced to 87.9%.
Embodiment 61-68：The influence of organic solvent constituent
Embodiment 61-64：In addition to organic solvent is replaced with into single solvent chlorobenzene, other operations are constant, so as to repeat Embodiment 1-4, obtains embodiment and obtains embodiment 61-64.
Embodiment 65-68：In addition to organic solvent is replaced with into single solvent DMSO, other operations are constant, so as to repeat A 1-4 is carried out, embodiment is obtained and obtains embodiment 65-68.
As a result 4 be see the table below.
Table 4
As can be seen here, when the compounded organic solvent system using chlorobenzene and DMSO, yield is enabled to be further enhanced, With best solvent effect.
In summary, the invention provides a kind of synthetic method of carbonyl substituted aryl sulfide compound, this method is used New recombination reaction system, by the comprehensive selection of catalyst, organic ligand, activator and alkali and organic solvent, from And purpose product can be obtained with high yield, and reaction process is gentle, meets chemical industry, the demand of medicine and other fields, market prospects It is wide.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention Enclose.In addition, it will also be appreciated that after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention Change, modification and/or variation are planted, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited Within the scope of shield.

Claims (5)

1. a kind of synthetic method of sulfide compound shown in lower formula (III), methods described includes：Under nitrogen atmosphere, organic In solvent, in the presence of catalyst, organic ligand, activator and alkali, lower formula (I) compound and following formula formula (II) compound occurs Reaction, reaction temperature is 60-90 DEG C, and the reaction time is 5-8 hours, reacts after terminating through post processing, obtains the formula (III) Compound,
Wherein, each R1It is each independently C1-C6Alkyl；
R2For C1-C6Alkyl, C1-C6Alkoxy, halogen or nitro；
X is halogen；
The catalyst is the mixture of organocopper compound and organo-nickel compounds, wherein organocopper compound and organic nickel The mol ratio of compound is 2:0.5-1；
The organocopper compound is triphenylphosphine cuprous bromide；
The organo-nickel compounds are nickel acetylacetonate；
The organic ligand is following formula L2,
The activator is p-methoxyphenyl tellurium oxide；
The alkali is cesium carbonate；
The organic solvent is the mixture of chlorobenzene and DMSO (dimethyl sulfoxide (DMSO)), and wherein the volume ratio of chlorobenzene and DMSO is 1:2；
Synthetic method as claimed in claim 1, it is characterised in that：Mole of formula (I) compound and formula (II) compound Than for 1:1.4-2.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of catalyst are 1:0.1-0.16。
3. synthetic method as claimed in claim 1, it is characterised in that：The mol ratio of formula (I) compound and organic ligand For 1:0.05-0.1.
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of activator are 1:0.1-0.2。
5. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of alkali are 1:2- 3。
CN201710215205.5A 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate sulfide compound Withdrawn CN107098835A (en)

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