CN106977435A - A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound - Google Patents

A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound Download PDF

Info

Publication number
CN106977435A
CN106977435A CN201710215228.6A CN201710215228A CN106977435A CN 106977435 A CN106977435 A CN 106977435A CN 201710215228 A CN201710215228 A CN 201710215228A CN 106977435 A CN106977435 A CN 106977435A
Authority
CN
China
Prior art keywords
compound
formula
synthetic method
catalyst
alkali
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN201710215228.6A
Other languages
Chinese (zh)
Inventor
不公告发明人
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CN201710215228.6A priority Critical patent/CN106977435A/en
Publication of CN106977435A publication Critical patent/CN106977435A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Landscapes

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

Abstract

The present invention relates to a kind of synthetic method of medicine intermediate carbonyl substituted aryl 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 carbonyl substituted aryl 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 (6)

1. a kind of synthetic method of carbonyl substituted aryl sulfide compound shown in lower formula (III), methods described includes：In blanket of nitrogen Under enclosing, 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,
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 double (triphenylphosphine) cuprous nitrates；
The organo-nickel compounds are nickel acetylacetonate；
The organic ligand is following formula L1,
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；
Post processing after reaction terminates is specific as follows：After completion of the reaction, reaction system is naturally cooled into room temperature, filtered, to filter The aqueous hydrochloric acid solution that mass percent concentration is 5-10% is added in liquid, then fully vibration adds ethyl acetate extraction 2-3 It is secondary, merge organic phase, through vacuum distillation, residue crosses the silica gel column chromatography of 300-400 mesh, with volume ratio 1:2 acetone and stone Oily ether is rinsed, so as to obtain the formula (III) compound.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound You are than being 1:1.4-2.
3. 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。
4. 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.
5. 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。
6. 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。
CN201710215228.6A 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound Withdrawn CN106977435A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710215228.6A CN106977435A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510646571.7A CN105367465B (en) 2015-10-08 2015-10-08 Synthetic method of medical intermediate carbonyl-replacement aryl thioether compound
CN201710215228.6A CN106977435A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201510646571.7A Division CN105367465B (en) 2015-10-08 2015-10-08 Synthetic method of medical intermediate carbonyl-replacement aryl thioether compound

Publications (1)

Publication Number Publication Date
CN106977435A true CN106977435A (en) 2017-07-25

Family

ID=55370158

Family Applications (9)

Application Number Title Priority Date Filing Date
CN201710215215.9A Withdrawn CN107011223A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate sulfide compound
CN201710215212.5A Withdrawn CN107098836A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate sulfide compound
CN201710215228.6A Withdrawn CN106977435A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201710215221.4A Withdrawn CN106986799A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201710215227.1A Withdrawn CN107098837A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate sulfide compound
CN201710215208.9A Withdrawn CN107011222A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201510646571.7A Expired - Fee Related CN105367465B (en) 2015-10-08 2015-10-08 Synthetic method of medical intermediate carbonyl-replacement aryl thioether compound
CN201710215209.3A Withdrawn CN106928107A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201710215205.5A Withdrawn CN107098835A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate sulfide compound

Family Applications Before (2)

Application Number Title Priority Date Filing Date
CN201710215215.9A Withdrawn CN107011223A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate sulfide compound
CN201710215212.5A Withdrawn CN107098836A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate sulfide compound

Family Applications After (6)

Application Number Title Priority Date Filing Date
CN201710215221.4A Withdrawn CN106986799A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201710215227.1A Withdrawn CN107098837A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate sulfide compound
CN201710215208.9A Withdrawn CN107011222A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201510646571.7A Expired - Fee Related CN105367465B (en) 2015-10-08 2015-10-08 Synthetic method of medical intermediate carbonyl-replacement aryl thioether compound
CN201710215209.3A Withdrawn CN106928107A (en) 2015-10-08 2015-10-08 The synthetic method of medicine intermediate carbonyl substituted aryl sulfide compound
CN201710215205.5A Withdrawn CN107098835A (en) 2015-10-08 2015-10-08 A kind of synthetic method of medicine intermediate sulfide compound

Country Status (1)

Country Link
CN (9) CN107011223A (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108409617B (en) * 2018-03-10 2019-09-27 湘潭大学 A kind of synthetic method of sulfide compound
CN110256400B (en) * 2019-07-05 2021-08-24 南京林业大学 Preparation method for synthesizing polysubstituted ring 1, 2-diketone by participation of sulfoxide in arylation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10237058A (en) * 1997-02-24 1998-09-08 Sumitomo Chem Co Ltd 2,2'-bis(5-oxotetrahydrofuran-2-carbonylamino)-5,5'-dinitrodiphenyl disulfide and its production
JP2004502672A (en) * 2000-06-29 2004-01-29 アボット・ラボラトリーズ Arylphenylcyclopropyl sulfide derivatives as cell adhesion inhibiting anti-inflammatory and immunosuppressants and uses thereof
CN104744325B (en) * 2013-12-30 2016-08-17 中国人民大学 A kind of Alpha-hydroxy thioether and preparation method and application
CN103922978A (en) * 2014-05-07 2014-07-16 江南大学 Method for preparing new material aromatic sulfide in simple and environmental friendly modes

Also Published As

Publication number Publication date
CN105367465B (en) 2017-04-12
CN107098837A (en) 2017-08-29
CN105367465A (en) 2016-03-02
CN107098835A (en) 2017-08-29
CN107011223A (en) 2017-08-04
CN106928107A (en) 2017-07-07
CN106986799A (en) 2017-07-28
CN107098836A (en) 2017-08-29
CN107011222A (en) 2017-08-04

Similar Documents

Publication Publication Date Title
CN105367465B (en) Synthetic method of medical intermediate carbonyl-replacement aryl thioether compound
CN105237372A (en) Catalytic synthesis method of drug intermediate aryl ketone compound
CN105218540A (en) The preparation method of a kind of C-3 position thiocarbamoyl imidazole also [1,2-a] pyridine compounds and their
WO2016141835A1 (en) Method for synthesizing pharmaceutical intermediate phenanthrene compound using copper trifluomethanesulfonate
CN105152826B (en) A kind of synthetic method of medicine intermediate biphenyl compounds
CN106916132A (en) A kind of synthetic method of medicine intermediate coumarin derivatives
CN106432001A (en) Synthesis method of dienyl sulfone compounds
CN105037420B (en) A kind of aromatic carbonyl replaces the synthetic method of phosphate compounds
CN105001133B (en) Synthetic method for medical intermediate diaryl sulfide compound
CN105001130B (en) A kind of synthetic method of 3-aryl-2-cyclopentene-1-one compound
CN105753620B (en) A method of synthesizing medicine intermediate phenanthrene compound using copper trifluoromethanesulfcomposite
CN105061391B (en) A kind of synthetic method of sweet-smelling alkynyl substituted heterocycle ketone compounds
CN105801342B (en) A kind of method that medicine intermediate phenanthrene compound is synthesized under diisopropylamine environment
CN106045887B (en) A kind of synthetic method of N- ethyls sulfenamide compound
CN105152828B (en) A kind of synthetic method of alkynyl assimilation compound
CN105753748B (en) A kind of synthetic method of medicine intermediate sulphonyl class compound
CN103922975A (en) Synthesis method of sulfonamide compound
CN105111072A (en) Synthesis method of benzoyloxy compound
CN105111057A (en) Synthetic method of aryl ketene compounds
CN105085426A (en) Synthesis method of isooxazole derivatives
CN105753619A (en) Method for synthesizing medical intermediate phenanthrene compound by using copper acetate
CN105669336A (en) Method for synthesizing medical intermediate phenanthrene compound in sodium ethoxide environment
CN105732246A (en) Method for synthesizing pharmaceutical intermediate phenanthrene compound by means of PdCl2(PPh3)2
CN105777462A (en) Method for synthesizing medical intermediate phenanthrene compound in potassium bicarbonate environment
CN105732247A (en) Method for synthesizing pharmaceutical intermediate phenanthrene compound by means of copper acetylacetonate

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication
WW01 Invention patent application withdrawn after publication

Application publication date: 20170725

DD01 Delivery of document by public notice
DD01 Delivery of document by public notice

Addressee: Qian Xiaoying

Document name: Notification of Approving Refund