CN105753748B - A kind of synthetic method of medicine intermediate sulphonyl class compound - Google Patents
A kind of synthetic method of medicine intermediate sulphonyl class compound Download PDFInfo
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- CN105753748B CN105753748B CN201610085872.1A CN201610085872A CN105753748B CN 105753748 B CN105753748 B CN 105753748B CN 201610085872 A CN201610085872 A CN 201610085872A CN 105753748 B CN105753748 B CN 105753748B
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- CRVXTAAEIOZDCZ-UHFFFAOYSA-N C=NS(C1=CC=CCC=C1)(=N)=O Chemical compound C=NS(C1=CC=CCC=C1)(=N)=O CRVXTAAEIOZDCZ-UHFFFAOYSA-N 0.000 description 1
- RIQLYTWSALCKHF-UHFFFAOYSA-O C[NH+](C)C1=CC=CCC=C1 Chemical compound C[NH+](C)C1=CC=CCC=C1 RIQLYTWSALCKHF-UHFFFAOYSA-O 0.000 description 1
- GCQKIMCDKPSDDS-FOWTUZBSSA-O Cc1cccc(S(/N=C/N(C)c2ccccc2)(=O)=[OH+])c1 Chemical compound Cc1cccc(S(/N=C/N(C)c2ccccc2)(=O)=[OH+])c1 GCQKIMCDKPSDDS-FOWTUZBSSA-O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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Abstract
The present invention relates to a kind of synthetic method of sulphonyl class compound shown in lower formula (III), the described method includes：In organic solvent into reactor, add in lower formula (I) compound, lower formula (II) compound, amine source compound, catalyst, alkali and auxiliary agent, be stirred to react at 80 100 DEG C 69 it is small when, reaction system is cooled to room temperature after completion of the reaction, adjusts pH value to neutrality, filtering, filter vacuum is concentrated, residue crosses silica gel post separation to get formula (III) compoundWherein, R1、R2It is each independently selected from H, C1‑C6Alkyl, C1‑C6Alkoxy or halogen；X is halogen.The method is by suitable reactions substrate, amine source compound, catalyst, alkali and the comprehensive selection of auxiliary agent and organic solvent with cooperateing with, purpose product is obtained so as to high yield, is had a good application prospect in medicine intermediate synthesis technical field and industrial production potential.
Description
Technical field
The present invention relates to a kind of synthetic method of sulfur-containing compound, more particularly to a kind of medicine intermediate that can be used as
The synthetic method of sulphonyl class compound belongs to medicine intermediate synthesis field.
Background technology
In organic chemical synthesis, sulphonyl class compound is a kind of special construction module, in field of medicaments and synthesis
Chemical field occupies highly important status, this is that especially the class formation makes frequently as synthetic intermediate or medicines structure segment
With widely used.
Based on such important role of sulphonyl class compound, therefore, the high-efficiency synthesis method of sulphonyl class compound is developed
It is very valuable.
In recent years, in the prior art it has been reported that the synthetic process of a variety of sulphonyl class compounds, such as：
(" the Highly Efficient One-Pot Synthesis of N- such as Bae Imhyuck
Sulfonylamidines by Cu-Catalyzed Three-Component Coupling of Sulfonyl Azide,
Alkyne, and Amine ", J.Am.Chem.Soc., 2005,127,2038-2039) report a kind of one kettle way of copper catalysis
The method for synthesizing N- sulphonyl class compounds, reaction equation are as follows：
(" the An Unexpected Diethyl Azodicarboxylate-Promoted such as Xu Xiaoliang
Dehydrogenation of Tertiaryamine and Tandem Reaction with Sulfonyl Azide”,
J.Am.Chem.Soc., 2008,130,14048-14049) it reports and a kind of uses tertiary amine and sulfonyl nitrine as raw material system
The method of standby sulfonyl amidine, reaction equation are as follows：
(" the Direct Condensation of Sulfonamide and Formamide such as Chen Shulin:NaI-
Catalyzed Synthesis of N-Sulfonyl Formamidine Using TBHP as Oxidant”,Organic
Letters, 2011,13,6152-6155) report a kind of sulfonamide and formamide condensation reaction prepares sulphonyl class compound
Method, reaction equation are as follows：
As described above, a variety of synthetic methods of sulphonyl class compound are disclosed in the prior art.However, these methods are still deposited
In some defects, such as the shortcomings of used hazardous reagents for example nitrine class or yield are undesirable, the process time is long.
To solve the problems of long-standing problem, the present inventor is reported by reading a large amount of summary property documents and forward position,
On the basis of experimental exploring repeatedly, it is proposed that a kind of synthetic method of sulphonyl class compound, this method are anti-using multiple elements design
System is answered, greatly improves material reaction, realizes and prepares product in high yield, there is extensive industrial value.
The content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth studies and exploration, are paying
After enough creative works, so as to complete the present invention.
Specifically, technical scheme and content are related to a kind of lower formula (III) institute that can be used as medicine intermediate
Show the synthetic method of sulphonyl class compound, the described method includes：In organic solvent into reactor, lower formula (I) chemical combination is added in
Object, lower formula (II) compound, amine source compound, catalyst, alkali and auxiliary agent, be stirred to react at 80-100 DEG C 6-9 it is small when, reaction
After reaction system is cooled to room temperature, adjust pH value to neutrality, filtering concentrates filter vacuum, residue crosses silicagel column
It separates to get formula (III) compound,
Wherein, R1、R2It is each independently selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
X is halogen.
In the synthetic method of the present invention, the C1-C6The meaning of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, it may be, for example, 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 meaning of alkoxy refers to the C with above-mentioned implication1-C6
The group that alkyl obtains after being connected with oxygen atom.
In the synthetic method of the present invention, the halogen is halogen, may be, for example, F, Cl, Br or I.
In the synthetic method of the present invention, the amine source compound is ammonium nitrate, ammonium ceric nitrate, ammonium sulfate or chlorination
Any one in ammonium is most preferably ammonium ceric nitrate.
In the synthetic method of the present invention, the catalyst is Cu (OAc)2(copper acetate), Cu (TFA)2(trifluoro second
Sour copper), Cu (acac)2Any one in (acetylacetone copper), trifluoroacetylacetone (TFA) copper or hexafluoroacetylacetone copper, most preferably
For hexafluoroacetylacetone copper.
In the synthetic method of the present invention, the alkali is NaOH, sodium carbonate, cesium carbonate, potassium phosphate, sodium acetate, carbon
Sour hydrogen sodium, potassium tert-butoxide, sodium ethoxide, dimethylamino naphthyridine (DMPA), 1,4- diazabicylos [2.2.2] octane (DABCO), three
Any one in isopropanolamine or diethanol amine is most preferably triisopropanolamine.
In the synthetic method of the present invention, the auxiliary agent is two (tricyclohexyl phosphine) nickel chloride (NiCl2(PCy3)2)
Or double (1,5- cyclo-octadiene) nickel (Ni (COD)2), it is most preferably double (1,5- cyclo-octadiene) nickel (Ni (COD)2)。
In the synthetic method of the present invention, the organic solvent is DMF (n,N-Dimethylformamide), DMSO (two
Methyl sulfoxide), toluene, benzene, any one in ethyl alcohol or acetonitrile, be most preferably acetonitrile.
Wherein, the dosage of the organic solvent can be according to actual conditions there is no stringent restriction, those skilled in the art
It carries out suitably selection and determines, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post processing
Thin description.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and formula (II) compound is 1:2-
3, it may be, for example, 1:2、1:2.5 or 1:3.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and amine source compound is 1:1-2,
It may be, for example, 1:1、1:1.5 or 1:2.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and catalyst is 1:0.1-0.2,
It may be, for example, 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and alkali is 1:1.5-2.5, such as
Can be 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and auxiliary agent is 1:0.06-0.1, example
Such as can be 1:0.06、1:0.08 or 1:0.1.
In the synthetic method of the present invention, silicagel column processing of crossing after reaction is the routine techniques in this field
Means, such as volume ratio can be used to be 1:2 ethyl acetate and the mixture of acetone collect elution fraction as solution is eluted,
After concentrating removing solvent, the formula (III) compound is obtained.
In conclusion the present invention provides a kind of synthetic method for the sulphonyl class compound that can be used as medicine intermediate, institutes
State comprehensive selection and association of the method by suitable reactions substrate, amine source compound, catalyst, alkali and auxiliary agent and organic solvent
Together, obtain purpose product so as to high yield, have a good application prospect in medicine intermediate synthesis technical field and
Industrial production potential.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
At room temperature, in the appropriate organic solvent acetonitrile into reactor, then add in 100mmol on formula (I) compound,
The upper formula (II) compounds of 200mmol, 100mmol amine source compounds ammonium ceric nitrate, 10mmol catalyst hexafluoroacetylacetones copper,
150mmol alkali triisopropanolamine and double (1,5- cyclo-octadiene) nickel (Ni (COD) of 6mmol auxiliary agents2), then heat to 80 DEG C, and
Be sufficiently stirred at such a temperature reaction 9 it is small when, reaction system is cooled to room temperature after completion of the reaction, adjusts pH value to neutrality, mistake
Filter, filter vacuum is concentrated, residue crosses silica gel post separation (using volume ratio as 1:2 ethyl acetate and the mixture of acetone are made
To elute solution) to get upper formula (III) compound, yield 96.1%.
1H NMR(CDCl3,400MHz):δ 8.57 (s, 1H), 7.95 (d, J=7.2Hz, 2H), 7.56-7.49 (m, 3H),
7.39-7.35 (m, 1H), 7.31-7.28 (m, 1H), 7.21 (t, J=2.0Hz, 1H), 7.12-7.10 (m, 1H), 3.44 (s,
3H)。
Embodiment 2
At room temperature, in the appropriate organic solvent acetonitrile into reactor, then add in 100mmol on formula (I) compound,
The upper formula (II) compounds of 250mmol, 150mmol amine source compounds ammonium ceric nitrate, 15mmol catalyst hexafluoroacetylacetones copper,
200mmol alkali triisopropanolamine and double (1,5- cyclo-octadiene) nickel (Ni (COD) of 8mmol auxiliary agents2), then heat to 90 DEG C, and
Be sufficiently stirred at such a temperature reaction 8 it is small when, reaction system is cooled to room temperature after completion of the reaction, adjusts pH value to neutrality, mistake
Filter, filter vacuum is concentrated, residue crosses silica gel post separation (using volume ratio as 1:2 ethyl acetate and the mixture of acetone are made
To elute solution) to get upper formula (III) compound, yield 96.4%.
1H NMR(CDCl3,400MHz):δ8.56(s,1H),7.96-7.95(m,2H),7.56-7.54(m,1H),7.52-
7.49 (m, 2H), 7.25 (d, J=4.0Hz, 2H), 7.11 (d, J=8.8Hz, 2H), 3.44 (s, 3H), 2.38 (s, 3H).
Embodiment 3
At room temperature, in the appropriate organic solvent acetonitrile into reactor, then add in 100mmol on formula (I) compound,
The upper formula (II) compounds of 300mmol, 200mmol amine source compounds ammonium ceric nitrate, 20mmol catalyst hexafluoroacetylacetones copper,
250mmol alkali triisopropanolamine and double (1,5- cyclo-octadiene) nickel (Ni (COD) of 10mmol auxiliary agents2), 100 DEG C are then heated to,
And be sufficiently stirred at such a temperature reaction 6 it is small when, reaction system is cooled to room temperature after completion of the reaction, adjusts pH value to neutrality,
Filtering, filter vacuum is concentrated, residue crosses silica gel post separation (using volume ratio as 1:2 ethyl acetate and the mixture of acetone
As elution solution) to get upper formula (III) compound, yield 95.9%.
1H NMR(CDCl3,400MHz):δ 8.55 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.45-7.44 (m, 2H),
7.32-7.28 (m, 1H), 7.20 (d, J=7.6Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 3.85 (s, 3H), 3.45 (s,
3H)。
Embodiment 4
At room temperature, in the appropriate organic solvent acetonitrile into reactor, then add in 100mmol on formula (I) compound,
The upper formula (II) compounds of 220mmol, 180mmol amine source compounds ammonium ceric nitrate, 13mmol catalyst hexafluoroacetylacetones copper,
270mmol alkali triisopropanolamine and double (1,5- cyclo-octadiene) nickel (Ni (COD) of 7mmol auxiliary agents2), then heat to 85 DEG C, and
Be sufficiently stirred at such a temperature reaction 7 it is small when, reaction system is cooled to room temperature after completion of the reaction, adjusts pH value to neutrality, mistake
Filter, filter vacuum is concentrated, residue crosses silica gel post separation (using volume ratio as 1:2 ethyl acetate and the mixture of acetone are made
To elute solution) to get upper formula (III) compound, yield 96.5%.
1H NMR(CDCl3,500MHz):δ 8.55 (s, 1H), 8.06 (t, J=2.0Hz, 1H), 7.89-7.86 (m, 1H),
7.67-7.64(m,1H),7.45-7.41(m,2H),7.37-7.32(m,2H),7.23-7.20(m,2H),3.45(s,3H)。
Embodiment 5-16
Embodiment 5-8：In addition to amine source compound ammonium ceric nitrate is replaced with ammonium nitrate, other operations are constant, so as to weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 5-8.
Embodiment 9-12：In addition to amine source compound ammonium ceric nitrate is replaced with ammonium sulfate, other operations are constant, so as to weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 9-12.
Embodiment 13-16：In addition to amine source compound ammonium ceric nitrate is replaced with ammonium chloride, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 13-16.
The result is shown in the following table 1.
Table 1
It can be seen that in amine source compound, ammonium ceric nitrate can obtain best technique effect, other amine source compounds
Then products collection efficiency is caused to be significantly reduced, this should be ammonium ceric nitrate while N atoms are provided, also simultaneously played oxygen
Change acts on, so as to promote significantly improving for yield.
Embodiment 17-32
Embodiment 17-20：Except catalyst hexafluoroacetylacetone copper is replaced with Cu (OAc)2Outside, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 17-20 is sequentially obtained.
Embodiment 21-24：Except catalyst hexafluoroacetylacetone copper is replaced with Cu (TFA)2Outside, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 21-24 is sequentially obtained.
Embodiment 25-28：Except catalyst hexafluoroacetylacetone copper is replaced with Cu (acac)2Outside, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 25-28 is sequentially obtained.
Embodiment 29-32：In addition to catalyst hexafluoroacetylacetone copper is replaced with trifluoroacetylacetone (TFA) copper, other operations are equal
It is constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 29-32.
Experimental result is as shown in table 2 below.
Table 2
It can be seen that in all catalyst, hexafluoroacetylacetone copper has a best catalytic effect, and even with
Its very similar trifluoroacetylacetone (TFA) copper, yield are also significantly reduced.This also directly confirms the selection of catalyst type
With the direct relation of product yield, and illustrate that the selection of catalyst type has not predictability.
Embodiment 33-43
In addition to following alkali is used to replace triisopropanolamine, other operations are constant, so as to repeat to implement implementation
Example 1-4, sequentially obtains embodiment 33-43, used alkali, correspondence and products collection efficiency are as shown in table 3 below.
Table 3
It can be seen that in all alkali, triisopropanolamine has a best effect, even very similar with it two
Ethanolamine, yield also has significant reduction, and the reduction of other alkali becomes apparent, especially potassium tert-butoxide and sodium ethoxide.
Embodiment 44-51
Embodiment 44-47：Except by auxiliary agent Ni (COD)2Replace with NiCl2(PCy3)2Outside, other operations are constant, so as to weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 44-47.
Embodiment 48-51：Except by auxiliary agent Ni (COD)2Outside being omitted, other operations are constant, so as to repeat to implement
Embodiment 1-4 sequentially obtains embodiment 48-51.
Experimental result is as shown in table 4 below.
Table 4
It can be seen that for as auxiliary agent, Ni (COD)2Effect to be significantly better than NiCl2(PCy3)2, still further it can be seen that,
When without using any auxiliary agent, products collection efficiency will slightly be better than NiCl instead2(PCy3)2, this proves NiCl2(PCy3)2Not
Play any promotion and improvement effect.
Embodiment 52-71
Embodiment 52-55：In addition to organic solvent acetonitrile is replaced with DMF, other operations are constant, so as to repeat to implement
Embodiment 1-4 sequentially obtains embodiment 52-55.
Embodiment 56-59：In addition to organic solvent acetonitrile is replaced with DMSO, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 56-59.
Embodiment 60-63：In addition to organic solvent acetonitrile is replaced with toluene, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 60-63.
Embodiment 64-67：In addition to organic solvent acetonitrile is replaced with benzene, other operations are constant, so as to repeat to implement
Embodiment 1-4 sequentially obtains embodiment 64-67.
Embodiment 68-71：In addition to organic solvent acetonitrile is replaced with ethyl alcohol, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 68-71.
Experimental result is as shown in table 5 below.
Table 5
It can be seen that in all organic solvents, acetonitrile has best solvent effect, can obtain highest product
Yield, and other organic solvents cause yield decrease to some degree, but still it is significantly higher than 80%.
In conclusion the present invention provides a kind of synthetic method for the sulphonyl class compound that can be used as medicine intermediate, institutes
State comprehensive selection and association of the method by suitable reactions substrate, amine source compound, catalyst, alkali and auxiliary agent and organic solvent
Together, obtain purpose product so as to high yield, have a good application prospect in medicine intermediate synthesis technical field and
Industrial production potential.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to the protection model of the limitation present invention
It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within the guarantor that the application the appended claims are limited
Within the scope of shield.
Claims (5)
1. the synthetic method of sulphonyl class compound shown in a kind of lower formula (III), the described method includes：It is organic molten into reactor
In agent, lower formula (I) compound, lower formula (II) compound, amine source compound, catalyst, alkali and auxiliary agent are added in, at 80-100 DEG C
Be stirred to react 6-9 it is small when, reaction system is cooled to room temperature after completion of the reaction, adjusts pH value to neutrality, filtering, by filter vacuum
Concentration, residue cross silica gel post separation to get formula (III) compound,
Wherein, R1、R2It is each independently selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
X is halogen；
The amine source compound is ammonium ceric nitrate；
The catalyst is hexafluoroacetylacetone copper；
The alkali is triisopropanolamine；
The auxiliary agent is double (1,5- cyclo-octadiene) nickel；
The organic solvent is acetonitrile.
2. synthetic method as described in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:2-3.
3. synthetic method as described in claim 1, it is characterised in that：Formula (I) compound and mole of amine source compound
Than for 1:1-2.
4. synthetic method as described in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of catalyst are
1:0.1-0.2。
5. such as claim 1-4 any one of them synthetic methods, it is characterised in that：Formula (I) compound and auxiliary agent rub
You are than being 1:0.06-0.1.
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| JPH01272565A (en) * | 1988-04-25 | 1989-10-31 | Shionogi & Co Ltd | N-benzenesulfonylamidine derivative and pesticide for rice blast containing the same derivative as active component |
| MXPA03011197A (en) * | 2001-06-06 | 2004-02-26 | Lilly Co Eli | Benzoylsulfonamides and sulfonylbenzamidines for use as antitumour agents. |
| CN102351621B (en) * | 2011-09-05 | 2013-10-09 | 苏州大学 | Method for preparing N-sulfonyl amidine |
| JP6112659B2 (en) * | 2013-04-22 | 2017-04-12 | 国立大学法人富山大学 | Methods for producing sulfonyl azide derivatives and acylsulfonamide derivatives and their use. |
| CN104016904B (en) * | 2014-06-04 | 2016-11-02 | 常州大学 | Polysubstituted amidine compound, preparation method and its usage |
| CN104447434B (en) * | 2014-12-04 | 2016-01-20 | 中国矿业大学 | A kind of method of catalyzed oxidation synthesis P―Carboxybenzenesulfonamide |
| CN104945287B (en) * | 2015-06-12 | 2017-06-13 | 苏州大学张家港工业技术研究院 | A kind of synthetic method of the acid inner salt compound of amidine |
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