CN100577653C - Process for producing dibenzo thionitrogen tropilidine derivative - Google Patents
Process for producing dibenzo thionitrogen tropilidine derivative Download PDFInfo
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- CN100577653C CN100577653C CN200610006965A CN200610006965A CN100577653C CN 100577653 C CN100577653 C CN 100577653C CN 200610006965 A CN200610006965 A CN 200610006965A CN 200610006965 A CN200610006965 A CN 200610006965A CN 100577653 C CN100577653 C CN 100577653C
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Abstract
The present invention provides a preparation method of dibenzothiazepine derivatives, which comprises the steps that after a nitrobenzene derivative and a thiosalicylic acid derivative react, an obtained 2-nitryl-2'-carboxyl-phenylene sulfide derivative is reduced, dehydrated and condensed to obtain the dibenzothiazepine derivative which is capable of preparing an initial raw material of a useful 11-[4-(2-(2-hydroxyethoxy)ethyl)]-1-piperazinyl dibenzothiazepine derivative used as an antipsychotic drug and is represented by dibenzo [b, f][1, 4] thiazepine-11-ketone. The present invention prepares dibenzo-[b, f](1, 4) sulfur-nitrogen-11-ketone and other dibenzo sulfur-nitrogen derivative as the initial material 11-(4-(2-(2-hydroxyl ethoxy)ethyl) )-1-piperazine dibenzo sulfur-nitrogen derivative useful as antipsychotic through the process including the reaction of nitrobenzene derivative and thio salicylic acid derivative to obtain 2-nitro-2'-carboxyl-phenyl sulfide derivative, reduction of the obtained derivative to obtain 2-amino-2'-carboxyl-phenyl sulfide derivative, dewatering and condensation of the 2-amino-2'-carboxyl-phenyl sulfide derivative.
Description
The application is that application number is that CN99816885.8 (international filing date is on July 9th, 1999), denomination of invention are " dibenzo sulphur nitrogen
The preparation method of derivative " the dividing an application of the PCT application that enters country's stage.
Technical field
The present invention relates to as the useful dibenzo sulphur nitrogen of the intermediate of medicine
The preparation method of derivative.The present invention be more particularly directed to as being used to prepare (4-(2-(2-hydroxyl-oxethyl) ethyl)-1-piperazinyl dibenzo sulphur nitrogen as the useful 11-of antipsychotic drug
And dibenzo sulphur nitrogen shown in the useful following general formula (5) of the intermediate of derivative
The preparation method of derivative.
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Can be identical or different, the expression hydrogen atom maybe can have substituent alkyl, alkoxyl group, alkyl-carbonyl, aryl, aryloxy or aryl carbonyl.)
Background technology
Dibenzo sulphur nitrogen for above-mentioned general formula (5)
Derivative, on the books in the EP-0282236-A1 communique, illustrate with this dibenzo sulphur nitrogen
Derivative is a raw material, can derive to obtain (the 4-(2-(2-hydroxyl-oxethyl) ethyl)-1-piperazinyl dibenzo sulphur nitrogen as the useful 11-of antipsychotic drug
Derivative.That is to say, illustrate the dibenzo sulphur nitrogen that makes general formula (5)
The representation compound dibenzo of derivative (b, f) (1,4) sulphur nitrogen
-11 ketone and Phosphorus Oxychloride reaction obtain 11-chloro-dibenzo sulphur nitrogen
Derivative then makes piperazine add to this 11-chloro-dibenzo sulphur nitrogen
On the derivative, obtain 11-piperazinyl-dibenzo sulphur nitrogen
Derivative makes this 11-piperazinyl-dibenzo sulphur nitrogen at last
Derivative and 2-chloroethoxy ethanol react under alkaline condition, can derive to obtain above-mentioned 11-(4-(2-(2-hydroxyl-oxethyl) ethyl)-1-piperazinyl dibenzo sulphur nitrogen
Derivative.
In above-mentioned EP-0282236-A1 communique, as dibenzo (b, f) (1,4) sulphur nitrogen
The preparation method of-11-ketone has also put down in writing the cyclization that utilizes 2-(thiophenyl) phenylcarbamic acid phenyl ester or its similar compound method of (Tripyrophosphoric acid exists down).
Helv.Chim.Acta, 42 volumes, 1263 pages (nineteen fifty-nine) put down in writing and made thio-methyl salicylate derivative and 2-halogenated nitrobenzene derivative carry out reacting by heating in the presence of sodium, Synthetic 2-nitro-2 '-carboxyl-diphenyl sulfide derivative, use Raney Ni that it is reduced, make 2-amino-2 '-carboxyl-diphenyl sulfide derivative, make it at last at high temperature to react, preparation dibenzo sulphur nitrogen
The method of derivative.
Org.Prep.Proced.Int., 287 pages (1974) have been put down in writing behind heating thiosalicylic acid ester derivative and 2-iodo nitrobenzene derivative in the presence of sodium methylate and the copper, carry out alkali and acid treatment, Synthetic 2-nitro-2 '-carboxyl-diphenyl sulfide derivative, use the ammonia soln of ferrous sulfate that it is reduced, make 2-amino-2 '-carboxyl-diphenyl sulfide derivative, under the heating reduced pressure, make it reaction at last, preparation dibenzo sulphur nitrogen
The method of derivative.
Put down in writing in the WO92/19607 communique make the reaction of 2-aminothiophenol and 2-fluorobenzonitrile obtain 2-(2-amino-benzene sulfenyl) cyanobenzene after, with this compound hydrolysis, make 2-(2-carboxyl thiophenyl) aniline, make this compound carry out cyclization at last, the dibenzo sulphur nitrogen of preparation general formula (5)
The method of derivative.
As mentioned above, as the dibenzo sulphur nitrogen of general formula (5)
The preparation method of derivative, though known several method, these methods exist yield low, need pyroreaction, need to use special raw material, the problem of perhaps using the compound etc. of industrial aftertreatment trouble must improve as industrial production process.
Disclosure of the Invention
Therefore, the object of the present invention is to provide the dibenzo sulphur nitrogen of a kind of above-mentioned general formula of industrial effective preparation (5)
The method of derivative that is to say, uses the starting compound that obtains easily, do not carry out numerous and diverse aftertreatment, and high yield obtains required dibenzo sulphur nitrogen
The preparation method of derivative.
The inventor has carried out concentrated research in order to solve above-mentioned problem, found that to use the nitrobenzene derivative that obtains easily and the thio-salicylic acid derivative can high yield and prepare the dibenzo sulphur nitrogen of general formula (5) by simple operations
The novel method of derivative, thus the present invention finished.
The present invention relates to the dibenzo sulphur nitrogen of following general formula (5) expression
The preparation method of derivative, it is characterized in that making the nitrobenzene derivative of general formula (1) expression and the thio-salicylic acid derivative reaction of following general formula (2) expression, after generating the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of following general formula (3) expression, with this 2-nitro-2 '-carboxyl-diphenyl sulfide derivative reduction, after generating the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of following general formula (4) expression, make this 2-amino-2 '-carboxyl-diphenyl sulfide derivative dehydrating condensation.
(in the formula, R
1, R
2, R
3And R
4Can be identical or different, the expression hydrogen atom maybe can have substituent alkyl, alkoxyl group, alkyl-carbonyl, aryl, aryloxy or aryl carbonyl, and X represents halogen atom)
(in the formula, R
5, R
6, R
7And R
8Can be identical or different, the expression hydrogen atom maybe can have substituent alkyl, alkoxyl group, alkyl-carbonyl, aryl, aryloxy or aryl carbonyl)
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent implication same as described above)
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent implication same as described above)
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent implication same as described above)
The invention still further relates to the dibenzo sulphur nitrogen of following general formula (5) expression
The preparation method of derivative, it is characterized in that making the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative reduction of following general formula (3) expression, after generating the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of following general formula (4) expression, make this 2-amino-2 '-carboxyl-diphenyl sulfide derivative dehydrating condensation.
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Can be identical or different, the expression hydrogen atom maybe can have substituent alkyl, alkoxyl group, alkyl-carbonyl, aryl, aryloxy or aryl carbonyl)
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent implication same as described above)
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent implication same as described above)
The invention still further relates to the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of above-mentioned general formula (3) expression.
The dibenzo sulphur nitrogen of general formula of the present invention (5)
Each step of the preparation method of derivative can be represented with following reaction scheme.
The preferred forms of invention
Dibenzo sulphur nitrogen of the present invention
In each general formula that the preparation method of derivative relates to, R
1To R
8Expression " can have substituent alkyl " is meant straight chain shape or the branched-chain alkyl with 1～10 of substituent carbonatoms, perhaps has the straight chain shape or the branched-chain alkyl of 1～10 of substituent carbonatoms.
As above-mentioned " the straight chain shape or the branched-chain alkyl that do not have 1～10 of substituent carbonatoms ", the straight chain shape or the branched-chain alkyl of preferred carbonatoms 1～8 (particularly carbonatoms is 1～5), methyl for example, ethyl, propyl group (comprising isomer), butyl (comprising isomer), amyl group (comprising isomer), hexyl (comprising isomer), heptyl (comprising isomer), octyl group (comprising isomer), nonyl (comprising isomer), decyl (comprising isomer) etc., preferable methyl, ethyl, propyl group (comprising isomer), butyl (comprising isomer), amyl group (comprising isomer), hexyl (comprising isomer), heptyl (comprising isomer), octyl group (comprising isomer), special preferable methyl, ethyl, propyl group (comprising isomer), butyl (comprising isomer), amyl group (comprising isomer).
In addition, as the moieties of " straight chain shape or branched-chain alkyl ", the alkyl described in for example above-mentioned (1) with 1～10 of substituent carbonatoms.
The substituting group of above-mentioned " straight chain shape or branched-chain alkyl with 1～10 of substituent carbonatoms " can be positioned at the optional position of moieties.As this substituent example; methoxyl group for example; oxyethyl group; propoxy-(comprising isomer); butoxy (comprising isomer); pentyloxy (comprising isomer); hexyloxy (comprising isomer); oxygen base in heptan (comprising isomer); octyloxy (comprising isomer); oxygen base in the ninth of the ten Heavenly Stems (comprising isomer); the last of the ten Heavenly stems 1～10 of oxygen base carbonatomss such as (comprising isomer) the straight or branched alkoxyl group; ethanoyl; propionyl (comprising isomer); butyryl radicals (comprising isomer); pentanoyl etc. have the alkyl-carbonyl of 2～6 of the carbonatomss of the straight chain shape of 1～5 of carbonatoms or branched-chain alkyl part; can substituted phenylcarbonyl group, or can substituted phenyl.
Above-mentioned " can substituted phenylcarbonyl group " be meant not have substituent phenylcarbonyl group or have substituent phenylcarbonyl group." can substituted phenyl " be meant not have substituent phenyl, perhaps has substituent phenyl.As each substituting group of " having substituent phenylcarbonyl group " or " having substituent phenyl ", for example phenyl, phenylcarbonyl group, abovementioned alkyl, above-mentioned alkoxyl group or abovementioned alkyl carbonyl.
Among the present invention, the R of above-mentioned general formula (2), (3), (4) and (5)
1To R
8" can have substituent alkoxyl group " of expression is meant the alkoxyl group of 1～10 of carbonatoms with the straight chain shape of not being with 1～10 of substituent carbonatoms or branched-chain alkyl part, perhaps has the alkoxyl group with 1～10 of the carbonatoms of the straight chain shape of 1～10 of substituent carbonatoms or branched-chain alkyl part.
As above-mentioned " alkoxyl group ", can exemplify above-mentioned alkoxyl group with 1～10 of carbonatoms of the straight chain shape of not being with 1～10 of substituent carbonatoms or branched-chain alkyl part.In addition, as the substituent example of " having alkoxyl group " with 1～10 of the carbonatoms of the straight chain shape of 1～10 of substituent carbonatoms or branched-chain alkyl part, for example the alkyl-carbonyl of 2～6 of abovementioned alkyls, carbonatoms, can substituted phenylcarbonyl group and can substituted phenyl.
Dibenzo sulphur nitrogen of the present invention
In each general formula that the preparation method of derivative relates to, R
1To R
8" can have substituent alkyl-carbonyl " of expression is meant the alkyl-carbonyl of 2～11 of carbonatomss with the straight chain shape of not being with 1～10 of substituent carbonatoms or branched-chain alkyl part, perhaps has the alkyl-carbonyl with 2～11 of the carbonatomss of the straight chain shape of 1～10 of substituent carbonatoms or branched-chain alkyl part.
As the moieties of above-mentioned " alkyl-carbonyl ", for example abovementioned alkyl with 2～11 of carbonatomss of the straight chain shape of not being with 1～10 of substituent carbonatoms or branched-chain alkyl part.As the substituting group of " having alkyl-carbonyl ", for example substituting group of abovementioned alkyl with 2～11 of the carbonatomss of the straight chain shape of 1～10 of substituent carbonatoms or branched-chain alkyl part.
Dibenzo sulphur nitrogen of the present invention
In each general formula that the preparation method of derivative relates to, R
1To R
8Expression " can have substituent aryl " is meant not have substituent aryl, perhaps has substituent aryl.
As above-mentioned " not having substituent aryl " for example phenyl, naphthyl, anthryl etc., preferred phenyl, naphthyl, preferred especially phenyl.As the substituting group of " having substituent aryl ", for example substituting group of abovementioned alkyl.
Dibenzo sulphur nitrogen of the present invention
In each general formula that the preparation method of derivative relates to, R
1To R
8Expression " can have substituent aryloxy " is meant to have the aryloxy of not being with substituent aryl moiety, perhaps has the aryloxy with substituent aryl moiety.
As the aryl of above-mentioned " having the aryloxy of not being with substituent aryl moiety ", for example above-mentioned aryl.And, as the substituting group of " having aryloxy ", for example substituting group of abovementioned alkyl with substituent aryl moiety.
Dibenzo sulphur nitrogen of the present invention
In each general formula that the preparation method of derivative relates to, R
1To R
8Expression " can have substituent aryl carbonyl " is meant to have the aryl carbonyl of not being with substituent aryl moiety, perhaps has the aryl carbonyl with substituent aryl moiety.
As the aryl of above-mentioned " having the aryl carbonyl of not being with substituent aryl moiety ", for example above-mentioned aryl.As the substituting group of " having aryl carbonyl ", for example substituting group of abovementioned alkyl with substituent aryl moiety.
R
1To R
8Can be identical or different, preferred hydrogen atom, alkyl, alkoxyl group, alkyl-carbonyl, aryl, aryloxy or aryl carbonyl, preferred especially hydrogen atom, alkyl, alkoxyl group or alkyl-carbonyl.
The halogen atom of representing as the X of general formula (1), for example fluorine atom, chlorine atom, bromine atoms or iodine atom, preferred fluorine atom, chlorine atom or bromine atoms.
Secondly, to dibenzo sulphur nitrogen of the present invention
Each step of the preparation method of derivative is elaborated.
At dibenzo sulphur nitrogen of the present invention
In the preparation method's of derivative the 1st step, preferably in the presence of alkali, in solvent, make the nitrobenzene derivative of general formula (1) expression and the thio-salicylic acid derivative reaction of general formula (2) expression, the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of preparation general formula (3) expression.
Specific examples as the nitrobenzene derivative of the general formula (1) that uses in above-mentioned the 1st step; 2-chloronitrobenzene for example; the 2-bromo nitrobenzene; the 2-fluoronitrobenzene; the 2-iodonitrobenzene; 2-chloro-5-methoxyl group-oil of mirbane; 2-bromo-5-methoxyl group-oil of mirbane; 2-fluoro-5-methoxyl group-oil of mirbane; 2-iodo-5-methoxyl group-oil of mirbane; 2-chloro-5-methyl-oil of mirbane; 2-bromo-5-methyl-oil of mirbane; 2-fluoro-5-methyl-oil of mirbane; 2-iodo-5-methyl-oil of mirbane; 2-chloro-5-phenyl-oil of mirbane; 2-bromo-5-phenyl-oil of mirbane; 2-fluoro-5-phenyl-oil of mirbane; 2-iodo-5-phenyl-oil of mirbane; 2-chloro-5-ethanoyl-oil of mirbane; 2-bromo-5-ethanoyl-oil of mirbane; 2-fluoro-5-ethanoyl-oil of mirbane and 2-iodo-5-ethanoyl-oil of mirbane, preferred 2-chloronitrobenzene and 2-bromo nitrobenzene.
Specific examples as the thio-salicylic acid derivative of the general formula that uses in the 1st step (2); for example thiosalicylic acid, 5-methoxyl group-thiosalicylic acid, 5-methyl-thiosalicylic acid, 5-phenyl-thiosalicylic acid and 5-ethanoyl-thiosalicylic acid, preferred thiosalicylic acid and 5-methoxyl group thiosalicylic acid.
The nitrobenzene derivative of general formula (1) uses with the amount of 0.7～10 molar range for 1 mole usually with respect to the thio-salicylic acid derivative of general formula (2), especially preferably uses with the consumption that reaches 1.0～5 times of molar ratios.
Above-mentioned the 1st step is implemented in the presence of solvent usually.As long as the solvent that uses in the 1st step is irrelevant with reaction, there is no particular limitation, for example can make water, N, dinethylformamide, N, amides organic solvents such as N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl-imidazolinone, aliphatics alcohols organic solvents such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, organic solvent of ketone such as acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), nitrile organic solvents such as acetonitrile, cyanobenzene.Preferably water, amides organic solvent and aliphatics alcohols organic solvent.
The solvent of the 1st step preferably uses with respect to the amount that the ratio " nitrobenzene derivative weight/weight of solvent " of weight of solvent reaches 0.05～1.0 scope with the nitrobenzene derivative weight of general formula (1), especially preferably uses with the amount that reaches 0.1～0.8 scope.
The temperature of reaction of the 1st step needs only the temperature below the boiling point of common solvent for use, preferred 0～150 ℃ scope, preferred especially 20～100 ℃ scope.The reaction times of the 1st step is subjected to the influence of temperature of reaction remarkable, reacts with interior end at 20 hours usually.
The reaction of the 1st step is implemented in the presence of alkali usually.As the preferred alkali that uses in the 1st step, for example salt of wormwood, yellow soda ash, Quilonum Retard, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium methylate, especially preferably salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide and sodium methylate.These alkali preferably reach the amount use of 1～10 times of molar ratio with the total amount with respect to the initial feed compound, the preferred especially amount that reaches 1.5～5 times of molar ratios of using.
When implementing the reaction of the 1st step, except that alkali, also can further add the additive that promotes reaction, as this additive, for example potassiumiodide, N, N-Dimethylamino pyridine etc.At this moment the consumption of additive reaches the amount of 0.0005～0.5 (mole number of the mole number/nitrobenzene derivative of additive) ratio in molar ratio preferably with respect to the nitrobenzene derivative of general formula (1), especially preferably reaches the amount of 0.001～0.1 (equally) ratio.
The chemical structure of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of the general formula (3) that preparation method's of the present invention the 1st step obtains is determined by the chemical structure of the thio-salicylic acid derivative of the chemical structure of the nitrobenzene derivative of general formula (1) and general formula (2); but as 2-nitro-2 '-carboxyl-diphenyl sulfide derivative, for example 2-nitro-2 '-carboxyl-diphenyl sulfide; 2-nitro-4-methoxyl group-2 '-carboxyl-diphenyl sulfide; 2-nitro-4-methyl-2 '-carboxyl-diphenyl sulfide; 2-nitro-4-phenyl-2 '-carboxyl-diphenyl sulfide; 2-nitro-4-ethanoyl-2 '-carboxyl-diphenyl sulfide and 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide.Preferred 2-nitro-2 '-carboxyl-diphenyl sulfide and 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide.
When reclaiming 2-nitro-the 2 '-carboxyl of the general formula (3) that the 1st step generates-diphenyl sulfide derivative, can be with the washing operation and the lock out operation combination of routine, acid is for example added in utilization in reaction mixture makes it to become acidity, the crystal that filtration is separated out obtains the method for crude product, or in reaction solution, add water and extraction solvent (organic solvent), be the tart method to wherein adding sour pH regulator with water layer.In addition, also can obtain crude product by the concentrating under reduced pressure organic layer.Even it is also no problem usually to be used for following steps with such state, makes with extra care by column chromatography or recrystallization operation when further refining and get final product.Preferably each compound is suitably selected about concrete process for purification.As the acid of using in the above-mentioned processing, preferred hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid.
The 2nd step among the preparation method of the present invention is the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative by reduction general formula (3), the method for the 2-amino-2 '-carboxyl-diphenyl sulfide of preparation general formula (4).
The restoring operation of adopting in the 2nd step so long as the operation of adopting in the general reduction of nitro get final product, there is no particular limitation, preferably adopts Raney Ni method (hereinafter referred to as reaction (A)), ferrous salt method (hereinafter referred to as reaction (B)) or use the method (hereinafter referred to as reaction (C)) of palladium or platinum or their compound to carry out.As the supply source of hydrogen in the reduction reaction, generally use hydrogen.
Reaction (A): Raney Ni method
The consumption of the Raney Ni that uses in this method generally with respect to the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3), is generally 1.0～80 weight % as the nickel amount, preferred 5.0～40 weight %.As the kind of utilizable Raney Ni, 10～60%Ni-Al alloy for example.In addition, also can use as additive to the alloy that has wherein added Cr and Mo.Also can use stabilization nickel.Even change the method for deploying of Raney Ni, also can not bring too much influence, but the method for known W-6 (is believed a youth with reference to the Kubo pine according to husband, Xiao Song to yield, " blue Buddhist nun's catalyzer ", fine chemistry Co., Ltd. is ground in the river, clear and on May 10th, 46,55 pages) obtained best result.Certainly, even utilize other method of deploying also to show sufficient activity.When adopting the Raney Ni method to react, under the hydrogen pressurized conditions, carry out usually, therefore in autoclave, carry out.Hydrogen pressure is high more, and the result who obtains is good more, carries out under 5～100 normal atmosphere usually.Also can under normal pressure, react, at this moment make hydrogen circulation, react simultaneously.
About the solvent that uses in the reaction (A), so long as get final product with reacting the material that has nothing to do, there is no particular limitation, aliphatics alcohols organic solvents such as preference such as methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol.These solvents preferably reach the scope of 0.05～0.6 times of amount (capacity of 2-nitro-2 '-carboxyl-diphenyl sulfide derivative weight/solvent) with respect to the ratio of the solvent of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3), especially preferably reach the ratio of 0.1～0.6 times of amount (equally).
As the temperature of reaction in the reaction (A), so long as the following temperature of the boiling point of solvent for use gets final product the temperature of preferred 20～200 ℃ of scopes, the temperature of preferred especially 25～150 ℃ of scopes usually.Reaction times is subjected to the influence of temperature of reaction and hydrogen pressure remarkable, reacts with interior end at 20 hours usually.
By reaction (A) reduce handle after, the recovery of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of the general formula (4) that generates can be with the washing operation and the lock out operation combination of routine, for example filter reaction mixture concentrates the filtrate decompression that obtains, and obtains crude product.Even it is also no problem usually to be used for following steps with this state, make with extra care by column chromatography or recrystallization operation when further refining and get final product, preferably each compound is suitably selected about process for purification.
Reaction (B): ferrous salt method
As the ferrous salt that uses in this method, for example ferrous sulfate or iron protochloride, this ferrous salt can use with hydrate or any one state of anhydride.Ferrous 7 hydrates of preferably sulfuric acid, anhydrous chlorides of rase are ferrous, iron protochloride 4 hydrates and iron protochloride n hydrate.The consumption of these compounds is amount in 0.1～30 times of weight range as the amount of iron atom with respect to the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3), the amount in preferred 0.5～10 times of weight range.
As the solvent that uses in the reaction (B), make the mixed solvent of water and ammoniacal liquor usually.The ammoniacal liquor that uses uses strong aqua (ammonia concentration is 25～28 weight %) to carry out usually, as long as the ammonia amount that contains is abundant, also can use the ammoniacal liquor of lower concentration, or feed ammonia in water.About water, the 2-nitro-2 ' of preferred formula (3)-carboxyl-diphenyl sulfide derivative reaches the ratio of 0.01～0.4 times of equivalent (capacity of 2-nitro-2 '-carboxyl-diphenyl sulfide derivative weight/water) scope with respect to the amount of water, especially preferably reaches the ratio of 0.02～0.2 times of equivalent (equally) scope.About ammonia, 2-nitro-2 '-carboxyl-diphenyl sulfide derivative preferably reaches the ratio of 0.005～0.5 times of equivalent (weight of 2-nitro-2 '-carboxyl-diphenyl sulfide derivative weight/ammonia) scope with respect to the consumption of ammonia, especially preferably reaches the ratio of 0.01～0.5 times of equivalent (equally).
Temperature of reaction in the reaction (B) is so long as the following temperature of the boiling point of common solvent for use gets final product the temperature of preferred 20～100 ℃ of scopes, the temperature of preferred especially 40～90 ℃ of scopes.Reaction times is subjected to reaction temperatures affect remarkable, reacts with interior end at 2 hours usually.
After the reduction processing by reaction (B), the recovery of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of the general formula (4) that generates, can be with the washing operation and the lock out operation combination of routine, for example can utilize filter reaction mixture, in filtrate, add acid (for example hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid) pH regulator to the method for acidic side etc. is carried out.In addition, by the filtrate that concentrating under reduced pressure obtains, can be used as crude product and obtain the purpose compound.Even it is also no problem usually this crude product to be used for following steps, make with extra care by column chromatography or recrystallization operation when further refining and get final product, preferably each compound is suitably selected about process for purification.
Reaction (C): the method for using palladium or platinum (or their compound)
In this method, use palladium (Pd) or platinum (Pt) as reducing catalyst (hydrogenation catalyst).The palladium or the platinum that use can be the monomers of palladium or platinum, also can be their compounds.In addition, the monomer of palladium or platinum or compound use to support in the state of carrier surfaces such as carbon (C) or barium sulfate usually.Preferred Pd/C, Pd/ barium sulfate and platinum oxide, preferred especially Pd/C.
Contain the consumption of the catalyst consumption of palladium or platinum with respect to the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3), converting by the monomeric weight of palladium or platinum preferably reaches the amount of 0.01～30 weight % scope, especially preferably reaches the amount of 0.05～10 weight % scope.In addition, palladium or platinum are preferably the scope of 1～10 weight % with respect to the loading (being the occasion of the compound of palladium or platinum, according to the monomer weight conversion of each metal) of support of the catalyst.In addition, use the occasion of Pd/C, generally can use the moisture content that is called dry product is dry product 5% below, and also can use moisture content is moisture product that are called the product of wetting more than 5%.As the example of moisture product, for example moisture content is the material of 10～70 weight % (ratio of the amount that amount of moisture is overall with respect to catalyzer).
In the reaction (C), when using platinum oxide as reducing catalyst, platinum oxide preferably reaches the amount of 0.1～50 weight % scope with respect to the consumption of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3), especially preferably reaches the amount of 1～30 weight % scope.
Reaction (C) is carried out under the hydrogen pressurized conditions usually.Therefore, reaction is carried out in autoclave usually.Hydrogen pressure is high more, and the result who obtains is good more, utilizes 2～100 atmospheric hydrogen pressurized conditions usually.Reaction also can be carried out under normal pressure, at this moment makes hydrogen circulation, carries out reduction reaction (hydrogenation reaction) simultaneously.
Reaction (C) is implemented in the presence of solvent usually.As the solvent that uses in the reaction (C), so long as get final product with the irrelevant material of reaction, there is no particular limitation, can use for example aliphatics alcohols organic solvents such as methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol, N, amides organic solvents such as dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone or dimethyl-imidazolinone.Preferred aliphat alcohol organic solvent wherein.These solvent phase preferably use with the amount of 2～70 weight % scopes for the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3), especially preferably use with the amount of 5～50 weight % scopes.
Reaction is implemented in reaction (C) usually in 10～200 ℃ temperature range, especially preferably utilize the temperature of reaction of 20～150 ℃ of scopes.In addition, it is bigger that the reaction times is influenced by temperature of reaction and hydrogen pressure, utilizes 30 hours usually with the interior reaction times.
After adopting the reduction processing (hydrotreatment) of reaction (C), the recovery of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of the general formula (4) that generates can be with the washing operation and the lock out operation combination of routine, for example can utilize filter reaction mixture, the filtrate decompression that obtains be concentrated the method that obtains crude product etc. and carry out.Even it is also no problem usually to be used for following steps with this state, make with extra care by column chromatography or recrystallization operation when further refining and get final product, preferably each compound is suitably selected about process for purification.
The chemical structure of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of the general formula (4) that preparation method's of the present invention the 2nd step (reduction step) obtains is determined by the chemical structure of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of the general formula (3) that is used as reaction raw materials in the 2nd step.As the example of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of general formula (4), for example 2-amino-2 '-carboxyl-diphenyl sulfide, 2-amino-4-methoxyl group-2 '-carboxyl-diphenyl sulfide, 2-amino-4-methyl-2 '-carboxyl-diphenyl sulfide, 2-amino-4-phenyl-2 '-carboxyl-diphenyl sulfide, 2-amino-4-ethanoyl-2 '-carboxyl-diphenyl sulfide and 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide.Preferred 2-amino-2 '-carboxyl-diphenyl sulfide and 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide.
Preparation method's of the present invention the 3rd step is with the 2-amino-2 ' of general formula (4)-carboxyl-diphenyl sulfide derivative dehydrating condensation, the dibenzo sulphur nitrogen of preparation general formula (5) expression
The method of derivative.
The reaction of the 3rd step can solvent-freely be carried out, but preferably use hydrophobicity and to the reaction carry out as organic solvent inert.Example as this organic solvent, aromatic hydrocarbon solvents such as toluene, dimethylbenzene, isopropyl benzene, benzene for example, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, bromobenzene, 1,2-dibromobenzene, 1,3-dibromobenzene, 1, aromatic halide kind solvents such as 4-dibromobenzene, aliphatic ester kind solvent such as cyclic hydrocarbon kind solvent such as hexanaphthene, suberane, cyclooctane or ethyl acetate, butylacetate, methyl-butyrate, ethyl butyrate, butyl butyrate etc.Preferred especially toluene, dimethylbenzene, isopropyl benzene and 1, the 2-dichlorobenzene.
There is no particular limitation for the consumption of the solvent that uses in the 3rd step, and the volume of solvent is preferably more than 3% the amount of preferred especially 4～40% scopes with respect to the ratio (W/V%) of the weight of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of general formula (4).In addition, in order to improve speed of response and the transformation efficiency in the 3rd step, also can use the Dean-Stark device to carry out azeotropic dehydration operation (removing the water of generation, the operation that refluxes simultaneously).The temperature of reaction of the 3rd step is as long as below the boiling point of used organic solvent, and there is no particular limitation, the temperature of preferred 100 ℃～200 ℃ of scopes.
The dibenzo sulphur nitrogen of the general formula that obtains in the 3rd step (5)
The chemical structure of derivative is determined by the chemical structure of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of general formula (4).Dibenzo sulphur nitrogen as general formula (5)
Derivative, for example dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone, 8-methyl-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone, 8-phenyl-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone, 8-methoxyl group-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone and 2-methoxyl group-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone.Preferred dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone and 2-methoxyl group-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone.
The dibenzo sulphur nitrogen of the general formula (5) that the 3rd step generates
The recovery of derivative can utilize reaction mixture to make dibenzo sulphur nitrogen
The method that the crystal of derivative is separated out is easily implemented.Therefore, can obtain highly purified dibenzo sulphur nitrogen by filtering this crystal
Derivative.When being necessary further to make with extra care, can carry out recrystallization, or adopt column chromatography.Perhaps also can utilize making before reaction mixture separates out crystal, add alkaline aqueous solution, separate water layer after, cool off, make dibenzo sulphur nitrogen
Derivative crystalline method.The example of the basic cpd that uses, for example sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydroxide and potassium hydroxide during as the alkaline aqueous solution of use in this operation of preparation.Alkaline aqueous solution neutral and alkali compound concentrations is preferably the scope of 0.5～30 weight %.In addition, there is no particular limitation for the consumption of alkaline aqueous solution, preferably with respect to product (the dibenzo sulphur nitrogen of general formula (5) of the 3rd step
Derivative) uses with the amount about 0.05～0.4 times of weight.
Optimal way of the present invention is as described below.
(1) nitrobenzene derivative of general formula (1) is 2-chloronitrobenzene or 2-bromo nitrobenzene.
(2) thio-salicylic acid derivative of general formula (2) is thiosalicylic acid or 5-methoxyl group thiosalicylic acid.
(3) dibenzo sulphur nitrogen of the present invention
In the preparation method's of derivative the 1st step, use the alkali of from salt of wormwood, sodium hydroxide and sodium methylate, selecting.
(4) the 2-nitro-2 ' of general formula (3)-carboxyl-diphenyl sulfide derivative is 2-nitro-2 '-carboxyl-diphenyl sulfide or 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide.
(5) dibenzo sulphur nitrogen of the present invention
In the preparation method's of derivative the 1st step, use N, dinethylformamide or methyl alcohol are as reaction solvent.
(6) dibenzo sulphur nitrogen of the present invention
In the reduction reaction of the preparation method's of derivative the 2nd step, use Raney Ni, use methyl alcohol or propyl carbinol as solvent as reductive agent.
(7) dibenzo sulphur nitrogen of the present invention
In the reduction reaction of the preparation method's of derivative the 2nd step, use ferrous sulfate 7 hydrates, use ammonia soln as solvent as reductive agent.
(8) dibenzo sulphur nitrogen of the present invention
The reduction reaction of the preparation method's of derivative the 2nd step in the presence of any one reducing catalyst, uses methyl alcohol or ethanol to carry out as solvent in Pd/C, Pd/ barium sulfate or platinum oxide.
(9) the 2-amino-2 ' of general formula (4)-carboxyl-diphenyl sulfide derivative is 2-amino-2 '-carboxyl-diphenyl sulfide, 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide or 2-methoxyl group-dibenzo (b, f) (1, a 4) sulphur nitrogen
-11-ketone.
(10) the dibenzo sulphur nitrogen of general formula (5) expression
Derivative is dibenzo (b, f) (1, a 4) sulphur nitrogen
-11-ketone or 2-methoxyl group-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone.
(11) as the nitrobenzene derivative of the general formula (1) of the 1st step reaction raw material, use 2-chloronitrobenzene or 2-bromo nitrobenzene; In addition, as the thio-salicylic acid derivative of general formula (2), use thiosalicylic acid or 5-methoxyl group thiosalicylic acid; As alkali, use salt of wormwood; As solvent, use N, dinethylformamide; Preparation is as 2-nitro-the 2 '-carboxyl diphenyl sulfide or 2-nitro-2 '-carboxyl-the 4 '-anisole thioether of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3).
(12) as the reaction raw materials of the 2nd step, use 2-nitro-2 '-carboxyl-diphenyl sulfide or 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide, with hydrogen it is reduced in the presence of platinum, palladium or their compound, preparation is as the 2-amino-2 '-carboxyl-diphenyl sulfide or the 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide of the 2-amino-2 '-carboxyl-diphenyl sulfide derivative of general formula (4).
(13) as the reaction raw materials of the 3rd step, use 2-amino-2 '-carboxyl-diphenyl sulfide or 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide, preparation is as the dibenzo sulphur nitrogen of general formula (5)
The dibenzo of derivative (b, f) (1,4) sulphur nitrogen
-11-ketone or 2-methoxyl group-dibenzo (b, f) (1,4) sulphur nitrogen
-11-ketone.
Below, illustrate in greater detail preparation method of the present invention in conjunction with embodiments of the invention and comparative example, but the present invention is not subjected to the qualification of these embodiment.
(embodiment 1)
2-chloronitrobenzene 94.5g (0.60 mole) and salt of wormwood 159.0g (1.15 moles) are dissolved in N, among the dinethylformamide 120mL.At the N that obtains, in the dinethylformamide solution, drip thiosalicylic acid 77.1g (0.50 mole) is dissolved in N, the solution that dinethylformamide 120mL obtains stirs under 70 ℃ and made it reaction in 6 hours.In the reaction solution that obtains, add entry 800mL and ethyl acetate 700mL.In isolated water layer, add ice 400g and concentrated hydrochloric acid 194mL, the pH of water layer is reconciled to after the acidity, at room temperature with this solution stirring 1 hour.The crystal of filter, drying being separated out obtains yellow powder shape 2-nitro-2 '-carboxyl-diphenyl sulfide 134.0g (0.49 mole).(with respect to the yield of thiosalicylic acid: 98%)
1H-N?MR(DMSO-d
6)：δ
7.1～8.3(m，8H)、13.1～13.5(br，1H)
(embodiment 2)
2-chloronitrobenzene 94.5g (0.60 mole) and salt of wormwood 159.0g (1.15 moles) are dissolved in N, among the dinethylformamide 120mL.At the N that obtains, in the dinethylformamide solution, drip thiosalicylic acid 77.1g (0.50 mole) is dissolved in N, the solution that dinethylformamide 120mL obtains stirs under 70 ℃ and made it reaction in 6 hours.In the reaction solution that obtains, add entry 200mL and concentrated hydrochloric acid 194mL, the pH of water layer is reconciled to after the acidity, at room temperature with this solution stirring 1 hour.The crystal of filter, drying being separated out obtains yellow powder shape 2-nitro-2 '-carboxyl-diphenyl sulfide 123.0g (0.45 mole).(with respect to the yield of thiosalicylic acid: 90%)
(embodiment 3)
Remove chloronitrobenzene, its consumption is changed into 121.2g (0.60 mole) in addition, carry out operation similarly to Example 1, obtain 2-nitro-2 '-carboxyl-diphenyl sulfide 134.0g (0.49 mole) with 2-bromo nitrobenzene replacement 2-.(with respect to the yield of thiosalicylic acid: 98%)
(embodiment 4)
Remove with 5-methoxyl group thiosalicylic acid replacement thiosalicylic acid, its consumption is changed into 93.8g (0.50 mole) in addition, carry out operation similarly to Example 1, obtain 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide 137.3g (0.45 mole).(with respect to the yield of 5-methoxyl group thiosalicylic acid: 90%).Fusing point: 185～187
(embodiment 5)
Remove solvent from N, dinethylformamide is changed into methyl alcohol, and temperature of reaction and time are changed into beyond 64 ℃ and 2 hours, carries out operation similarly to Example 1, obtains 2-nitro-2 '-carboxyl-diphenyl sulfide 131.3g (0.48 mole).(with respect to the yield of thiosalicylic acid: 96%)
(embodiment 6)
Remove salt of wormwood is changed into sodium hydroxide, its consumption is changed into 46.0g (1.15 moles) in addition, carry out operation similarly to Example 5, obtain 2-nitro-2 '-carboxyl-diphenyl sulfide 130.0g (0.47 mole).(with respect to the yield of thiosalicylic acid: 94%)
(embodiment 7)
Remove salt of wormwood is changed into sodium methylate, its consumption is changed into 62.1g (1.15 moles), and beyond will changing in the reaction times 5 hours, carry out operation similarly to Example 5, obtain 2-nitro-2 '-carboxyl-diphenyl sulfide 131.8g (0.48 mole).(with respect to the yield of thiosalicylic acid: 96%)
(embodiment 8)
Except that in reaction soln, adding potassiumiodide 3.9g (0.02 mole) in advance, carry out operation similarly to Example 7, obtain 2-nitro-2 '-carboxyl-diphenyl sulfide 133.8g (0.49 mole).(with respect to the yield of thiosalicylic acid: 97%)
(embodiment 9)
In the autoclave of 300mL, add Raney Ni (as 50% alloy, Ni amount is 4g), the 2-nitro-2 '-carboxyl-diphenyl sulfide 13.8g (0.05 mole) and the methyl alcohol 100mL that obtain according to the method for embodiment 1, reconcile be 20 normal atmosphere to hydrogen pressure after, at room temperature stir and made it reaction in 5 hours.The reaction soln that filtration obtains, concentrating under reduced pressure filtrate obtains colourless powder shape 2-amino-2 '-carboxyl-diphenyl sulfide 11.3g (0.046 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 92%)
1H-NMR(DMS?O-d
6)：δ
5.0～5.9(br，2H)、6.5～8.1(m，8H)、12.8～13.5(br，1H)
(embodiment 10)
Raney Ni (as 50% alloy, Ni amount is 1g) and 2-nitro-2 '-carboxyl-diphenyl sulfide 4.0g (14.5 mmole) of obtaining according to the method for embodiment 1 is outstanding turbid in propyl carbinol 50mL.In the propyl carbinol suspension liquid that obtains, feed hydrogen, stir down at 100 ℃ simultaneously and made it reaction in 15 hours.The reaction suspension liquid that filtration obtains, concentrating under reduced pressure filtrate obtains colourless powder shape 2-amino-2 '-carboxyl-diphenyl sulfide 3.24g (13.2 mmole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 91%)
(embodiment 11)
2-nitro-2 '-carboxyl-diphenyl sulfide 2.75g (10.0 mmole) that embodiment 1 is obtained is dissolved among concentrated ammonia solution (ammonia concentration=28 weight %) 40mL.Drip the solution that the water-soluble 70mL of ferrous sulfate 7 hydrate 21.6g (77.8 mmole) is obtained in the ammonia mixed solution that obtains, heating made it reaction in 10 minutes under 80 ℃.After the reaction soln that obtains is cooled to room temperature, filter, filtrate decompression is concentrated into 30mL, add ethyl acetate 70mL and acetic acid 2mL.Make isolated organic layer drying with anhydrous magnesium sulfate, remove by filter siccative after, concentrating under reduced pressure filtrate obtains the 2-amino-2 '-carboxyl-diphenyl sulfide 2.33g (9.50 mmole) of colourless powder shape.(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 95%)
(embodiment 12)
Except that 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide 15.2g (0.05 mole) that the method for using according to embodiment 4 obtains, carry out operation similarly to Example 10, obtain colourless powder shape 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide 12.7g (0.046 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide: 92%)
Fusing point: 150～151 ℃
(embodiment 13)
2-nitro-2 '-carboxyl-diphenyl sulfide the 13.7g (0.05 mole) and the methyl alcohol 95mL that in the autoclave of 300mL, fill Pd (5wt%)/C of 1.37g, obtain according to the method for embodiment 1, hydrogen pressure is reconciled to 10 normal atmosphere, stirred 6 hours down at 25 ℃, carry out hydrogenation reaction.Filter reaction mixture, concentrating under reduced pressure filtrate obtains colourless powder shape 2-amino-2 '-carboxyl-diphenyl sulfide 11.7g (0.048 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 95%)
Fusing point: 150～151 ℃
(embodiment 14)
Remove temperature of reaction is changed into 50 ℃, beyond will changing in the reaction times 4 hours, carry out operation similarly to Example 13, obtain 2-amino-2 '-carboxyl-diphenyl sulfide 12.0g (0.049 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 98%)
(embodiment 15)
Except that Pd (the 5wt%)/C with 1.37g changes into Pd (5wt%)/C (water ratio: 52.9wt%), carry out operation similarly to Example 14, obtain 2-amino-2 '-carboxyl-diphenyl sulfide 11.9g (0.049 mole) of 2.91g.(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 97%)
(embodiment 16)
Remove the consumption of methyl alcohol is changed into 50mL, and beyond will changing in the reaction times 6 hours, carry out operation similarly to Example 14, obtain 2-amino-2 '-carboxyl-diphenyl sulfide 11.9g (0.049 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 97%)
(embodiment 17)
Remove the consumption of methyl alcohol is changed into 180mL, and beyond will changing in the reaction times 6 hours, carry out operation similarly to Example 14, obtain 2-amino-2 '-carboxyl-diphenyl sulfide 11.2g (0.046 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 91%)
(embodiment 18)
Except that methyl alcohol being changed into ethanol, carry out operation similarly to Example 14, obtain 2-amino-2 '-carboxyl-diphenyl sulfide 11.2g (0.046 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 92%)
(embodiment 19)
Remove the platinum oxide (PtO that Pd (5wt%)/C of 1.37g is changed into 640mg
2) in addition, carry out operation similarly to Example 14, obtain 2-amino-2 '-carboxyl-diphenyl sulfide 10.8g (0.044 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-diphenyl sulfide: 88%)
(embodiment 20)
Except that 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide 15.2g (0.05 mole) that the method for using according to embodiment 4 obtains, carry out operation similarly to Example 14, obtain 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide 12.7g (0.046 mole).(with respect to the yield of 2-nitro-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide: 92%)
(embodiment 21)
2-amino-2 '-carboxyl-diphenyl sulfide the 24.5g (0.10 mole) that will obtain according to the method for embodiment 9 is dissolved among the toluene 300mL.The toluene solution that obtains is refluxed to react in 20 hours.After the reaction soln that obtains is cooled to room temperature, filter the crystal of separating out.With the filtrate drying that obtains, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 15.7g of-11-ketone (0.069 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 69%).Fusing point: 259～260 ℃
1H-NMR(DMSO-d
6)：δ
7.05～7.80(m，8H)、10.7(s，1H)
(embodiment 22)
2-amino-2 '-carboxyl-diphenyl sulfide the 24.5g (0.10 mole) that will obtain according to the method for embodiment 9 is dissolved among the toluene 300mL.(use Dean-Stark device) refluxed simultaneously and made it reaction to make the toluene solution that obtains carry out azeotropic dehydration 20 hours.After the reaction soln that obtains is cooled to room temperature, filters and collect the crystal of separating out.Then, with the filtrate drying that obtains, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 18.2g of-11-ketone (0.080 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 80%).
(embodiment 23)
Remove reaction solvent is changed into dimethylbenzene, beyond will changing in the reaction times 15 hours, carry out reaction similarly to Example 22, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 22.3g of-11-ketone (0.098 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 98%).
(embodiment 24)
Remove reaction solvent is changed into isopropyl benzene, beyond will changing in the reaction times 10 hours, carry out reaction similarly to Example 22, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 22.3g of-11-ketone (0.098 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 98%).
(embodiment 25)
2-amino-2 '-carboxyl-diphenyl sulfide the 24.5g (0.10 mole) that will obtain according to the method for embodiment 14 is dissolved among the dimethylbenzene 300mL.(use Dean-Stark device) refluxed simultaneously and made it reaction to make the xylene solution that obtains carry out azeotropic dehydration 15 hours.After the reaction soln that obtains is cooled to 75 ℃,, stirred 30 minutes down at 75 ℃ again to wherein adding saturated sodium bicarbonate aqueous solution 240mL.Then, filter the crystal that collection is separated out.With the filtrate drying that obtains, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 21.5g of-11-ketone (0.095 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 95%).
(embodiment 26)
Remove saturated sodium bicarbonate aqueous solution is changed into the 1N aqueous sodium hydroxide solution, its consumption is changed into beyond the 200mL, carry out reaction similarly to Example 25, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 21.1g of-11-ketone (0.093 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 93%).
(embodiment 27)
Remove reaction solvent is changed into isopropyl benzene, beyond will changing in the reaction times 10 hours, carry out reaction similarly to Example 25, obtain dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 22.0g of-11-ketone (0.097 mole).(with respect to the yield of 2-amino-2 '-carboxyl-diphenyl sulfide: 97%).
(embodiment 28)
Use is carried out reaction similarly to Example 23 according to 2-amino-2 '-carboxyl-4 '-methoxyl group-diphenyl sulfide 27.5g (0.10 mole) that the method for embodiment 12 obtains, and obtains 2-methoxyl group-dibenzo (b, f) (1,4) sulphur nitrogen
The colourless acicular crystal 23.6g of-11-ketone (0.092 mole).(with respect to the yield of 2-amino-4-methoxyl group-2 '-carboxyl-diphenyl sulfide: 92%).Fusing point: 220～223 ℃
Industrial applicibility
According to dibenzo sulphur nitrogen of the present inventionThe preparation method, by making the reaction of nitrobenzene derivative and thio-salicylic acid derivative, after generating 2-nitro-2 '-carboxyl-diphenyl sulfide derivative, with this product reduction, generate 2-amino-2 '-carboxyl-diphenyl sulfide derivative, then with this product dehydrating condensation, can and adopt the shirtsleeve operation preparation as the dibenzo sulphur nitrogen of the high general formula of the intermediate practicality of medicine (5) expression with high yield
Derivative.
Claims (6)
1. the preparation method of the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of following general formula (3) expression is characterized in that,
In the formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent hydrogen atom independently of one another or have the alkoxyl group of 1-10 carbon atom,
This method comprises:
Make the nitrobenzene derivative of following general formula (1) expression and the thio-salicylic acid derivative reaction of following general formula (2) expression, generate the 2-nitro-2 '-carboxyl-diphenyl sulfide derivative of general formula (3) expression,
In the formula, R
1, R
2, R
3And R
4Represent implication same as described above separately, X represents halogen atom;
In the formula, R
5, R
6, R
7And R
8Represent implication same as described above separately.
2. preparation method as claimed in claim 1 is characterized in that R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Represent hydrogen atom or methoxyl group independently of one another.
3. preparation method as claimed in claim 1 is characterized in that, described being reflected under the alkali existence carried out, and wherein this alkali is selected from salt of wormwood, yellow soda ash, Quilonum Retard, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium methylate.
4. preparation method as claimed in claim 1 is characterized in that, described being reflected under the alkali existence carried out, and wherein this alkali is selected from salt of wormwood, sodium hydroxide, potassium hydroxide and sodium methylate.
5. preparation method as claimed in claim 3 is characterized in that, described being reflected under the additive existence carried out, and wherein this additive is selected from potassiumiodide or N, the N-Dimethylamino pyridine.
6. preparation method as claimed in claim 3 is characterized in that, described being reflected under the potassiumiodide existence carried out.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610006965A CN100577653C (en) | 1999-07-09 | 1999-07-09 | Process for producing dibenzo thionitrogen tropilidine derivative |
| HK07104553.4A HK1098142A1 (en) | 1999-07-09 | 2006-11-23 | Process for producing dibenzothiazepine derivatives |
| HK06112872.2A HK1092460A1 (en) | 1999-07-09 | 2006-11-23 | Process for producing dibenzothiazepine derivatives |
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| CN200610006965A CN100577653C (en) | 1999-07-09 | 1999-07-09 | Process for producing dibenzo thionitrogen tropilidine derivative |
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| CN2006101003178A Division CN1872846B (en) | 1999-07-09 | 1999-07-09 | Method of preparing 2-benzothiazepines derivative |
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Non-Patent Citations (4)
| Title |
|---|
| A Novel Synthesis of Dibenzo[b,f][1,4]thiazepin-11(10H)one5,5-Dioxides. O.Francis Bennett, et al.JOURNAL OF HETEROCYCLIC CHEMISTRY,Vol.12 No.6. 1975 |
| A Novel Synthesis of Dibenzo[b,f][1,4]thiazepin-11(10H)one5,5-Dioxides. O.Francis Bennett, et al.JOURNAL OF HETEROCYCLIC CHEMISTRY,Vol.12 No.6. 1975 * |
| SYNTHESIS OF2-METHOXYDIBENZO[b,f](1,4)-THIAZEPIN-11(10H)-ONE-5,5-DIOXIDE. O. Francis Bennett, et al.Org.Prep.Proced.Int.,Vol.6 No.6. 1974 |
| SYNTHESIS OF2-METHOXYDIBENZO[b,f](1,4)-THIAZEPIN-11(10H)-ONE-5,5-DIOXIDE.O.Francis Bennett,et al.Org.Prep.Proced.Int.,Vol.6 No.6. 1974 * |
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| CN1810792A (en) | 2006-08-02 |
| HK1092460A1 (en) | 2007-02-09 |
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