CN1248247A - Method of producing N, N'-diazole compounds - Google Patents
Method of producing N, N'-diazole compounds Download PDFInfo
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- CN1248247A CN1248247A CN 98802686 CN98802686A CN1248247A CN 1248247 A CN1248247 A CN 1248247A CN 98802686 CN98802686 CN 98802686 CN 98802686 A CN98802686 A CN 98802686A CN 1248247 A CN1248247 A CN 1248247A
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- unsubstituted
- organic bases
- dihalide
- azole compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The invention describes a method of producing N, N'-diazole compounds such as N, N'-carbonyldiimidazole, by reacting in an inert solvent, e.g., toluene, a 1-unsubstituted 1H-azole compound, e.g., 1H-imidazole, and a dihalide compound, e.g., phosgene, in the presence of an organic base, e.g., a tertiary amine such as tri(n-butyl)amine. The molar ratio of the 1-unsubstituted 1H-azole compound to the dihalide compound may range from 1.7:1 to 2.3:1. The molar ratio of the organic base to 1-unsubstituted 1H-azole compound is 1:1 when the molar ratio of the 1-unsubstituted 1H-azole compound to the dihalide compound is less than 2:1. The organic base has a basicity greater than that of the 1-unsubstituted 1H-azole compound, and along with its hydrohalide salt is soluble in the inert solvent.
Description
Summary of the invention
The present invention relates to be selected from N, N '-carbonyl diazole, N, N-thiocarbonyl diazole, and N, the preparation method of N ' the N '-diazole compounds of N '-sulfinyl diazole compounds.More particularly, the present invention relates to use unsubstituted 1H-azole compounds of 1-and dihalide, for example, phosgene, at inert solvent and organic bases, for example, tertiary amine exists prepared in reaction such as N down, the method for N '-diazole compounds.In the scheme of the inventive method, the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide should not surpass 2: 1, has found to use the N of the inventive method preparation, and N '-diazole compounds has acceptable color.
N, N '-diazole compounds, as N, N '-carbonyl diazole, N, N '-thiocarbonyl diazole and N, N '-sulfinyl diazole compounds is used as to other compound carbonylate, thiocarbonyl, sulfinyl or pyrryl and do not form the reagent of haloid acid by product.They are than dihalide, as the easier control of phosgene and be easier to tolerance.They are often used in and relate to dehydration, in the reaction that ester forms and isocyanic ester forms, and as enzyme and casco.In addition, these diazole compounds also are used as intermediate synthetic drugs and agricultural compound.For example, U.S. Patent No. 4,237 is described in 709 in the preparation of microbiotic and peptide and has used N, N '-carbonyl diazole compound.
Known N; N '-carbonyl diazole; N; N '-thiocarbonyl diazole; and N; N '-sulfinyl diazole compounds can use respectively relate to the unsubstituted 1H-azole compounds of 1-and dihalide (as, be respectively phosgene, thiocarbonyl dichloride and thionyl chloride) prepare with 4: 1 reaction of mol ratio respectively.Referring to, for example, W.Forest, preparative organic chemistry novel method (Newermethods of Preparative Organic Chemistry) volume V, academic press, New York (1968), 61-108 page or leaf.For example, with N, N '-carbonyl diazole compound is an example, N more particularly, and N '-carbonyl dimidazoles, the method for this prior art can be represented with following flow process I.
Flow process I
Among the flow process I, the mole number of the unsubstituted 1H-azole compounds of employed 1-is with respect to the N that will prepare in the above, 2 times of N '-carbonyl diazole compound mole number.The by-product hydrochloric acid salify that forms in reaction, needing to use the unsubstituted 1H-azole compounds of excessive 1-and react.In addition, in flow process I, N, the unsubstituted 1H-pyrroles's hydrochloride of N '-carbonyl diazole compound and 1-is precipitated out from solution simultaneously, and this just needs to separate two tight blended solids.This separation may be a multistep process, and needs more times and material.
The method cost of flow process I is very expensive, because: (a) the unsubstituted 1H-azole compounds of the 1-that has only half youngster to exist when beginning to react is used to form required N, N '-carbonyl diazole; And (b) N of precipitation separation from the unsubstituted 1H-pyrroles's hydrochloride of sedimentary 1-, N '-carbonyl diazole compound generally is a multistep process, needs more times and material.As long as use suitable dihalide, for example, use thiocarbonyl dichloride or thionyl chloride, replace phosgene respectively, the method for flow process I also can be used for preparing N, N '-thiocarbonyl imidazoles and N, N '-sulfinyl imidazoles.
United States Patent (USP) 3,991,071,4,080,462 and 4,154,945 disclose a kind of method for preparing the two imidazoles of carbonyl, are included in the inert solvent, and phosgene and 1H-imidazoles react in the presence of acid binding agent.It can be tertiary amine such as triethylamine that acid binding agent is described to, pyridine or excessive imidazoles.The level of preferred acid binding agent and the mol ratio of acid binding agent and 1H-imidazoles be at United States Patent (USP) 3,991, and be unexposed in 071,4,080,462 and 4,154,945.
United States Patent (USP) 5,552,554 disclose a kind of carbonylation agent for preparing in position, as N, N '-carbonyl dimidazoles or N, N '-carbonyl diurethane (1,2,4-triazole) method, this method is by in the presence of hydroxy-functional ester and inert solvent, phosgene and 1H-imidazoles or 1H-1,2, the reaction of one of 4-triazole, and organic bases is selected from trialkylamine, pyridine, the pyridine of picoline or other replacement.Preferred organic bases and 1H-imidazoles or 1H-1,2, the mol ratio of 4-triazole is at United States Patent (USP) 5,552, and is unexposed in 554.United States Patent (USP) 5,552,554 intermediate hurdles 7,8 and 10 embodiment 2,5 and 11 has described in-situ preparing N, N '-diazole, wherein when the mol ratio of unsubstituted 1H-azole compounds of 1-and phosgene during less than 2: 1, the mol ratio of organic bases and 1H-azole compounds is in each case all greater than 1: 1.
Have been found that the phenomenon of fading, for example brown, N, N '-diazole compounds can be by in inert solvent, the unsubstituted 1H-azole compounds of 1-, for example, 1H-imidazoles and excessive dihalide, for example, phosgene, reaction obtains in the presence of excessive organic bases such as tertiary amine.Especially in the mol ratio of organic bases and the unsubstituted 1H-azole compounds of 1-greater than the mol ratio of 1: 1 and while unsubstituted 1H-azole compounds of 1-and dihalide less than observing the phenomenon of fading at 2: 1 o'clock.
People expect a kind of N of the phenomenon minimum of fading, N '-diazole compounds, as N, N '-carbonyl diazole, N, N '-thiocarbonyl diazole and N, the preparation method of N '-sulfinyl diazole compounds, this method initiator use with separate required product aspect more effective.
Have been found that N now, N '-diazole compounds, as N, N '-carbonyl diazole can be by making unsubstituted 1H-azole compounds of 1-and dihalide, and for example, phosgene need not surpass 2: 1 ratio prepared in reaction with mol ratio.Also find the N according to the inventive method preparation, N '-carbonyl diazole compound has the minimum phenomenon of fading.
According to the present invention; provide a kind of preparation to be selected from N; N '-carbonyl diazole; N, N '-thiocarbonyl diazole and N, the N of N '-sulfinyl diazole compounds; the method of N '-diazole compounds; be included in the inert solvent, and in the presence of organic bases, below the unsubstituted 1H-azole compounds of 1-of general formula I representative:
X wherein
1, X
2And X
3Be respectively CR
1Or nitrogen-atoms, condition is X
1, X
2, X
3In at least one is a nitrogen-atoms, R
1And R
2Be respectively hydrogen independently, halogen such as chlorine or bromine, C
1-C
6Alkyl, phenyl, the phenyl of replacement, or work as X
3Be CR
1The time, R
1With R
2Link to each other and comprise that two carbon atoms in the unsubstituted 1H-pyrrole ring of 1-form the ring that a condensed has 4-6 carbon atom together; React with the dihalide that is selected from down group:
Wherein Z is oxygen or sulphur, and Y is fluorine independently, chlorine or bromine, preferred chlorine.
The mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide can change between 1.7: 1～2.3: 1, preferably at 1.8: 1～2: 1, and more preferably 1.9: 1～2: 1.Organic bases is soluble in inert solvent, and basicity is greater than the unsubstituted 1H-azole compounds of 1-, and formed halogen acid salt also is soluble in inert solvent.When the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide during less than 2: 1, the mol ratio of the unsubstituted 1H-azole compounds of organic bases and 1-is 1: 1.
Except embodiment, or explanation is arranged in addition, the amount of all components that uses in specification sheets or claim or the numerical expression of reaction conditions should be understood to be in all occasions and all use " pact " to revise.
Detailed Description Of The Invention
The unsubstituted 1H-azole compounds of the 1-that uses in the inventive method only contains a secondary amino group 1 at pyrrole ring, as above shown in the general formula I.As for the R in the above-mentioned general formula I
1And R
2, the phenyl of replacement is meant C
1-C
6The phenyl that alkyl replaces, halogen, for example, chlorine and bromine, the phenyl of replacement or C
1-C
6The phenyl that alkyl and halogen replace.Substituent R
1And R
2As be selected from those not overslaughs at 1 substituting group that carries out required reaction.
In the unsubstituted 1H-azole compounds of 1-shown in the general formula I, X wherein
2Be nitrogen-atoms, and X
1And X
3Be respectively CR
1Compound, typically refer to unsubstituted 1H-imidazoles of 1-or 1H-imidazoles.The example of the 1H-imidazoles of Shi Yonging includes but not limited in the methods of the invention: the 1H-imidazoles; The 1H-4-Methylimidazole; The 1H-5-Methylimidazole; 1H-4-ethyl-5-Methylimidazole; 1H-2, the 4-methylimidazole; The 1H-2-phenylimidazole; The 1H-4-phenylimidazole; The 1H-5-phenylimidazole; 1H-2,4,5-triphenyl imidazoles; 1H-2-methyl-4, the 5-diphenyl-imidazole; 1H-4-bromine imidazoles; 1H-5-bromine imidazoles; 1H-4-bromo-5-Methylimidazole; 1H-4-methyl-5-bromine imidazoles; 1H-4-bromo-5-phenylimidazole; 1H-4-phenyl-5-bromine imidazoles; 1H-2,4-two bromo-5-Methylimidazoles; 1H-2,5-two bromo-4-methylimidazoles; With the 1H-benzoglyoxaline.
In the unsubstituted 1H-azole compounds of 1-shown in the general formula I, X wherein
1Be nitrogen-atoms, and X
2And X
3Be respectively CR
1Compound, typically refer to unsubstituted 1H-pyrazoles of 1-or 1H-pyrazoles.The example of the 1H-pyrazoles of Shi Yonging includes but not limited in the methods of the invention: the 1H-pyrazoles; 3,5-dimethyl-1H-pyrazoles; With the 1H-indazole.
In the unsubstituted 1H-azole compounds of 1-shown in the general formula I, X wherein
1And X
2All be nitrogen-atoms, and X
3Be CR
1Compound, typically refer to the unsubstituted 1H-1 of 1-, 2,3-triazole or 1H-1,2,3-triazole.The 1H-1 of Shi Yonging in the methods of the invention, 2, the example of 3-triazole includes but not limited to: 1H-1,2,3-triazole; And 1H-1,2, the 3-benzotriazole.
In the unsubstituted 1H-azole compounds of 1-shown in the general formula I, X wherein
2And X
3All be nitrogen-atoms, and X
1Be CR
1Compound, typically refer to the unsubstituted 1H-1 of 1-, 2,4-triazole or 1H-1,2,4-triazole.The 1H-1 of Shi Yonging in the methods of the invention, 2, the example of 4-triazole includes but not limited to: 1H-1,2,4-triazole; With the 1H-5-methyl isophthalic acid, 2, the 4-triazole.
In the azole compounds shown in the general formula I, X wherein
1, X
2And X
3All be the compound of nitrogen-atoms, typically refer to tetrazolium.These tetrazoliums can be represented with two kinds of tautomeric forms, 1H-tetrazolium and 2H-tetrazolium.Conversion between two kinds of tautomers is considered to because proton shifting causes.When the tetrazolium of general formula I representative has 2H-tetrazolium tautomeric forms, mean that also its representative has more general 1H-tetrazolium tautomeric forms.The example of the tetrazolium of Shi Yonging includes but not limited in the methods of the invention: 1H-tetrazolium, 1H-5-methyl-tetrazolium, 1H-5-benzyl-tetrazolium and 1H-5-phenyl-tetrazolium.
The unsubstituted 1H-azole compounds of 1-that preferably is used for the inventive method comprises: the 1H-imidazoles; The 1H-benzoglyoxaline; The 1H-pyrazoles; The 1H-indazole; 1H-1,2, the 3-triazole; 1H-1,2, the 3-benzotriazole; And 1H-1,2, the 4-triazole.The unsubstituted 1H-azole compounds of particularly preferred 1-is the 1H-imidazoles.Can use the mixture of the unsubstituted 1H-azole compounds of single 1-or these compounds as required.The preferred unsubstituted 1H-azole compounds of single 1-that uses.
In the methods of the invention, unsubstituted 1H-azole compounds of 1-and dihalide reaction as mentioned above, form N, N '-carbonyl diazole, N, N '-thiocarbonyl diazole or N, N '-sulfinyl diazole compounds.The mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide can be at 1.7: 1～2.3: 1, in the scope of preferred 1.8: 1～2: 1 and more preferably 1.9: 1～2: 1.Because the required product that obtains of the inventive method is N, N '-carbonyl diazole, N, N '-thiocarbonyl diazole and N, N '-sulfinyl diazole compounds, the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide preferably 2: 1.But, one skilled in the art should appreciate that in the scale operation practice, that is,, can use excessive dihalide at commercial manufacture level, for example, phosgene.Excessive dihalide, for example, phosgene often uses up to 20% molar excess, because under employed reaction conditions, employed dihalide generally is the accurate measurement that is difficult to of gas phase.
Method of the present invention is carried out in the presence of the inert solvent as reaction medium, and this solvent is preferred solvent for reactant.As for inertia, be meant that solvent does not disturb or hinders reaction between unsubstituted 1H-pyrroles of 1-and the dihalide.The classification of the actual inert solvent that uses includes but not limited in the present invention: alkane, aromatic solvent, halogenated solvent, ether ， diox, ester, acid amides and urea.Halogenated and aromatic solvent is preferred inert solvent.The example more specifically of spendable inert solvent comprises: alkane such as hexane, heptane and octane; Aromatic solvent such as toluene, benzene, isopropyl benzene, mesitylene, propylbenzene, phenylmethylether and dimethylbenzene; Halogenated solvent, as methylene dichloride, chlorobenzene and 1,2 ,-ethylene dichloride; Ether such as tetrahydrofuran (THF), ether and 1,2-dimethoxy ethane; Diox is as 1, the 4-diox; Ester such as methyl acetate and ethyl acetate; Acid amides such as N, dinethylformamide and N-methyl isophthalic acid, 2-tetramethyleneimine; With urea as 1,3-dimethyl-2-imidazolone.Preferred inert solvent is organic solvent dichloromethane and toluene.Particularly preferred inert solvent is a toluene.In the methods of the invention, the amount of inert solvent should be enough to the solubilizing reaction thing.
Method of the present invention is also carried out in the presence of the organic bases of basicity unsubstituted 1H-azole compounds greater than 1-.The reaction of unsubstituted 1H-azole compounds of 1-and dihalide forms the haloid acid by product, for example, produces hydrochloric acid when using phosgene.Basicity is meant that the halogen acid salt that forms organic bases is more favourable aspect thermodynamics at least than forming the unsubstituted 1H-pyrroles's halogen acid salt of 1-, and also is favourable aspect kinetics greater than the unsubstituted 1H-azole compounds of 1-.Mainly between organic bases and haloid acid, form halogen acid salt, so that the unsubstituted 1H-azole compounds of 1-does not react with dihalide.
Basicity is greater than any organic bases of the unsubstituted 1H-azole compounds of 1-, or the mixture of organic bases; Can not form covalent linkage with dihalide; And is soluble with its halogen acid salt in the inert solvent of reaction mixture, can be used in the practice of the present invention.
In practice of the present invention, the mol ratio of the unsubstituted 1H-azole compounds of organic bases and 1-is 1: 1, and condition is that the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide was less than 2: 1.When the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide during less than 2: 1, need the ratio of the unsubstituted 1H-azole compounds of organic bases and 1-to be no more than 1: 1, so that the N that fades, the formation minimum of N '-diazole compounds.And do not mean that and be limited to any theory; can believe and for example in the presence of excess phosgene, to prepare N; during N '-carbonyl dimidazoles; excessive phosgene and N; N '-carbonyl dimidazoles reaction forms imidazoles formamyl chlorine; it is at excessive organic bases, and for example, there are the still not special atrament of formation down in a kind of tertiary amine such as tri-n-butyl amine.
The unsubstituted 1H-azole compounds of organic bases and 1-exists with 1: 1 mol ratio, also makes and has only the unsubstituted 1H-azole compounds of 1-of aequum to form N by covalent linkage, the product of N '-diazole compounds.For example, using the inventive method to prepare N, in the process of N '-carbonyl dimidazoles, need 1H-imidazoles and dihalide, for example, the ratio of phosgene can not be above 2: 1.
In addition, in practice of the present invention, when the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide equaled 2: 1, the mol ratio of the unsubstituted 1H-azole compounds of organic bases and 1-can be 1: 1 or bigger.Because method of the present invention does not need excessive organic bases to exist, the mol ratio of preferred organic bases in the case and the unsubstituted 1H-azole compounds of 1-is 1: 1.
In addition, in practice of the present invention, when the mol ratio of unsubstituted 1H-azole compounds of 1-and dihalide during greater than 2: 1, the mol ratio of the unsubstituted 1H-azole compounds of organic bases and 1-can be 1: 1 or bigger, or the mol ratio of organic bases and dihalide can be 2: 1 or bigger.Because method of the present invention does not need excessive organic bases to exist, preferably in the case, the mol ratio of organic bases and dihalide is 2: 1.
In practice of the present invention, organic bases and halogen acid salt thereof all are soluble in the inert solvent of reaction mixture.This makes the N of halogen acid salt of the essentially no organic bases of separate easily, N '-diazole compounds.For example, prepare N according to method of the present invention, N '-carbonyl dimidazoles, the product of the halogen acid salt of essentially no organic bases can sedimentary form be separated from reaction mixture.Although at sedimentary N, can there be the halogen acid salt of a small amount of organic bases in N '-diazole compounds, one skilled in the art will understand that N, N '-diazole degree of purity of production can solvent wash is dry then further to be improved by adding.
In practice of the present invention, organic bases is tertiary amine preferably.The example of spendable tertiary amine comprises in the methods of the invention: three (aryl) amine, and for example, wherein each aryl contains 6-9 carbon atom, as triphenylamine and tribenzyl amine; Three (alkyl) amine, as Trimethylamine 99, triethylamine, N, N-dimethyl amine, three (n-propyl) amine, three (sec.-propyl) amine, three (normal-butyl) amine, three amylamines, three hexyl amines, trioctylphosphine amine, three decyl amine and tridodecylamine.Other available tertiary amine comprises the 1-crassitude, 1-methylpyrrole and 1-methyl piperidine.Preferred three (alkyl) amine, wherein each alkyl contains 1-12,1-6 carbon atom for example, preferred especially three (normal-butyl) amine.
Unsubstituted 1H-diazole compounds of 1-and dihalide can any order add reactor.They can add concurrently or successively.Adding can be successive or intermittence.In a preferred version of the present invention, the dihalide of appropriate amount slowly added contain the appropriate amount inert solvent, in the suitable reaction vessel of unsubstituted 1H-diazole compounds of 1-and tertiary amine.
The temperature of the reaction of carrying out according to the inventive method can change in a big way, but general in solvent is the temperature range of liquid, generally at 15 ℃-150 ℃.Preferred temperature is at 50 ℃-80 ℃, particularly when inert solvent is toluene.
The pressure of the reaction of carrying out according to the inventive method also can change in a big way.Although can use higher or lower pressure, generally use normal atmosphere or a little higher than atmospheric pressure in the liquid phase owing to be reflected at.Preferred reaction is under atmospheric pressure carried out.
The present invention also is described with the following examples especially, because a lot of modification and variation are conspicuous for a person skilled in the art, these embodiment only are used to illustrate the present invention.Except as otherwise noted, all parts and per-cent all are weight.
Embodiment 1
This embodiment has described with the method that is similar to flow process 1 and has prepared N, and N '-carbonyl dimidazoles has used following component.Amounts of components
The gram mole
1 toluene, 605.5 6.61H-imidazoles 102.2 1.5 feed intake
2 phosgene 40.8 0.41 feed intake
One liter of four neck flask of 1 adding will feed intake, this flask equipped has a motor-driven agitating vane, one temperature probe and heating mantles (both is connected on the Temperature Feedback control device), one phosgene and nitrogen inlet tube, its outlet is located at the condenser that a caustic scrubber is led in flask interior liquid level top and.Under purging with nitrogen gas, the material in the flask is heated to about 65 ℃.Turn off nitrogen, will feed intake added flask in 2 usefulness 20-30 minutes, and during this period, observing the exotherm peak value is 82 ℃.Feed intake 2 add after, with material cooling in the flask and under purging with nitrogen gas, outgas.After deaeration stage is finished, with material in the flask be heated to 80 ℃ and under nitrogen atmosphere the 70-100 micron fritted glass filter by a heat filter.The solid of collecting is each with the 173g toluene wash that is heated to 80 ℃, twice totally.In filtrate collection to a container, under nitrogen atmosphere, make it slowly cool to room temperature under stirring, during this period, beginning adularescent crystalline deposit comes out from filtrate.With 70-100 micron fritted glass filter collecting precipitation under nitrogen atmosphere.The precipitation of collecting is used the 99g hexane wash at every turn, totally four times, to remove unnecessary toluene.The heat drying precipitation of collecting a little under nitrogen purge.Isolate 28g exsiccant precipitation altogether.Yield percentage and concise and to the point step are listed in table 1.Table 2 is listed in sedimentary analysis in detail.
Embodiment 2
This embodiment has described and has used three (normal-butyl) amine to prepare N as organic bases, N '-carbonyl dimidazoles, and wherein the mol ratio of three (normal-butyl) amine and 1H-imidazoles is 1.1: 1.0, and the mol ratio of 1H-imidazoles and phosgene was less than 2.0: 1.0.Amounts of components
The gram mole
1 toluene 250 2.7 3 (normal-butyl) amine, 103.0 0.561H-imidazoles 34.0 0.50 feed intake
2 phosgene 25.5 0.26 feed intake
One liter of four neck flask of 1 adding will feed intake, this flask equipped has a motor-driven agitating vane, one temperature probe and heating mantles (both is connected on the Temperature Feedback control device), one phosgene and nitrogen inlet tube, its outlet is located at the condenser that a caustic scrubber is led in flask interior liquid level top and.Under purging with nitrogen gas, the material in the flask is heated to about 65 ℃-70 ℃.Turn off nitrogen, 2 usefulness that will feed intake added flask in about 20 minutes, and kept the interior material of flask at about 70 ℃-75 ℃.Feed intake 2 add after, material slowly cooled off and remain on room temperature.During this period, observing crystalline deposit forms.Brown with isolating in the material of 70-100 micron fritted glass filter from flask under nitrogen atmosphere to dark brown crystalline deposit.The brown precipitate of collecting is used the 150g toluene wash at every turn, totally three times, then use the 200g hexane wash, twice totally more at every turn.With the precipitation after the washing, its color still is brown to dark brown, and is dry under nitrogen purge.Isolate 26.5g exsiccant brown precipitate altogether.Yield percentage and concise and to the point step are listed in table 1.Table 2 is listed in sedimentary analysis in detail.
Embodiment 3
Use following component, prepare N, N '-carbonyl dimidazoles according to the inventive method.Amounts of components
The gram mole
1 toluene 173 1.9 3 (normal-butyl) amine, 92.7 0.501H-imidazoles 34.1 0.50 feed intake
2 phosgene 26.0 0.26 feed intake
Four neck flasks with 1 adding, one 500ml that feeds intake, this flask equipped has a motor-driven agitating vane, one temperature probe and heating mantles (both is connected on the Temperature Feedback control device), one phosgene and nitrogen inlet tube, its outlet is located at the condenser that a caustic scrubber is led in flask interior liquid level top and.Under purging with nitrogen gas, the material in the flask is heated to about 65 ℃-70 ℃.Turn off nitrogen, will feed intake added flask in 2 usefulness 20-30 minutes, and kept the interior material of flask at about 70 ℃-75 ℃.Feed intake 2 add after, make under constantly stirring that material was cooled to 20 ℃-25 ℃ in the flask through 1-1.5 hour, kept again 30-45 minute in this temperature then.Under nitrogen atmosphere, precipitate with isolating white crystals in the material of 70-100 micron fritted glass filter from flask.With the precipitation 346g toluene wash of collecting, heat drying a little under nitrogen purge then.Isolate 32.5g exsiccant precipitation altogether.Yield percentage and concise and to the point step are listed in table 1.Table 2 is listed in sedimentary analysis in detail.
Table 1
The result
Embodiment 1 embodiment 2 embodiment 3 test productive rate %
a42% 65% 76% filter number of times
b211 gram numbers for the 1H-imidazoles of every grams precipitation institute 3.7 1.3 1.1 uses of collecting
c aProductive rate % uses following Equation for Calculating, and 100 * (the theory gram number of the actual gram number/product of collecting precipitation)
bIsolate the required filtration number of times of final precipitated product from flask, finishing to be reacted to
cThe amount of the 1H-imidazoles that adds when the reaction beginning is divided by the sedimentary gram number of collecting
The data presentation of table 1 is preparing N, N '-carbonyl dimidazoles aspect, and method of the present invention is more effective than the method for the prior art of flow process 1 representative.When compared with prior art, such as embodiment 1, method of the present invention as embodiment 3, is used raw material still less, and promptly the 1H-imidazoles obtains higher productive rate.
Table 2
Embodiment 1,2, the analysis of 3 isolating precipitated products
The result
The brown white N of embodiment 1 embodiment 2 embodiment, 3 test visual effect whites, the weight % of N '-carbonyl dimidazoles
d98.7% N.D.
1100.7% (uses CO
2Volatilization is analyzed) N, the weight % of N '-carbonyl dimidazoles
eThe weight % of N.D. 99.5% (analyzing) three (normal-butyl) amine with G.C
eN.A.
2N.D. the weight % of 0.08% (analyzing) toluene with G.C
eThe weight % of N.D. 0.06% (analyzing) chlorion with G.C
f0.44% N.D. 0.07% (uses AgNO
3Volumetry)
1N.D.=does not measure
2N.A.=is improper
dThis analysis is based on reaction: 1 mole of N, N '-carbonyl dimidazoles+1 mole H
2O in the presence of protonic acid, will produce 2 moles of 1H-imidazoles and 1 mole of CO
2 eG.C. (gas-chromatography).Measured N in embodiment 1 and 2 with the standard gas chromatograph method, N '-carbonyl dimidazoles, the weight percent that three (normal-butyl) amine and toluene exist in isolating precipitated product.What use is the pillar that is equipped with following specification, and HP-5 30M * 0.32mm i.d. has the Hewlett Packard 5890E gas chromatograph of 0.25 micron membranes.
fThe isolating precipitated product of known quantity is used the nitric acid acidifying in water, then use AgNO
3Use silver electrode endpoint detection potentiometric titration chlorion (negatively charged ion).This method is not specific for chloride-ion source.
The data presentation of table 2 method of the present invention, as embodiment 3, prepared N, N '-carbonyl dimidazoles are white, prior art with embodiment 1 representative is identical basically for it.When the data of table 2 had shown that also mol ratio when 1H-imidazoles and phosgene was less than 2: 1, the mol ratio that keeps tertiary amine and 1H-imidazoles was 1: 1 a importance, as the comparison of embodiment 2 and 3.
The present invention has described the detail about its concrete scheme.These details should not regarded limitation of the scope of the invention as, except comprise in the appended claims and to its expansion.
Claims (20)
1, be selected from N, N '-carbonyl diazole, N, N '-thiocarbonyl diazole, and N, the preparation method of N ' the N '-diazole compounds of N '-sulfinyl diazole compounds is included in the inert solvent,
(a) the unsubstituted 1H-azole compounds of 1-of general formula representative below:
X wherein
1, X
2And X
3Be respectively CR independently
1Or nitrogen-atoms, condition is X
1, X
2, X
3In at least one is a nitrogen-atoms, R
1And R
2Be respectively hydrogen independently, halogen, C
1-C
6Alkyl, phenyl, the phenyl of replacement, or work as X
3Be CR
1The time, R
1With R
2Link to each other and comprise that two carbon atoms in the unsubstituted 1H-pyrrole ring of 1-form the ring that a condensed has 4-6 carbon atom together; With
(b) dihalide that is selected from down group reacts:
Wherein Z is oxygen or sulphur, and Y is fluorine independently, chlorine or bromine,
The mol ratio of unsubstituted 1H-azole compounds of 1-and described dihalide is 1.7: 1～2.3: 1, be reflected under the organic bases existence and carry out, this organic bases is dissolved in described inert solvent and its basicity greater than the unsubstituted 1H-azole compounds of described 1-, when the mol ratio of unsubstituted 1H-azole compounds of 1-and described dihalide during less than 2: 1, the mol ratio of the unsubstituted 1H-azole compounds of described organic bases and 1-is 1: 1, thereby prepare described N, the halogen acid salt of N '-diazole compounds and described organic bases, this halogen acid salt are soluble in described inert solvent.
2, the process of claim 1 wherein and work as X
3Be CR
1And R
1And R
2When forming fused rings together, described fused rings is a phenyl ring.
3, the process of claim 1 wherein X
1And X
3Be CR
1And X
2Be nitrogen.
4, the method for claim 3, wherein R
1And R
2All be hydrogen.
5, the process of claim 1 wherein that Y is a chlorine or bromine.
6, the method for claim 5, wherein Y is a chlorine.
7, the method for claim 6, wherein said dihalide is a phosgene.
8, the process of claim 1 wherein that the mol ratio of unsubstituted 1H-azole compounds of described 1-and described dihalide is 1.8: 1～2: 1.
9, the method for claim 8, the mol ratio of unsubstituted 1H-azole compounds of wherein said 1-and described dihalide is 1.9: 1～2: 1.
10, the process of claim 1 wherein that described organic bases is a tertiary amine.
11, the method for claim 10, wherein said organic bases is selected from N, N-dimethyl amine, three (n-propyl) amine, at least one in three (sec.-propyl) amine and three (normal-butyl) amine.
12, the method for claim 11, wherein said organic bases are three (normal-butyl) amine.
13, the process of claim 1 wherein that described inert solvent is selected from aromatic solvent and halogenated solvent.
14, the method for claim 13, wherein said inert solvent is an aromatic solvent.
15, the method for claim 14, wherein inert solvent is a toluene.
16, preparation N, the method for N '-carbonyl diazole compound is included in the inert solvent,
(a) the unsubstituted 1H-azole compounds of 1-of general formula representative below:
X wherein
1, X
2And X
3Be respectively CR independently
1Or nitrogen-atoms, condition is X
1, X
2, X
3In at least one is a nitrogen-atoms; R
1And R
2Be respectively hydrogen independently, halogen, C
1-C
6Alkyl, phenyl, the phenyl of replacement, or work as X
3Be CR
1The time, R
1With R
2Link to each other and comprise that two carbon atoms in the unsubstituted 1H-pyrrole ring of 1-form the ring that a condensed has 4-6 carbon atom together; With
The dihalide reaction of general formula representative (b):
Wherein Y is fluorine independently, chlorine or bromine, the mol ratio of unsubstituted 1H-azole compounds of 1-and described dihalide is 1.7: 1～2.3: 1, be reflected under the organic bases existence and carry out, this organic bases is dissolved in described inert solvent and its basicity greater than the unsubstituted 1H-azole compounds of described 1-, when the mol ratio of unsubstituted 1H-azole compounds of described 1-and described dihalide during less than 2: 1, the mol ratio of the unsubstituted 1H-azole compounds of described organic bases and 1-is 1: 1, thereby prepare described N, the halogen acid salt of N '-carbonyl diazole compound and described organic bases, this halogen acid salt are soluble in described inert solvent.
17, the method for claim 16 is wherein worked as X
3Be CR
1And R
1And R
2When forming fused rings together, described fused rings is a phenyl ring.
18, the method for claim 16, wherein X
1And X
3Be CR
1And X
2Be nitrogen, Y is a chlorine, and described inert solvent is selected from aromatic solvent and halogenated solvent, and described organic bases is a tertiary amine.
19, the method for claim 18, wherein R
1And R
2All be hydrogen, described organic bases is three (normal-butyl) amine, and described inert solvent is an aromatic solvent, and the mol ratio of unsubstituted 1H-azole compounds of described 1-and described dihalide is 1.8: 1～2: 1.
20, the method for claim 19, wherein said inert solvent is a toluene, and the mol ratio of unsubstituted 1H-azole compounds of described 1-and described dihalide is 1.9: 1～2: 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78562697A | 1997-01-17 | 1997-01-17 | |
| US08/785,626 | 1997-01-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1248247A true CN1248247A (en) | 2000-03-22 |
| CN1109021C CN1109021C (en) | 2003-05-21 |
Family
ID=25136102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98802686A Expired - Fee Related CN1109021C (en) | 1997-01-17 | 1998-01-09 | Method of producing N, N'-diazole compounds |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1019381A1 (en) |
| CN (1) | CN1109021C (en) |
| CA (1) | CA2278179A1 (en) |
| WO (1) | WO1998031672A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321026A (en) * | 2011-08-02 | 2012-01-18 | 海门瑞一医药科技有限公司 | The production technique of carbonyl dimidazoles |
| CN104496908A (en) * | 2014-12-24 | 2015-04-08 | 江苏康乐新材料科技有限公司 | Preparation method of carbonyl diimidazole |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19830556A1 (en) * | 1998-07-08 | 2000-01-13 | Basf Ag | Process for the preparation of carbonyldiimidazoles |
| DE19833913A1 (en) * | 1998-07-28 | 2000-02-03 | Bayer Ag | Process for the preparation of N, N'-carbonyldiazoles |
| DE10035011A1 (en) | 2000-07-19 | 2002-01-31 | Bayer Ag | Pure N,N'-carbonyl-diazole preparation in high yield, by reacting azolide salt with phosgene in aromatic or ether solvent |
| US6455702B1 (en) * | 2001-05-16 | 2002-09-24 | Aims Fine Chemicals, Inc. | Process for the production of N,N-carbonyl diimidazole |
| DE10359797A1 (en) | 2003-12-19 | 2005-07-21 | Bayer Chemicals Ag | Process for the preparation of N, N'-carbonyldiazoles |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1469772A (en) * | 1973-06-21 | 1977-04-06 | Boots Co Ltd | Fungicidal imidazole derivatives |
| US3997071A (en) * | 1975-08-14 | 1976-12-14 | Laserplane Corporation | Method and apparatus for indicating effective digging depth of a backhoe |
| EP0668859B1 (en) * | 1992-11-13 | 1997-02-26 | E.I. Du Pont De Nemours And Company | Processes for preparing 2,4-oxazolidinediones |
-
1998
- 1998-01-09 WO PCT/US1998/000592 patent/WO1998031672A1/en active Application Filing
- 1998-01-09 EP EP98901791A patent/EP1019381A1/en not_active Withdrawn
- 1998-01-09 CN CN98802686A patent/CN1109021C/en not_active Expired - Fee Related
- 1998-01-09 CA CA002278179A patent/CA2278179A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321026A (en) * | 2011-08-02 | 2012-01-18 | 海门瑞一医药科技有限公司 | The production technique of carbonyl dimidazoles |
| CN104496908A (en) * | 2014-12-24 | 2015-04-08 | 江苏康乐新材料科技有限公司 | Preparation method of carbonyl diimidazole |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998031672A1 (en) | 1998-07-23 |
| CN1109021C (en) | 2003-05-21 |
| EP1019381A1 (en) | 2000-07-19 |
| CA2278179A1 (en) | 1998-07-23 |
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