CN101589027A - Process for the sulfinylation of a pyrazole derivative - Google Patents

Abstract

The present invention relates to a process for the sulfinylation of a pyrazole derivative, characterized in that 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (II) is reacted with a sulfinylating agent S in the presence of at least one amine acid complex wherein the amine(s) are selected from secondary and/or tertiary amines and the acid(s) are selected from hydrofluoric, hydrochloric, hydrobromic and hydroiodic acid and sulfonic acid derivatives, and with the addition of a halogenating agent, wherein S is [CF3S(O)]2O; or CF3S(O)X wherein X means fluoro, chloro, bromo, iodo, a hydroxy group, or an alkaline or alkaline earth metal salt of the hydroxy group; or mixtures thereof, wherein the temperature of the reaction mixture at no time exceeds 39 DEG C.

Description

The sulfination method of pyrazole derivatives

The present invention relates to a kind of novel method of sulfination pyrazole derivatives, it is characterized in that making 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and sulfination agent S reacting in the presence of at least a amino acid title complex and under the adding halide reagent, wherein amine is selected from and is selected from the second month in a season and/or tertiary amine and acid hydrofluoric acid, hydrochloric acid, Hydrogen bromide and hydroiodic acid HI and sulfonic acid, and wherein S is [CF ₃S (O)] ₂O; Or CF ₃S (O) X, wherein X refers to the basic metal or the alkaline earth salt of fluorine, chlorine, bromine, iodine, hydroxyl or hydroxyl; Or its mixture, wherein whenever the temperature of reaction mixture also is no more than 39 ℃.

The sulfination of pyrazole compound relate on the pyrazole heterocycle carbon atom hydrogen atom by RS (=O)-group replaces.

Utilize P (O) Cl ₃And CF ₃The mixture of S (O) ONa has been described in T.Billard with the direct sulfination of each organic molecular species (not comprising pyrazole derivatives), A.Greiner, and B.R.Langlois, Tetrahedron 55 (1999), in the 7243-7250 page or leaf.Equally, C.Wakselman, M.Tordeux, C.Freslon, L.Saint-Jalmes, the direct sulfination of Synlett 2001, the 550-552 pages or leaves instruction aromatic substance passes through CF ₃S (O) ONa or CF ₃S (O) OK is at trifluoromethanesulfonic acid (CF ₃S (O) ₂OH) carry out under the existence.

5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-the direct sulfination method of 1H-pyrazoles-3-formonitrile HCN (II) has been described in EP-A 668 269, EP-A 1 331 222, CN-A 1374298 and Y.Huilong, M.Zengeng, W.Shujuan, J.Hebei University of Science ofTechnology, the the 25th (2) volume, total the 69th phase (2004) is among sequence number 1008-1542 (2004) 02-0018-03.

In EP 668 269, described and used trifluoromethanesulpacidc acidc CF ₃S (O) OH and derivative CF thereof ₃S (O) Cl, CF ₃S (O) ONa, CF ₃S (O) N (CH ₃) ₂Or CF ₃S (O) N (CH ₂CH ₃) ₂Sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II).Phosgene, chloro-formic ester, PCl have been mentioned as chlorination reagent ₅And SOCl ₂Described can choose wantonly in the presence of the tosic acid of equimolar amount add be selected from primary, the second month in a season or tertiary amine, tosylate, hydrochloride and the mesylate of preferred dimethylamine, pyridine, Trimethylamine 99, diethylamine or isopropylamine or the reagent (" Compound C ") of gaseous hydrogen chloride so that this react completely.This reaction can be carried out under 30-55 ℃ temperature.Provided the example of following reactants and temperature combination:

CF ₃S (O) Cl, dimethylamine tosilate, 50 ℃;

CF ₃S (O) Cl, pyridine hydrochloride, 50 ℃;

CF ₃S (O) N (CH ₃) ₂, tosic acid, hydrochloric acid, 50 ℃;

CF ₃S (O) Cl, dimethylamine tosilate, hydrochloric acid, 50 ℃; With

CF ₃S (O) ONa, dimethylamine tosilate, SOCl ₂According to this specific embodiment, SOCl ₂At first add down, will react then and at room temperature keep several hours, be warming up to 50 ℃ afterwards at 5 ℃.Use CF ₃The reaction that S (O) Cl carries out as the sulfination agent obtains the end product of maximum output.

Developed some shortcoming that the method described in the CN-A 1374298 overcomes EP 668 269 described methods.CN-A 1374298 has illustrated CF ₃S (O) Cl is extremely unstable, CF ₃S (O) N (CH ₃) ₂And CF ₃The difficult preparation of SOOH, and CF ₃Productive rate in the not high and inferior sulfonation reaction of the reactivity of S (O) ONa is correspondingly lower.CN-A 1374298 has described the sylvite CF that uses trifluoromethanesulpacidc acidc ₃The mixture C F of S (O) OK or trifluoromethanesulpacidc acidc potassium and sodium salt ₃S (O) OK/CF ₃S (O) ONa sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II), wherein with sulfination agent and POCl ₃, PCl ₃, SOCl ₂, COCl ₂Or trichloro-methyl chloroformate combination.Choose wantonly and can add amino acid title complex dimethylamine tosilate to finish this reaction.

Provided the example of following reactants combination:

CF ₃S (O) OK; The dimethylamine tosilate; POCl ₃With

CF ₃S (O) OK/Na; The dimethylamine tosilate; SOCl ₂

The temperature of this embodiment reaction mixture is 40-60 ℃.

Huilong etc. have described 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and trifluoromethanesulpacidc acidc sodium (CF ₃S (O) ONa), dimethylamine tosilate and SOCl ₂Reaction, and add the DMF (dimethyl formamide) of catalytic amount.Temperature kept 10 minutes down at 3 ℃, rose to room temperature (keeping 1 hour) then, rose to 50 ℃ (keeping 10 hours) again.

As described in EP-A 1 331 222; use N-trifluoromethyl sulphinyl base succinimide as the sulfination agent in the presence of the triethylamine and do not add sulfination 5-amino-1-[2 under the chlorination reagent; 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II), wherein temperature rises to room temperature by 10 ℃.Separation of intermediates N-trifluoromethyl sulphinyl amino-pyrazol is also changing into end product 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl under 35-55 ℃ temperature under the Thia-Fries rearrangement condition]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.

Therefore; 5-amino-1-[2; 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) is to end product 5-amino-1-[2; 6-two chloro-4-(trifluoromethyl) phenyl]-(popular name: sulfination sharp strength spy (fipronil)) is subjected to obvious attention to 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN in the literature, and focus is the optimization of sulfination agent.The improvement of method described in the document has used dimethylamine tosilate and about 50 ℃ temperature as the standard reaction condition.

Yet, also as recent survey article " progress of synthetic sharp strength spy and main intermediate thereof ", Chinese Journal of Pesticides, 2004, the 43 volumes, the 12nd phase, 529-531 is described, and the sulfination of still finding the pyrazoles intermediate usually and be not suitable for large-scale commercial production.

The reaction product of sulfination of the present invention is sharp strength spy, and it is the commercially available sterilant with remarkable importance.The industrially preparing process of agricultural chemicals be owing to the profit reason should satisfy high request usually on the productive rate of product and purity, and the most important thing is for fear of there being potential deleterious by product.This is special relevant especially for sharp strength, because it also is used for the animal health product and therefore also contacts with pet.

In addition, be amplified to by laboratory scale in plant-scale process, unpredictalbe problem in the laboratory may occur in technology.

-for example, and the filling of big content of starting materials and/or be dissolved in may be than needing the much longer time on extensive in small vessels, bearing reaction kinetics significantly changes, thereby transformation efficiency and production spectra are changed.

-another example that can mention is the appearance of by product, and these by products are owing to the reason of solubleness or characteristic is difficult to separate with required principal product on a large scale.The problem of extraction, filtration and filter stoppage may take place.Insoluble raw material or reaction (pair) product also may influence stirring, heat dissipation or pumping, therefore produces uneven reaction mixture.

-another difficulty is the control of temperature of reaction in the extensive technology.Temperature grade is lower usually, and this may influence the by product spectrum.Because high reaction temperature and/or aggressiveness reaction medium may cause corrosion, and since economic cause, preferred mild reaction conditions (as low temperature according to the present invention).

-solid hygroscopic property may make the reaction of advantageously carrying out under substantially anhydrous conditions complicated.For example, acid is H when above-mentioned technology is used wherein ₂SO ₄Rather than the amino acid title complex of the defined acid of the inventive method is when carrying out, the reaction yield extreme difference.

-preferably with non-reactive catalysts-as tertiary amine (for example triethylamine)/acid-be used for the inventive method to avoid side reaction.Specific secondary amine or primary amine may react with the sulfination agent.

-in order to be beneficial to aftertreatment, the reagent that preferred use can be removed by distillation.Solid is by removing with acidity or basic solvent washing.The reagent that use has the phase-transfer catalysis performance that is separated in the possibility obstruction last handling process is not favourable.

At this background and one of the necessary raw material of existing industrial production that faces sharp strength spy for having the CF that high environmental toxicity and the Montreal Protocol on Substances that Deplete the OzoneLayer regulation can not be used to produce ₃Br (may only be used as raw material at that time) this fact (for example referring to WO 01/30760), the objective of the invention is to develop a kind of new large-scale industry method of making sharp strength spy, this method obtains sharp strength spy with high purity and productive rate, the problem of avoiding using hazardous agents simultaneously and having avoided industrial reaction to control.

Therefore, found the defined method of beginning.The sharp strength spy of products therefrom is suitable as the sterilant of agricultural application and the application of non-crop with pest control.In addition, the sharp strength spy of gained is applicable to the animal health field with control animal health insect and parasite, flea and tick on the especially long-acting control Mammals.

Therefore, the invention still further relates to the 5-amino-1-[2 that contains by the inventive method preparation, 6-two chloro-4-(trifluoromethyl) phenyl]-desinsection or the parasite killing composition of 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.

Equally, the present invention relates to a kind of method of preventing and treating insect, acarid or nematode, comprise the 5-amino-1-[2 that makes insect, acarid or nematode or its provand source, habitat, breeding spot or its place and insecticidal effective dose, 6-two chloro-4-(trifluoromethyl) phenyl by the inventive method preparation]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN contact; And a kind of growing plants of protecting is with protection against insect, acarid or nematosis or the method that infects; comprise the 5-amino-1-[2 that in the soil of the blade face of plant or seed or wherein their growths or water, uses insecticidal effective dose, 6-two chloro-4-(trifluoromethyl) phenyl by the inventive method preparation]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.According to these methods, 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN uses with the amount of 5-2000g/ha usually.

In addition; the present invention relates to a kind of processing, control, prevent or watch for animals to avoid the method for parasite infestation or infection; comprise to animal or its habitat per os, part or parenteral admin or use the 5-amino-1-[2 by the inventive method preparation of parasiticide significant quantity, 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt.

The invention still further relates to a kind of preparation is used to handle, prevent and treat, prevent or watches for animals to avoid the method for compositions of parasite infestation or infection; comprising will be by the 5-amino-1-[2 of the inventive method preparation, 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its enantiomorph or can salt for animals with can mix by carrier for animals.Said composition can be enriched material or contain 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl with the parasiticide significant quantity]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.

Although for having provided example in when beginning or some amino acid title complex of in the inferior sulfonation reaction process, adding, with regard to the specific nature of amino acid title complex for reaction control or the sharp strength spy's of end product the productive rate and/or the not instruction of most important property of purity.

In EP-A1 668 269, be recommended in 0-100 ℃ prevailingly, preferred 3-60 ℃, most preferably react under 30-55 ℃.According to the embodiment program, temperature of reaction reaches 50 ℃ and kept several hours in each case on this temperature spot.

Similarly, in the two, the temperature range that provides among the embodiment is 40-60 ℃ (CN-A 1374298) and 50 ℃ (Huilong etc.) at CN-A 1374298 and Huilong etc.

The prior art document is not all mentioned or is advised reacting being lower than under 39 ℃ the temperature.In fact, prior art document even do not mention and optimize reaction control to obtain the sharp strength spy's of high purity end product problem.Although consider and do not pay special attention to this fact of temperature-for example discussed the selection of sulfination agent fully in the prior art, especially shockingly find temperature of reaction remarkably influenced by product spectrum.

Therefore new theme of the present invention is a kind of novel method of sulfination pyrazole derivatives, it is characterized in that making 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and sulfination agent S reacting in the presence of at least a amino acid title complex and under the adding halide reagent, wherein amine is selected from and is selected from the second month in a season and/or tertiary amine and acid hydrofluoric acid, hydrochloric acid, Hydrogen bromide and hydroiodic acid HI and sulfonic acid, wherein S such as the beginning definition, wherein whenever the temperature of reaction mixture also is no more than 39 ℃.

Reaction scheme can be described below:

The sharp strength spy of II

Temperature of reaction preferably is no more than 36 ℃.Top temperature is preferably 25-39 ℃, even more preferably 31-39 ℃, preferred 32-36 ℃.

The sulfination agent is preferably selected from trifluoromethyl sulphinyl fluorine, trifluoromethyl sulphinyl chlorine, trifluoromethyl sulphinyl bromine, trifluoromethyl sulphinyl iodine, trifluoromethanesulpacidc acidc, trifluoromethanesulpacidc acidc acid anhydride, trifluoromethanesulpacidc acidc sodium, trifluoromethanesulpacidc acidc potassium and composition thereof.

The sulfination agent more preferably is selected from trifluoromethanesulpacidc acidc, trifluoromethanesulpacidc acidc acid anhydride, trifluoromethanesulpacidc acidc sodium, trifluoromethanesulpacidc acidc potassium and composition thereof.

According to the preferred embodiments of the invention, with trifluoromethyl sulphinyl fluorine, trifluoromethyl sulphinyl chlorine, trifluoromethyl sulphinyl bromine or trifluoromethyl sulphinyl iodine, more preferably trifluoromethyl sulphinyl chlorine is as the sulfination agent.

According to the preferred embodiments of the invention, trifluoromethanesulpacidc acidc sodium is used as the sulfination agent.

According to another preferred embodiment of the present invention, trifluoromethanesulpacidc acidc potassium is used as the sulfination agent.

According to a preferred embodiment more of the present invention, trifluoromethanesulpacidc acidc is used as the sulfination agent.

According to another preferred embodiment of the present invention, the trifluoromethanesulpacidc acidc acid anhydride is used as the sulfination agent.

According to the preferred embodiments of the invention, be 0.01: 99.99 weight %-50 with ratio of mixture: the trifluoromethanesulpacidc acidc sodium of 50 weight % and the mixture of sylvite are as the sulfination agent.

Preferably with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN uses 1.0-1.35 molar equivalent, the most preferably sulfination agent of 1.2 molar equivalents.

In preferred embodiments, dry sulfination agent before using is up to substantially anhydrous." anhydrous " is meant that the water-content in the solid is no more than 5ppm to 100ppm.

Halide reagent is selected from thionyl chloride, thionyl bromide, phosphoryl chloride, oxalyl chloride, phosgene, triphosgene ((CCl ₃) ₂C (=O)), chloro-formic ester, phosphorus pentachloride, phosphorus trichloride, trichloro-methyl chloroformate (trichloromethylchloromethanoat) and xylenesulfonyl chloride.

According to the preferred embodiments of the invention, chlorination reagent is used as halide reagent.Preferably thionyl chloride or phosphoryl chloride are used as chlorination reagent.

According to another preferred embodiment of the present invention, phosphoryl chloride is used as chlorination reagent.

Most preferably thionyl chloride is used as chlorination reagent.

Preferably with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN uses 1.15-1.35 molar equivalent, the most preferably from about halide reagent of 1.2 molar equivalents.

We find except temperature of reaction, the amino acid title complex be chosen in 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-play a crucial role in the sulfination of 1H-pyrazoles-3-formonitrile HCN.The key property that influences inferior sulfonation reaction is space (volume) performance, pKs value, solubleness and molecular weight.

Inferior sulfonation reaction of the present invention is that single still of two-step reaction is synthetic.The first step relates to CF ₃S (the O)-addition of group on the amino of pyrazoles ring.In second step, reset the sharp strength spy of formation via Thia-Fries:

The sharp strength spy of II sulfinyl amine intermediate

The amino acid title complex has two kinds of functions in this two-step reaction: (1) when with the sulfination thing when the sulfination agent, it is via the activation to the sulfination thing of the formation catalytic halogenation reagent of-sulfinic acid intermediate.For this reason, the amino acid title complex that needs 0.01-1.0 molar equivalent catalytic amount with respect to pyrazole compound II.(2) it quickens the Thia-Fries rearrangement and selectivity is had remarkably influenced.In order to obtain high yield and high purity, advantageously will be used for step 2 with respect to the amino acid title complex that pyrazole compound II total amount surpasses 1 molar equivalent.

Preferably have agent of low hygroscopicity or do not have hygroscopic amino acid title complex substantially, because sulfination method of the present invention is advantageously carried out not existing substantially under the water (promptly being lower than 5-100ppm water).

The amine that is preferred among the present invention is tertiary amine such as alkylamine, for example Trimethylamine 99, triethylamine, tripropyl amine, tri-isopropyl amine, Tributylamine, dimethylethyl amine, diethylmethyl amine, dimethyl n propyl group amine, diisopropyl ethyl amine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), DBN (1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene), methylmorpholine, ethyl morpholine, N, accelerine, methyl piperidine, crassitude or methyl dibenzyl amine; Or aromatic amine such as pyridine, DMAP (Dimethylamino pyridine), collidine, lutidine, pyrimidine, pyrazine or piperazine; Or secondary amine such as alkylamine, for example dimethylamine, diethylamine, dipropyl amine, Diisopropylamine, dibutylamine, ethyl dimethylamine, sec.-propyl methylamine or sec.-propyl ethamine; Or formula NHR ¹R ²Cyclic secondary amine, R wherein ¹And R ²Form the saturated or part unsaturated heterocycle system of 3-10 person with the nitrogen-atoms that they connected, this heterocyclic system is not substituted or by 1-3 C ₁-C ₈Alkyl or C ₁-C ₈Haloalkyl replaces and can contain 1-3 other heteroatomss that are selected from oxygen, nitrogen and sulphur.

The amine that is preferred among the present invention is secondary amine.

Preferred secondary amine is alkylamine, for example dimethylamine, diethylamine, dipropyl amine, Diisopropylamine, dibutylamine, ethyl dimethylamine, sec.-propyl methylamine or sec.-propyl ethamine.

The cyclic secondary amine of amino acid title complex is preferably by formula NHR ¹R ²Definition, wherein R ¹And R ²Form the saturated or part unsaturated heterocycle system of 3-10 person with the nitrogen-atoms that they connected, preferred 5-6 person's saturated heterocyclic system, this heterocyclic system is not substituted or by 1-3 C ₁-C ₈Alkyl or C ₁-C ₈Haloalkyl, preferred 1-3 C ₁-C ₃Alkyl or C ₁-C ₃Haloalkyl, most preferably 1-3 C ₁-C ₃Alkyl, most preferably 1-3 methyl substituted and can contain 1-3 and be selected from oxygen, nitrogen and sulphur is preferably selected from other heteroatomss of oxygen or nitrogen.

In addition, preferred secondary amine is cyclic secondary amine such as piperidines, by C ₁-C ₈Alkyl or C ₁-C ₈Haloalkyl, preferred C ₁-C ₂Alkyl or C ₁-C ₂The piperidines that haloalkyl replaces, as pipecoline or 4-methyl piperidine, tetramethyleneimine, imidazolidine, the pyrroles, piperazine or morpholine, preferred morpholine, piperidines, tetramethyleneimine is by C ₁-C ₈Alkyl or C ₁-C ₈The tetramethyleneimine that haloalkyl replaces is as 2-crassitude and 3-crassitude.

Under the situation of using secondary amine, the respective acids of amino acid title complex is preferably selected from sulfonic acid.

Especially the amine that is preferred among the present invention is tertiary amine.

Preferred tertiary amine is: alkylamine such as Trimethylamine 99, triethylamine, tripropyl amine, tri-isopropyl amine, Tributylamine, dimethylethyl amine, diethylmethyl amine, dimethyl n propyl group amine, diisopropyl ethyl amine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), DBN (1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene), methylmorpholine, ethyl morpholine, N, accelerine, methyl piperidine, crassitude or methyl dibenzyl amine; Or aromatic amine such as pyridine, DMAP (Dimethylamino pyridine), collidine, lutidine, pyrimidine, pyrazine or piperazine.

In another preferred embodiment, tertiary amine is selected from triethylamine, tripropyl amine, tri-isopropyl amine, Tributylamine, diisopropyl ethyl amine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), DBN (1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene), methylmorpholine, ethyl morpholine, N, accelerine, methyl piperidine, crassitude, methyl dibenzyl amine, DMAP (Dimethylamino pyridine), collidine, lutidine, pyrimidine, pyrazine and piperazine.

In another preferred embodiment, tertiary amine is selected from Trimethylamine 99, triethylamine, dimethylethyl amine, diethylmethyl amine, dimethyl n propyl group amine, methylmorpholine, N, accelerine, methyl piperidine, crassitude, methyl dibenzyl amine and pyridine.

Especially preferred Trimethylamine 99, triethylamine, dimethylethyl amine, dimethyl n propyl group amine or pyridine.Very preferably triethylamine and pyridine.In highly preferred embodiment, amine is triethylamine.In highly preferred embodiment, amine also is pyridine.In highly preferred embodiment, amine also is Trimethylamine 99.In highly preferred embodiment, with at least one also is methyl in the alkyl that the nitrogen-atoms of amine is connected.In highly preferred embodiment, the nitrogen-atoms of amido also is sp ³Hydridization, promptly it does not form two keys with adjacent atom.

The preferred acid that is used for amino acid title complex of the present invention is hydrochloric acid, hydrofluoric acid, Hydrogen bromide, hydroiodic acid HI or sulfonic acid such as aromatic sulfonic acid, for example tosic acid, Phenylsulfonic acid, 4-ethyl phenenyl azochlorosulfonate acid, 4-chlorobenzenesulfonic acid, xylene monosulfonic acid, 2,3-acid dimethyl, 2,4-acid dimethyl, 2,5-acid dimethyl, 2, the mixture of two or more in 6-acid dimethyl, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, the acid dimethyl isomer, or mesitylene sulfonic acid; Or alkylsulphonic acid, for example methylsulfonic acid or camphorsulfonic acid; Or haloalkyl sulfonic acid, for example trifluoromethane sulfonic acid.Especially preferred pKs value is less than 2 acid.

Most preferred acid is hydrochloric acid and tosic acid, xylene monosulfonic acid, Phenylsulfonic acid, methylsulfonic acid, trifluoromethane sulfonic acid, mesitylene sulfonic acid, especially tosic acid, xylene monosulfonic acid and Phenylsulfonic acid.

At amine is under the situation of secondary amine, preferably uses sulfonic acid.

In the selection that is used for amino acid title complex of the present invention, preferred pKa is less than 6, preferred 5 and greater than 10 those.

Preferred amino acid title complex Q is listed in the table below in 1.

Table 1

Sequence number	Amine	Acid
			Q-1	N(CH 3) 3	HF
Q-2	N(CH 3) 3	HCl
			Q-3	N(CH 3) 3	HBr
Q-4	N(CH 3) 3	HI
			Q-5	N(CH 3) 3	Tosic acid
Q-6	N(CH 3) 3	Phenylsulfonic acid
			Q-7	N(CH 3) 3	Xylene monosulfonic acid
Q-8	N(CH 3) 3	Methylsulfonic acid
			Q-9	N(CH 3) 3	Trifluoromethane sulfonic acid
Q-10	N(CH 3) 3	Mesitylene sulfonic acid
			Q-11	N(CH 2CH 3) 3	HF
Q-12	N(CH 2CH 3) 3	HCl
			Q-13	N(CH 2CH 3) 3	HBr
Q-14	N(CH 2CH 3) 3	HI
			Q-15	N(CH 2CH 3) 3	Tosic acid
Q-16	N(CH 2CH 3) 3	Phenylsulfonic acid
			Q-17	N(CH 2CH 3) 3	Xylene monosulfonic acid
Q-18	N(CH 2CH 3) 3	Methylsulfonic acid
			Q-19	N(CH 2CH 3) 3	Trifluoromethane sulfonic acid
Q-20	N(CH 2CH 3) 3	Mesitylene sulfonic acid
			Q-21	N(CH 2CH 2CH 3) 3	HF
Q-22	N(CH 2CH 2CH 3) 3	HCl
			Q-23	N(CH 2CH 2CH 3) 3	HBr
Q-24	N(CH 2CH 2CH 3) 3	HI
			Q-25	N(CH 2CH 2CH 3) 3	Tosic acid
Q-26	N(CH 2CH 2CH 3) 3	Phenylsulfonic acid
			Q-27	N(CH 2CH 2CH 3) 3	Xylene monosulfonic acid
Q-28	N(CH 2CH 2CH 3) 3	Methylsulfonic acid
			Q-29	N(CH 2CH 2CH 3) 3	Trifluoromethane sulfonic acid
Q-30	N(CH 2CH 2CH 3) 3	Mesitylene sulfonic acid
			Q-31	N(CH 2CH 2CH 2CH 3) 3	HF
Q-32	N(CH 2CH 2CH 2CH 3) 3	HCl
			Q-33	N(CH 2CH 2CH 2CH 3) 3	HBr
Q-34	N(CH 2CH 2CH 2CH 3) 3	HI
			Q-35	N(CH 2CH 2CH 2CH 3) 3	Tosic acid
Q-36	N(CH 2CH 2CH 2CH 3) 3	Phenylsulfonic acid
			Q-37	N(CH 2CH 2CH 2CH 3) 3	Xylene monosulfonic acid
Q-38	N(CH 2CH 2CH 2CH 3) 3	Methylsulfonic acid

Sequence number	Amine	Acid
			Q-39	N(CH 2CH 2CH 2CH 3) 3	Trifluoromethane sulfonic acid
Q-40	N(CH 2CH 2CH 2CH 3) 3	Mesitylene sulfonic acid
			Q-41	N[CH(CH 3) 2] 3	HF
Q-42	N[CH(CH 3) 2] 3	HCl
			Q-43	N[CH(CH 3) 2] 3	HBr
Q-44	N[CH(CH 3) 2] 3	HI
			Q-45	N[CH(CH 3) 2] 3	Tosic acid
Q-46	N[CH(CH 3) 2] 3	Phenylsulfonic acid
			Q-47	N[CH(CH 3) 2] 3	Xylene monosulfonic acid
Q-48	N[CH(CH 3) 2] 3	Methylsulfonic acid
			Q-49	N[CH(CH 3) 2] 3	Trifluoromethane sulfonic acid
Q-50	N[CH(CH 3) 2] 3	Mesitylene sulfonic acid
			Q-51	N(CH 2CH 3)[(CH(CH 3) 2) 2	HF
Q-52	N(CH 2CH 3)[(CH(CH 3) 2] 2	HCl
			Q-53	N(CH 2CH 3)[(CH(CH 3) 2] 2	HBr
Q-54	N(CH 2CH 3)[(CH(CH 3) 2) 2	HI
			Q-55	N(CH 2CH 3)[(CH(CH 3) 2] 2	Tosic acid
Q-56	N(CH 2CH 3)[(CH(CH 3) 2] 2	Phenylsulfonic acid
			Q-57	N(CH 2CH 3)[(CH(CH 3) 2] 2	Xylene monosulfonic acid
Q-58	N(CH 2CH 3)[(CH(CH 3) 2] 2	Methylsulfonic acid
			Q-59	N(CH 2CH 3)[(CH(CH 3) 2] 2	Trifluoromethane sulfonic acid
Q-60	N(CH 2CH 3)[(CH(CH 3) 2] 2	Mesitylene sulfonic acid
			Q-61	DBU	HF
Q-62	DBU	HCl
			Q-63	DBU	HBr
Q-64	DBU	HI
			Q-65	DBU	Tosic acid
Q-66	DBU	Phenylsulfonic acid
			Q-67	DBU	Xylene monosulfonic acid
Q-68	DBU	Methylsulfonic acid
			Q-69	DBU	Trifluoromethane sulfonic acid
Q-70	DBU	Mesitylene sulfonic acid
			Q-71	DBN	HF
Q-72	DBN	HCl
			Q-73	DBN	HBr
Q-74	DBN	HI
			Q-75	DBN	Tosic acid
Q-76	DBN	Phenylsulfonic acid

Sequence number	Amine	Acid
			Q-77	DBN	Xylene monosulfonic acid
Q-78	DBN	Methylsulfonic acid
			Q-79	DBN	Trifluoromethane sulfonic acid
Q-80	DBN	Mesitylene sulfonic acid
			Q-81	Methylmorpholine	HF
Q-82	Methylmorpholine	HCl
			Q-83	Methylmorpholine	HBr
Q-84	Methylmorpholine	HI
			Q-85	Methylmorpholine	Tosic acid
Q-86	Methylmorpholine	Phenylsulfonic acid
			Q-87	Methylmorpholine	Xylene monosulfonic acid
Q-88	Methylmorpholine	Methylsulfonic acid
			Q-89	Methylmorpholine	Trifluoromethane sulfonic acid
Q-90	Methylmorpholine	Mesitylene sulfonic acid
			Q-91	Ethyl morpholine	HF
Q-92	Ethyl morpholine	HCl
			Q-93	Ethyl morpholine	HBr
Q-94	Ethyl morpholine	HI
			Q-95	Ethyl morpholine	Tosic acid
Q-96	Ethyl morpholine	Phenylsulfonic acid
			Q-97	Ethyl morpholine	Xylene monosulfonic acid
Q-98	Ethyl morpholine	Methylsulfonic acid
			Q-99	Ethyl morpholine	Trifluoromethane sulfonic acid
Q-100	Ethyl morpholine	Mesitylene sulfonic acid
			Q-101	N, accelerine	HF
Q-102	N, accelerine	HCl
			Q-103	N, accelerine	HBr
Q-104	N, accelerine	HI
			Q-105	N, accelerine	Tosic acid
Q-106	N, accelerine	Phenylsulfonic acid
			Q-107	N, accelerine	Xylene monosulfonic acid
Q-108	N, accelerine	Methylsulfonic acid
			Q-109	N, accelerine	Trifluoromethane sulfonic acid
Q-110	N, accelerine	Mesitylene sulfonic acid
			Q-111	Methyl piperidine	HF
Q-112	Methyl piperidine	HCl

Sequence number	Amine	Acid
			Q-113	Methyl piperidine	HBr
Q-114	Methyl piperidine	HI
			Q-115	Methyl piperidine	Tosic acid
Q-116	Methyl piperidine	Phenylsulfonic acid
			Q-117	Methyl piperidine	Xylene monosulfonic acid
Q-118	Methyl piperidine	Methylsulfonic acid
			Q-119	Methyl piperidine	Trifluoromethane sulfonic acid
Q-120	Methyl piperidine	Mesitylene sulfonic acid
			Q-121	Crassitude	HF
Q-122	Crassitude	HCl
			Q-123	Crassitude	HBr
Q-124	Crassitude	HI
			Q-125	Crassitude	Tosic acid
Q-126	Crassitude	Phenylsulfonic acid
			Q-127	Crassitude	Xylene monosulfonic acid
Q-128	Crassitude	Methylsulfonic acid
			Q-129	Crassitude	Trifluoromethane sulfonic acid
Q-130	Crassitude	Mesitylene sulfonic acid
			Q-131	The methyl dibenzyl amine	HF
Q-132	The methyl dibenzyl amine	HCl
			Q-133	The methyl dibenzyl amine	HBr
Q-134	The methyl dibenzyl amine	HI
			Q-135	The methyl dibenzyl amine	Tosic acid
Q-136	The methyl dibenzyl amine	Phenylsulfonic acid
			Q-137	The methyl dibenzyl amine	Xylene monosulfonic acid
Q-138	The methyl dibenzyl amine	Methylsulfonic acid
			Q-139	The methyl dibenzyl amine	Trifluoromethane sulfonic acid
Q-140	The methyl dibenzyl amine	Mesitylene sulfonic acid
			Q-141	Pyridine	HF
Q-142	Pyridine	HCl
			Q-143	Pyridine	HBr
Q-144	Pyridine	HI
			Q-145	Pyridine	Tosic acid
Q-146	Pyridine	Phenylsulfonic acid
			Q-147	Pyridine	Xylene monosulfonic acid
Q-148	Pyridine	Methylsulfonic acid

Sequence number	Amine	Acid
			Q-149	Pyridine	Trifluoromethane sulfonic acid
Q-150	Pyridine	Mesitylene sulfonic acid
			Q-151	DMAP	HF
Q-152	DMAP	HCl
			Q-153	DMAP	HBr
Q-154	DMAP	HI
			Q-155	DMAP	Tosic acid
Q-156	DMAP	Phenylsulfonic acid
			Q-157	DMAP	Xylene monosulfonic acid
Q-158	DMAP	Methylsulfonic acid
			Q-159	DMAP	Trifluoromethane sulfonic acid
Q-160	DMAP	Mesitylene sulfonic acid
			Q-161	Collidine	HF
Q-162	Collidine	HCl
			Q-163	Collidine	HBr
Q-164	Collidine	HI
			Q-165	Collidine	Tosic acid
Q-166	Collidine	Phenylsulfonic acid
			Q-167	Collidine	Xylene monosulfonic acid
Q-168	Collidine	Methylsulfonic acid
			Q-169	Collidine	Trifluoromethane sulfonic acid
Q-170	Collidine	Mesitylene sulfonic acid
			Q-171	Lutidine	HF
Q-172	Lutidine	HCl
			Q-173	Lutidine	HBr
Q-174	Lutidine	HI
			Q-175	Lutidine	Tosic acid
Q-176	Lutidine	Phenylsulfonic acid
			Q-177	Lutidine	Xylene monosulfonic acid
Q-178	Lutidine	Methylsulfonic acid
			Q-179	Lutidine	Trifluoromethane sulfonic acid
Q-180	Lutidine	Mesitylene sulfonic acid
			Q-181	Pyrimidine	HF
Q-182	Pyrimidine	HCl
			Q-183	Pyrimidine	HBr
Q-184	Pyrimidine	HI
			Q-185	Pyrimidine	Tosic acid

Sequence number	Amine	Acid
			Q-186	Pyrimidine	Phenylsulfonic acid
Q-187	Pyrimidine	Xylene monosulfonic acid
			Q-188	Pyrimidine	Methylsulfonic acid
Q-189	Pyrimidine	Trifluoromethane sulfonic acid
			Q-190	Pyrimidine	Mesitylene sulfonic acid
Q-191	Pyrazine	HF
			Q-192	Pyrazine	HCl
Q-193	Pyrazine	HBr
			Q-194	Pyrazine	HI
Q-195	Pyrazine	Tosic acid
			Q-196	Pyrazine	Phenylsulfonic acid
Q-197	Pyrazine	Xylene monosulfonic acid
			Q-198	Pyrazine	Methylsulfonic acid
Q-199	Pyrazine	Trifluoromethane sulfonic acid
			Q-200	Pyrazine	Mesitylene sulfonic acid
Q-201	Piperazine	HF
			Q-202	Piperazine	HCl
Q-203	Piperazine	HBr
			Q-204	Piperazine	HI
Q-205	Piperazine	Tosic acid
			Q-206	Piperazine	Phenylsulfonic acid
Q-207	Piperazine	Xylene monosulfonic acid
			Q-208	Piperazine	Methylsulfonic acid
Q-209	Piperazine	Trifluoromethane sulfonic acid
			Q-210	Piperazine	Mesitylene sulfonic acid
Q-211	N(CH 3) 2CH 2CH 3	HF
			Q-212	N(CH 3) 2CH 2CH 3	HCl
Q-213	N(CH 3) 2CH 2CH 3	HBr
			Q-214	N(CH 3) 2CH 2CH 3	HI
Q-215	N(CH 3) 2CH 2CH 3	Tosic acid
			Q-216	N(CH 3) 2CH 2CH 3	Phenylsulfonic acid
Q-217	N(CH 3) 2CH 2CH 3	Xylene monosulfonic acid
			Q-218	N(CH 3) 2CH 2CH 3	Methylsulfonic acid
Q-219	N(CH 3) 2CH 2CH 3	Trifluoromethane sulfonic acid
			Q-220	N(CH 3) 2CH 2CH 3	Mesitylene sulfonic acid
Q-221	N(CH 3) 2CH 2CH 2CH 3	HF
			Q-222	N(CH 3) 2CH 2CH 2CH 3	HCl

Sequence number	Amine	Acid
			Q-223	N(CH 3) 2CH 2CH 2CH 3	HBr
Q-224	N(CH 3) 2CH 2CH 2CH 3	HI
			Q-225	N(CH 3) 2CH 2CH 2CH 3	Tosic acid
Q-226	N(CH 3) 2CH 2CH 2CH 3	Phenylsulfonic acid
			Q-227	N(CH 3) 2CH 2CH 2CH 3	Xylene monosulfonic acid
Q-228	N(CH 3) 2CH 2CH 2CH 3	Methylsulfonic acid
			Q-229	N(CH 3) 2CH 2CH 2CH 3	Trifluoromethane sulfonic acid
Q-230	N(CH 3) 2CH 2CH 2CH 3	Mesitylene sulfonic acid
			Q-231	NCH 3(CH 2CH 3) 2	HF
Q-232	NCH 3(CH 2CH 3) 2	HCl
			Q-233	NCH 3(CH 2CH 3) 2	HBr
Q-234	NCH 3(CH 2CH 3) 2	HI
			Q-235	NCH 3(CH 2CH 3) 2	Tosic acid
Q-236	NCH 3(CH 2CH 3) 2	Phenylsulfonic acid
			Q-237	NCH 3(CH 2CH 3) 2	Xylene monosulfonic acid
Q-238	NCH 3(CH 2CH 3) 2	Methylsulfonic acid
			Q-239	NCH 3(CH 2CH 3) 2	Trifluoromethane sulfonic acid
Q-240	NCH 3(CH 2CH 3) 2	Mesitylene sulfonic acid
			Q-241	NH(CH 3) 2	Tosic acid
Q-242	NH(CH 3) 2	Phenylsulfonic acid
			Q-243	NH(CH 3) 2	Xylene monosulfonic acid
Q-244	NH(CH 3) 2	Methylsulfonic acid
			Q-245	NH(CH 3) 2	Trifluoromethane sulfonic acid
Q-246	NH(CH 3) 2	Mesitylene sulfonic acid
			Q-247	NH(CH 2CH 3) 2	Tosic acid
Q-248	NH(CH 2CH 3) 2	Phenylsulfonic acid
			Q-249	NH(CH 2CH 3) 2	Xylene monosulfonic acid
Q-250	NH(CH 2CH 3) 2	Methylsulfonic acid
			Q-251	NH(CH 2CH 3) 2	Trifluoromethane sulfonic acid
Q-252	NH(CH 2CH 3) 2	Mesitylene sulfonic acid
			Q-253	NH(CH 2CH 2CH 3) 2	Tosic acid
Q-254	NH(CH 2CH 2CH 3) 2	Phenylsulfonic acid
			Q-255	NH(CH 2CH 2CH 3) 2	Xylene monosulfonic acid
Q-256	NH(CH 2CH 2CH 3) 2	Methylsulfonic acid
			Q-257	NH(CH 2CH 2CH 3) 2	Trifluoromethane sulfonic acid
Q-258	NH(CH 2CH 2CH 3) 2	Mesitylene sulfonic acid
			Q-259	NH(CH(CH 3) 2) 2	Tosic acid

Sequence number	Amine	Acid
			Q-260	NH(CH(CH 3) 2) 2	Phenylsulfonic acid
Q-261	NH(CH(CH 3) 2) 2	Xylene monosulfonic acid
			Q-262	NH(CH(CH 3) 2) 2	Methylsulfonic acid
Q-263	NH(CH(CH 3) 2) 2	Trifluoromethane sulfonic acid
			Q-264	NH(CH(CH 3) 2) 2	Mesitylene sulfonic acid
Q-265	NHCH 3(CH(CH 3) 2)	Tosic acid
			Q-266	NHCH 3(CH(CH 3) 2)	Phenylsulfonic acid
Q-267	NHCH 3(CH(CH 3) 2)	Xylene monosulfonic acid
			Q-268	NHCH 3(CH(CH 3) 2)	Methylsulfonic acid
Q-269	NHCH 3(CH(CH 3) 2)	Trifluoromethane sulfonic acid
			Q-270	NHCH 3(CH(CH 3) 2)	Mesitylene sulfonic acid
Q-271	NHCH 3(CH 2CH 3)	Tosic acid
			Q-272	NHCH 3(CH 2CH 3)	Phenylsulfonic acid
Q-273	NHCH 3(CH 2CH 3)	Xylene monosulfonic acid
			Q-274	NHCH 3(CH 2CH 3)	Methylsulfonic acid
Q-275	NHCH 3(CH 2CH 3)	Trifluoromethane sulfonic acid
			Q-276	NHCH 3(CH 2CH 3)	Mesitylene sulfonic acid
Q-277	Morpholine	Tosic acid
			Q-278	Morpholine	Phenylsulfonic acid
Q-279	Morpholine	Xylene monosulfonic acid
			Q-280	Morpholine	Methylsulfonic acid
Q-281	Morpholine	Trifluoromethane sulfonic acid
			Q-282	Morpholine	Mesitylene sulfonic acid
Q-283	Piperidines	Tosic acid
			Q-284	Piperidines	Phenylsulfonic acid
Q-285	Piperidines	Xylene monosulfonic acid
			Q-286	Piperidines	Methylsulfonic acid
Q-287	Piperidines	Trifluoromethane sulfonic acid
			Q-288	Piperidines	Mesitylene sulfonic acid
Q-289	The 4-methyl piperidine	Tosic acid
			Q-290	The 4-methyl piperidine	Phenylsulfonic acid
Q-291	The 4-methyl piperidine	Xylene monosulfonic acid
			Q-292	The 4-methyl piperidine	Methylsulfonic acid
Q-293	The 4-methyl piperidine	Trifluoromethane sulfonic acid
			Q-294	The 4-methyl piperidine	Mesitylene sulfonic acid
Q-295	Tetramethyleneimine	Tosic acid

Sequence number	Amine	Acid
			Q-296	Tetramethyleneimine	Phenylsulfonic acid
Q-297	Tetramethyleneimine	Xylene monosulfonic acid
			Q-298	Tetramethyleneimine	Methylsulfonic acid
Q-299	Tetramethyleneimine	Trifluoromethane sulfonic acid
			Q-300	Tetramethyleneimine	Mesitylene sulfonic acid
Q-301	Imidazoles	Tosic acid
			Q-302	Imidazoles	Phenylsulfonic acid
Q-303	Imidazoles	Xylene monosulfonic acid
			Q-304	Imidazoles	Methylsulfonic acid
Q-305	Imidazoles	Trifluoromethane sulfonic acid
			Q-306	Imidazoles	Trifluoromethane sulfonic acid
Q-307	Imidazoles	Mesitylene sulfonic acid
			Q-308	The pyrroles	Tosic acid
Q-309	The pyrroles	Phenylsulfonic acid
			Q-310	The pyrroles	Xylene monosulfonic acid
Q-311	The pyrroles	Methylsulfonic acid
			Q-312	The pyrroles	Trifluoromethane sulfonic acid
Q-313	The pyrroles	Mesitylene sulfonic acid
			Q-314	Piperazine	Tosic acid
Q-315	Piperazine	Phenylsulfonic acid
			Q-316	Piperazine	Xylene monosulfonic acid
Q-317	Piperazine	Methylsulfonic acid
			Q-318	Piperazine	Trifluoromethane sulfonic acid
Q-319	Piperazine	Mesitylene sulfonic acid
			Q-320	The 4-methyl piperidine	Tosic acid
Q-321	The 4-methyl piperidine	Phenylsulfonic acid
			Q-322	The 4-methyl piperidine	Xylene monosulfonic acid
Q-323	The 4-methyl piperidine	Methylsulfonic acid
			Q-324	The 4-methyl piperidine	Trifluoromethane sulfonic acid
Q-325	The 4-methyl piperidine	Mesitylene sulfonic acid
			Q-326	The 2-crassitude	Tosic acid
Q-327	The 2-crassitude	Phenylsulfonic acid
			Q-328	The 2-crassitude	Xylene monosulfonic acid
Q-329	The 2-crassitude	Methylsulfonic acid
			Q-330	The 2-crassitude	Trifluoromethane sulfonic acid
Q-331	The 2-crassitude	Mesitylene sulfonic acid

When amine was tertiary amine, preferably wherein acid was the amino acid title complex of hydrochloric acid or Hydrogen bromide, the especially table 1 of hydrochloric acid.

In addition, preferred wherein amine is that tertiary amine and acid are the amino acid title complex of the table 1 of tosic acid, Phenylsulfonic acid or xylene monosulfonic acid.

Preferred wherein amine is the amino acid title complex of the table 1 of tertiary amine Q-2, Q-5, Q-12, Q-17, Q-22, Q-32, Q-42, Q-52, Q-142, Q-145, Q-147, Q-162, Q-165, Q-172, Q-175, Q-212, Q-215, Q-222, Q-225, Q-232 or Q-235.

Even more preferably wherein amine be tertiary amine Q-2, Q-5, Q-6, Q-7, Q-12, Q-82, Q-85, Q-86, Q-87, Q-102, Q-105, Q-106, Q-107, Q-112, Q-115, Q-116, Q-117, Q-122, Q-125, Q-126, Q-127, Q-132, Q-135, Q-136, Q-137, Q-142, Q-145, Q-146, Q-147, Q-212, the amino acid title complex of the table 1 of Q-215, Q-216, Q-217, Q-222, Q-225, Q-226, Q-227, Q-232, Q-235, Q-236 or Q-237.

Most preferably wherein amine is the amino acid title complex of the table 1 of tertiary amine Q-2, Q-5, Q-6, Q-7, Q-12, Q-142, Q-145, Q-146, Q-147, Q-212, Q-215, Q-216, Q-217, Q-222, Q-225, Q-226, Q-227, Q-232, Q-235, Q-236 or Q-237.

Preferred wherein amine is the amino acid title complex of the table 1 of alkylamine Q-241, Q-242, Q-243, Q-247 or Q-249.

Preferred wherein amine is the amino acid title complex of the table 1 of cyclic secondary amine Q-277, Q-278, Q279, Q-283, Q-284, Q285, Q-295, Q-296, Q-297, Q-314, Q-315, Q-316, Q-320, Q-321, Q-323, Q-326, Q-327 or Q-328.

For they purposes in the methods of the invention, the combination that especially preferred following table is given sulfination agent and amino acid title complex.

Table 2

Trifluoromethanesulpacidc acidc sodium is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 3

Trifluoromethanesulpacidc acidc potassium is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 4

Trifluoromethanesulpacidc acidc is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 5

The trifluoromethanesulpacidc acidc acid anhydride is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 6

With ratio of mixture is 0.01: 99.99 weight % to 50: the sodium salt of the trifluoromethanesulpacidc acidc of 50 weight % and sylvite mixture are as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 7

The trifluoromethyl sulphinyl fluorine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 8

Trifluoromethyl sulphinyl chlorine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 9

The trifluoromethyl sulphinyl bromine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

Table 10

Trifluoromethyl sulphinyl iodine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.

In addition, in another preferred embodiment of the present invention, can be with Lewis acid such as AlCl ₃, FeCl ₃, CaCl ₂, ZnCl ₂, BF ₃, TiCl ₄Or ZrCl ₄Be used to replace above-mentioned protonic acid.

Maybe advantageously with a collection of incessantly, as adding the amino acid title complex in two batches, for example a collection ofly be used for step 1 and a collection of adding after the pyrazoles that adds formula II.

Maybe advantageously in reaction process, use two kinds of different amino acid title complexs.For example, can be in step 1 add the first amino acid title complex with the amount of 0.2-1 molar equivalent, with of the activation of catalytic halogenation reagent to the sulfination thing with respect to pyrazoles II.After the pyrazoles that adds formula II, in resetting, the Thia-Fries of step 2 adds the second amino acid title complex different with the amount of 0.2-1 molar equivalent with the first amino acid title complex with respect to pyrazoles II.

With respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN, preferably use the 1.4-2.2 molar equivalent, most preferably the amino acid title complex of the present invention of 1.5-1.8 molar equivalent.

When the sulfination agent is a trifluoromethanesulpacidc acidc or when containing the mixture of trifluoromethanesulpacidc acidc, preferably produce the amino acid title complex that molar weight equates with the molar weight of trifluoromethanesulpacidc acidc on the spot, and add the required residue molar weight of the required 1.4-2.2 molar equivalent of acquisition as the amino acid title complex by adding amine.

In preferred embodiments, dry amino acid title complex before using is up to substantially anhydrous." anhydrous " is meant that the water-content in the solid is no more than 5ppm to 100ppm.

Can advantageously other additives be added reaction mixture, as Potassium monofluoride, Pentafluorophenol, dimethyl formamide or 2,2, 4-dinitrophenol.These additives preferably add in reaction mixture or material solution or the suspension before the reaction beginning or when the reaction beginning.Most preferably additive adds under 5-10 ℃ low temperature.

In preferred embodiments, in when beginning reaction or will be 5-10 ℃ under before the reaction beginning with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN is in the Potassium monofluoride adding reaction mixture or material solution or suspension of 0.1-1.5 molar equivalent.

Advantageously with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN adds Pentafluorophenol, dimethyl formamide or 2,2, 4-dinitrophenol with catalytic amount or 0.10 molar equivalent.

In preferred embodiments, dry additive before using is up to substantially anhydrous." anhydrous " is meant that the water-content in the solid is no more than 5ppm to 100ppm.

This reaction can be carried out in inert organic solvents, and described solvent is preferably selected from:

The optional halohydrocarbon such as the organic hydrocarbon of aromatics of-aliphatic, alicyclic or aromatics, for example toluene, dimethylbenzene, trifluoromethylbenzene, benzene, oil of mirbane, mono chloro benzene, dichlorobenzene and ethylbenzene, preferred toluene and dimethylbenzene, most preferably toluene; Aliphatic or alicyclic optional halohydrocarbon such as hexane, hexanaphthene, benzene, 1,2-ethylene dichloride, methylene dichloride, trichloromethane (chloroform), tetracol phenixin, preferred 1,2-ethylene dichloride, methylene dichloride, trichloromethane; With

-ethers, as ether, diox, tetrahydrofuran (THF), 2-methyltetrahydrofuran or ethylene glycol dimethyl-or Anaesthetie Ether; With

-ketone, as acetone or butanone and

-nitrile, as acetonitrile or propionitrile and

-amides is as dimethyl formamide, DMI (1,3-dimethyl-2-imidazolidone), N,N-DIMETHYLACETAMIDE, N-methyl formyl aniline, N-Methyl pyrrolidone or HMPA; With

-sulfoxide is as methyl-sulphoxide;

Or its mixture.

In preferred embodiments, use substantially anhydrous solvent." anhydrous " is meant that the water-content in the solvent is no more than 5ppm to 100ppm.Most preferred solvent is a dry toluene.

This is reflected under the inert gas atmosphere and carries out, and for example carries out under argon gas or nitrogen atmosphere.

In preferred embodiments,, 6-two chloro-4-(trifluoromethyl) phenyl with respect to 5-amino-1-[2]-1H-pyrazoles-3-formonitrile HCN uses 3.0-8.0 molar equivalent altogether, more preferably 4.0-7.5 molar equivalent, the most preferably solvent of 4.5-6.5 molar equivalent.The raw material of this higher concentration makes the conversion maximization to the sulfinyl amine intermediate.

Raw material its in conjunction with before respectively separately under dissolving and/or the situation about suspending, will about 25-40% solvent be used for dissolving and/or suspension 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN.

Usually can freely select to add raw material 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-order of 1H-pyrazoles-3-formonitrile HCN, amino acid title complex, sulfination agent and halide reagent.

Before preferably in adding reaction mixture each raw material is dissolved respectively or be suspended in the reaction solvent.

Preferably in reaction mixture, do not exist and halide reagent do not added 5-amino-1-[2 under amino acid title complex or the sulfination agent, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN in.In preferred embodiments, halide reagent is dissolved in the solvent and adds contain 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-reaction mixture of 1H-pyrazoles-3-formonitrile HCN, amino acid title complex and sulfination agent in, back three is all dissolved or is suspended in the solvent.

In preferred embodiments, with halide reagent and amino acid title complex and solvent and adding 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-the sulfination agent adding reaction mixture that will dissolve or suspend before 1H-pyrazoles-3-formonitrile HCN in.

In preferred embodiments, with 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and the mixture merging that contains sulfination agent, amino acid title complex and halide reagent.Maybe advantageously (equal first part to about 1 molar equivalent this moment, with respect to Compound I I) halide reagent be included in the mixture that contains sulfination agent, amino acid title complex and halide reagent, adding Compound I I and adding second section (equaling about 0.1-0.2 molar equivalent) after stir about 30-60 minute and before temperature is risen to 30-50 ℃ immediately then with respect to Compound I I.

When the sulfination agent is trifluoromethanesulpacidc acidc, preferably trifluoromethanesulpacidc acidc and halide reagent are added in the solution or suspension of amino acid title complex simultaneously, then with 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN solution adds in the reaction mixture.

In another preferred embodiment, sulfination agent, amino acid title complex and halide reagent dissolving or the suspended mixture in solvent (preferred toluene) is cooled to about 3-10 ℃, and will be heated to 5-amino-1-[2 of about 90-110 ℃, 6-two chloro-4-(trifluoromethyl) phenyl]-solution of 1H-pyrazoles-3-formonitrile HCN in solvent (preferred toluene) combines with this cooling mixture.The volume ratio of solvent should be to guarantee that temperature of reaction is no more than 39 ℃ mode and selects.

In preferred embodiments, with 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-after 1H-pyrazoles-3-formonitrile HCN, sulfination agent, amino acid title complex and chlorination reagent merge, in 5-60 minute, temperature is risen to 30-39 ℃, preferably be no more than 35 ℃.

Also preferably temperature of reaction was kept 5-60 minute down at-20 ℃ to 10 ℃ at first, preferred 20-40 minute, the speed with 5-45 ℃/min rose to 30-55 ℃ with temperature then.Preferably, reaction mixture is risen to temperature be no more than 35 ℃ in order to obtain high-purity product.When the sulfination agent for or contain CF ₃During S (O) OH, initial reaction temperature is preferably-20 ℃ to 5 ℃, and under the situation of trifluoromethanesulpacidc acidc basic metal or alkaline earth salt, initial reaction temperature is preferably-5 ℃ to 10 ℃.

Reaction times is generally about 5-15 hour, preferred 10-15 hour.

In another preferred embodiment, this is reflected at 1.013 crust (1 normal atmosphere) and carries out in pressurizing vessel to the pressure of about 4 crust.

After reaction was finished, sharp strength spy can separate by using ordinary method, and these methods are as using supercarbonate such as NaHCO ₃, carbonate such as NaCO ₃Or oxyhydroxide such as NaOH termination reaction, extract sharp strength spy with non-polar organic solvent such as ethyl acetate or methyl tertiary butyl ether, for example use supercarbonate such as NaHCO ₃The washing extraction liquid concentrates extract, vacuum concentration for example, the sharp strength top grade of crystallization.The special necessary words of isolating sharp strength can be purified by the technology such as chromatography, recrystallization etc.

End product 5-amino-1-[2; 6-two chloro-4-(trifluoromethyl) phenyl]-crystallization of 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN undertaken by the solution in following solvent usually: nonpolar; inertia; preferred aromatic solvent, it has non-reacted substituting group such as chlorine, fluorine, cyano group, nitro, C ₁-C ₈Alkyl or C ₁-C ₈Haloalkyl; Especially undertaken by the solution in following solvent: benzene, ethylbenzene, mono chloro benzene, phenyl-monofluoride, 1, the 2-dichlorobenzene, 1, the 3-dichlorobenzene, 1, the 4-dichlorobenzene, toluene, o-Xylol, m-xylene, p-Xylol, vinylbenzene, isopropyl benzene, n-propylbenzene, the 2-toluene(mono)chloride, the 3-toluene(mono)chloride, the 4-toluene(mono)chloride, tert.-butylbenzene, sec-butylbenzene, isobutyl-benzene, n-butylbenzene, 1, the 3-diisopropyl benzene, 1, the 4-diisopropyl benzene, the 2-nitrotoluene, the 3-nitrotoluene, the 4-nitrotoluene, oil of mirbane, benzonitrile, mesitylene, trifluoromethylbenzene, 1, the 2-ethylene dichloride, acetonitrile, methyl-sulphoxide, tetrahydrofuran (THF), acetone, alcohols is (as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the 2-butanols or the trimethyl carbinol) or its mixture; Preferably undertaken by the solution in mono chloro benzene, dichlorobenzene, ethylbenzene or toluene.

Maybe advantageously add about 1-30% polar solvent such as ketone, acid amides, alcohols, ester class or ethers, preferred ester class, ketone or ethers, as acetone, methyl ethyl ketone, penta-2-ketone, metacetone, 4-methyl-2 pentanone, 3-methyl-2-butanone, tertiary butyl methyl ketone, pimelinketone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethyl carbonate, acetate 2-butoxy ethyl ester, dimethyl formamide, N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, Nitromethane 99Min., nitroethane, water, ethanol, methyl alcohol, the 1-propyl alcohol, the 2-propyl alcohol, the 1-butanols, the 2-butanols, the trimethyl carbinol, 2-methyl isophthalic acid-propyl alcohol, 2-methyl-2-propyl alcohol, the 3-amylalcohol, 2-methyl-1-butene alcohol, 3-methyl isophthalic acid-butanols, 1,2-ethylene glycol, 1, ammediol, 1, the 2-propylene glycol, hexalin diox, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, the 2-methyltetrahydrofuran, acetonitrile, propionitrile or its mixture.

In another embodiment, sharp strength spy chooses the about 1-30% polar organic solvent of adding wantonly by crystallization in the water.

Preferably by the mono chloro benzene crystallization.

Preferably by the dichlorobenzene crystallization.

Preferably by the ethylbenzene crystallization.

Preferably by the toluene crystallization.

The purification of crude product can also or wash with water and carries out via the filtration on charcoal or silicon-dioxide.

When obtaining according to the inventive method, the sharp strength spy of the products therefrom in crude product mixture is at the compound F 17-hydroxy-corticosterone that contains before the crystallization less than 3.0 weight % (not having to calculate under the solvent), and the latter is a common biological activity by product during sharp strength spy synthesizes.

Compound F 17-hydroxy-corticosterone

By suitable method as the washing and (again) crystallization and purification crude product after, sharp strength spy obtained by the method for the present invention is contained the compound F 17-hydroxy-corticosterone less than 1.0 weight %.

In addition, the sharp strength spy of products therefrom is contained the Compound D less than 10ppm, and the latter is the common by product of existing large-scale industry method as described in WO01/30760 for example, even also exists after purifying.The sharp strength spy who is prepared under inert atmosphere by the inventive method is contained and is contained the compound of sulphur less than 200ppm with its oxidation state (IV).It does not contain the compd E that may occur with the by product of existing commercial run usually yet.

The Compound D compd E

In addition, the sharp strength spy of products therefrom does not contain the trifluoroacetic acid as agents useful for same in the existing commercial run yet.

In addition, when with chlorination reagent when the halide reagent, the sharp strength special product of gained thing is not brominated substantially, this means that it does not contain bromine above 5-20ppm.

Embodiment

HPLC is being equipped with J ' Sphere ODS-H80,4m, 4.6 the HewlettPackard HP 1200 of * 250mm (YMC) post, carry out on the Chemstation, eluent A:90 weight % water+10 weight % acetonitriles, eluent B:10 weight % water+90 weight % acetonitriles, flow velocity: 0.85ml/min, detect: 235nm

Gradient: the time [minute] 02 17 25 35

A[％] 60 60 25 0 0

B[％] 40 40 75 100 100。

Following productive rate is the molecular fraction of the crystallized product of aftertreatment gained purification afterwards.Purity provides with gained solid weight percentage.

Embodiment 1: with triethylamine hydrochloride, trifluoromethanesulpacidc acidc potassium and thionyl chloride in 4.5 molar equivalent toluene in 35 ℃ of following sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN

Under argon gas atmosphere, be equipped with in the 50mL three neck round-bottomed flasks of magnetic stirring bar and thermometer and putting into vacuum drying trifluoromethanesulpacidc acidc potassium (5.16g, 30mmol), vacuum drying triethylamine hydrochloride (5.16g, 37.5mmol) and 10.4g dry toluene (4.5 molar equivalents, with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN).Be cooled to ice bath after 0-5 ℃, when keeping temperature of reaction to be lower than 5 ℃, in 15 minutes, add thionyl chloride (3.57g, 30mmol).Behind the restir 30 minutes, add vacuum drying 5-amino-1-(2,6-dichlor-4-trifluoromethyl phenyl)-1H-pyrazoles-3-formonitrile HCN (8.03g, 25mmol down at 5 ℃, 99% purity) and with reaction mixture kept 60 minutes down at 5 ℃, then at 45 minutes internal heating to 35 ℃.35 ℃ temperature were kept 3 hours again, add 4.6g toluene then.Under 35 ℃ after 7 hours, with 20g sodium hydroxide solution (10 weight %) termination reaction.

Gained suspension dilutes with the 30mL ethyl acetate.After being separated organic layer is washed once with sodium hydroxide solution (10 weight %).After being separated organic layer is analyzed (80.4% productive rate) with quantitative HPLC.The content of compound F 17-hydroxy-corticosterone in crude mixture (not containing solvent) is less than 4.9 weight %.Product obtains white crystalline powder shape title compound (recording purity by quantitative HPLC is 98% for 7.98g, 73% productive rate) by the crystalline mixture of ethyl acetate and toluene.

Embodiment 2: with triethylamine hydrochloride, trifluoromethanesulpacidc acidc potassium and thionyl chloride in 6.5 molar equivalent toluene in 35 ℃ of following sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN

Under argon gas atmosphere, having in the 750mL reactor of mechanical stirrer and thermometer and putting into vacuum drying trifluoromethanesulpacidc acidc potassium (50.4g, 296mmol), vacuum drying triethylamine hydrochloride (51.1g, 368mmol) with 147g dry toluene (6.5 molar equivalents, with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN).With exterior cooling after 0-5 ℃, when keeping temperature of reaction to be lower than 5 ℃, in 15 minutes, add thionyl chloride (35.7g, 294mmol).Behind the restir 30 minutes, add vacuum drying 5-amino-1-(2,6-dichlor-4-trifluoromethyl phenyl)-1H-pyrazoles-3-formonitrile HCN (79.5g, 245mmol down at 5 ℃, 99% purity) and with reaction mixture kept 60 minutes down at 5 ℃, then at 45 minutes internal heating to 35 ℃.This temperature was kept 10 hours again, use 200g sodium hydroxide solution (10 weight %) termination reaction then.

Gained suspension dilutes with the 176mL ethyl acetate.After being separated organic layer is washed once with sodium hydroxide solution (10 weight %).After being separated organic layer is analyzed with quantitative HPLC, obtained unsegregated sharp strength spy's productive rate.

Embodiment 3: with triethylamine hydrochloride, trifluoromethanesulpacidc acidc potassium and thionyl chloride in 6.5 molar equivalent toluene in 45 ℃ of following sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN

Compare routine C1 according to program described in the embodiment 2, but reaction mixture kept 60 minutes down at 5 ℃, then 45 minutes internal heating to 45 ℃ rather than 35 ℃.

Embodiment	Temperature of reaction	Unsegregated sharp strength spy's productive rate	Compound F 17-hydroxy-corticosterone, weight % does not contain solvent
				2	35℃	78.9％	3.0％
C1	45℃	72.3％	6.0％

Embodiment 4: with thionyl chloride, triethylamine hydrochloride and the trifluoromethanesulpacidc acidc potassium sulfination 5-amino-1-[2 that feeds intake, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN

Under argon gas atmosphere, having in the 750mL reactor of mechanical stirrer and thermometer and putting into vacuum drying triethylamine hydrochloride (51.1g, 368mmol), 147g dry toluene (6.5 molar equivalents, with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN) and thionyl chloride (35.7g, 294mmol).With exterior cooling after 0-5 ℃, when keeping temperature of reaction to be lower than 5 ℃ per 10 minutes with three equivalent partly add vacuum drying trifluoromethanesulpacidc acidc potassium (50.4g, 296mmol).Behind the restir 30 minutes, add vacuum drying 5-amino-1-(2,6-dichlor-4-trifluoromethyl phenyl)-1H-pyrazoles-3-formonitrile HCN (79.5g, 245mmol down at 5 ℃, 99% purity) and with reaction mixture kept 60 minutes down at 5 ℃, then at 45 minutes internal heating to 35 ℃.35 ℃ temperature were kept 10 hours again, use 200g sodium hydroxide solution (10 weight %) termination reaction then.

Gained suspension dilutes with the 176mL ethyl acetate.After being separated organic layer is washed once with sodium hydroxide solution (10 weight %).After being separated organic layer is analyzed (86% productive rate) with quantitative HPLC.The content of compound F 17-hydroxy-corticosterone in crude mixture (not containing solvent) is less than 2.5 weight %.Product obtains white crystalline powder shape title compound (recording purity by quantitative HPLC is 98% for 80.3g, 75% productive rate) by the crystalline mixture of ethyl acetate and toluene.

Embodiment 5: with thionyl chloride, morpholine tosylate and the trifluoromethanesulpacidc acidc potassium sulfination 5-amino-1-[2 that feeds intake, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN

As above be prepared in the face of embodiment 3 described programs.After being separated, organic layer is analyzed (83% productive rate) with quantitative HPLC.The content of compound F 17-hydroxy-corticosterone in crude mixture (not containing solvent) is less than 0.5 weight %.Product obtains white crystalline powder shape title compound (recording purity by quantitative HPLC is 98% for 67g, 72% productive rate) by the toluene crystallization.

Comparative Examples C2 carries out according to embodiment 4 described programs, but reaction mixture kept 60 minutes at 5 ℃, then 45 minutes internal heating to 50 ℃ rather than 35 ℃.Product obtains white crystalline powder shape title compound (69% productive rate, recording purity by quantitative HPLC is 98%) by the toluene crystallization.This embodiment repeats twice.

Embodiment	Temperature of reaction	Unsegregated sharp strength spy's productive rate	Compound F 17-hydroxy-corticosterone, weight % does not contain solvent
				4	35℃	83％	0.5％
C2	50℃	72-79％	0.9-1.4％

Claims (29)

1. the method for a sulfination pyrazole derivatives, it is characterized in that making 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and sulfination agent S reacting in the presence of at least a amino acid title complex and under the adding halide reagent, wherein said amine is selected from and the second month in a season and/or tertiary amine and described acid is selected from hydrofluoric acid, hydrochloric acid, Hydrogen bromide and hydroiodic acid HI and sulfonic acid, and wherein S is [CF ₃S (O)] ₂O; Or CF ₃S (O) X, wherein X refers to the basic metal or the alkaline earth salt of fluorine, chlorine, bromine, iodine, hydroxyl or hydroxyl; Or its mixture, wherein whenever the temperature of reaction mixture also is no more than 39 ℃.

2. according to the process of claim 1 wherein that described halide reagent is selected from thionyl chloride, thionyl bromide, phosphoryl chloride, oxalyl chloride, phosgene, triphosgene ((CCl ₃) ₂C (=O)), chloro-formic ester, phosphorus pentachloride, phosphorus trichloride, trichloro-methyl chloroformate and xylenesulfonyl chloride.

3. according to the method for claim 1 or 2, wherein said halide reagent is the chlorination reagent that is selected from thionyl chloride and phosphoryl chloride.

4. according to each method among the claim 1-3, the described amine of wherein said amino acid title complex is selected from alkyl amine Trimethylamine 99, triethylamine, tripropyl amine, tri-isopropyl amine, Tributylamine, dimethylethyl amine, diethylmethyl amine, dimethyl n propyl group amine, diisopropyl ethyl amine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), DBN (1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene), methylmorpholine, ethyl morpholine, N, accelerine, methyl piperidine, crassitude or methyl dibenzyl amine; Aromatic uncle amine pyridine, DMAP (Dimethylamino pyridine), collidine, lutidine, pyrimidine, pyrazine or piperazine; Secondary alkylamine dimethylamine, diethylamine, dipropyl amine, Diisopropylamine, dibutylamine, ethyl dimethylamine, sec.-propyl methylamine or sec.-propyl ethamine; And the cyclic secondary amine piperidines, by C ₁-C ₈Alkyl or C ₁-C ₈The piperidines that haloalkyl replaces is as pipecoline or 4-methyl piperidine, tetramethyleneimine, imidazolidine, pyrroles, piperazine and morpholine.

5. according to each method among the claim 1-4, the described amine of wherein said amino acid title complex is selected from Trimethylamine 99, triethylamine, tripropyl amine, tri-isopropyl amine, dimethylethyl amine, diethylmethyl amine, dimethyl n propyl group amine, diisopropyl ethyl amine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), DBN (1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene), methylmorpholine, ethyl morpholine, N, accelerine, methyl piperidine, crassitude, the methyl dibenzyl amine, pyridine, DMAP (Dimethylamino pyridine), collidine, lutidine, pyrimidine, pyrazine and piperazine.

6. according to each method among the claim 1-4, the described amine of wherein said amino acid title complex is selected from dimethylamine, diethylamine, dipropyl amine, Diisopropylamine, dibutylamine, ethyl dimethylamine, sec.-propyl methylamine, sec.-propyl ethamine; Piperidines is by C ₁-C ₈Alkyl or C ₁-C ₈The piperidines that haloalkyl replaces, as pipecoline or 4-methyl piperidine, tetramethyleneimine is by C ₁-C ₈Alkyl or C ₁-C ₈The tetramethyleneimine that haloalkyl replaces is as 2-crassitude and 3-crassitude, imidazolidine, pyrroles, piperazine and morpholine.

7. according to each method among the claim 1-5, the described acid of wherein said amino acid title complex is selected from hydrochloric acid, hydrofluoric acid, tosic acid, Phenylsulfonic acid, the 4-ethyl phenenyl azochlorosulfonate acid, the 4-chlorobenzenesulfonic acid, xylene monosulfonic acid, 2, the 3-acid dimethyl, 2, the 4-acid dimethyl, 2, the 5-acid dimethyl, 2, the 6-acid dimethyl, 1-naphthalene sulfonic aicd, the 2-naphthene sulfonic acid, the mixture of two or more in the acid dimethyl isomer, mesitylene sulfonic acid, methylsulfonic acid, camphorsulfonic acid or trifluoromethane sulfonic acid, preferred hydrochloric acid, tosic acid, Phenylsulfonic acid or xylene monosulfonic acid.

8. according to each method among the claim 1-6, the described acid of wherein said amino acid title complex is selected from tosic acid, Phenylsulfonic acid, 4-ethyl phenenyl azochlorosulfonate acid, 4-chlorobenzenesulfonic acid, xylene monosulfonic acid, 2,3-acid dimethyl, 2,4-acid dimethyl, 2,5-acid dimethyl, 2, the mixture of two or more, mesitylene sulfonic acid, methylsulfonic acid, camphorsulfonic acid or trifluoromethane sulfonic acid in 6-acid dimethyl, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, the acid dimethyl isomer, preferred tosic acid, Phenylsulfonic acid or xylene monosulfonic acid.

9. according to each method among the claim 1-8, wherein said sulfination agent S is selected from CF ₃S (O) Cl, CF ₃S (O) OH, [CF ₃S (O)] ₂O, CF ₃S (O) ONa, CF ₃S (O) OK and composition thereof.

10. according to each method among the claim 1-9, wherein said being reflected in the organic solvent that is selected from toluene, benzene, dimethylbenzene, trifluoromethylbenzene, mono chloro benzene, dichlorobenzene and ethylbenzene carried out.

11. according to each method among the claim 1-10, wherein adding 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-described sulfination agent is added in the reaction soln mixture of described amino acid title complex and described halide reagent before 1H-pyrazoles-3-formonitrile HCN.

12.,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with 5-amino-1-[2 according to each method among the claim 1-11]-1H-pyrazoles-3-formonitrile HCN adds in the reaction mixture of described sulfination agent, described amino acid title complex and described halide reagent.

13.,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with respect to 5-amino-1-[2 according to each method among the claim 1-12]-1H-pyrazoles-3-formonitrile HCN uses the described amino acid title complex of 1.4-2.2 molar equivalent.

14.,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with respect to 5-amino-1-[2 according to each method among the claim 1-13]-1H-pyrazoles-3-formonitrile HCN uses the described halide reagent of 1.15-1.35 molar equivalent.

15.,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with respect to 5-amino-1-[2 according to each method among the claim 1-14]-1H-pyrazoles-3-formonitrile HCN uses the described sulfination agent of 1.0-1.35 molar equivalent.

16. according to each method among the claim 1-15, wherein merging 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN, described sulfination agent, described amino acid title complex and described halide reagent after, in 5-60 minute, temperature is risen to 30-39 ℃.

17. by the 5-amino-1-[2 as the method preparation that each limited among the claim 1-16,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.

18. by the 5-amino-1-[2 as the method preparation that each limited among the claim 3-16,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN, it contains the bromine less than 20ppm.

19. by as the preparation of each limited among the claim 1-16 method or according to the 5-amino-1-[2 of claim 18 or 19; 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN, it contains the Compound D less than 10ppm:

Compound D.

20. by as the preparation of each limited among the claim 1-16 method or according to 5-amino-1-[2 claim 18 or 19 and that be arranged in inert atmosphere; 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN, it contains and contains the compound of sulphur less than 200pm with its oxidation state (IV).

21. desinsection or parasite killing composition contain just like each defined 5-amino-1-[2 among the claim 17-20,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.

22. by as the preparation of each limited among the claim 1-16 method or as each defined 5-amino-1-[2 among the claim 17-20,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-purposes of 3-formonitrile HCN in pest control.

23. by as the preparation of each limited among the claim 1-16 method or as each defined 5-amino-1-[2 among the claim 17-20,6-two chloro-4-(trifluoromethyl) phenyl]-purposes of 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN in preventing and treating animal health insect and parasite.

24. method of preventing and treating insect, acarid or nematode; comprise make insect, acarid or nematode or its provand source, habitat, breeding spot or its place and insecticidal effective dose by as the preparation of each limited among the claim 1-16 method or as each defined 5-amino-1-[2 among the claim 17-20,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN contacts.

25. protect growing plants with protection against insect, acarid or nematosis or the method that infects for one kind; comprise that the method by each limited in as claim 1-16 of using insecticidal effective dose in the soil of the blade face of plant or seed or wherein their growths or water prepares or as claim 17-20 in each defined 5-hydrogen base-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.

26., 5-amino-1-[2 wherein, 6-two chloro-4-(trifluoromethyl) phenyl as claim 23 or 24 desired methods]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN uses with the amount of 5-2000g/ha.

27. handle, prevent and treat, prevent or watch for animals to avoid the method for parasite infestation or infection for one kind; comprise to animal or its habitat per os, part or parenteral admin or use the parasiticide significant quantity by each limited in as claim 1-16 method preparation or as claim 17-20 in each defined 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt.

28. one kind prepares and is used to handle, prevent and treat, prevent or watches for animals to avoid the method for compositions of parasite infestation or infection; comprise will by as the preparation of each limited among the claim 1-16 method or as each defined 5-amino-1-[2 among the claim 17-20,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt with can mix by carrier for animals.

29., 5-amino-1-[2 wherein, 6-two chloro-4-(trifluoromethyl) phenyl according to the method for claim 28]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt exist with the parasiticide significant quantity.