CN104529899A - Method for preparing 1-alkyl-3-halogenated alkyl pyrazole derivative with high regioselectivity - Google Patents
Method for preparing 1-alkyl-3-halogenated alkyl pyrazole derivative with high regioselectivity Download PDFInfo
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- CN104529899A CN104529899A CN201410798253.8A CN201410798253A CN104529899A CN 104529899 A CN104529899 A CN 104529899A CN 201410798253 A CN201410798253 A CN 201410798253A CN 104529899 A CN104529899 A CN 104529899A
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- alkyl
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- 0 C*N1C(C)=C=C(*)C(*)=C1 Chemical compound C*N1C(C)=C=C(*)C(*)=C1 0.000 description 1
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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
- C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a method for preparing 1-alkyl-3-halogenated alkyl pyrazole derivative with high regioselectivity. The method comprises the following steps: 1) carrying out reacting on a compound shown in a formula II and substituted hydrazine shown in IIIb or the compound shown in the formula II and substituted hydrazine shown in IIIa and then carrying out reaction with an alkylating reagent to obtain a compound shown in a formula VI; and 2) treating 1-alkyl-3-halogenated alkyl pyrazole compound shown in the formula I by acid under the presence of water or acylating hydrazone imine acrylate shown in the formula VI by a compound shown in a formula XII to obtain an intermediate shown in formula IVb, wherein Q is selected from one of fluorine, chlorine, bromine and iodine; and cyclizing the intermediate shown in formula IVb to obtain the 1-alkyl-3-halogenated alkyl pyrazole compound shown in the formula I. The method has the characteristics of being few in operating steps, high in yield, good in selectivity and simple in equipment and does not generate a lot of byproducts.
Description
Technical field
The present invention relates to a kind of method that high regioselectivity prepares 1-alkyl-3-haloalkylpyrazol derivative.
Background technology
The pyrazoles of formula I is the important source material for many active constituents of medicine and crop protection active composition; in particular for 1; the important source material of the pyrazoles-4-base carboxylic acylaniline that 3-replaces; such as US5498634, EP545099A1, EP589301A1; WO9212970, WO03066610, WO2006024389; described in WO2007003603, WO2007006806.
1 of formula I, the pyrazole compound that 3,4-replaces passes through with 1,3-suitable difunctional's compound of the hydrazine compound cyclisation replaced or by making 1 usually, 3-difunctional compound and hydrazine reaction, then alkylation is to prepare at nitrogen (1) upper introducing substituting group.In this program, main drawback is the hydrazine compound cyclisation 1 with replacing, 3-difunctional compound lacks regioselectivity and lacks the alkylating regioselectivity of N-of pyrazoles, thus 1 of required formula I is not only formed in both cases, the pyrazole compound (1,3-isomer) that 3,4-replaces, and form 1 of formula I ', the isomer (1,5-isomer) that 4,5-replaces.
Do not consider that lacking selectivity causes this fact of yield losses, the separation that 1,3-isomer of formula I and 1,5-isomer of formula I ' usually only can be difficult.In order to realize acceptable selectivity, therefore must react at low temperatures, this significantly improves equipment complexity in addition, and regioselectivity is not also entirely satisfactory in cold conditions.
US5498624 and other document descriptions one prepares the method for (3-difluoromethyl-1-methyl-pyrazol-4-yl) carboxylicesters, wherein uses the fluoro-3-oxobutanoic acid esters of methyl hydrazine cyclisation α-ethoxymeyhylene-4,4-bis-and obtains pyrazole compound.WO9212970 discloses a kind of similar approach, wherein makes the fluoro-3-oxobutanoic acid esters of 4,4-bis-and triethyl orthoformate and methyl hydrazine react successively, defines the fluoro-3-oxobutanoic acid esters of ethoxymeyhylene-4,4-bis-as intermediate.The selectivity of required isomer is also unsatisfactory.
WO2003051820 and WO2005042468 describes with alkyl hydrazine cyclisation 2-halogenacyl-3-amino acrylates and obtains 1-alkyl-3-haloalkylpyrazol-4-carboxylicesters.The selectivity of required isomer is also unsatisfactory.
WO2008022777 describes a kind of method preparing 3-(dihalomethyl) pyrazoles-4-carboxylicesters that 1-replaces, and wherein makes the hydrazine reaction that can be belonged to amidine salt and replacement by the vinylogy making α-3-(dihalomethyl) difluoromethyl amine and acrylate react in the presence of a lewis acid and obtain.The selectivity of required isomer is also unsatisfactory.
Summary of the invention
The object of the present invention is to provide a kind of high regioselectivity to prepare the method for 1-alkyl-3-haloalkylpyrazol derivative, the present invention has that operation steps is few, yield is high, selectivity is good, equipment is simple, can not produce the feature of by product in a large number.
For achieving the above object, technical scheme of the present invention is:
High regioselectivity prepares a method for 1-alkyl-3-haloalkylpyrazol derivative, comprises the steps: 1) by formula II compound and the replacement hydrazine reaction of formula III b or the replacement hydrazine reaction with IIIa, then be obtained by reacting formula VI with alkylating reagent; Variable X in formula II is CX
1x
2x
3group, wherein X
1, X
2and X
3be hydrogen or fluorine or chlorine, wherein X independently
1can also be C
1-C
6alkyl or C
1-C
4haloalkyl and wherein radicals X
1, X
2in at least one is not hydrogen; R
2for CN, CO
2r
2a, CONR
2br
2cin one, wherein R
2afor C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxy-C
1-C
6alkyl, optional phenyl, the C replaced
1-C
4alkoxyl group, phenyl, C
3-C
6one in alkyl; R
2band R
2cfor hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
y2and R
y3be the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle also comprises 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms, and Z-is negatively charged ion; Y is oxygen, group NR
y1or group [NR
y2r
y3]
+z
-in one, wherein R
y1, R
y2and R
y3be C independently of one another
1-C
6alkyl, C
3-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
y2and R
y3be the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle can also comprise 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms, and Z-is negatively charged ion; R
3for OR
3aor group NR
3br
3cin one, wherein R
3a, R
3band R
3cbe C independently of one another
1-C
6alkyl, C
5-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
3band R
3cbe the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle also comprise 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms; R
4for the tertiary butyl, tertiary amyl, by the one in a halogen substiuted tertiary butyl, tertiary amyl; Described alkylating reagent is the one in halogenated alkane, dialkyl sulfate, methanesulfonate ester, trifluoromethane sulfonic acid ester; 2) the vinylformic acid hydrazone imines acylations of formula VI is made to obtain intermediate formula IVb with the 1-alkyl-3-haloalkylpyrazol compound of acid treatment gained formula I or the formula XII of utilization in the presence of water, wherein Q is selected from fluorine, chlorine, bromine, one in iodine, then obtains the 1-alkyl-3-haloalkylpyrazol compound of formula I by intermediate formula IVb cyclisation; Wherein X is CX
1x
2x
3group, wherein X
1, X
2and X
3be hydrogen or fluorine or chlorine, wherein X independently
1for C
1-C
6alkyl or C
1-C
4haloalkyl and wherein radicals X
1, X
2in at least one is not hydrogen, R
1for C
1-C
4alkyl or cyclopropyl; R
2for CN, CO
2r
2a, CONR
2br
2cin one, wherein R
2afor C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxy-C
1-C
6alkyl, optional phenyl, the C replaced
1-C
4alkoxyl group, phenyl, C
3-C
6one in alkyl; R
2band R
2cfor hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
y2and R
y3be the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle can also comprise 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms, and Z-is negatively charged ion.
R in described formula II
3for OR
3a, wherein R
3afor C
1-C
4alkyl; Described R
2group CN or CO
2r
2agroup, wherein R
2afor C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxy-C
1-C
6one in alkyl; Described R
1for C
1-C
6alkyl; Described R
4for the tertiary butyl, tertiary amyl, by the tertiary butyl of a halogen substiuted, by the tertiary amyl of a halogen substiuted; Described alkylating reagent is the one in monobromethane, methyl iodide, methyl-sulfate, methyl mesylate, Methyl triflate, monobromethane, iodoethane, ethyl sulfate, ethyl methane sulfonate, trifluoromethanesulfonic acid ethyl ester;
Described R
1for being methyl or ethyl; Described R
4for the tertiary butyl or tertiary amyl; R
2afor C
1-C
6alkyl, cyclopropyl, C
1-C
4alkoxy-C
1-C
6one in alkyl.
Described step 2) in intermediate formula IVb 2-acidylate after obtain 2-imines alkylating diazanyl vinylformic acid (nitrile) derivative.
Described step 2) Chinese style IVb vinylformic acid hydrazone adopt (2E)-3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-olefin(e) acid ethyl ester, (2Z)-3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-olefin(e) acid ethyl ester, 3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-e pioic acid methyl ester, (2E)-3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-olefin(e) acid propyl ester, (2E)-3-[1-methyl-2-(3, 3-diformazan fourth-2-subunit) diazanyl] the third-2-e pioic acid methyl ester, 3-[1-methyl-2-(phenylmethylene) diazanyl] the third-2-e pioic acid methyl ester, (2E) one in-3-[1-methyl-2-(phenylmethylene) diazanyl] the third-2-alkene nitrile and 3-[1-ethyl-2-(the third-2-subunit) diazanyl] the third-2-e pioic acid methyl ester.
Term " C used herein
1-C
6alkyl " represent 1-6 carbon atom, especially the saturated side chain of 1-4 carbon atom or branched hydrocarbyl radical, such as methyl, ethyl, propyl group, 1-methylethyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1, 1-dimethyl ethyl, amyl group, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 2, 2-dimethyl propyl, 1-ethyl propyl, hexyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethyl-butyl, 2-ethyl-butyl, 1, 1, 2-thmethylpropyl, 1, 2, 2-thmethylpropyl, 1-ethyl-1-methyl-propyl, 1-Ethyl-2-Methyl propyl group and isomer thereof.C
1-C
4alkyl such as comprises methyl, ethyl, propyl group, 1-methylethyl, butyl, 1-methyl-propyl, 2-methyl-propyl or 1,1-dimethyl ethyl.
Can optionally by C
1-C
4alkoxyl group, phenyl or C
3-C
6term " the C of cycloalkyl substituted
1-C
6alkyl " represent unsubstituted C as defined above
1-C
6alkyl or wherein one of hydrogen atom are by C
1-C
4alkoxyl group, phenyl or C
3-C
6the C that cycloalkyl substitutes
1-C
6alkyl.
Term " C used herein
1-C
4haloalkyl " represent that there is side chain or the branched-alkyl of 1-4 carbon atom, wherein these groups hydrogen moiety or all replaced by halogen atom, especially replaced by fluorine and bromine or chlorine, such as chloromethyl, dichloromethyl trichloromethyl.Methyl fluoride, difluoromethyl, trifluoromethyl, chlorine methyl fluoride, dichloro one methyl fluoride, a chlorodifluoramethyl-, 1-chloroethyl, 1-fluoro ethyl, 2-fluoro ethyl, 2,2-bis-fluoro ethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoro ethyl, 2-chloro-2,2-bis-fluoro ethyl, 2, the chloro-2-fluoro ethyl of 2-bis-, 2,2,2-trichloroethyl, pentafluoroethyl group etc.
Term " C used herein
1-C
4alkoxyl group " represent the side chain or the branching saturated alkyl that comprise 1-6 carbon atom, described group is via oxygen atoms bond.Example comprises C
1-C
6alkoxyl group, such as methoxyl group, oxyethyl group, OCH
2-C
2h
5, OCH (CH
3)
2, n-butoxy, OCH (CH
3)-C
2h
5, OCH
2-CH (CH
3)
2, OCH (CH
3)
3, n-pentyloxy, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1, 1-dimethyl propoxy-, 1, 2-dimethyl propoxy-, 2, 2-dimethyl propoxy-, 1-ethylpropoxy, positive hexyloxy, 1-methyl pentyloxy, 2-methyl pentyloxy, 2-methyl pentyloxy, 4-methyl pentyloxy, 1, 1-dimethyl butoxy, 1, 2-dimethyl butoxy, 1, 3-dimethyl butoxy, 2, 2-dimethyl butoxy, 3, 3-dimethyl butoxy, 1-ethyl-butoxy, 2-ethyl-butoxy, 1-ethyl-butoxy, 1, 1, 2-trimethylammonium propoxy-, 1, 2, 2-trimethylammonium propoxy-, 1-ethyl-1-methyl propoxy-, 1-Ethyl-2-Methyl propoxy-etc.
Term " C used herein
1-C
4alkoxy-C
1-C
6alkoxyl group " represent that one of them hydrogen atom is by C
1-C
4the C that alkoxyl group is replaced
1-C
6alkoxyl group.The example is CH
2-OCH
3, CH
2-OC
2h
5, n-propoxymethyl, CH
2-O CH (CH
3)
2, n-butoxy methyl, (1-methyl propoxy-) methyl, (2-methyl propoxy-) methyl, CH
2-O C (CH
3)
3, 2-methoxy ethyl, 2-ethoxyethyl group, 2-positive propoxy ethyl, 2-(1-methyl ethoxy) ethyl, 2-n-butoxyethyl, 2-(1-methyl propoxy-) propyl group, 2-(2-methyl propoxy-) ethyl, 2-(1,1-dimethylethyloxy) ethyl, 2-methoxy-propyl, 2-ethoxycarbonyl propyl, 2-positive propoxy propyl group, 2-(1-methyl ethoxy) propyl group, 2-n-butoxy propyl group, 2-(1-methyl propoxy-) propyl group, 2-(2-methyl propoxy-) propyl group, 2-(1,1-dimethylethyloxy) propyl group, 3-methoxy-propyl, 3-ethoxycarbonyl propyl, 3-positive propoxy propyl group, 3-(1-methyl ethoxy) propyl group, 3-n-butoxy propyl group, 3-(1-methyl propoxy-) propyl group, 3-(2-methyl propoxy-) propyl group, 3-(1,1-dimethylethyloxy) propyl group, 2-methoxybutyl, 2-ethoxybutyl, 2-positive propoxy butyl, 2-(1-methyl ethoxy) butyl, 2-n-butoxy butyl, 2-(1-methyl propoxy-) butyl, 2-(2-methyl propoxy-) butyl, 2-(1,1-dimethylethyloxy) butyl, 3-methoxybutyl, 3-ethoxybutyl, 3-positive propoxy butyl, 2-(1-methyl propoxy-) butyl, 3-(2-methyl propoxy-) butyl, 3-(1,1-dimethylethyloxy) butyl, 4-methoxybutyl, 4-ethoxybutyl, 4-positive propoxy butyl, 4-(1-methyl ethoxy) butyl, 4-n-butoxy butyl, 4-(1-methyl propoxy-) butyl, 4-(2-methyl propoxy-) butyl, 4-(1,1-dimethylethyloxy) butyl etc.
Term " C used herein
1-C
6cycloalkyl " represent the monocyclic saturated hydrocarbon group base comprising 3-6 carbon atom.The example of monocyclic groups comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Term used herein " the optional phenyl replaced " represents unsubstituted phenyl or represents with 1,2,3,4 or 5, especially 1,2 or 3 substituent phenyl at reaction conditions in inertia.The example of inert substituent is halogen, especially fluorine, chlorine or bromine, CN, NO
2, C
1-C
6alkyl, C
1-C
6alkylthio, C
1-C
6alkyl sulphonyl, C
1-C
4haloalkyl, C
1-C
6alkoxyl group, C
1-C
6cycloalkyl and C
1-C
4alkoxy-C
1-C
6alkyl.
Term used herein " optional phenyl-the C replaced
1-C
6alkyl " represent the C that the phenyl that one of them hydrogen atom is optionally substituted replaces
1-C
6alkyl.Example is benzyl, 4-methyl-benzyl, phenylethyl etc.
Term " heterocycle of saturated, the optional replacement of the 5-8 person of N-bonding " represents via theheterocyclic nitrogen atom bonding and has the saturated heterocyclic of 5,6,7 or 8 annular atomses, wherein except nitrogen-atoms, annular atoms can also comprise other heteroatomss and this heterocycle is not substituted or with 1,2,3,4 or 5, especially 1,2 or 3 is the substituting group of inertia at reaction conditions.The example of inert substituent is CN, C
1-C
6alkyl, C
1-C
6alkylthio, C
1-C
6alkyl sulphonyl, C
1-C
4haloalkyl, C
1-C
6alkoxyl group, C
1-C
6cycloalkyl and C
1-C
4alkoxy-C
1-C
6alkyl.This heterocycle except comprising 1 or 2 heteroatoms being selected from N, O and S as annular atoms except the nitrogen-atoms of 1 and ring carbon atom.The example of the heterocycle of saturated, the optional replacement of N-bonding 5-8 person is pyrrolidin-1-yl, piperidin-1-yl, morpholine-4-base, piperazine-1-base and N methyl piperazine-1-base.
Beneficial effect of the present invention is: the present invention has that operation steps is few, yield is high, selectivity is good, equipment is simple, can not produce the feature of by product in a large number.
Embodiment
Embodiment 1
The fluoro-2-of 4,4-bis-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } methylene radical]-ethyl 3-oxobutanoate
29.6g (0.2mol) 1-BOC-2-methyl hydrazine and 150ml toluene and the fluoro-ethyl 3-oxobutanoate of 47.5g (0.2mol) 2-ethoxymeyhylene-4,4-bis-are mixed, result internal temperature rises to 30 DEG C.Reaction mixture is stirred at a reflux temperature within 3 hours, underpressure distillation is concentrated again obtains 66g product.
3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid
First 20 hours are reacted by from the fluoro-2-of 66g 4,4-bis-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } the methylene radical]-ethyl 3-oxobutanoate of step 1.1. and dichloromethane solution 20-30 DEG C of (0.2mol) trifluoroacetic acid.This solution comprises 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate needed for 15.2 % by weight (HPLC analyzes, and uses interior scalarization), is 93% corresponding to yield.Isomer 5-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate ratio is only 0.04 % by weight (isomer proportion is about 82:1).The dichloromethane solution of trifluoroacetic acid is reclaimed in underpressure distillation.
Add q. s. toluene, then at 25-27 DEG C, in 5 minutes, be metered into 104g (0.26mol) 10% sodium hydroxide solution.Reaction mixture is stirred 2 hours at 60 DEG C.Steam except 320g solvent (ethanol/water) under 58 DEG C/370 millibars, leave two-phase distillation residue.Be separated after by 100ml dilution with toluene every.Upper strata is toluene phase.Lower floor's aqueous phase comprises the sodium salt of required 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid as major constituent.By aqueous phase 29.7 (0.26mol) concentrated hydrochloric acid acidifying (pH < 2) taken out, title compound is precipitated.Obtain the 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid of 60.9g humidity after filtration.HPLC analyzes the content that (using outer scalarization) demonstrates 52.6 % by weight, is 91% corresponding to yield based on 4,4-bis-fluoro-2-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } the methylene radical]-ethyl 3-oxobutanoate for reacting.
Embodiment 2
First 20 hours are reacted by from the fluoro-2-of 66g 4,4-bis-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } the methylene radical]-ethyl 3-oxobutanoate of step 1.1. and hydrogen chloride solution 20-30 DEG C of dioxane.This solution comprises 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate needed for 17.2 % by weight (HPLC analyzes, and uses interior scalarization), is 92% corresponding to yield.Isomer 5-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate ratio is only 0.02 % by weight (isomer proportion is about 160:1).Dioxane is reclaimed in underpressure distillation.
Add q. s. toluene, be then metered into 168.3g (0.3mol) 10% potassium hydroxide solution and reaction mixture is stirred 3 hours at 60 DEG C.Separation of phases after being cooled to 25 DEG C.Upper toluene layer.Lower floor's aqueous phase comprises the sylvite of required 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid as principal constituent.Toluene water is washed twice again, uses 50g water at every turn.The aqueous phase merged is used 66g (0.58mol) concentrated hydrochloric acid (32%) acidifying (pH < 2) at 55 DEG C, required title compound is precipitated.At 3 DEG C, leach solid and wash with water and obtain 32.1g 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid with the purity of 99 % by weight after drying.Yield based on the fluoro-ethyl 3-oxobutanoate of 2-ethoxymeyhylene-4,4-bis-of reaction used is 90.3%.Undesirable 1,5-isomer can not be detected again.
Embodiment 3
By 29.6g (0.2mol) 1-BOC-2-methyl hydrazine and 150ml toluene and 47.5g (0.2mol) 2-dimethylin methylene radical-4, the fluoro-ethyl 3-oxobutanoate mixing of 4-bis-, result internal temperature rises to 30 DEG C, is then warming up to 90 DEG C of reactions 3 hours.Reaction mixture is stirred at a reflux temperature within 3 hours, underpressure distillation is concentrated again obtains 67g product.
20 hours are reacted by from 4,4-bis-fluoro-2-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } the methylene radical]-ethyl 3-oxobutanoate of upper step and the ethyl acetate solution of 3M hydrogenchloride.This solution comprises 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate needed for 13.6 % by weight (HPLC analyzes, and uses interior scalarization), is 89.2% corresponding to yield.Isomer 5-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate ratio is only 0.02 % by weight (isomer proportion is about 175:1).Ethyl acetate solution is reclaimed in underpressure distillation.
Add q. s. toluene, then at 25-27 DEG C, in 5 minutes, be metered into 104g (0.26mol) 10% sodium hydroxide solution.Reaction mixture is stirred 2 hours at 60 DEG C.Upper strata is toluene phase, and lower floor's aqueous phase comprises the sodium salt of required 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid as principal constituent.Toluene water is washed twice again, uses 50g water at every turn.The aqueous phase merged is used 66g (0.58mol) concentrated hydrochloric acid (32%) acidifying (pH < 2) at 55 DEG C, required title compound is precipitated.At 3 DEG C, leach solid and wash with water and obtain 30.5g 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid with the purity of 98.6 % by weight after drying.Yield based on the fluoro-ethyl 3-oxobutanoate of 2-dimethylin methylene radical-4,4-bis-of reaction used is 85.7%.Undesirable 1,5-isomer can not be detected.
Embodiment 4
29.6g (0.2mol) 1-BOC-2-methyl hydrazine and 150ml toluene and the fluoro-ethyl 3-oxobutanoate of 48g (0.2mol) 2-acetoxyl group methylene radical-4,4-bis-are mixed, result internal temperature rises to 30 DEG C.Reaction mixture is stirred at a reflux temperature within 3 hours, underpressure distillation is concentrated again obtains 66g product.
First 20 hours are reacted by from 4,4-bis-fluoro-2-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } the methylene radical]-ethyl 3-oxobutanoate of upper step and dichloromethane solution 20-30 DEG C of trifluoroacetic acid.This solution comprises 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate needed for 4.12 % by weight (HPLC analyzes, and uses interior scalarization), is 89.2% corresponding to yield.Isomer 5-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate ratio is only 0.05 % by weight (isomer proportion is about 82:1).The dichloromethane solution of trifluoroacetic acid is reclaimed in underpressure distillation.
Add q. s. toluene, then at 25-27 DEG C, in 5 minutes, be metered into 104g (0.26mol) 10% sodium hydroxide solution.Reaction mixture is stirred 2 hours at 60 DEG C.Separation of phases after being cooled to 25 DEG C.Upper toluene layer.Lower floor's aqueous phase comprises the sylvite of required 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid as principal constituent.Toluene water is washed twice again, uses 50g water at every turn.The aqueous phase merged is used 66g (0.58mol) concentrated hydrochloric acid (32%) acidifying (pH < 2) at 55 DEG C, required title compound is precipitated.At 3 DEG C, leach solid and wash with water and obtain 32.1g 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid with the purity of 99 % by weight after drying.Yield based on the fluoro-ethyl 3-oxobutanoate of 2-acetoxyl group methylene radical-4,4-bis-of reaction used is 90.3%.Undesirable 1,5-isomer can not be detected again.
Embodiment 5
The fluoro-2-of 4,4-bis-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } methylene radical]-3-oxo butyronitrile
29.6g (0.2mol) 1-BOC-2-methyl hydrazine and 150ml toluene and the fluoro-3-oxo butyronitrile of 47.5g (0.2mol) 2-dimethylin methylene radical-4,4-bis-are mixed, result internal temperature rises to 30 DEG C.Reaction mixture is stirred at a reflux temperature within 3 hours, underpressure distillation is concentrated again obtains 66g product.
3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid
First in the future upper step obtains. 4,4-bis-fluoro-2-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } methylene radical]-3-oxo butyronitrile and dioxane solution 20-30 DEG C of hydrogenchloride react 20 hours.This solution comprises 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate needed for 14.2 % by weight (HPLC analyzes, and uses interior scalarization), is 89.2% corresponding to yield.Isomer 5-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate ratio is only 0.05 % by weight (isomer proportion is about 82:1).Dioxane is reclaimed in underpressure distillation.
In above-mentioned raffinate, add the aqueous sodium hydroxide solution of 10%, be heated to 70-75 DEG C of stirring reaction, HPLC tracking monitor, to reacting end, adds the sulphuric acid soln of 30% to PH=1-2, title compound is precipitated.Obtain the 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-formic acid of 57.6g humidity after filtration.HPLC analyzes the content that (using outer scalarization) demonstrates 52.6 % by weight, is 86% corresponding to yield based on 4,4-bis-fluoro-2-[1-{N-methyl-N '-[1-carboxylic acid tert-butyl ester] diazanyl } the methylene radical]-3-oxo butyronitrile for reacting.
Claims (5)
1. a high regioselectivity prepares the method for 1-alkyl-3-haloalkylpyrazol derivative, it is characterized in that, comprise the steps: 1) by formula II compound and the replacement hydrazine reaction of formula III b or the replacement hydrazine reaction with IIIa, then be obtained by reacting formula VI with alkylating reagent; Variable X in formula II is CX
1x
2x
3group, wherein X
1, X
2and X
3be hydrogen or fluorine or chlorine, wherein X independently
1can also be C
1-C
6alkyl or C
1-C
4haloalkyl and wherein radicals X
1, X
2in at least one is not hydrogen; R
2for CN, CO
2r
2a, CONR
2br
2cin one, wherein R
2afor C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxy-C
1-C
6alkyl, optional phenyl, the C replaced
1-C
4alkoxyl group, phenyl, C
3-C
6one in alkyl; R
2band R
2cfor hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
y2and R
y3be the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle also comprises 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms, and Z-is negatively charged ion; Y is oxygen, group NR
y1or group [NR
y2r
y3]
+z
-in one, wherein R
y1, R
y2and R
y3be C independently of one another
1-C
6alkyl, C
3-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
y2and R
y3be the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle can also comprise 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms, and Z-is negatively charged ion; R
3for OR
3aor group NR
3br
3cin one, wherein R
3a, R
3band R
3cbe C independently of one another
1-C
6alkyl, C
5-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
3band R
3cbe the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle also comprise 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms; R
4for the tertiary butyl, tertiary amyl, by the one in a halogen substiuted tertiary butyl, tertiary amyl; Described alkylating reagent is the one in halogenated alkane, dialkyl sulfate, methanesulfonate ester, trifluoromethane sulfonic acid ester; 2) the vinylformic acid hydrazone imines acylations of formula VI is made to obtain intermediate formula IVb with the 1-alkyl-3-haloalkylpyrazol compound of acid treatment gained formula I or the formula XII of utilization in the presence of water, wherein Q is selected from fluorine, chlorine, bromine, one in iodine, then obtains the 1-alkyl-3-haloalkylpyrazol compound of formula I by intermediate formula IVb cyclisation; Wherein X is CX
1x
2x
3group, wherein X
1, X
2and X
3be hydrogen or fluorine or chlorine, wherein X independently
1for C
1-C
6alkyl or C
1-C
4haloalkyl and wherein radicals X
1, X
2in at least one is not hydrogen, R
1for C
1-C
4alkyl or cyclopropyl; R
2for CN, CO
2r
2a, CONR
2br
2cin one, wherein R
2afor C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxy-C
1-C
6alkyl, optional phenyl, the C replaced
1-C
4alkoxyl group, phenyl, C
3-C
6one in alkyl; R
2band R
2cfor hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, optional phenyl, the optional phenyl-C replaced replaced
1-C
4alkyl, R
y2and R
y3be the one in the heterocycle of saturated, the optional replacement of 5-8 person of N-bonding together with the nitrogen-atoms of their institute's bondings, and this heterocycle can also comprise 1 or 2 heteroatoms being selected from N, O and S in addition as annular atoms except nitrogen-atoms, and Z-is negatively charged ion.
2. a kind of high regioselectivity as claimed in claim 1 prepares the method for 1-alkyl-3-haloalkylpyrazol derivative, it is characterized in that, the R in described formula II
3for OR
3a, wherein R
3afor C
1-C
4alkyl; Described R
2group CN or CO
2r
2agroup, wherein R
2afor C
1-C
6alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxy-C
1-C
6one in alkyl; Described R
1for C
1-C
6alkyl; Described R
4for the tertiary butyl, tertiary amyl, by the tertiary butyl of a halogen substiuted, by the tertiary amyl of a halogen substiuted; Described alkylating reagent is the one in monobromethane, methyl iodide, methyl-sulfate, methyl mesylate, Methyl triflate, monobromethane, iodoethane, ethyl sulfate, ethyl methane sulfonate, trifluoromethanesulfonic acid ethyl ester.
3. a kind of high regioselectivity as claimed in claim 2 prepares the method for 1-alkyl-3-haloalkylpyrazol derivative, it is characterized in that, described R
1for being methyl or ethyl; Described R
4for the tertiary butyl or tertiary amyl; R
2afor C
1-C
6alkyl, cyclopropyl, C
1-C
4alkoxy-C
1-C
6one in alkyl.
4. a kind of high regioselectivity as claimed in claim 1 prepares the method for 1-alkyl-3-haloalkylpyrazol derivative; it is characterized in that, described step 2) in intermediate formula IVb 2-acidylate after obtain 2-imines alkylating diazanyl vinylformic acid (nitrile) derivative.
5. a kind of high regioselectivity as claimed in claim 1 prepares the method for 1-alkyl-3-haloalkylpyrazol derivative, it is characterized in that, described step 2) Chinese style IVb vinylformic acid hydrazone adopt (2E)-3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-olefin(e) acid ethyl ester, (2Z)-3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-olefin(e) acid ethyl ester, 3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-e pioic acid methyl ester, (2E)-3-[1-methyl-2-(the third-2-subunit) diazanyl] the third-2-olefin(e) acid propyl ester, (2E)-3-[1-methyl-2-(3, 3-diformazan fourth-2-subunit) diazanyl] the third-2-e pioic acid methyl ester, 3-[1-methyl-2-(phenylmethylene) diazanyl] the third-2-e pioic acid methyl ester, (2E) one in-3-[1-methyl-2-(phenylmethylene) diazanyl] the third-2-alkene nitrile and 3-[1-ethyl-2-(the third-2-subunit) diazanyl] the third-2-e pioic acid methyl ester.
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