CN1826332A

CN1826332A - Method for preparing 3-halo-4,5-dihydro-1H-pyrazoles

Info

Publication number: CN1826332A
Application number: CN 03818171
Authority: CN
Inventors: G·D·安尼斯
Original assignee: EI Du Pont de Nemours and Co
Current assignee: FMC Agro Singapore Pte Ltd; FMC Corp
Priority date: 2002-07-31
Filing date: 2003-07-29
Publication date: 2006-08-30
Anticipated expiration: 2023-07-29
Also published as: CN100537561C; ES2363413T3; CN101607957B; CN101607957A; ZA200409856B; UA79799C2

Abstract

This invention relates to a method for preparing 3-halo-4,5-dihydro-1H-pyrazole compound of Formula (I), comprising contacting with HX<1> a different 4,5-dihydro-1H-pyrazole compound of Formula (II), wherein X<1> is halogen and L, R, k and X<2> are as defined in the disclosure. This invention also discloses preparation of compounds of Formula (III) wherein X<1>, R<3>, R<6>, R<7>, R<8a>, R<8b>, and n are as defined in the disclosure.

Description

Preparation 3-halo-4, the method for 5-dihydro-1 h-pyrazole

Background of invention

Still need other preparation 3-halo-4 at present, the method for 5-dihydro-1 h-pyrazole.These compounds comprise useful as intermediates, and described intermediate is used to prepare crop protection agent, medicine and other fine chemical product.

More existing preparation 3-halos-4, the report of 5-dihydro-1 h-pyrazole method.For example, J.P.CHUPP, J.Heterocyclic Chem.1994,31, the 1377-1380 report is by making corresponding oxo pyrazoles alkane and phosphoryl chloride prepared in reaction 3-chloro-4,5-dihydro-1 h-pyrazole.M.V.Gorelik et al., Journal of Organic Chemistry U.S.S.R.1985,21,773-781 (Zhurnal Organicheskoi Khimii 1985,21 (4), the English translation of 851-859) discloses, by from corresponding 3-amino-4, the 5-dihydro-1 h-pyrazole prepares the diazonium salt intermediate, thus preparation 3-chloro-4, the 5-dihydro-1 h-pyrazole.K.K.Bach et al., Tetrahedron 1994,50 (25), 7543-7556 announces, by making acrylate and the cycloaddition of hydrazine acyl chlorides intermediate dipole prepare 3-chloro-4, the 5-dihydro-1 h-pyrazole, wherein hydrazine acyl chlorides intermediate forms the hydrazone generation decarboxylation chlorization of oxoethanoic acid with N-chlorosuccinimide.Still need the alternate method, especially have wider chemical structure ubiquity and use the low-cost compositions and methods of industrial business supply.

Summary of the invention

The present invention relates to the 3-halo-4 of preparation formula I, the method for 5-dihydro-1 h-pyrazole compound:

Wherein L is the optional carbon part that replaces;

Each R independently is selected from the optional carbon part that replaces;

K is the integer of 0-4;

And X ¹Be halogen.

Present method comprises makes 4 of formula II, 5-dihydro-1 h-pyrazole compound and formula HX ¹Compound in being fit to solvent, react:

X wherein ²Be OS (O) _mR ¹, OP (O) _p(OR ²) ₂Or be different from X ¹Halogen;

M is 1 or 2;

P is 0 or 1;

R ¹Be selected from alkyl and haloalkyl and optional by 1 to 3 phenyl that is selected from the substituting group replacement of alkyl and halogen; And

Each R ²Independently be selected from alkyl and haloalkyl and optional by 1 to 3 phenyl that is selected from the substituting group replacement of alkyl and halogen.

The invention still further relates to the method for preparing the formula III compound:

X wherein ¹Be halogen;

Each R ³Independent is C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, C ₂-C ₄Alkynyl, C ₃-C ₆Cycloalkyl, C ₁-C ₄Haloalkyl, C ₂-C ₄Haloalkenyl group, C ₂-C ₄Halo alkynyl, C ₃-C ₆Halogenated cycloalkyl, halogen, CN, NO ₂, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Alkylthio, C ₁-C ₄Alkyl sulphinyl, C ₁-C ₄Alkyl sulphonyl, C ₁-C ₄Alkylamino, C ₂-C ₈Dialkyl amido, C ₃-C ₆Cycloalkyl amino, (C ₁-C ₄Alkyl) (C ₃-C ₆Cycloalkyl) amino, C ₂-C ₄Alkyl-carbonyl, C ₂-C ₆Alkoxy carbonyl, C ₂-C ₆Alkyl amino-carbonyl, C ₃-C ₈Dialkyl amino carbonyl or C ₃-C ₆Trialkylsilkl;

Z is N or CR ⁵

R ⁵Be H or R ³

R ⁶Be CH ₃, F, Cl or Br;

R ⁷Be F, Cl, Br, I or CF ₃

R ^8aBe C ₁-C ₄Alkyl;

R ^8bBe H or CH ₃And

N is the integer of 0-3,

This method is used the compound of following formula I a:

R wherein ⁴Be H or the optional carbon part that replaces.

Present method be characterized as compound (i.e. the formula I compound of a subclass) by top described method preparation formula Ia.

Detailed Description Of The Invention

In the present invention, term " carbon part " is meant carbon atom and 4, the substituting group that 5-dihydro-1 h-pyrazole ring skeleton links to each other.Because carbon part L and R (comprise R ⁴) substituting group for being separated by reactive center, they can comprise a large amount of various carbon type groups by modern synthetic organic chemistry method preparation.Method of the present invention can generally be applicable to various formula I initial compounds and formula II product.Those skilled in the art can find, some group is to the hydrogen halide sensitivity, and can be transformed under reaction conditions.Those skilled in the art also can find, some group is an alkalescence, and can with the hydrogen halide salify, therefore method of the present invention may also need other hydrogen halide.

Therefore " carbon part " comprises alkyl, thiazolinyl and alkynyl, and they can be straight or branched." carbon part " also comprises carbocyclic ring and heterocycle, and they can be saturated, fractional saturation or complete unsaturated ring.And if satisfy the Huckel rule, unsaturated ring can be an aromatic ring.The carbocyclic ring of carbon part and heterocycle can form the multi-loop system that comprises a plurality of rings that are connected together.Term " carbocyclic ring " is meant that the atom that forms the ring skeleton is the ring of carbon.Term " heterocycle " is meant that at least one ring skeletal atom is not the ring of carbon." saturated carbon ring " is that finger ring skeleton carbon atom is by singly-bound ring connected to one another; Except as otherwise noted, remaining carbon valency is occupied by hydrogen atom.Term " aromatic ring system " complete unsaturated carbocyclic of expression and heterocycle, at least one ring is an aromatics in the multi-loop system.Aromatics is represented each annular atoms basically on same plane, and has and the vertical p track of plane of a loop, and on the ring (4n+2) individual πDian Zi is arranged, and n is 0 or positive integer, meets the Buckel rule.Term " aromatic carbocyclic system " comprises that at least one ring is the carbocyclic ring of aromatics in Wholly aromatic carbocyclic ring and the multi-loop system.Complete saturated carbon ring of term " non-aromatics carbon-loop system " expression and unsaturated carbocyclic partially or completely, wherein in the loop systems not ring aromatic ring is arranged.Term " aromatic heterocycle system " and " hetero-aromatic ring " comprise that at least one ring is the heterocycle of aromatics in Wholly aromatic heterocycle and the multi-loop system.Complete saturated heterocyclic of term " non-aromatic heterocyclic system " expression and unsaturated heterocycle partially or completely have aromatic ring without any ring in the unsaturated heterocycle.Term " aryl " represents that at least one ring is carbocyclic ring or the heterocycle that aromatic ring and this aromatic ring are connected with the molecule other parts.

About L, R and R ⁴Carbon part be optional the replacement.The term of relevant these carbon parts " optional replacement " is meant not to be had replacement or has at least one non-hydrogen substituent carbon part.The optional substituting group of illustrative comprises alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, aromatic group, hydroxycarbonyl group, formyl radical, alkyl-carbonyl, alkenyl carbonyl, the alkynyl carbonyl, alkoxy carbonyl, hydroxyl, alkoxyl group, alkenyloxy, alkynyloxy group, cycloalkyloxy, aryloxy, alkylthio, the thiazolinyl sulfenyl, the alkynyl sulfenyl, cycloalkylthio, arylthio, alkyl sulphinyl, the thiazolinyl sulfinyl, the alkynyl sulfinyl, the cycloalkyl sulfinyl, aryl sulfonyl kia, alkyl sulphonyl, the thiazolinyl alkylsulfonyl, the alkynyl alkylsulfonyl, the naphthene sulfamide base, aryl sulfonyl, amino, alkylamino, alkenyl amino, alkynyl amino, arylamino, aminocarboxyl, alkyl amino-carbonyl, the alkenyl amino carbonyl, the alkynyl aminocarboxyl, aromatic yl aminocarbonyl, alkyl amino-carbonyl, the alkenyl amino carbonyl, the alkynyl aminocarboxyl, the amino carbonyl oxygen base of virtue, alkoxycarbonyl amino, the alkenyloxy carbonylamino, alkynyloxy group carbonylamino and aryloxycarbonyl amino, each substituting group is optional further to be replaced; And halogen, cyano group and nitro.Further optional substituting group independently is selected from the above groups of enumerating with regard to substituting group itself such as substituting group, thereby forms L, R and R ⁴New substituting group is as haloalkyl, haloalkenyl group and halogenated alkoxy.In further example, alkylamino can further be replaced by alkyl, forms dialkyl amido.Substituting group also can link together, figuratively speaking, each substituting group from two substituting groups or from a substituting group and described supportive molecular structure, remove one or two hydrogen atom, described then group couples together and produces ring texture and polynuclear plane, and described ring texture and polynuclear plane condense or additional being connected supported on the described substituent molecular structure.For example, hydroxyl adjacent on the phenyl ring is connected with methoxyl group, forms and contain-O-CH ₂-O-group condense the dioxolane structure.The coupled molecular structure of hydroxyl couples together, and can form the cyclic ethers that comprises epoxide.The illustrative substituting group also comprises oxygen, forms the carbonyl functional group when it links to each other with carbon.Form thiocarbonyl functionality when equally, sulphur links to each other with carbon.In carbon part L or R, substituting group connects can form ring or polynuclear plane.Carbon part L and R illustrative embodiment are: comprise at least two R parts in the same substituting group or comprise L part and at least one R part (promptly forming loop systems).Because 4, the 5-pyrazoline partly constitutes a ring, in same group, comprise the R part of two vicinals or comprise two vicinal L and R part, can form thick two ring or multi-loop systems.In same substituting group, comprise two and can form spirane structure together with position R part.

In the present invention, no matter " alkyl " is to use separately or the use of compound part of speech, as " alkylthio " or " haloalkyl ", include straight chained alkyl or branched-chain alkyl, for example methyl, ethyl, n-propyl, sec.-propyl or different butyl, amyl group or hexyl isomer.Term " 1-2 alkyl " but the described substituting group 1-2 of expression the position of substitution can be independent selected alkyl." thiazolinyl " comprises normal olefine or branched-chain alkene, as vinyl, 1-propenyl, 2-propenyl and different butenyl, pentenyl and hexenyl isomer." thiazolinyl " also comprises the polyenoid alkyl, for example 1, and 2-propadiene base and 2,4-hexadienyl." alkynyl " comprises straight or branched alkynes, as ethynyl, 1-proyl, 2-propynyl and different butynyl, pentynyl and hexin base isomer." alkynyl " also can comprise a plurality of triple-linked parts, as 2, and 5-hexadiyne base." alkoxyl group " comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy and different butoxy, pentyloxy and hexyloxy isomer." alkenyloxy " comprises straight or branched alkenyloxy part.The example of " alkenyloxy " comprises H ₂C=CHCH ₂O, (CH ₃) ₂C=CHCH ₂O, (CH ₃) CH=CHCH ₂O, (CH ₃) CH=C (CH ₃) CH ₂O and CH ₂=CHCH ₂CH ₂O." alkynyloxy group " comprises straight or branched alkynyloxy group part.The example of " alkynyloxy group " comprises HC ≡ CCH ₂O, CH ₃C ≡ CCH ₂O and CH ₃C ≡ CCH ₂CH ₂O." alkylthio " comprises side chain or straight chain alkylthio part, for example methylthio group, ethylmercapto group and different rosickyite bases, butylthio, amyl group sulphur and own sulfenyl isomer." alkyl sulphinyl " comprises two kinds of optically active enantiomorphs of alkyl sulphinyl group.The example of " alkyl sulphinyl " comprises CH ₃S (O), CH ₃CH ₂S (O), CH ₃CH ₂CH ₂S (O), (CH ₃) ₂CHS (O) and different butyl sulfinyls, amyl group sulfinyl and hexyl sulfinyl isomer.The example of " alkyl sulphonyl " comprises CH ₃S (O) ₂, CH ₃CH ₂S (O) ₂, CH ₃CH ₂CH ₂S (O) ₂, (CH ₃) ₂CHS (O) ₂With different butyl alkylsulfonyls, amyl group alkylsulfonyl and hexyl alkylsulfonyl isomer.Example above the definition of terms such as " alkylamino ", " thiazolinyl sulfenyl ", " thiazolinyl sulfinyl ", " thiazolinyl alkylsulfonyl ", " alkynyl sulfenyl ", " alkynyl sulfinyl ", " alkynyl alkylsulfonyl " is similar.The example of " alkyl-carbonyl " comprises C (O) CH ₃, C (O) CH ₂CH ₂CH ₃And C (O) CH (CH ₃) ₂The example of " alkoxy carbonyl " comprises CH ₃OC (=O), CH ₃CH ₂OC (=O), CH ₃CH ₂CH ₂OC (=O), (CH ₃) ₂CHOC (=O) with different butoxy carbonyls or pentyloxy carbonyl isomer." cycloalkyl " comprises for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Term " cycloalkyloxy " comprises the same group that links to each other by Sauerstoffatom, as cyclopentyloxy and cyclohexyloxy." cycloalkyl amino " is meant that amino nitrogen atom links to each other with a hydrogen atom with group of naphthene base, comprises as cyclopropyl amino, cyclobutyl amino, cyclopentyl amino and cyclohexyl amino." (alkyl) (cycloalkyl) amino " is meant the group that the hydrogen atom on the nitrogen is replaced by alkyl in the cycloalkyl amino; Example comprises (methyl) (cyclopropyl) amino, (butyl) (cyclobutyl) amino, (propyl group) cyclopentyl amino, (methyl) cyclohexyl amino etc." cycloalkenyl group " comprises for example cyclopentenyl and cyclohexenyl and has the group that surpasses two keys, as 1 base and 1 base.

Term " halogen " no matter uses separately or compound part of speech is used, and as " haloalkyl ", comprises fluorine, chlorine, bromine or iodine.One or two desirable subrogating can be independent selected halogen on the described substituting group of term " 1-2 halogen " expression.And when being used for compound word as " haloalkyl ", described alkyl can partially or completely be replaced by halogen, described halogen atom can be identical also can be different.The example of " haloalkyl " comprises F ₃C, ClCH ₂, CF ₃CH ₂And CF ₃CCl ₂

The total number of carbon atoms in the substituting group is by prefix " C _i-C _j" expression, wherein i and j for example are 1 to 3 numeral; C for example ₁-C ₃Alkyl represents that methyl is to propyl group.

Though do not have clear and definite size restriction for formula I that is fit to the inventive method and II, preferred formula II comprises 4-100 carbon atom, is more preferably 4-50, most preferably be 4-25, and comprise 3-25 heteroatoms, more preferably 3-15, most preferably 3-10.Heteroatoms is selected from halogen, oxygen, sulphur, nitrogen and phosphorus usually.Two heteroatomss among formula I and the II are pyrazoline theheterocyclic nitrogen atoms; X ¹Be halogen, X ²Contain at least one heteroatoms.

Though (comprise R for L and R ⁴) there is not clear and definite size restriction, L and R (comprise R ⁴) in the alkyl chain of the optional moieties that replaces generally include 1-6 carbon atom, more preferably 1-4 carbon atom most preferably is 1-2 carbon atom.L and R (comprise R ⁴) in the alkenyl or alkynyl chain of the optional thiazolinyl that replaces and alkynyl part generally include 2-6 carbon atom, more preferably 2-4 carbon atom most preferably is 2-3 carbon atom.

Equally, for R ¹And R ²The group of listing does not have clear and definite size restriction, but alkyl comprises derivative such as alkoxyl group and haloalkyl, is generally C ₁-C ₆, C more preferably ₁-C ₄, most preferably be C ₁-C ₂

As mentioned above, carbon part L, R and R ⁴Can be aromatic ring or aromatic ring system (except other group).The example of aromatic ring or aromatic ring system comprises that 8 yuan, 9 yuan or 10 yuan of phenyl ring, 5 yuan or 6 yuan of hetero-aromatic rings, aromatics condense two carbon-loop systems and aromatics condenses two heterocyclic ring systems for 8 yuan, 9 yuan or 10 yuan, and each ring or loop systems are optional in the second cycle line system is substituted.About the term of these L and R carbon part " optional replacement () " refer to that carbon part is not substituted or has at least one non-hydrogen substituting group.These carbon parts can be replaced by its optional substituting group that can hold maximum number, and the hydrogen atom on its all commutable carbon or the nitrogen-atoms is replaced by non-hydrogen substituting group.Preferred optional substituting group number (when existing) is 1-4.Optional by the U-1 in the example of the phenyl of 1-4 substituting group replacement such as the legend displaying 1, wherein R ^vBe optional non-hydrogen substituting group, r is the integer of 0-4.Optional 8 yuan, 9 yuan or 10 yuan examples that condense two carbon-loop systems of aromatics that replaced by 1-4 substituting group comprise the optional naphthyl that is replaced by 1-4 substituting group, show U-85 in 1 as legend, and choose wantonly by 1 of 1-4 substituting group replacement, 2,3, the 4-tetralyl, show U-86, wherein R in 1 as legend ^vBe any substituting group, r is the integer of 0-4.Choose wantonly by 1-4 the example of getting 5 yuan or 6 yuan hetero-aromatic rings of shape base replacement and comprise the ring of legend displaying 1U-2 to U-53, wherein R ^vFor any substituting group and r are the integer of 1-4.Optional 8 yuan, 9 yuan or 10 yuan examples that condense two heterocyclic ring systems of aromatics that replaced by 1-4 substituting group comprise legend displaying 1U3-54 to U-84, wherein R ^vIt for any substituting group and r 0 to 4 integer.The example of other L and R comprises the optional phenmethyl that is replaced by 1-4 substituting group, shows 1U-87 as legend, and the optional benzoyl that is replaced by 1-4 substituting group, shows 1U-88, wherein R as legend ^vBe any substituting group, r is the integer of 0-4.

Though have R in structure U-1 diagram in the U-85 ^vGroup, but notice that they not necessarily exist, because they are optional substituting groups.Need substituting group to fill its valent nitrogen-atoms with H or R ^vTo its replacement.Notice that some U groups can only be less than 4 R ^vGroup replace (as U-14, U-15, U-18 can only be by a R to U-34 to U-21 and U-32 ^vReplace).Note as (R ^v) _rAnd the binding site between the U is shown when not fixing (R ^v) _rCan be connected in any commutable carbon atom and nitrogen-atoms on the U group.Note being shown when not fixing when the binding site on the U group, the U group can be connected in formula I and II rest part by choosing attachable carbon atom on the U group wantonly by replacing hydrogen atom.

Legend shows 1

Or

As mentioned above, carbon part L, R and R ⁴May be for (except other group) saturated or fractional saturation carbocyclic ring and heterocycle, they further are optionally substituted.Refer to that about the term of these L and R carbon part " optional replace " carbon part is not substituted or at least one non-hydrogen substituting group arranged.These carbon parts can be replaced by its optional substituting group that can hold maximum number, and the hydrogen atom on its all commutable carbon or the nitrogen-atoms is replaced by non-hydrogen substituting group.In general, optional substituting group number (when existing) is 1-4.Saturated or fractional saturation isocyclic example comprises the optional C that replaces ₃-C ₈Cycloalkyl and the optional C that replaces ₃-C ₈Cycloalkyl.Saturated or fractional saturation heterocyclic example comprises 5 yuan or 6 yuan of non-aromatic heterocyclics, its optional one or two ring integral part that comprises, this part be selected from C (=O), SO or S (O) ₂, described heterocycle is optional to be substituted.The example of such L and R carbon part comprises that G-1 is to G-35 in the legend displaying 2.Note being shown when not fixing when the connection site on these G groups, the G group can by the replacement hydrogen atom, be connected in formula I and II rest part by optional commutable carbon or nitrogen-atoms on the G group.Described optional substituting group can be connected in any commutable carbon atom and nitrogen-atoms (described substituting group does not show that in legend 2 mark, because they are optional substituting group) by replacing hydrogen atom.Note comprising when being selected from G-24 Q to the ring of G-31, G-34 and G-35 as G ²Can be selected from O, S, NH or substituted N.

Legend shows 2

With

Note L, R and R ⁴Carbon part can be optional replacement.As implied above, except other group, L and R carbon part can comprise usually further optional by 1-4 substituting group replacement U group or G group.Like this, L and R carbon part can comprise and be selected from U or G group and its of U-1 to U-88 or G-1 to G-35 and further replaced by other substituting group, described substituting group comprises 1-4 U or G group (they can be identical or different), makes it have core U or G group and optional substituting group U or the G group that further replaces like this.It should be noted that especially and comprise the optional U group L carbon part of being chosen wantonly replacement by 1-3 other substituting group.For example, L can be the U-41 group.

Shown in Figure 1 as flow process, the method according to this invention, 4 of formula II, 5-dihydro-1 h-pyrazole and HX ¹Reaction forms different formula I3-halos-4,5-dihydro-1 h-pyrazole compound.

Schema 1

Wherein L, R, X ¹, X ²With the definition among k invention summary together.

Above-mentioned being reflected in the suitable solvent carried out.Reach the optimum solvent and should be non-nucleophilicity solvent, it is to HX ¹The compound of relative inertness and solubilized formula II.Suitable solvent comprises methylene bromide, methylene dichloride, acetate, ethyl acetate and acetonitrile.Reaction can under atmospheric pressure or carried out near being higher than under the normal atmosphere under the normal atmosphere or in pressurized vessel.Starting raw material HX ¹Can add in the reaction mixture of formula II compound and solvent with the form of gas.X in formula II compound ²During for halogen such as Cl, the HX that preferred reaction produces ²Remove by spraying or other appropriate method.In addition, can at first make starting raw material HX ¹Be dissolved in its highly soluble inert solvent (for example acetate), then directly or in solution, contact with the compound of formula II.Work as X in the compound of formula II equally ²During for halogen such as Cl, need substantially exceed the HX of monovalent usually ¹(as 4 to 10 equivalents), this depends on the level of conversion of expectation.Work as X ²Be OS (O) _mR ¹Or OP (O) _p(OR ²) ₂The time, the HX of monovalent ¹High conversion can be provided, but when the compound of formula II contains at least one basic functionality (as nitrogen heterocyclic ring), need to surpass the HX of monovalent usually ¹Reaction can be carried out between 0 to 100 ℃, most convenient be temperature (10-40 ℃ according to appointment) near surrounding environment, most preferably be about 20 to 30 ℃.Add lewis acid catalyst and (, be used for preparation formula I, wherein X as aluminum bromide ¹Be Br) can promote reaction.The product of formula I separates with usual method well known to those skilled in the art, comprises extraction, distillation and crystallization.

The preferred initial compounds of the inventive method comprises formula II compound, and wherein m is 2, and p is 1.X in preferred ²Be halogen or OS (O) _mR ¹The formula II initial compounds of (preferably wherein m is 2) its.Further preferred initial compounds is such formula II compound: X wherein ²Be Cl or OS (O) _mR ¹, m is 2, R ¹Be C ₁-C ₆Alkyl, CF ₃Or optional be selected from C by 1 to 3 ₁-C ₄The phenyl that the substituting group of alkyl replaces, more preferably R ¹Be C ₁-C ₂Alkyl, phenyl or 4-aminomethyl phenyl.The particularly preferred method of the present invention comprises uses such formula II initial compounds: X wherein ²Be Cl or OS (O) ₂R ¹, and R ¹Be methyl, phenyl or 4-aminomethyl phenyl.In the formula II initial compounds that the particularly preferred method of the present invention is used, X ²Be Cl or OS (O) ₂R ¹, and R ¹Be phenyl or 4-aminomethyl phenyl.

The preferred product of the inventive method comprises such formula I compound: X wherein ¹Be Cl, Br or I.Preferred product comprises such formula I compound: X wherein ¹Be Cl or Br.Most preferred product comprises wherein X ¹Formula I compound for Br.The useful especially embodiment of the inventive method comprises preparation I compound, wherein X ¹Be Cl or Br, described formula I compound obtains with formula II compound, X in its Chinese style II compound ²Be OS (O) ₂R ¹, R wherein ¹For example be methyl, phenyl or 4-aminomethyl phenyl, more preferably phenyl or 4-aminomethyl phenyl.

The preferred process of the present invention comprises such method: its Chinese style II initial compounds is formula IIa, and formula I product is formula Ia, and following surface current journey is shown in Figure 2.

Schema 2

X wherein ¹And X ²Cotype I and II definition;

R ⁴Be H or the optional carbon part that replaces;

Z is N or CR ⁵

R ⁵Be H or R ³And

N is selected from 1 to 3 integer.

The formula Ia of those skilled in the art will appreciate that is the subclass compound of formula I, and formula IIa is the subclass compound of formula II.

Though for the method for schema 2, the carbon part of the various optional replacements of having introduced in the ester of formula Ia as R ⁴Be useful, but common R ⁴For containing the group of 18 carbon atoms at most, and it is selected from alkyl, thiazolinyl and alkynyl; And phenmethyl and phenyl, each group is optional to be replaced by alkyl and halogen.R ⁴Most preferably be C ₁-C ₄Alkyl.

It should be noted that in the method shown in the schema 2 that Z is N, n is 1, R ³For Cl or Br and on 3.It should be noted that the method shown in the schema 2 equally, wherein X ²Be halogen or OS (O) ₂R ¹, preferred R ¹Be methyl, phenyl or 4-aminomethyl phenyl.It should be noted that the method shown in the schema 2 equally, wherein X ¹Be Br or Cl and preferred X ¹Be Br.Especially it should be noted that the method shown in the schema 2, wherein X ¹Be Br, X ²Be Cl or OS (O) _mR ¹, m is 2, R ¹Be phenyl or 4-aminomethyl phenyl.

(as Z is N and/or R basic functionality in formula IIa compound ³Be alkylamino, dialkyl amido, cycloalkyl amino or (alkyl) (cycloalkyl) amino) time, the typical case needs to surpass the HX of monovalent ¹Reaching satisfied transformation efficiency, though this moment X ²Be OS (O) _mR ¹Or OP (O) _p(OR ²) ₂Z is N in formula IIa, R ³Not alkylamino, dialkyl amido, cycloalkyl amino or (alkyl) (cycloalkyl) amino, and X ²Be S (O) ₂R ¹The time, use as few as 1.5 to 2 normal HX ¹Can reach splendid transformation efficiency.

X wherein ²For the formula II initial compounds of halogen can be from corresponding formula 1 compound, shown in Figure 3 as flow process.

Schema 3

X wherein ²Be halogen, L, R and k ditto define.

The compound of formula 1 is handled with halide reagent, in solvent, obtained corresponding formula II halogenated compound usually.The available halide reagent comprises phosphoryl halogen, phosphorus trihalide, phosphorus pentahalides, thionyl chloride, dihalo trialkyl phosphorane, dihalo phenylbenzene phosphorane, oxalyl chloride, carbonyl chloride, sulfur tetrafluoride and (diethylamino) sulfur trifluoride.Be preferably phosphoryl halogen and phosphorus pentahalides.Transform for reaching fully, will use 0.33 normal phosphoryl halogen (mol ratio that is phosphoryl halogen and formula 1 is at least 0.33) at least with respect to formula 1 compound, preferably between 0.33 and 1.2 equivalents.Transform for reaching fully, will use 0.20 normal phosphorus pentahalides at least with respect to formula 1 compound, preferably between 0.20 and 1.0 equivalents.The typical solvent of this halogenating reaction comprises halogenated alkane such as methylene dichloride, chloroform, chlorobutane and analogue, aromatic solvent such as benzene, dimethylbenzene, chlorobenzene and analogue, ether such as tetrahydrofuran (THF), P-Dioxane, diethyl ether and analogue, polar aprotic solvent such as acetonitrile, N, dinethylformamide and analogue.Can choose the adding organic bases wantonly, as triethylamine, pyridine, N, accelerine and analogue.Also can choose the adding catalyzer wantonly, as N, dinethylformamide.Preferable methods is that solvent is acetonitrile and does not have alkali.Typically, when using acetonitrile, do not need alkali or catalyzer.The carrying out of preferred method is for sneaking into the compound of formula 1 in acetonitrile.Add halide reagent again in the suitable time, mixture is placed on the temperature of requirement and finishes down to reaction.The type reaction temperature is about 20 ℃ and arrives between the boiling point of acetonitrile that the type reaction time is for being less than 2 hours.Use mineral alkali such as sodium bicarbonate, sodium hydroxide and analogue then, or use organic bases, as sodium acetate, the neutralization reaction material.The product that needs is that formula II compound can separate by method well-known to those having ordinary skill in the art, comprises extraction, crystallization and distillation.

Shown in Figure 4 as flow process, R wherein ¹Be OS (O) _mR ¹Or OP (O) _p(OR ²) ₂Formula II initial compounds can be equally from corresponding formula 1 compound, its preparation method is to make it and X ³S (O) _mR ¹(2) or X ³P (O) _p(OR ²) ₂(3) react respectively, wherein X ³Be the nucleophilic reaction leavings group.Halogen such as Cl are to X ³Particularly useful.To X ³S (O) _mR ¹X equally usefully ³Be OS (O) _mR ¹(be that formula 2 is R ¹S (O) _mOS (O) _mR ¹); Work as R ¹Be CF ₃The time X ³Be OS (O) _mR ¹Particularly useful.From the aspect of reaction feasibility and relatively low cost, X ³For Cl is usually preferred.

Schema 4

X wherein ²Be OS (O) _mR ¹Or OP (O) _p(OR ²) ₂, X ³Be leavings group, L, R, R ¹, k, m and p ditto define.

In the method, formula 1 compound is having in the presence of solvent or the alkali and formula 2 compound (X usually ²Be OS (O) _mR ¹The time) or formula 3 compound (X ²Be OP (O) _p(OR ²) ₂The time) reaction.Suitable solvent comprises methylene dichloride, tetrahydrofuran (THF), acetonitrile and analogue.Suitable alkali comprises tertiary amine (as triethylamine, N, the N-diisopropylethylamine) and ion alkali such as salt of wormwood and analogue.Preferred alkali is tertiary amine.Usually the alkali that uses monovalent (it is excessive slightly to be preferably, as 5-10%) formula 2 compounds or formula 3 compounds at least and relate to formula 1 compound is to transform fully.Usually be reflected at approximately-50 ℃ and under the temperature between the solvent boiling point, carry out, more preferably about 0 ℃ to (promptly about 15 to 30 ℃) between the envrionment temperature.Typically be reflected in several hours to several days and finish; Reaction process can be used technical monitoring well-known to those having ordinary skill in the art, as thin-layer chromatography and ¹The HNMR spectroscopic analysis.Reaction mixture subsequently, as wash with water, dry organic phase and evaporating solvent.Needed product is that formula II compound can separate by method well-known to those having ordinary skill in the art, comprises extraction, crystallization and distillation.

Because formula IIa is the subclass compound of formula II, formula IIa compound can pass through schema 3 and 4 described methods, and from corresponding formula 1a compound, back one compound is the subclass compound of formula 1.

R wherein ³, R ⁴, Z and n cotype IIa definition.

Formula 1 compound can be equipped with by many modern synthetic method lengths of schooling well-known to those having ordinary skill in the art.For example, formula 1a compound can be shown in Figure 5 as flow process, from formula 4 and formula 5 compound.

Schema 5

R wherein ³, R ⁴, Z and n cotype IIa definition.

In the method, the hydrazine compound of formula 4 and formula 5 compounds (can use fumaric acid esters or maleate or their mixture) are having reaction in the presence of alkali and the solvent.Described alkali is typically metal alkoxide, as sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, potassium tert.-butoxide, trimethyl carbinol lithium and analogue.Should use above 0.5 normal alkali formula 4 compounds, between the preferred 0.9-1.3 equivalent.Should use to surpass 1.0 normal formula 5 compounds, between the preferred 1.0-1.3 equivalent.Can use polar protic organic solvent and polar non-proton organic solvent, as alcohol, acetonitrile, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide and analogue.Preferred solvent is an alcohol, as methyl alcohol and ethanol.Special preferred alcohols is pure identical with the pure and mild alkoxide base of forming fumaric acid esters or maleate.Carry out this reaction normally mixing type 4 compounds and alkali in solvent.Mixture can be heated or cooled desired temperatures, with for some time adding formula 5 compounds.Common temperature of reaction is 0 ℃ and arrives between the boiling point of solvent for use.Reaction can be carried out under superatmospheric pressure, to improve the boiling point of solvent.Usually preferred temperature is between 30-90 ℃.The time of adding formula 5 compounds can be soon to the time of heat passage permission.Typical case's joining day is between 1 minute to 2 hours.Optimum reacting time and joining day, the compound characteristic was different changes according to formula 4 and formula 5.After the adding, reaction mixture remains on following for some time of temperature of reaction.According to temperature of reaction, the required hold-time may be 0 to 2 hour.Usually the hold-time is 10 to 60 minutes.Pass through then to add organic acid, as acetate and analogue, or mineral acid, example hydrochloric acid, sulfuric acid and analogue, acidification reaction material.According to reaction conditions and separate mode, on the formula 1a compound-CO ₂R ⁴Functional group can be hydrolyzed to-CO ₂H; For example, exist water can promote this hydrolysis in the reaction mass.If form carboxylic acid (CO ₂H), can adopt esterification process well known in the art, make that carboxyl is reverse to be converted into-CO ₂R ⁴, R wherein ⁴For example be C ₁-C ₄Alkyl.Needed product is that formula 1a compound can separate by method well-known to those having ordinary skill in the art, as crystallization, extraction or distillation.

Can think, utilize description those skilled in the art of front can farthest utilize the present invention.Therefore, embodiment subsequently only is illustrative, and limits the disclosure of invention never in any form.Step in following examples has illustrated the per step program in the whole synthetic method for transformation, and the starting raw material in per step can be by the specific preparation method's preparation described in other embodiment or the step.Except the chromatography solvent mixture or have in addition the explanation, per-cent is weight percentage.Except as otherwise noted, the part of chromatography solvent mixture or per-cent are volume percent. ¹The HNMR spectral representation is the downfield ppm of tetramethyl-silicomethane; " s " expression is unimodal, and " d " expression is bimodal, and " t " represents three peaks, and " q " represents four peaks, and " m " represents multiplet, and two of " dd " expressions are bimodal, and " dt " represents two three peaks, and " brs " expression is wide unimodal.

Embodiment 1

By replace the chlorine preparation with bromine

3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1 h-pyrazole-5-ethyl formate

Steps A: preparation 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidine-ethyl formate

In the 2-L four neck flasks that mechanical stirring device, thermometer, addition funnel, reflux exchanger and nitrogen inlet are housed, add straight alcohol (250mL) and sodium ethylate ethanolic soln (21%, 190mL, 0.504mol).Mixture is heated to backflow under about 83 ℃.(68.0g 0.474mol) handles to use 3-chloro-2 (1H)-pyridone hydrazone then.The mixture reheat refluxed about 5 minutes.Yellow slurry drips diethyl maleate again, and (88.0mL 0.544mol) handled about 5 minutes.Return velocity obviously increases in the adding method.Starting raw materials all when adding is finished dissolve.The gained orange-red solution keeps refluxing about 10 minutes.After being cooled to 65 ℃, reaction mixture with glacial acetic acid handle (50.0mL, 0.873mol).Form precipitation.Mixture water (650mL) dilution makes resolution of precipitate.Orange solution cools off in ice bath.Product begins precipitation in the time of 28 ℃.Slurry was placed 2 hours down at 2 ℃.Product is by filtering separation, with aqueous ethanolic solution (40%, 3 * 50mL) washing, and on filter about 1 hour of dry air.The title product that obtains is the bright orange powder (70.3g, 55% productive rate) of highly crystalline. ¹HNMR does not observe tangible impurity.

¹H NMR(DMSO-d ₆)δ1.22(t，3H)，2.35(d，1H)，2.91(dd，1H)，4.20(q，2H)，4.84(d，1H)，7.20(dd，1H)，7.92(d，1H)，8.27(d，1H)，10.18(s，1H)。

Step B: preparation 3-chloro-1-(3-chloro-2-pyridyl)-4,5-dihydro-1 h-pyrazole-5-ethyl formate

In the 2-L four neck flasks that mechanical stirring device, thermometer, reflux exchanger and nitrogen inlet are housed, add acetonitrile (1000mL), 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidine ethyl formate (being the product of steps A) (91.0g, 0.337mol) and phosphoryl chloride (35.0mL, 0.375mol).When adding phosphoryl chloride, mixture self is heated to 25 ℃ and formation precipitation from 22 ℃.The glassy yellow slurry is heated to 83 ℃ and refluxed 35 minutes down, and precipitation is dissolving therefore.The gained orange solution keeps refluxing 45 minutes, thereby becomes blackish green.Replace reflux exchanger with still head, the 650mL solvent is removed in distillation.In second 2-L four neck flask that mechanical stirring device is housed, add sodium bicarbonate (130g, 1.55mol) and water (400mL).Spissated reaction mixture joined in the sodium bicarbonate slurry with 15 minutes.The two-phase mixture vigorous stirring of gained 20 minutes stops venting this moment.Mixture stirred 50 minutes then with methylene dichloride (250mL) dilution.Mixture Celitex ^545 super-cells (11g) are handled, and remove by filter the isolating black gunk of inhibitory phase.Because filtrate knows that phase-splitting is slow, it with methylene dichloride (200mL) and water (200mL) dilution, is used more Colite again ^545 (15g) handle.Filtering mixt, filtrate is transferred to separating funnel.Separate heavier deep green organic layer.Again filter debris layer (rag layer) (50mL) and add organic phase.This organic solution (800mL) is handled slurry magnetic agitation 30 minutes with Tai-Ace S 150 (30g) and silica gel (12g).Filter slurry, remove Tai-Ace S 150 and silica gel, solution becomes dark blue-green.Filter cake washs with methylene dichloride (100mL).Filtrate concentrates with Rotary Evaporators.Product is stantienite look oil (92.0g, 93% productive rate). ¹The observable impurity of HNMR only has 1% starting raw material and 0.7% acetonitrile.

¹HNMR(DMSO-d6)δ1.15(t，3H)，3.26(dd，1H)，3.58(dd，1H)，4.11(q，2H)，5.25(dd，1H)，7.00(dd，1H)，7.84(d，1H)，8.12(d，1H)。

Step C: preparation 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1 h-pyrazole-5-ethyl formate

To 3-chloro-1-(3-chloro-2-pyridyl)-4, (8.45g feeds hydrogen bromide in methylene bromide 29.3mmol) (85mL) solution to 5-dihydro-1 h-pyrazole-5-ethyl formate (being the product of step B).Stop air-flow after 90 minutes, reaction mixture washs with sodium bicarbonate aqueous solution (100mL).Dry and reduction vaporization organic phase obtains oily title product (9.7g, 99% productive rate), and product leaves standstill crystallization.

¹H NMR (CDCl ₃) δ 1.19 (t, 3H), 3.24 (in the ABX system 1/2 of AB, J=9.3,17.3Hz, 1H), 3.44 (in the ABX system 1/2 of AB, J=11.7,17.3Hz, 1H), 4.18 (q, 2H), 5.25 (the X part among the ABX, 1H, J=9.3,11.9Hz), 6.85 (dd, J=4.7,7.7Hz, 1H), 7.65 (dd, J=1.6,7.8Hz, 1H), 8.07 (dd, J=1.6,4.8Hz, 1H).

Embodiment 2

By replace the preparation of toluenesulphonic acids base with bromine

3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1 h-pyrazole-5-ethyl formate

Steps A: preparation 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base]-1H-pyrazoles-5-ethyl formate

Under 0 ℃, to 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidine ethyl formate (being the product of embodiment 1 steps A) (10.0g, 37.1mmol) and Tosyl chloride (7.07g, 37.1mmol) drip in the mixture in methylene dichloride (100mL) triethylamine (3.75g, 37.1mmol).Add once more Tosyl chloride (0.35g, 1.83mmol) and triethylamine (0.19g, 1.88mmol).Making reaction mixture rise to room temperature and stir then spends the night.Mixture is used methylene dichloride (200mL) to dilute again and is washed (3 * 70mL) with water.Drying is also evaporated organic phase, stays oily title product (13.7g, 87% productive rate), and product slowly forms crystallization.With the product of ethyl acetate/hexane recrystallization in 99.5-100 ℃ of fusion.

IR(nujol)：1740，1638，1576，1446，1343，1296，1228，1191，1178，1084，1027，948，969，868，845cm ^-1。

¹H NMR (CDC ₁3) δ 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (in the ABX system 1/2 of AB, J=17.3,9Hz, 1H), 3.33 (in the ABX system 1/2 of AB, J=17.5,11.8Hz, 1H), 4.16 (q, 2H), 5.72 (the X part among the ABX, J=9,11.8Hz, 1H), 6.79 (dd, J=4.6,7.7Hz, 1H), 7.36 (d, J=8.4Hz, 2H), 7.56 (dd, J=1.6,7.8Hz, 1H), 7.95 (d, J=8.4Hz, 2H), 8.01 (dd, J=1.4,4.6Hz, 1H).

Step B: preparation 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1 h-pyrazole-5-ethyl formate

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base]-(5g feeds hydrogen bromide in methylene bromide 11.8mmol) (50mL) solution to 1H-pyrazoles-5-ethyl formate (being the product of steps A).Air-flow stops after 60 minutes, and reaction mixture washs with sodium bicarbonate aqueous solution (50mL).Dry and reduction vaporization organic phase obtains oily title product (3.92g, 100% productive rate), and product leaves standstill crystallization.Product ¹HNMR spectrum is identical with embodiment 1 step C product.

Embodiment 3

By preparing with bromine substituted benzenesulfonic acid base

3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1 h-pyrazole-5-ethyl formate

Steps A: preparation 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenyl sulfonyl) oxo]-1H-pyrazoles-5-ethyl formate

Under 0 ℃, with 1 hour to 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidine ethyl formate (is embodiment 1, the product of steps A) (5.0g, 18.5mmol) and benzene sulfonyl chloride (3.27g, 18.5mmol) drip in the mixture in methylene dichloride (20mL) triethylamine (1.85g, 18.5mmol).Temperature does not allow above 1 ℃.Continued stirred reaction mixture 2 hours, add again benzene sulfonyl chloride (0.5g, 1.85mmol).(0.187g is 1.85mmol) to mixture further to drip triethylamine again.Restir 0.5 hour, mixture distribute between water (100mL) and methylene dichloride (100mL).Dry (MgSO ₄) and evaporate organic layer, obtain orange solids title product (7.18g, 94% productive rate).With the product of ethyl acetate/hexane recrystallization in 84-85 ℃ of fusion.

IR(nujol)：1737，1639，1576，1448，1385，1346，1302，1233，1211，1188，1176，1088，1032，944，910，868，846cm ^-1。

¹H NMR (CDCl ₃) δ 1.19 (t, 3H), 3.15 (in the ABX system 1/2 of AB, J=8.8,17.3Hz, 1H), 3.36 (in the ABX system 1/2 of AB, J=11.8,17.3Hz, 1H), 4.17 (q, 2H), 5.23 (the X part of ABX, J=8.8,11.8Hz, 1H), 6.78 (dd, J=2.8,4.8Hz, 1H), 7.71-7.55 (m, 4H), 8.01 (dd, J=1.6,4.6Hz, 2H), 8.08 (dd, J=1.0,2.6Hz, 2H).

With 1-(3-chloro-2-pyridyl)-4; 5-dihydro-3-[(phenyl sulfonyl) oxygen base]-1H-pyrazoles-5-ethyl formate (being the product of steps A) (1.0g; 2.44mmol) acetic acid solution (4mL) add hydrogen bromide acetic acid solution (33%, 1.2g, 4.89mmol).After about 1 hour reaction mixture is added in the saturated sodium bicarbonate aqueous solution (100mL).The mixture ethyl acetate extraction (2 * 50mL), dry (MgSO ₄) and evaporation merging extract, obtain oily title product (0.69g, 85% productive rate), the slow crystallization of product. ¹HNMR spectrum is identical with the product of embodiment 1 step C.

Combine with method well known in the art by methods described herein, formula II compound can be converted into formula I compound, as the formula Ia that lists in the table 1 and the explanation of formula IIa.That uses in the table is abbreviated as: t is uncle, and s is secondary, and n is for just, and i is different, and Me is a methyl, and Et is an ethyl, and Pr is a propyl group, and i-Pr is a sec.-propyl, and t-Bu is the tertiary butyl, and Ph is a phenyl.

Table 1

X ¹Be Br; X ²Be OS (O) ₂Ph

Z is N				Z is CH				Z is CCl				Z is CBr
Z is N				Z is CH				Z is CCl				Z is CBr				R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴
3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl 3-Cl	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br	H Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴	R ³	R ⁴

X ¹Be Br; X ²Be OS (O) ₂Ph-4-Me

X ¹Be Br; X ²Be OS (O) ₂Me

X ¹Be Br, X ²Be Cl

X ¹Be Cl; X ²Be OS (O) ₂Ph-4-Me

X ¹Be Br; X ²Be OS (O) ₂Me

R ³	R ⁴	Z	R ³	R ⁴	Z	R ³	R ⁴	Z	R ³	R ⁴	Z
R ³	R ⁴	Z	R ³	R ⁴	Z	R ³	R ⁴	Z	R ³	R ⁴	Z	3-Me 5-Cl 4-n-Bu 5-NMe ₂ 3-OCH ₂F 4-OCH ₃	H Me Et n-Pr i-Pr n-Bu	N CH N CH N CH	4-Me 3-OEt 2-OCF ₃ 3-cyclo-Pr H 4-F	H Me Et n-Pr i-Pr n-Bu	CH N N CH N CCl	3-Br 4-I 3-CN 3-NO ₂ 3-S(O) ₂CH ₃ 4-SCH ₃	H Me Et n-Pr i-Pr n-Bu	N CH CH CH CH CH	3-CF ₃ 5-CF ₂H 6-CH ₃ 3-CH ₂CF ₃ 6-oyclohexyl 4-CH ₂CH＝CH ₂	H Me Et n-Pr i-Pr n-Bu	N CH N CH CH CH

X ¹Be Br

R ³	R ⁴	Z	X ²	R ³	R ⁴	Z	X ²
R ³	R ⁴	Z	X ²	R ³	R ⁴	Z	X ²	3-Cl 3-Br 3-Cl 3-Br 3-Cl 3-Br	H Me Et n-Pr i-Pr n-Bu	N CH N CH N CH	OS(O) ₂Et OS(O)Me OP(O)(OMe) ₂ OP(OMe) ₂ OP(O)(OEt) ₂ OP(O)(OPh) ₂	3-Cl 3-Br 3-Cl 3-Br 3-Cl 3-Br	H Me Et n-Pr i-Pr n-Bu	N CH N CH N CH	OS(O) ₂CF ₃OS(O) ₂-n-Bu OP(O)(O-i-Pr) ₂OS(O) ₂Ph-2，4，6-tri-Me OP(O)(OPh-4-Me) ₂OS(O) ₂Ph-4-Cl

3-halo-4 of the present invention, 5-dihydro-1 h-pyrazole preparation method can be used for preparing various formula I compounds, and these compounds are useful intermediates of the agent of preparation crop protection, medicine and other fine chemical product.Legend shows that 3 have listed 3-halo-4 that can be prepared according to the methods of the invention, the example of 5-dihydro-1 h-pyrazole, and described examples of compounds can be from having OS (O) _mR ¹(as OS (O) ₂CH ₃Or OS (O) ₂Ph), OP (O) _p(OR ²) ₂((OMe) as OP (O) ₂) or different halogenic substituent (replace Br as Cl, or Br replacing Cl) is corresponding 4, the preparation of 5-dihydro-1 h-pyrazole, useful 3-halo-4 when being included in the compound that preparation has fungicidal, weeding or plant growth regulating purposes, 5-dihydro-1 h-pyrazole.These embodiment scope that explains rather than limit the inventive method different application.Other can be used for preparing medicinal products by compound prepared according to the methods of the invention, as anti-inflammatory agent, transformation reactions inhibitor, anticonvulsive agent, tranquilizer etc.

Legend shows 3

In compound that can be prepared according to the methods of the invention, formula Ia compound is particularly useful to preparation formula III compound.

Wherein Z, X ¹, R ³Ditto define with n; R ⁶Be CH ₃, F, Cl or Br; R ⁷Be F, Cl, Br, I or CF ₃R ^8aBe C ₁-C ₄Alkyl; R ^8bBe H or CH ₃Preferred Z is N, and n is 1, R ³For Cl or Br and on 3.

The formula III compound is useful during as sterilant, for example referring to September 27 calendar year 2001 disclosed PCT publication number WO 01/70671 and September 21 calendar year 2001 the application U.S. Patent application 60/324,173, the U.S. Patent application 60/323 of application on September 21 calendar year 2001, the U.S. Patent application 60/369,661 of application on April 2nd, 941 and 2002.The method of preparation formula 8 and formula III compound is seen the U.S. Patent application 60/400352[BA9308US PRV of application on July 31st, 2002]; The U.S. Patent application 60/446438[BA9308US PRV1 of on February 11st, 2003 application], they by reference integral body be attached to herein; And the U.S. Patent application 60/369,660 of application on April 2nd, 2002.

The formula III compound can be by method shown in the schema 6-9 from corresponding formula Ia compound.

As shown in schema 6, formula Ia compound is chosen wantonly in the presence of acid, uses oxidizer treatment.

Schema 6

R wherein ³, R ⁴, Z, X ¹Definition with n cotype Ia.

Formula Ia compound is preferably as the starting raw material of this step, wherein R ⁴Be C ₁-C ₄Alkyl.Oxygenant can be hydrogen peroxide, organo-peroxide, Potassium Persulphate, Sodium Persulfate, ammonium persulfate, potassium hydrogen persulfate (as Oxone ^) or potassium permanganate.Be to transform fully, should use at least one normal oxygenant, be preferably from about one to two equivalent to the compound of formula Ia.Typical this oxidizing reaction is carried out in the presence of solvent.Solvent can be ether such as tetrahydrofuran (THF), P-Dioxane and analogue, organic ester such as ethyl acetate, methylcarbonate and analogue, or polar aprotic solvent such as N, dinethylformamide, acetonitrile and analogue.The acid that this oxidation step is fit to use comprises mineral acid such as sulfuric acid, phosphoric acid and analogue, organic acid such as acetate, phenylformic acid and analogue.When using acid, should use above 0.1 normal acid formula Ia compound.For transforming fully, can use one to five normal acid.To Z wherein is CR ⁵Formula Ia compound, preferred oxidant is that hydrogen peroxide and oxidation are preferably carried out under anacidity.To Z wherein is the formula Ia compound of N, and preferred oxidant is that Potassium Persulphate and oxidation are preferably carried out in the presence of sulfuric acid.Reaction is carried out passing through mixing type Ia compound and acid in the solvent of needs, if use acid.Add oxygenant with suitable speed subsequently.Usually temperature of reaction the reasonable reaction time to obtain to finish reaction, preferably is less than 8 hours for from being low to moderate 0 ℃ of boiling point to height to solvent.The product of expectation is that formula 6 compounds can separate by method well-known to those having ordinary skill in the art, comprises extraction, chromatography, crystallization and distillation.

R in formula 6 carboxylic acid cpds ⁴During for H, it can be by the corresponding formula 6 ester cpds preparation of hydrolysis, wherein R ⁴For example be C ₁-C ₄Alkyl.Carbonate can be by many methods, comprise the nucleophilic cracking under the anhydrous condition or relate to the hydrolysis method of using acid or alkali (about the summary of method referring to T.W.Greene and P.G.M.Wuts, Protective Groups in OrganicSynthesis, 2nd ed., John Wiley﹠amp; Sons, Inc., New York, 1991, pp.224-269), be converted into carboxylic acid cpd.To formula 6 compounds, preferred bases catalytic hydrolysis method.Suitable alkali comprises basic metal (as lithium, sodium or potassium) oxyhydroxide.For example, ester is dissolvable in water water and pure as the alcoholic acid mixture.After with sodium hydroxide or potassium hydroxide treatment, ester is by sylvite or the sodium salt of saponification so that carboxylic acid to be provided.With strong acid example hydrochloric acid or sulfuric acid acidation, the carboxylic acid of acquisition formula 6, wherein R ⁴Be H.This carboxylic acid can separate by method well known to those skilled in the art, comprises extraction, distillation and crystallization.

With the pyrazole carboxylic acid of formula 6, wherein R ⁴Be H,, obtain the benzoxazinone of formula 8 with the anthranilic acid coupling of formula 7.In schema 7, by in the presence of tertiary amine such as triethylamine or pyridine, to R ⁴Add methylsulfonyl chloride successively in the pyrazole carboxylic acid for the formula 6 of H, add the anthranilic acid of formula 7 then, add tertiary amine and methylsulfonyl chloride more for the second time, directly the benzoxazinone of preparation formula 8.

Schema 7

(R ⁴Be H) 3. tertiary amine

4.MeS(O) ₂Cl

R wherein ³, R ⁶, R ⁷, X ¹, Z and n be with the definition of formula III.

This method obtains benzoxazinone productive rate preferably usually.

Schema 8 is described the another kind of method of preparation formula 8 benzoxazinones, relates to formula 10 pyrazoles acyl chlorides and formula 9 isatoic anhydride couplings, directly obtains formula 8 benzoxazinones.

Schema 8

For example pyridine or pyridine/acetonitrile equal solvent is fit to this reaction.The acyl chlorides of formula 10 can be by currently known methods as with thionyl chloride or oxalyl chloride chlorination, from corresponding R ⁴For the acid of the formula 6 of H obtains.

The compound of formula III can be by making formula 8 benzoxazinone and the C of formula 11 ₁-C ₄Alkylamine and (C ₁-C ₄Alkyl) (methyl) amine prepared in reaction is shown in Figure 9 as flow process.

Schema 9

R wherein ³, R ⁶, R ⁷, R ^8a, R ^8b, X ¹, Z and n ditto define.

This reaction can be carried out and carry out in various suitable solvents under solvent-free, and solvent comprises acetonitrile, tetrahydrofuran (THF), diethyl ether, methylene dichloride or chloroform, and best temperature of reaction is the reflux temperature from the room temperature to the solvent.Benzoxazinone and amine reaction produce generally being reflected in the chemical literature of anthranilamide and are documented.See Jakobsen et al. about the summary of benzoxazinone chemistry, BIORGANIC AND MEDICINAL CHEMISTRY2000,8,2095-2103 and the reference of listing thereof.Also can be referring to Coppola, J.Heterocyclic Chemistry 1999,36,563-588.

Claims

1. 3-halo-4 for preparing following formula I, the method for 5-dihydro-1 h-pyrazole compound,

Wherein L is the optional carbon part that replaces;

Each R independently is selected from the optional carbon part that replaces;

K is the integer of 0-4;

And X ¹Be halogen;

Described method comprises:

Make 4 of Formula Il, 5-dihydro-1 h-pyrazole compound and formula HX ¹Compound react in the presence of the solvent being fit to,

M is 1 or 2;

P is 0 or 1;

R ¹Be selected from alkyl and haloalkyl; And it is optional by 1 to 3 phenyl that is selected from the substituting group replacement of alkyl and halogen; And

Each R ²Independently be selected from alkyl and haloalkyl; And it is optional by 1 to 3 phenyl that is selected from the substituting group replacement of alkyl and halogen.

2. the process of claim 1 wherein m be 2 and p be 1.

3. the method for claim 2, wherein X ²Be halogen or OS (O) _mR ¹

4. the method for claim 3, wherein X ²Be Cl or OS (O) _mR ¹, and R ¹Be C ₁-C ₂Alkyl, phenyl or 4-aminomethyl phenyl.

5. the process of claim 1 wherein X ¹Be Cl or Br.

6. the process of claim 1 wherein that formula I compound is a following formula I a compound:

And formula II compound is a Formula Il a compound:

Each R wherein ³Independent is C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, C ₂-C ₄Alkynyl, C ₃-C ₆Cycloalkyl, C ₁-C ₄Haloalkyl, C ₂-C ₄Haloalkenyl group, C ₂-C ₄Halo alkynyl, C ₃-C ₆Halogenated cycloalkyl, halogen, CN, NO ₂, C ₁-C ₄Alkoxyl group, C ₁-C ₄Halogenated alkoxy, C ₁-C ₄Alkylthio, C ₁-C ₄Alkyl sulphinyl, C ₁-C ₄Alkyl sulphonyl, C ₁-C ₄Alkylamino, C ₂-C ₈Dialkyl amido, C ₃-C ₆Cycloalkyl amino, (C ₁-C ₄Alkyl) (C ₃-C ₆Cycloalkyl) amino, C ₂-C ₄Alkyl-carbonyl, C ₂-C ₆Alkoxy carbonyl, C ₂-C ₆Alkyl amino-carbonyl, C ₃-C ₈Dialkyl amino carbonyl or C ₃-C ₆Trialkylsilkl;

R ⁴Be H or the optional carbon part that replaces;

Z is N or CR ⁵

R ⁵Be H or R ³And

N is the integer of 0-3.

7. the method for claim 6, wherein R ⁴Be C ₁-C ₄Alkyl.

8. the method for claim 7, wherein Z is N, n is 1, R ³For Cl or Br and on 3.

9. the method for claim 7, wherein X ¹Be Br, X ²Be Cl or OS (O) _mR ¹, m is 2, and R ¹Be phenyl or 4-aminomethyl phenyl.

10. method for preparing Formula Il I compound,

X wherein ¹Be halogen;

Z is N or CR ⁵

R ⁵Be H or R ³

R ⁶Be CH ₃, F, Cl or Br;

R ⁷Be F, Cl, Br, I or CF ₃

R ^8aBe C ₁-C ₄Alkyl;

R ^8bBe H or CH ₃And

N is the integer of 0-3;

Described method is used following formula I a compound:

R wherein ⁴Be H or the optional carbon part that replaces;

The method that is characterized as by claim 6 of described method prepares described formula Ia compound.

11. the method for claim 10, wherein R ⁴Be C ₁-C ₄Alkyl.

12. the method for claim 11, wherein Z is N, and n is 1, R ³For Cl or Br and on 3.

13. the method for claim 11, wherein X ¹Be Br, X ²Be Cl or OS (O) _mR ¹, m is 2, R ¹Be phenyl or 4-aminomethyl phenyl.