CN1024317C - Antifungal agents based on amides containing phenyl group - Google Patents

Abstract

CYCLE surrounded by a semicircle represents, with the two carbon atoms to which the semicircle is linked, a carbon-containing, optionally heterocyclic, ring containing at least one ethylenic or aromatic bond between the two carbon atoms which carry the -C(Z)-Y group and the phenyl group, Y is oxygen or sulphur, Z is NR1R2, R1 and R2, each represents optionally substituted alkyl, alkoxy or cycloalkyl; alkenyl or alkynyl; or -NR1R2 represents saturated or unsaturated heterocyclyl; R3, R4 and R5, each represents a hydrogen or halogen atom (at least one of R3, R4 and R5 being other than hydrogen or halogen); optionally substituted amino; optionally halogenated or hydroxylated alkyl, alkoxy, alkylalkoxy or alkylthio; or R3 and R4 (in the 3- and 4-positions) can together form a single divalent radical; The compounds are useful as agricultural fungicides.

Description

Antifungal agents based on amides containing phenyl group

The present invention seeks in order to introduce a series of new phenyl and the derivative (or its analog) of acid amides, and their preparation, they avoid the application of the active material of fungal infection as protective plant, are required intermediate and its preparation method of its preparation.

In introducing now, all kinds molecule (structure) formula of being quoted from all is listed in the ending (before the claim fund) of this paper together.Below be used for those terms that contain the carbochain group and mean that this carbochain has 1-4 carbon atom (or 2-4 carbon atom arranged at unsaturated carbon chains).

New product according to the present invention be have suc as formula (I) like that feature at compound, wherein:

* two carbon atoms that connected by " Cycle " symbol that semi-ring enclosed and this semi-ring are represented a carbocyclic ring with 4-7 chain link (preferably 5 or 6), at random are heterocycle, it

Have a unsaturated bond alkene or aroma properties in the middle of two carrier carbon atoms of group and phenyl at least, described ring may by maximum 30 carbon atoms of tool organic group replaced.

* Y is oxygen or sulphur atom.

Z is a chlorine atom, group OW ', a NHR ₁Or NR ₁R ₂(when being used for resisting plant disease, Z preferentially is NR in these compound molecule formulas ₁R ₂, and Z is a chlorine atom, an OW ' group or a NHR in the formula ₁Those compounds of group mainly are used as chemical intermediate.

* W ' is a hydrogen atom; Or a low alkyl group, or alkali metal or alkaline earth metal.

* R ₁And R ₂, identical or different, its representative:

-one low alkyl group or lower alkoxy are (at R ₁And R ₂In to have one at least be not alkoxyl), or the cycloalkyl of 3-7 carbon atom, these groups perhaps by at least one hydrogen and/or hydroxyl or lower alkoxy or alkoxyl (rudimentary) alkyl (rudimentary) or acyloxy (rudimentary) or phenyl or contain 1 or 2 hetero atom (O, N or S) the 4-6 annular atoms heterocyclic radical replaced by the low alkyl group list or disubstituted amino etc. replace.

The alkenyl or the alkynyl of-a tool 3-7 carbon atom.

* or R ₁And R ₂Link to each other together with nitrogen-atoms and to form a saturated or undersaturated heterocycle, it contains 4-7 chain link (being preferably 5 or 6) and 1,2 or 3 hetero atom (O, N or S, this heterocycle can be by low alkyl group or lower alkoxy, or hydroxyl, or oxo group, or one or several halogen atom, or alkoxyl-(rudimentary) alkyl replaces.

* R ₃, R ₄And R ₅, identical or different, its representative:

* hydrogen atom or halogen atom, and R at least ₃, R ₄And R ₅One of group is not a hydrogen atom or halogen atom.

* amino that is perhaps replaced by one or two low alkyl group.

* low alkyl group or lower alkoxy or alkyl (rudimentary)-alkoxyl (rudimentary) or low alkyl group sulfo-, perhaps halo or hydroxylated.

* R ₃And R ₄(position and contraposition) can form a unique group of divalence with 3 or 4 chain links together, and it comprises 1 or 2 non-conterminous oxygen atom.

The present invention more peculiarly relates to those compounds that is used for resisting mycotic infection of plant especially, and in the clear and definite as described above compound, Z is NR ₁R ₂, wherein different groups and substituting group are being allowed a choice aspect its character and their positions, so that in the scope of decimal logarithm (lgoP) between 2 and 5 of their n-octyl alcohol/water partition coefficient (P), are preferably between 2.5 and 4.5.

N-octyl alcohol/the water partition coefficient of a chemical product can be measured according to the method that everybody is familiar with.

According to experiment, this coefficient is that a kind of material is dissolved in a two-phase system by two kinds of immiscible solvent compositions, promptly by the ratio of equilibrium concentration in the two-phase system that descends hot alcohol and water to form, that is to say:

* P=(C n-octyl alcohol)/(C water)

Measure out of phase three different concentration and ratio at 20 ℃, in order to draw identical P value from three phase ratios of these three phase concentrations.

If it is more water-soluble to relate to a product, three concentration of aqueous solution that then prepare this product, be 0.25g/l, 0.5g/l and 1g/l, the solution of each concentration mixes by following proportional quantities and n-octyl alcohol then, the volume ratio that is product water solution/n-octyl alcohol is respectively 80/20,90/10,95/5.Stir these mixtures then, inclining the upper strata, and is dissolved in every product amount in mutually with high-performance liquid chromatogram determination, and according to the formula calculation of distribution coefficient of above introduction.

On the contrary, more be dissolved in n-octyl alcohol and product if relate to one, three variable concentrations n-octyl alcohol solution that then prepare this product, be 0.25g/l, 0.5g/l and 1g/l, each solution is measured in proportion with water and is mixed then, the volume ratio that is the n-octyl alcohol solution/water of product is respectively 80/20,90/10,95/5.

If product is seldom water-soluble or n-octyl alcohol, thereby all can not reaches with any mode solution and to be equivalent to 0.25,0.5 and the concentration level of 0.1g/l, then can operate, for example 0.05,0.1 and 0.2g/l or lower concentration grade again by the low concentration grade.

In any case, three P values that obtain under these conditions should be consistent (if these values are inequality, should seek lower concentration, to allow to reach three identical values), and this is that three common, unique values of mensuration are equivalent to distribution coefficient P(or its logarithm logP), this is the peculiar character of this product.

But, in fact, calculate its distribution coefficient value according to molecular structure and replace its mensuration to become more common.The utilization of these computational methods is provided by C.Hansch and A.Leo institute in " the applied substituent constant of correlation analysis in the chemistry and biology " book (Ed.John Wiley, 1979, Page18-43).This method is slowly development in recent years, but towards the direction evolution of refining more, that is to say, and is more and more approaching to the real value that direct mensuration obtains.Therefore, the computational methods of distribution coefficient, correlative factor when interacting, improve (A.Leo, J.Chom Pdrkin Trans, II PP825-838,1983) for explanation.For the ease of these calculating, computer program commercialization, it can directly carry out the calculating of distribution coefficient (logP) voluntarily.Equally, we have utilized the data that " Medchem " program provides in this article, this program is described in " Medchem Software Manual; release 3.52 " book (in November, 1987 version is edited by the Pomona College of California state Claremont).

Even a computer program like this also will further develop in the future, its differentiation also will be carried out towards the direction of accuracy more, that is to say, more will approach the experimental value of logP.

It is so common replacing the principle of its measured value by the calculated value of logP, so that this method is accepted by Environmental Protection Agency USA (Environmental Protection Agency).

In this article, we have adopted as the logP calculated value that shows above.

Then, when we indicated the implication of multiple group, for example (R) n that is to say n R group, and it can be identical or different then being understood to various R groups according to complete general mode, comes to this for all types of groups and substituting group.

In the big class of formula (I) compound, it is particularly advantageous returning the different subclass of branch.

So, pay the utmost attention to have following this or that or several characteristic:

-R ₁And R ₂Representative:

* low alkyl group; Cycloalkyl with 3-7 carbon atom; The alkenyl or the alkynyl of a tool 3-7 carbon atom; The alkoxyalkyl of a tool 3-8 carbon atom.

* or R ₁And R ₂Can link to each other together with nitrogen-atoms forms a saturated or undersaturated heterocycle, and it comprises 4-7 chain link and 1 or 2 hetero atom (O, N, S), and the alcoxyl alkyl alkyl that this heterocycle can be had the alkyl of 1-3 carbon atom or have a 2-3 carbon atom replaces.

-R ₃, R ₄And R ₅Position, contraposition and a position between laying respectively on the phenyl that replaces CYCLE (locate in conjunction with making comparisons with the valence link that above-mentioned phenyl is connected with above-mentioned CYCLE these positions).

* R ₃, R ₄And R ₅Represent a hydrogen atom or halogen atom (having one at least in these three groups is not hydrogen atom or halogen atom); Or a low alkyl group or a lower alkoxy; Or alkoxyalkyl with 2-4 carbon atom; Or low alkyl group sulfo-; Or hydroxyl; Or one perhaps replaced or disubstituted amino by the low alkyl group list.

* R ₃And R ₄(position and contraposition between being in) can form a unique divalent group with 3 or 4 chain links together, and it comprises 1 or 2 non-conterminous oxygen atom.

Symbol CYCLE is enclosed by a semi-ring, and it represents a divalent group-K ₆-K ₇-K ₈-K ₉-or-K ₆-K ₇-K ₁₀-, so that and its two carbon atoms that connected constitute a tool 5-6 chain link ring [as molecular formula (I a) and use in (I b) scheme indicated], group K ₆, K ₇, K ₈, K ₉And K ₁₀Be like this:

K ₆Representative-N=or-C(R ₆)=

K ₇Representative-N=or-C(R ₇)=

K ₈Representative-N=or-C(R ₈)=

K ₉Representative-N=or-C(R ₉)=

K ₁₀Representative-N=or-C(R ₁₀)=

In addition, as the CYCLE symbology K that is surrounded by a semi-ring ₆, K ₇, K ₁₀The time, these groups K ₆, K ₇And K ₁₀Can also be like this:

K ₆Representative-N(R ₆)-or-C(R ₆) ₂-or-O-or-S(O) _n

K ₇Representative-N(R ₇)-or-C(R ₇) ₂-or-O-or-S(O) _n

K ₁₀Representative-N(R ₁₀)-or-C(R ₁₀) ₂-or-O-or-S(O) _nOr-CO-n equals 0,1 or 2 integer, at CYCLE symbology-K ₆-K ₇-K ₈-K ₉With-K ₆-K ₇-K ₁₀Two kinds of situations under be understood to: at K ₆And K ₇In have a group representative-(R at least ₆)=or-(R ₆) ₂-or-C(R ₇)=or-C(R ₇) ₂, in addition, these divalent group-K ₆-K ₇-K ₈-K ₉-and-K ₆-K ₇-K ₁₀-in its main chain, only comprise 0,1 or 2 hetero atom (N, O or S), and without any-O-O-or-the S-S-chain connects.

(it may be noted that in fact-K ₆-K ₇-K ₈-K ₉Form a ring) with fragrance characters

-R ₆, R ₇, R ₈, R ₉Or R ₁₀, wherein each is identical or is different from other groups, their representatives:

* hydrogen atom or halogen atom are at R ₆Or R ₇In to have a group at least be not hydrogen atom.

* cyano group, nitro, thiocyano, hydroxyl or carboxyl.

* alkyl, cycloalkyl, alkenyl, alkynyl, the n(n=0 of alkyl-S(O), 1 or 2), alkoxyl has the cycloalkyloxy of 3-8 carbon atom, alkenyloxy, alkynyloxy group; These groups preferably have 1-8 carbon atom, are perhaps replaced by one or several halogen atom.

* phenyl, naphthyl, the n(n=0 of phenyl-S(O), 1 or 2), phenoxy group, the n(low alkyl group of phenylalkyl (low alkyl group) phenylalkyl-S(O)); N=0,1 or 2), phenyl alkoxyl (lower alkoxy) or the heterocyclic radical that 5-6 chain link and band 1-3 hetero atom (being selected in oxygen, sulphur and nitrogen group) are arranged, it perhaps is that replace, saturated or unsaturated, each contained benzene nucleus or heterocyclic nucleus can be replaced by at least one substituting group in these groups, and this substituting group is selected in following group:

* halogen atom,

* nitro, cyano group, carboxyl, hydroxyl, sulfydryl, thiocyano, alkoxyl (rudimentary) carbonyl ,-CO-NR ' R ", NR ' R " and ,-N(R ')-CO-R " ,-O-CO-R ' ,-O-CO-NR ' R ", or

* low alkyl group, lower alkoxy, alkyl (rudimentary)-S(O) n(n=0,1 or 2), cycloalkyl (3-7 carbon atom), phenyl, phenoxy group, the n(n=0 of phenyl-S(O), 1, or 2), benzene alkyl, phenyl alkoxyl, the n(n=0 of phenylalkyl-S(O), 1 or 2), these groups may be by halo, and moieties has 1-4 carbon atom.

* an alkoxyl (rudimentary) carbonyl, CONR ' R ", NR ' R " and, N(R ') COR ", O-CO-R ', O-CONR ' R ".

* R ' and R ", identical or different, respectively be a hydrogen atom; A low alkyl group; The cycloalkyl of 3-7 carbon atom; May be by the phenyl of halo; May be by the phenylalkyl of halo (low alkyl group); Alkenyl or an alkynyl with 3-7 carbon atom; Alkoxyalkyl with 3-8 carbon atom.

* work as K ₆And K ₇Representative-C(R ₆)=or-C(R ₆) ₂-or C(R ₇)=or-C(R ₇) ₂The time, R then ₆And R ₇, perhaps R ₆One and R in the base ₇Energy and carrier band R in the base ₆And R ₇Two carbon atoms form a carbocyclic ring, or saturated or unsaturated and heterocycle with 5 or 6 chain links and 0,1 or 2 non-conterminous hetero atom (O, N or S).

* work as K ₆Or K ₇Or K ₈, K ₉Or K ₁₀For-N(R ₆)-,-N(R ₇)-N(R ₈)-,-N(R ₉)-,-N(R ₁₀) in one, so, corresponding group, i.e. R ₆, R ₇, R ₈, R ₉Or R ₁₀(but R in the following connotation is arranged ₆Or R ₇In to have a group at least must not be hydrogen atom):

Hydrogen atom; The alkyl of 1-6 carbon atom; Phenyl or phenylalkyl (low alkyl group), it may be by one or several halogen atom, or by cyano group, or nitro, or by low alkyl group, or lower alkoxy replaces.

According to introducing just now the front, formula (I a) and the compound of (I b) constituted special several big class products among the present invention.

Belong to the formula of the scope of the invention (I), (I is a) or in all cpds of (I b), and different, special subclass compound makes us especially interest, especially in the properties of resultant product and all the more so aspect easy to prepare.These subclass compounds are classified with following more definite mode, are especially determined according to the mode of formula (II), (III), (IV), (V), (VI) and (VIII).

In these subclass compounds, during the general sense of those groups that provided when the reference front, no matter this is for common definition, or all benefits with the implication of getting property earlier that mode of priority is made for those.

Equally, for useful product, especially can be used to prevent and treat the product of mycotic infection of plant, those have the compound of a undefined logP value in front our priority application.

According to the present invention, product first subclass is made of formula (II) product, wherein:

* K ₁₁₀It is an oxygen atom; A S(O) n ₁The n of ,-wherein ₁Be one and equal 0,1 or 2 integer; Or NR ₁₁₀Or C(R ₁₁₀) group, or an oxo group.

* Z ₁Be a halogen atom or an OW ₁Base (wherein, W ₁Have one of implication to aforementioned W ') or a NHR ₁₁, or NR ₁₁R ₁₂Base, wherein R ₁₁And R ₁₂, identical or different, have respectively to aforesaid R ₁And R ₂One of implication.

* R ₁₃-R ₁₅, identical or different, have to aforementioned R ₃, R ₄And R ₅One of implication.

* R ₁₃And R ₁₄Can form a methylene-dioxy or ethylenedioxy together equally, their carbon atom itself can be replaced by low alkyl group or halogen atom.

* R ₁₆-R ₁₉, identical or different, have to aforementioned R ₆-R ₉One of implication.

If K * ₁₁₀Be=C(R ₁₁₀)-or-C(R ₁₁₀)

The time, R then ₁₁₀Represent a hydrogen atom or low alkyl group or a benzyl or a hydroxyl, or a lower alkanoyloxy (for example acetoxyl group) or a lower alkoxy.

If K * ₁₁₀Be-N(R ₁₁₀)-, be R then ₁₁₀Represent a hydrogen atom or a low alkyl group or a benzyl.

Work as Z ₁Be a NR ₁₁R ₁₂Base, then these derivatives have formula (II ') structure, and work as Z ₁Be OW ₁During base, those derivatives have formula (II ") structure.

In molecular formula (II) derivative, pay the utmost attention to the derivative of following design feature:

* K ₁₁₀Be an oxygen atom, sulphur atom, or representative-N(R ₁₁₀)-or-C(R ₁₁₀) ₂-.

* Z ₁Be an OW ₁Group, implication as described above; A NHR ₁₁Or NR ₁₁R ₁₂Base, wherein R ₁₁And R ₁₂Be low alkyl group, as R ₁₁And R ₁₂Comprise 6 carbon atoms altogether at most, perhaps form a morpholino or thiomorpholine generation together.

* R ₁₃-R ₁₅Have as R ₃, R ₄, R ₅Identical meanings.

The formula II derivative of following feature is given special priority for:

* Z ₁Be OW ₁Group, implication as described above; Perhaps NR ₁₁R ₁₂Group, it is a morpholino, thiomorpholine generation, N-methyl-N-ethylamino or N, the N-lignocaine.

* R ₁₃-R ₁₅, identical or different, be a hydrogen atom or halogen atom, a low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₁₆, R ₁₈, R ₁₉Be a hydrogen atom or fluorine atom.

* R ₁₇Be hydrogen or halogen atom; A low alkyl group, lower alkoxy, low alkyl group sulfo-, low-grade halogenated alkyl, elementary halogenated alkoxy, low-grade halogenated alkyl sulfo-; A nitro, cyano group; A low-grade alkenyl, a low-grade alkynyl, or an alkoxyl (rudimentary)-carbonyl.

In addition, for the application of agricultural chemicals, the above-mentioned product that has logP and be 2.5-4.0 gives special priority for.

In belonging to formula I all cpds of the present invention, make us the interested especially second subclass derivative and be being constituted by the phenyl amide of formula III, wherein:

* Z ₂Representative:

-one halogen atom, or

-OW ₂Group (W wherein ₂Have one of implication to W ') or a NHR ₂₁Base, or

-one NR ₂₁R ₂₂Base, wherein R ₂₁And R ₂₂, identical or different, have to R respectively ₁And R ₂One of implication.

* R ₂₃-R ₂₅, identical or different, have to R respectively ₃, R ₄, R ₅One of implication.

* R ₂₃And R ₂₄Can form a methylene-dioxy or ethylenedioxy together equally, the carbon atom in these groups itself can be replaced by some low alkyl groups or halogen atom.

* R ₂₆And R ₂₇, identical or different, have to R respectively ₆, R ₇One of implication, condition is R ₂₆And R ₂₇Can not be a hydrogen atom simultaneously.

* R ₂₈And R ₂₉, identical or different, can be hydrogen or halogen atom; Hydroxyl; A low alkyl group; Lower alkoxy; Alkoxyl (rudimentary)-alkyl (rudimentary); Alkoxyl base (rudimentary)-carbonyl.

In formula III derivative, pay the utmost attention to the compound of following feature:

* Z ₂Be an OW ₂Group (W wherein ₂Has one of implication to W '); A NHR ₂₁Base or a NR ₂₁R ₂₂Base, wherein R ₂₁And R ₂₂Be low alkyl group, as R ₂₁And R ₂₂Comprise altogether mostly being most 6 carbon atoms, perhaps form a morpholino or thiomorpholine generation jointly.

* R ₂₃-R ₂₅, identical or different, have R ₃, R ₄And R ₅Identical meanings.

* R ₂₈And R ₂₉, identical or different, can be a hydrogen atom or halogen atom or a hydroxyl.Following structural formula III derivative gives special priority for:

* Z ₂Be OW ₂Group, as above definite, perhaps NR ₂₁R ₂₃-Ji, it is a morpholino, thiomorpholine generation, N-methyl-N-ethylamino or N, N-lignocaine.

* R ₂₃-R ₂₅, identical or different, be a hydrogen atom or halogen atom, a low alkyl group, a lower alkoxy; A low alkyl group sulfo-.

* R ₂₆-R ₂₇, identical or different, be a hydrogen atom or halogen atom, a low alkyl group, a low-grade alkenyl, a lower alkoxy, a low alkyl group sulfo-, a low-grade halogenated alkyl, elementary halogenated alkoxy or low-grade halogenated alkyl sulfo-.

* R ₂₈And R ₂₉, identical or different, be a hydrogen atom or fluorine atom.

In addition, for the product that agricultural chemicals is used, pay the utmost attention to and have the above-mentioned product that logP is 2.5-4.0.

In belonging to the formula of this patent (I) compound, make us interested especially the 3rd subclass and be being constituted by the nicotinic acid derivates of formula (IV), wherein:

* Z ₃Representative:

-one halogen atom, or

-one OW ₃Group (W wherein ₃Have one of implication to W ') or a NHR ₃₁The base or

-one NR ₃₁R ₃₂, R wherein ₃₁And R ₃₂, identical or different, have to R respectively ₁And R ₂One of implication.

* R ₃₃-R ₃₅, identical or different, have to R respectively ₃, R ₄And R ₅One of implication.

* R ₃₃And R ₃₄, can form a methylene-dioxy or ethylenedioxy jointly equally, the carbon atom of these groups itself can be replaced by some low alkyl groups or halogen atom.

* R ₃₇Have to R ₇One of implication, but be limited to R ₇It or not a hydrogen atom.

* R ₃₈And R ₃₉, identical or different, can be a hydrogen atom or halogen atom, a low alkyl group, lower alkoxy, alkoxyl (rudimentary)-alkyl (rudimentary) or elementary alkoxy carbonyl, perhaps a cyano group.And, work as R ₃₇When being phenyl, R ₃₈Energy and the ortho position R that links to each other with pyridine nucleus ₃₇Carbon atom form a Y ₃-(CH ₂) n ₃Chain,

Y wherein ₃Be oxygen atom or sulphur atom or methylene and n ₃Be 0,1 or 2.

In formula (IV) compound, pay the utmost attention to the compound of following structural formula: R wherein ₃₃-R ₃₅, identical or different, be a hydrogen atom or halogen atom (having one at least in these three groups is not hydrogen atom or halogen atom), perhaps low alkyl group, a lower alkoxy, or low alkyl group sulfo-.

In belonging to formula of the present invention (I) compound, make us interested especially the 4th subclass and constituted by the formula with following characteristics (V) derivative:

-Z ₄Representative:

* halogen atom, or

* OW ₄Group 9 is W wherein ₄Have one of implication to W '), a NHR ₄₁Base or NR ₄₁R ₄₂Base, wherein R ₄₁And R ₄₂, identical or different, have respectively

Give R ₁And R ₂One of implication.

* R ₄₃, R ₄₄, R ₄₅, identical or different, have to R respectively ₃, R ₄, R ₅One of implication.

* R ₄₇Have to R ₇One of implication, but be not hydrogen atom.

* R ₄₉Can be a hydrogen atom or a low alkyl group.

In formula (V) derivative, following structural compounds is for paying the utmost attention to:

* Z ₄Be an OW ₄Group (W wherein ₄Have to one of W ' implication), a NHR ₄₁Base or a NR ₄₁R ₄₂Base, wherein R ₄₁And R ₄₂Be low alkyl group, i.e. R ₄₁And R ₄₂Comprise maximum 6 carbon atoms altogether, perhaps form a morpholino or thiomorpholine generation jointly.

* R ₄₃-R ₄₅, identical or different, be hydrogen atom or halogen atom, a low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₄₉It is a hydrogen atom.

Product the 5th subclass by formula (I) is made of formula (VI) product, wherein:

* Z ₅Represent a halogen atom or an OW group (W ₅Have one of implication to W '),

Perhaps NHR ₅₁Base or a NR ₅₁R ₅₂Base, wherein R ₅₁And R ₅₂, identical or different, have to R respectively ₁And R ₂One of implication.

* R ₅₃, R ₅₄, R ₅₅, identical or different, have to R respectively ₇, R ₄, R ₅One of implication.

* R ₅₃And R ₅₄Can form methylene-dioxy or ethylenedioxy jointly equally, the carbon atom of these groups itself can be replaced by some low alkyl groups or halogen atom.

* R ₅₆And R ₅₇Have to R ₆And R ₇One of implication, but be limited to R ₆And R ₇Can not be a hydrogen atom simultaneously.

* R ₅₉Can be hydrogen or halogen atom, a low alkyl group, a hydroxyl, lower alkoxy, or low-grade alkoxy alkyl, these groups can be by halo.

In formula (VI) compound, top-priority compound, R in its formula ₅₃-R ₅₅, identical or different, be a hydrogen atom or halogen atom, or a low alkyl group, a lower alkoxy, or a low alkyl group sulfo-.

R ₅₉Be a hydrogen atom or a low alkyl group.

Product the 6th subclass according to general formula (I) is made of formula (VII) product, wherein:

* Z ₆Representative:

-one halogen atom,

-one OW ₆Group (W wherein ₆Have one of implication to W ') NHR ₆₁Base or a NR ₆₁R ₆₂Base, wherein R ₆₁And R ₆₂, identical or different, have to R respectively ₁And R ₂One of implication.

* K ₆₆In a substituted nitrogen atom-N(R ₆₆)-, or-N-, or sulphur atom or oxygen atom, or an alternate c atoms=C(R ₆₆)-.

* K ₆₇Be a sulphur atom or oxygen atom, or a substituted nitrogen atom-N(R ₆₇)-, or-N=, or alternate c atoms=C(R ₆₇)-, but K ₆₆And K ₆₇Can not be simultaneously-N(R ₆₆)-and-N(R ₆₇)-.

* K ₆₁₀Be a substituted nitrogen atom-N(R ₆₁₀)-, or-N=, or sulphur atom or oxygen atom, or an alternate c atoms=C(R ₆₁₀)-, but K ₆₁₀And K ₆₇Can not be simultaneously-N(R ₆₁₀) and N(R ₆₇)-.

* R ₆₃-R ₆₅, identical or different, have to R ₃, R ₄, R ₅One of implication.

* R ₆₆, R ₆₇And R ₆₁₀, identical or different, have to R respectively ₆, R ₇, R ₁₀One of implication.

In formula (VIII) derivative, pay the utmost attention to the compound of following characteristics:

* Z ₆Be an OW ₆Group (W wherein ₆Have to one of W ' implication), a NHR ₆₁Base or a NR ₆₁R ₆₂Base, wherein R ₆₁And R ₆₂Comprise maximum 6 carbon atoms altogether, perhaps form a morpholino or thiomorpholine generation jointly.

* K ₆₆Be the nitrogen-atoms-N(R of a replacement ₆₆)-.

* K ₆₇Be a nitrogen-atoms-N=or an alternate c atoms=C(R ₆₇).

* K ₆₁₀Be a carbon atom=CH-.

* R ₆₃, R ₆₄, R ₆₅, identical or different, be a hydrogen atom or halogen atom, perhaps low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₆₆And R ₆₇Be a hydrogen atom, an alkyl, phenyl, the benzene alkyl that may be replaced by halogen or haloalkyl, but R ₆₆And R ₆₇Can not be a hydrogen atom simultaneously.

Making us interested especially according to derivative of the present invention is, as intermediate and because the antimycotic character of their brilliances, especially agriculturally, and as the synthetic intermediate of derivative, especially other derivatives of formula (I).

(a) compound and formula (I b) compound, other all is a preferred compound of the present invention to I except following formula.

* (I product a), wherein Y is an oxygen atom to formula, simultaneously K ₈And K ₉Or-CH=, perhaps one of them is-N-, another is-CH=, and while K ₆And K ₇Common form a unsaturated carbocyclic, and be connected to and comprise K ₁₀The ring with 5 chain links.

* the product of formula (I b), wherein Y is an oxygen atom, simultaneously K ₁₀Be O, S or SO or SO ₂Or NR ₁₀(R ₁₀Have the above implication that provides), or CH ₂Or CO, and while K ₆And K ₇Common form a unsaturated carbocyclic, and be connected to and comprise K ₁₀The ring with 5 chain links.

The preparation method:

Can be prepared with SOME METHODS according to derivative of the present invention.

The preparation of following narrative (II) compound.

According to first method (method A), it is specially adapted to formula (II) compound, wherein K ₁₁₀Be-O--S-or NR ₁₁₀, be raw material with the benzophenone of a molecular formula (XII '), at XII ' middle R ₁₃-R ₁₉Implication (comprise top-priority implication) as hereinbefore, and A ₁Be a commutable halogen atom (, or paying the utmost attention to chlorine or fluorine) or a nitro as bromine, with XII ' and the derivative of a following molecular formula react: H-K ₁₁₀-CH ₂-CO-Z ₁, K wherein ₁₁₀And Z ₁Have aforementioned identical meanings, pass through A ₁Displacement and cyclisation and obtain the derivative of formula (II).

This reaction is preferably in alcohol solvent (for example low-level chain triacontanol) at corresponding alkanoate (CH for example ₃ONa, C ₂H ₅Na, C ₃H ₇ONa) or a kind of organic base, as preferably selecting a tertiary amine (triethylamine), or a kind of inorganic base,, under existing, carbonate or bicarbonate (these inorganic bases are derivatives of alkali metal such as sodium, potassium or calcium or alkaline earth metal) carry out as hydroxide.

Reaction equally can be in a non-proton dipolar nature solvent such as methyl-sulfoxide in the presence of above alkali, dimethyl formamide, and N,N-dimethylacetamide, N-methyl-pyrrolidones, or carry out in the hexamethylphosphorictriamide etc.

Formula (in II ") the derivative example, methods availalbe G is translated into formula (II ') derivative, promptly according to following formula with II " and excess amine HNR ₁₁R ₁₂In 100-200 ℃ of heating, perhaps carry out ∷ adding to depress sometimes

（Ⅱ″）HNR ₁₁R ₁₂→Ⅱ′+W ₁OH

(when W was a hydrogen atom in the II "), these derivatives at first carried out the activation of (functional acid), can be at II ' and amine HNR in formula ₁₁R ₁₂Use thionyl chloride (SOCl before the reaction ₂), phosphoryl chloride phosphorus oxychloride (POCl ₃), trichlorine or five phosphorous oxide (PCl ₃PCl ₅), dicyclohexyl carbodiimide, diimidazole base phosphinylidyne, reagent such as ethyl chloroformate or trifluoroacetic anhydride are handled in oxolane (THF) or chlorinated solvent (especially aliphatic series or aromatic hydrocarbon) in 0-50 ℃, and are preferably in excess amine HNR ₁R ₁₂, or a kind of inorganic or organic base (as triethylamine) reacts under existing.

Set out by formula (II ') derivative, might come other derivatives of preparation formula (II ') with modified with functional group method classical in the organic chemistry.

As preparing nitro substitutive derivative (R in formula (II) ₁₆Or R ₁₇Or R ₁₈Or R ₁₉Be NO ₂) example in, it can be reduced into amination derivative (method B), used reductant such as metal (iron, tin) or its esters (as stannic chloride) are in inorganic acid (HCl, H ₂SO ₄) or organic acid (ethanol or carboxylic acid, especially an acetate) medium in reduce.As reductant, also can use hydrogen (will pressurize sometimes) equally, or its precursor (sodium borohydride, formic acid derivates, cyclic ethylene) reduces in the presence of transition metal as palladium.In this case, preferably adopt ethyl acetate, acetate or alcohol (as ethanol) as solvent.

Resulting amination derivative (R in the formula (II) ₁₆Or R ₁₇Or R ₁₈Or R ₁₉Be NH ₂) can itself stand acidylate (method C) or diazo-reaction.Anti-ization of acidylate is that nationality helps carboxylic acid derivates (acyl chlorides or acid anhydrides) at organic base (triethylamine; pyridine) or inorganic base (alkali-metal hydroxide; carbonate or bicarbonate) exist down in aprotic solvent such as chlorinated solvent (carrene, chloroform) or aromatic hydrocarbons (benzene, toluene) or aliphatic ether (ether, oxolane; 1,2-dimethoxy-ethane) carries out in.

Diazotising (method D) reaction promptly uses alkali-metal nitrite (natrium nitrosum) to handle a kind of amination derivative (R in the formula (II) under-10-15 ℃ temperature ₁₆Or R ₁₇Or R ₁₈Or R ₁₉Be NH ₂) solution in a kind of strong inorganic acid (hydrochloric acid, bromine hydracid, sulfuric acid).The diazol that so obtains under 15 °-100 ℃ temperature in different reagent such as stannous chloride, cuprous bromide, potassium iodide, decompose under the existence such as cuprous oxide or ethyl sulfuration potassium xanthate, can obtain different derivatives respectively, promptly wherein amino by chlorine atom, bromine atoms, iodine atom, hydroxyl or sulfydryl are replaced.

In introducing the example of bromine atoms, can be with a boric acid R ₁₇B(OH) ₂Realize aryl coupling reaction (method E), wherein R ₁₇(these groups can be as R to can be a heterocycle or phenyl or a vinyl ₇Show in the definition and be substituted like that), can generate like this according to other derivatives of the present invention.

This reaction for Z ₁=OW ₁(W ₁=H or alkyl, or alkali metal) or and Z ₁=NR ₁₁R ₁₂Compound can realize too.

As catalyzer, can utilize commercial palladium compound-four [triphenyl phasphine] to close palladium: Pd[P(C ₆H ₅) ₃] ₄, perhaps make raw material and make freshly by palladium salt such as palladium and a kind of phosphine such as triphenyl phasphine or 3-O-tolylphosphine.As alkali, can utilize a kind of as alkali-metal carbonate or bicarbonate (Na ₂CO ₃, NaHCO ₃) inorganic base, or a kind of organic base as amine (triethylamine).Reacting available a kind of inorganic base carries out in comprising the heterogeneous medium of an organic facies, this organic facies can be the solvent such as the benzene of a hydrocarbonaceous, or toluene, or high boiling point ether such as glyme or its higher derivative diethylene glycol dimethyl ether, triglyme, another is alkaline aqueous solution mutually.Equally, react also available organic base and carry out in equal phase medium in the presence of a solvent, this solvent is as dimethyl formamide or N-methyl-pyridine alkane ketone.Used boric acid can be commercial compound, perhaps uses a kind of Organometallic derivatives R ₁₇M ₁, R wherein ₁₇Has implication (M as the aforementioned ₁=Li or MgX, X=Cl is Br) with a boric acid alkyl ester B(OR ') ₃(R '=CH ₃, C ₂H ₅, C ₃H ₇, i-C ₃H ₇, C ₄H ₉) interact, according to Or-ganic Synthesis Coll Vol 4P.68 or J.Org.Chem.49, P5237-5243(1984) method of operating of Jie Shaoing is carried out acidic hydrolysis then.The proportioning of agents useful for same is as follows:

Boric acid R ₁₇B(OH) ₂: the 1.05-1.50 equivalent

Alkali: 4.00-6.00 equivalent

Catalyzer: 0.005-0.03 equivalent

Formula I " ' agent: 1.00 equivalents

Be reflected under 50-150 ℃ the temperature and carry out, preferably allow reaction mixture refluxed, the reaction time continues 2-48 hour.Formula (II " ') derivative separates with conventional method, extracts, or adds water and make in the reactant mixture and separate out solid, is recrystallized with a kind of suitable solvent then or carries out purifying with chromatography.

In another method (method F), i.e. the version of method D promptly heats under the temperature between 40 ℃ and the solvent boiling point, makes formula (II) compound (wherein, substituent R ₁₆-R ₁₉One of be unsubstituted amino, and Z ₁, R ₁₃-R ₁₅Implication as preceding showing) and a kind of nitrous acid low alkyl group such as nitrite tert-butyl react at a kind of solvent such as oxolane or dimethyl formamide, wherein amino to obtain a kind of formula (II) derivative, and Z by a hydrogen atom displacement ₁And R ₁₃-R ₁₉Has the implication as preceding showing.

Formula (XII ') derivative can react with Friedel-Crafts and prepare, as shown in the formula:

（Ⅻ″′）+（Ⅻ″）→（Ⅻ′）

A wherein ₁And R ₁₃-R ₁₉Have implication as preceding showing, compound (XII " ') and (XII ") know.

This is reflected at the lewis' acid (FeCl of catalytic amount or stoichiometric amount ₃, AlCl ₃, ZnCl ₂, SnCl ₄) exist down and carry out having under solvent or solvent-free (solvent such as nitrobenzene, aliphatic chlorinated solvent, the two sulfo-carbon).Reaction is carried out in-10-200 ℃ scope according to used experiment condition.

According to other method (method G), this method is suitable for the K of formula (II) compound-wherein especially ₁₁₀Be a C(R ₁₁₀) ₂Base, and R ₁₃-R ₁₉Have identical meanings (comprising the priority implication) as described above, can be with the benzophenone of a kind of formula (X XII ') (Z wherein ₁=OH, and R ₁₃-R ₁₉Have identical meanings as described above, comprise that the priority implication is also like this) and thionyl chloride (SOCl ₂), phosphoryl chloride phosphorus oxychloride (POCl ₃), phosphorus trichloride (PCl ₃) or phosphorus pentachloride (PCl ₅) react, to obtain a kind of benzophenone of formula (X XII '), wherein Z ₁=Cl, and R ₁₃-R ₁₉Has identical meanings as described above.

Generally, the compound that so obtains can not separate; The lower alkyl esters of it and malonic acid (preferably alkanoic acid magnesium, as magnesium ethylate) in the presence of alkali reacts.The formula that the so obtains (W of X XII ") compound-wherein ₁It is a low alkyl group, use the alkanoate of a kind of alkali such as alkali metal or alkaline earth metal then, or a kind of inorganic base such as alkali-metal hydroxide or carbonate are in water-based or alcohol medium, or at a kind of non-proton dipolar nature solvent such as methyl-sulfoxide, dimethyl formamide, react in N-methyl-pyrrolidones, to obtain a kind of formula (II) compound, wherein K ₁₁₀Be oxo group, and R wherein ₁₃-R ₁₉Have as aforesaid implication, and Z ₁Be an OW ₁Group, wherein W is a low alkyl group.

With this compound and excessive amine HNR ₁₁R ₁₂In that solvent or solvent-free heating under 100-200 ℃ are down arranged, need add sometimes and depress reaction, can obtain formula (II) compound, wherein K ₁₁₀Be oxo group, and R wherein ₁₃-R ₁₉Have following with aforesaid implication, and Z ₁Be to have determined NR ₁₁R ₁₂Base.This latter compound can as existing down in cerous chloride with sodium borohydride, react in a kind of alkanol such as ethanol with the reduction of suitable reductant, to obtain formula (II) compound, and K wherein ₁₁₀Be CH(OH) base, and Z ₁Be clear and definite NR ₁₁R ₁₂Base.

Back two class products can stand classical organic chemical reactions (for the first kind, by a kind of addition of organo-metallic compound; And for second class, by acidylate or alkylated reaction) make other derivatives of formula (II).

According to another kind of method (method H), the special fortune of this method should be in the K of formula (II) compound-wherein ₁₁₀Be C(R ₁₁₀) ₂Base, and R wherein ₁₃-R ₁₉Have as aforesaid implication (comprising top-priority implication), with the Z of a kind of derivative of formula (XX XII ')-wherein ₁Be an OW ₁Or NR ₁R ₂Base, the R of the benzyl halide of a formula (XX XII ')-wherein ₁₆-R ₁₁₀Have as aforesaid implication, and wherein Hal shows a halogen atom such as chlorine or bromine, interact.This is reflected at the alkanoate that a kind of alkali exists following-preferably a kind of alkali metal or alkaline earth metal, or in the presence of a kind of inorganic base such as alkali-metal hydroxide in the alkanol medium or at a kind of non-proton dipolar nature solvent such as methyl-sulfoxide, carry out in dimethyl formamide or the N-Methyl pyrrolidone, to obtain the formula (R of XX XII ") compound-wherein ₁₃-R ₁₉Have as aforesaid implication with Z.With organic acid or inorganic acid, being preferably polyphosphoric acid is having solvent (toluene, dimethylbenzene) or solvent-freely down above-claimed cpd is being handled under 0-150 ℃ of temperature, can obtain the K of a kind of formula (II) derivative-wherein ₁₁₀Be C(R ₁₁₀) ₂Base, and R ₁₃-R ₁₉Have as aforesaid implication.If Z ₁=OW ₁(W ₁Be low alkyl group or hydrogen atom) derivative obtained, then can be used on the classical technique of organic chemistry of introducing in the first method, be translated into Z ₁=NR ₁R ₂Derivative.

Be suitable for the K of formula (II) compound-wherein especially according to another ₁₁₀Be C(R ₁₁₀) ₂, and R wherein ₁₃-R ₁₉Have as the aforesaid implication method of (comprising top-priority implication) (method I, the just capitalization of i), can be with the Z of formula (XX XII ') derivative-wherein ₁Be OW ₁Base or NR ₁₁R ₁₂Base and one are by R ₁₆, R ₁₇, R ₁₈Or R ₁₉The benzaldehyde that replaces Deng group reacts.This is reflected in a kind of solvent and realizes, can be a kind of aromatic hydrocarbons or a kind of carboxylic acid exist next this catalyzer preferably two to replace amine such as piperidines at a kind of catalyzer with this solvent, thereby obtains the R of a kind of formula (XXX XII ') compound-wherein ₁₃-R ₁₅And Z ₁All have as aforesaid implication.This compound appropriate reductant as sodium borohydride, is reacted under the chlorination existence of having introduced in above second method then.The allyl alcohol of mentioning, with a catalytic amount be higher than the organic acid of stoichiometric amount or inorganic acid having under solvent (toluene, dimethylbenzene) or the condition of no solvent, under 0-150 ℃, handle, can cyclisation obtain the K of a formula (II) derivative-wherein ₁₁₀Be CH ₂, and R ₁₃-R ₁₉Have as aforesaid implication.If obtain Z ₁=OW ₁Derivative, W is low alkyl group or hydrogen atom, then can be used on the classical technique of organic chemistry of introducing in the first method and is translated into Z ₁=NR ₁R ₂Derivative.

Below introduce the preparation of formula (III) compound:

According to also belonging to a kind of method of the present invention, the preparation of formula (III) compound is by a boric acid R ₂₇B(OH) ₂[R wherein ₂₇Can be a heterocycle, (these groups can be substituted, as at R for phenyl or vinyl ₇Definition in indicated like that] and the bromo derivative of a formula (X III ') between the aryl coupling reaction finish, thereby other any substituting groups can not be bromine atoms or iodine atom simultaneously.This aryl coupling reaction formula is as follows:

This reaction is implemented in Z equally ₂=OW ₂(W ₂=H or alkyl, or alkali metal) and Z ₂=NR ₂₁R ₂₂Example.

As catalyzer, can use commercial palladium compound four [triphenyl phasphines] and close palladium: Pd[P(C ₆H ₅) ₃] ₄Or make raw material by a kind of palladium salt such as palladium and a kind of phosphorus such as triphenyl phasphine or 3-0-tolylphosphine and prepare freshly.As alkali, can use inorganic base such as alkali-metal carbonate and bicarbonate (Na ₂CO ₃, NaHCO ₃), or organic base such as amine (triethylamine).This reaction is carried out in the heterogeneous medium that contains an organic facies and an alkaline water with inorganic base, its organic facies can be a kind of hydrocarbon solvent such as benzene or toluene of containing, or high boiling point ether such as glyme or its higher derivative such as diethylene glycol dimethyl ether, triglyme.Carry out in the same equal phase medium of available a kind of organic base in the presence of a kind of solvent such as dimethyl formamide or N-Methyl pyrrolidone of this reaction.Used boric acid can be commercial prod or with a kind of Organometallic derivatives R ₂₇M ₂(R wherein ₂₇Have as aforesaid implication, M ₂-Li or MgX, X=Cl, Br) and a boric acid alkyl ester B(OR ') (R '=CH wherein ₃, C ₂H ₅, C ₃H ₇, i-C ₃H ₇, C ₄H ₉) react, then according to Org, Synth, Coll, Vol 4P.68 or J.Org.Chem.49.pp.5237-5243(1984) mode of operation narrated carries out acidic hydrolysis.The agents useful for same proportioning is as follows:

Boric acid R ₂₇B(OH) ₂: the 1.05-1.50 equivalent

Alkali: 4.00-6.00 equivalent

Catalyzer: 0.005-0.03 equivalent

Formula X III ' agent: 1.00 equivalents

Be reflected under 50-150 ℃ and carry out, best reaction mixture refluxed, time remaining 2-48 hour.Formula (III) derivative separates with conventional method, extracts, or water is added to product is precipitated out, and available then a kind of appropriate solvent is recrystallized or chromatography is come purifying.

The bromo derivative of formula (X III ') can (the heavy helium reaction of the amine of X III ") obtains with formula.

This reaction can be implemented in Z in the formula equally ₂=OW ₂(W ₂=H or alkyl) derivative, or Z in the formula ₂=NR ₂₁R ₂₂Derivative.By with amination derivative (X III ') at a kind of strong inorganic acid (sulfuric acid or bromine hydracid), also contain sometimes in the organic acid (acetate) with a kind of alkali metal ite (natrium nitrosum) and under-10-+10 ℃ temperature, handle and realization response.The heavy helium salt that so obtains decomposes in 5-90 ℃ in the presence of bromine hydracid and bromize alpha ketone.

Formula (X III ') product separates with conventional method, extracts or adds water in reactant mixture product to be precipitated out, and be recrystallized or chromatography is carried out purifying with a kind of suitable solvent.

Amine (the available formula A of X III ") ₂By R ₂₃, R ₂₄, R ₂₅Suitably the phenylboric acid of Qu Daiing and a kind of formula (halo (bromine or iodine) of X III ") (and prepare with the aryl coupling reaction before the derivative, as shown in the formula:

Wherein, group Z ₂, R ₂₆, R ₂₈And R ₂₉Have as aforesaid implication, but condition is R ₂₆, R ₂₈And R ₂₉Can not be a bromine atoms or iodine atom simultaneously, get and Hal represents a halogen atom, particularly bromine or iodine.

Reaction also is implemented in Z ₂=OW ₂(W ₂=H or alkyl/or alkali metal) and Z ₂=NR ₂₁R ₂₂Reaction condition is same as the aforementioned situation that carries out the transition to (III) from (X III ').

Amine (X III) can passing type (X III " ") contain also obtaining originally of nitro-derivative.

This reaction also can be implemented in Z ₂=OW ₂(W ₂=H or alkyl) derivative and Z ₂=NR ₂₁R ₂₂Derivative.As reductant, the salt (for example stannic chloride) that can use a kind of metal (for example iron, tin) or these metals is at inorganic acid (HCl, H ₂SO ₄) or organic acid (acetic acid) medium in react.Can use equally hydrogen as reductant (pressurization) possibly or its precursor (sodium borohydride, formic acid derivates, cyclohexene) in the presence of a kind of transition metal such as palladium or platinum.In this example, the most handy Methane Carboxylic Acid solvent, acetic acid or alcohol as ethanol as solvent.Formula (X III " ') product separates with conventional method.Extract or add water and make in the reactant liquor and separate out precipitation, and available a kind of suitable solvent is recrystallized or carries out purifying with chromatography.The derivative of formula (X III " ') type is a known compound.

(compound of III ") and (X III ') is if obtain wherein Z for formula ₂=OW ₂Derivative, might be translated into Z with the technology of modified with functional group classical in the organic chemistry ₂=NR ₂₁R ₂₂Derivative.Therefore, work as Z ₂Be OW ₂(W ₂=alkyl), might under 100-200 ℃ of temperature, (pressurize possibly) and a kind of excess amine HNR ₂₁R ₂₂Add thermal response and be converted into Z ₂=NR ₂₁R ₂₂Derivative, as shown in the formula:

Compound (III ') has CO-OW ₂The compound (III) of base+

HNR ₂₁R ₂₂-→ compound (III ') [has CO-NR ₂₁R ₂₂The compound (III) of base]+W ₂OH

From formula (III "), (X III ') or (the X III " initial (Z wherein of the compound of ") ₂Equal OW ₂, W ₂=alkyl), can obtain Z in the formula equally ₂Equal OM ₂(M wherein ₂Be a kind of alkali metal) compound, promptly by a kind of and saponification inorganic base, inorganic base such as soda alcohol or alcoholic potash.These compounds can obtain (III), (X III ') or (X III " ") (Z respectively with a kind of inorganic acid example hydrochloric acid, sulfuric acid treatment ₂=OH) derivative.

From Z wherein ₂The formula of=OH (III), the derivative of (X III ') or (X III " ") is initial can to obtain wherein Z equally ₂=NR ₂₁R ₂₂Compound, promptly with thionyl chloride (SOCl ₂), phosphoryl chloride phosphorus oxychloride (POCl ₃), phosphorus trichloride (PCl ₃), or phosphorus pentachloride (PCl ₅) dicyclohexyl carbodiimide, diimidazole base phosphinylidyne is after alkyl chloroformate or trifluoroacetic anhydride activate carboxylic-acid functional and amine HNR ₂₁R ₂₂In the presence of organic or inorganic alkali in a kind of organic solvent as reacting among chloro or aromatic solvent or the etherificate THF.

The preparation of following narrative (IV) compound:

The preparation of formula (IV) compound, for example the cyclisation of passing type (X IV ') derivative realizes

Ar wherein ₃Be that (group of X IV ") that is to say by R a formula ₃₃, R ₃₄And R ₃₅The phenyl that replaces, and Z ₃, R ₃₃-R ₃₉Have as aforesaid implication, this is reflected in the acid medium provides the body existence to be undertaken by heating down in a kind of ammonia.

The midbody derivant of formula (X IV ') is to belong to noval chemical compound of the present invention.It can prepare according to a kind of method, and this method is characterised in that 3-acetone and a kind of benzoyl acetate of suitable replacement or the reaction of acetamide in the presence of a kind of strong inorganic base and a kind of solvent.As shown in the formula:

Z wherein ₃With R ₃₃-R ₃₉Has the middle identical meanings of formula (X IV) as described above, T ₃Appointment is that a leaving group is as a halogen atom or quaternary ammonium.

Work as T ₃Be under the situation of a quaternary ammonium, can be with a kind of Mannich alkali derivant, promptly a kind of formula:

R ₃₇The derivative of-CO-CH-CH-N+I and a kind of formula

R ₃₈R ₃₉

Ar ₃-CO-CH ₂-CO-Z ₃Derivative reacts under a ferment kind solvent exists in alkaline medium.

These derivatives of the latter are known.

Formula (IV) derivative (Z wherein ₃Be the OH base, formula (IV ") derivative, wherein W just ₃=H), also can be according to so that (IV ") formula ester (W wherein ₃Be low alkyl group) saponification is that the method for feature makes through acidifying then.

At last, can be with formula (IV ") derivative (W ₃=low alkyl group) is converted into (IV ') formula derivative (Z wherein ₃Be NR ₃₁R ₃₂), promptly, as illustrated in the past, then these sour halogenations are become corresponding acyl halide, again with formula HNR by saponification ₃₁R ₃₂Amine (R wherein ₃₁And R ₃₂Have as aforesaid implication) react and get.

The preparation of following narrative (V) product:

According to first method, can be with as shown in the formula (the ketenes of X V ")

Z ₄CO

Ar ₄

Ar wherein ₄Has formula (X V ")

R ₄₃, R ₄₄, R ₄₅, R ₄₉And Z ₄Have with the formula V in identical meanings

X is the amidine of a dialkyl group (rudimentary)-amino or alkoxyl (rudimentary) and a kind of following formula

R ₄₇-C=NH or its salt

NH ₂

R ₄₇-C＝N ⁺H ₂

NH ₂Anion ^-

(R wherein ₄₇Have as aforesaid implication), in the presence of a kind of solvent, in alkaline medium, react.This reaction is preferably in organic solvent, be preferably alcohol solvent example methyl alcohol, ethanol, propyl alcohol, and at corresponding alcoholates or a kind of organic base such as amine, be preferably tertiary amine, or the hydroxide of a kind of inorganic base such as metal, alkaline earth metal, carbonate or bicarbonate such as sodium salt, sylvite or calcium salt carry out under existing.This reaction can be carried out under above-mentioned inorganic base exists in water equally.In the example of formula (V ') derivative, that is to say (V) formula compound, wherein Z ₄Be a NR as former clear and definite implication ₄₁R ₄₂, can be with a kind of formula (V ") derivative, just formula (V) derivative (Z wherein ₄Be OW ₄Group was as in the past clear and definite) and a kind of formula HNR ₄₁R ₄₂Amine react, and lose W ₄OH.As formula (W in the V ") ₄When being an oxygen atom, these derivatives are at first used dicyclohexyl carbodiimide, diimidazole base carboxylic acyl, oxygen Ethyl formate and trifluoro acid anhydrides, thionyl chloride (SOCl ₂), phosphoryl chloride phosphorus oxychloride (POCl ₃), phosphorus trichloride (PCl ₃) or phosphorus pentachloride (PCl ₅) wait reagent to activate functional acid, use amine HNR then ₄₁R ₄₂In the presence of a kind of organic base, see among solvent (especially a kind of hydro carbons) or a kind of ether such as the THF in a kind of organic solvent such as chlorinated solvent or virtue and to react.

Initial from formula (V ') derivative, by modified with functional group technology classical in the organic chemistry, might other derivatives of preparation formula (V ').

Formula (X V ') derivative can be according to preparing as the method, is about to formula (X V " ') derivative:

(Ar wherein ₄, R ₄₃, R ₄₄And R ₄₅And Z ₄Have as aforesaid implication) and a kind of formula (X V) derivative

（ⅩⅤ″″）

(R wherein ₄₉And X ₄Have as aforesaid implication, R ₄₁₀Be a low alkyl group) one react.

Second kind of preparation method, R therein according to preparation formula (V) derivative ₄₇Not under the situation of an alkyl or benzyl-sulfinyl or sulfonyl, can be a kind of formula (XX V ') derivative (R wherein ₄₃-R ₄₅, R ₄₉And Z ₄Have as aforesaid implication, and A ₄Be alkyl (rudimentary) sulfonyl or benzyl sulfonyl] and a kind of formula R ₄₇H(is R wherein ₄₇Be and R ₇Identical meanings is arranged, just at R ₄₇The middle valency chain that connects a hydrogen atom can connect a hetero atom such as O, Sn or HR equally ₄₇

This has been reflected in solvent and the alkaline medium and has carried out, and is preferably in proton or the aprotic solvent, and at hydroxide, carbonate, the bicarbonate of a kind of organic or inorganic alkali such as alkali metal or alkaline earth metal, for example there are reaction down in its sodium, potassium or calcium salt.

Some formulas (XX V ') but the oxidation reaction of derivative passing type (V) derivative makes (R in (V) ₄₇Be a low alkyl group sulfo-or dibenzylsulfide generation), promptly by means of a kind of oxidant, for example hydrogen peroxide and some are crossed (oxygen) acid as peracetic acid, ask chlorine benzylhydroperoxide or the adjacent magnesium formate of mistake.

The preparation of following narrative (VI) compound:

According to this method, with the 2-alkene benzophenone and a kind of β-carbonyl ester or the acid amides of a kind of formula (X VI), promptly formula is R ₅₉-CO-CH ₂-COZ ₅, R wherein ₅₃-R ₅₇And Z ₅Have as aforesaid implication, in the presence of a kind of organic or inorganic alkali, the barium monoxide of for example using partial dehydration reacts (Michael reaction) in temperature range between 0 ℃ and the solvent for use boiling point in low-level chain triacontanol such as ethanol.Gained formula (the R of X VI ") compound-wherein ₅₃-R ₅₉And Z ₅Have as aforesaid implication, in the carboxylic acid medium, be preferably acetate, and provide (as ammonia or a kind of organic or inorganic ammonium salt) in the presence of the body reagent, simply heat down until solvent refluxing, thereby cyclization takes place in 40 ℃ at a kind of ammonia.Thereby obtain a kind of formula (compound of V ") or (VI '), wherein R ₅₃-R ₅₉Have as aforesaid implication, and Z ₅Dividing in addition is OW ₅And NR ₅₁R ₅₂

If formula (VI) derivative is obtained, the vitochemical classical technology of introducing in the then available previous method is translated into formula (VI ') derivative.

The preparation of following narrative (VII) compound:

According to the compound of formula (VII), altogether middle K ₆₆Be O, K ₆₇Be-C(R ₆₇)=and K ₄₇Be-C(R ₆₇)=, by β. γ-dicarbapentaborane ester or acid amides (formula X VII ') be by in alcohol or carboxylic acid such as acetate, in catalytic amount (0,1-5%) strong acid (inorganic or organic acid, for example hydrochloric acid and sulfuric acid) exist down, 40-120 ℃ of down simple heating and cyclisation prepares, this reaction be according to KRAFF and DAAL at Chem.Ber, 21, p3053(1888) in and TREBAUL and TESTE at Bull, Soch, chim, Fr.p2272(1970) conventional method of middle narration.

By the compound of formula (VII), altogether middle K ₆₆Be NR ₆₆, K ₆₇Be-C(R ₆₇)=K ₆₁₀Be-C(R ₆₁₀)=, can be by β. and γ-dicarbapentaborane acid amides or ester (formula X VII ') are initial, by in acid medium, in a kind of formula NHR ₆₆Amine (R ₆₆Have as aforesaid implication) there is heating down and cyclisation makes.As solvent, can utilize a kind of carboxylic acid such as acetate, it brings into play catalyst action simultaneously.The strong inorganic acid that also can add catalytic amount, for example hydrochloric acid or sulfuric acid.Be reflected between the boiling point of 40 ° and solvent for use and carry out under the temperature.

, obtain product and have formula (VII), wherein K with under the situation of ammonia in reaction ₆₆Be NH, K ₆₇Be-C(R ₆₇)=, K ₆₁₀Be-C(R ₆₁₀)=.This compound can be with a kind of halo derivatives R ₆₆Hal, wherein Hal is a halogen (can be a chlorine atom bromine atoms or iodine atom), in a kind of solvent such as methyl-sulfoxide, reacts in dimethyl formamide or the N-Methyl pyrrolidone in the presence of inorganic or organic base, to obtain the derivative of a kind of formula (VII), wherein K ₆₆Be NR ₆₆, K ₆₇Be-C(R ₆₇)=, and K ₆₁₀Be-C(R ₆₁₀)=.

The dicarbapentaborane ester class and the amide-type of formula (X VII ') can be according to preparing as the method, and this method is characterised in that a kind of formula (X VII ') halogenated ketone (may be by R ₆₇) and R ₆₁₀The base replace) and a kind of benzoyl acetate or acetamide of suitable replacement react by following formula:

Ar wherein ₆Be a formula ((X VII " ') group, that is to say by R ₆₃, R ₆₄And R ₆₅The phenyl that replaces, wherein Z ₆And R ₆₃-R ₆₁₀All have as aforesaid implication, Hal represents that a leaving group is as a halogen atom.

By the compound of formula (VII), wherein K ₆₆Be-N=or-N(R ₆₆)-and K ₆₇Be-N=or-N(R ₆₇)-, condition is K ₆₆And K ₆₇Can not be simultaneously-N(R ₆₆)-and N(R ₆₇)-, it can be by the ketenes of a kind of formula (XX VII ') and a hydrazine reaction and make Ar in (XX VII ') ₆Be a formula (X VII ') group, that is to say one by R ₆₃, R ₆₄And R ₆₅The phenyl that is replaced; Z ₆, R ₆₁₀Have as aforesaid implication, and X is dialkyl group (rudimentary) amino or alkoxyl, and this hydrazine may be at most by a R ₆₆Base replaces.

Ar ₆（ⅩⅩⅦ′）

Be reflected in a kind of alkanol such as the ethanol, under a kind of inorganic or organic base such as triethylamine exist, carry out.

At R ₆₆Be in the situation of low alkyl group or rudimentary aralkyl, might obtain two kinds of position isomers: formula (VII ') and (VII ") wherein is respectively: K ₆₆Be-N=and K ₆₇Be-N-(R ₆₇)-or K ₆₆Be-N(R ₆₆)-and K ₆₇Be-N=that the latter generally is a primary product.

The ketenes that is used as initiation material is that the method according to aforementioned preparation formula (V) compound prepares.

For the compound of all formulas (VII), if Z wherein ₆=OW ₆Derivative be made, then might use in the organic chemistry classical modified with functional group technology and be translated into Z in the formula ₆=NR ₆₁R ₆₂Derivative.Therefore, work as Z ₆Be OW ₆, wherein during the W=low alkyl group, might be down and a kind of excessive amine HNR at 100-200 ℃ ₆₁R ₆₂Add thermal response, perhaps need pressurize sometimes, be translated into Z ₆=NR ₆₁R ₆₂Derivative.

By (VII) compound (Z wherein ₆Be the O-alkyl) initial, can make Z in the formula equally ₆Be OM ₆(M wherein ₆Be an alkali metal) compound, promptly carry out saponification and get with a kind of inorganic base such as soda alcohol liquid or alcoholic potash.This compound can generate Z with inorganic acid example hydrochloric acid or sulfuric acid treatment ₆The derivative of=OH (VII).

By Z ₆The formula of=OH (VII) derivative is initial, can obtain Z equally ₆Be NR ₆₁R ₆₂Compound, promptly with thionyl chloride (SOCl ₂), p chloromethylbenzoic acid (POCl ₃), phosphorus trichloride (PCl ₃) or phosphorus pentachloride (PCl ₅), dicyclohexyl carbodiimide, diimidazole base phosphinylidyne is after reagent such as alkyl chloroformate or trifluoroacetic anhydride activate carboxylic-acid functional and amine HNR ₆₁R ₆₂In the presence of a kind of organic or inorganic alkali, in a kind of organic solvent such as chloro or aromatic solvent (especially being a kind of hydrocarbon) or a kind of ether such as THF, react.

The example that following non-limited way provides has illustrated the present invention, and shows how they implement.

Compound structure is determined with nuclear magnetic resonance spectrometry in these different examples.

In these examples, we used following liquid slightly symbol: PF be fusing point ℃.If a product does not provide the logP value, then this product is a chemical intermediate, and is not useful product concerning the plant anti-fungal infection.

Example 101-170 relates to a series of products of formula (II) subclass.

Example 101:2-(4-morpholino carbonyl)-and 5-iodo-3-(3, the 4-dimethoxy phenyl) benzothiophene-(method D; Compound n ° 101)

In 100ml round bottom alkane burns, add the 1.47g(0.0037 mole) the 2-(4-morpholino carbonyl)-5-amino-3-(3, the 4-dimethoxy phenyl) benzothiophene, 10ml distilled water and the 1.0ml98% concentrated sulfuric acid.Make reaction mixture temperature remain on below 50 ℃ simultaneously or, add a kind of 0.27g(0.0039 of containing mole more gradually at 50 ℃) solution of natrium nitrosum in 5ml water.Stirred 1 hour, and reactant mixture poured into contained 10ml water and 0.65g(0.0039 mole then) in the solution of potassium iodide.The mixture that so obtains slowly is heated to 60 ℃, and kept 1 hour in this temperature.After the cooling, reactant mixture extracts with 3 * 50ml methane dioxide; Organic facies washes with water, and is dry on magnesium sulfate, and boils off solvent.Use the silica gel column chromatography purifying, can get the 0.9g2-(4-morpholino carbonyl)-5-iodo-3-(3, the 4-Dimethoxyphenyl) benzothiophene, 214 ℃ of (yields 48% of fusing point; Compound n ° 101).

Example 102:2-(4-morpholino carbonyl)-5-(4-chloro-benzamido)-3-(3, the 4-dimethoxy phenyl) benzothiophene-(method C, compound n ° 102):

In the 100ml round-bottomed flask, add the 2.0g(0.005 mole in succession) the 2-(4-morpholino carbonyl)-5-amino-3-(3, the 4-dimethoxy phenyl) benzothiophene, 50ml carrene, 0.74ml(0.0052 mole) triethylamine and 0.70ml(0.0052 mole) 4-chloro-chlorobenzoyl chloride.Stirred 1 hour at 20 ℃, boil off solvent, wash with water,, use the solid of 20ml washed with dichloromethane gained then in air drying.Obtain 1.0g(37%) the 2-(4-morpholino carbonyl)-5-(4-chloro-benzamido)-3-(3, the 4-dimethoxy phenyl) benzothiophene, 247 ℃ of fusing points (compound n ° 102).

Example 103:2-(4-morpholino carbonyl)-and 5-amino-3-(3, the 4-dimethoxy phenyl) benzothiophene-(method B; Compound n103):

In the 250ml round-bottomed flask, add the 10.7g(0.025 mole in succession) the 2-(4-morpholino carbonyl)-5-nitro-3-(3, the 4-dimethoxy phenyl) benzothiophene, 100ml absolute ethyl alcohol, 3ml concentrated hydrochloric acid and 4.2g(0.075 mole) iron powder.Reaction mixture refluxed 2 hours, cooling then is to the 200ml saturated sodium bicarbonate solution.After extracting with 6 * 100ml ethyl acetate, organic facies is dry on anhydrous magnesium sulfate, filters, boil off solvent, obtain the 9.2g2-(4-morpholinyl carbonyl)-5-amino-3-(3, the 4-dimethoxy phenyl) benzothiophene, yield 92%, 213 ℃ of fusing points (compound n ° 103).

Example 104:2-(4-morpholino carbonyl)-and 5-nitro-3-(3, the 4-dimethoxy phenyl) benzothiophene-(method A, compound n104):

In a round-bottomed flask, add the 9.0g(0.0056 mole in succession), α sulfydryl acetyl morphine, 13.8 gram (0.1 mole) potash, 14.8 gram (0.046 mole) 2-chloro-3 ', 4 '-dimethoxy-5-nitro benzophenone and 200ml ethanol.Mixture under agitation added hot reflux 2 hours, was as cold as room temperature then; Pour in 1 premium on currency; Yellow mercury oxide filtrate with separating out washes with water, and is dry under air flow then.So obtain the 2-(4-morpholino carbonyl of 18.1 grams (92%))-5-nitro-3-(3, the 4-dimethoxy phenyl) benzothiophene, molten point is 144.5 ℃ (compound n ° 104).

Example 105:2-(4-morpholino carbonyl)-5-(propylene-2-yl)-3-(3, the 4-dimethoxy phenyl)-benzothiophene (method E; Compound n ° 105).

In a round-bottomed flask, under inert atmosphere, add 2.0 gram (0.005 mole) 2-(4-morpholino carbonyls in succession)-5-bromo-3-(3, the 4-dimethoxy phenyl)-benzothiophene (press A method preparation), 50ml1, the 2-dimethoxy-ethane, 0.2 gram four [triphen phosphorus] closes palladium, 0.5 gram (0.006 mole) propylene-2-ylboronic acid and 20cm ³The 2M aqueous sodium carbonate.Mixture refluxed 8 hours, poured into then in the mixture of water and ice.By the cream-coloured product of precipitation gained, separate after filtration, wash with water and the air drying, obtain n ° of 105 compounds of 1.5 grams (yield 81.5%), 135 ℃ of fusing points through the silicic acid chromatographic purifying.

Example 106:2-(4-morpholino carbonyl)-and the 3-(4-anisyl) benzothiophene (method F; Compound n ° 106).

In a round-bottomed flask, add down 1.0 gram (0.0027 mole) 5-amino-2-(4-morpholino carbonyls in inert atmosphere)-the 3-(4-anisyl) oxolane of benzothiophene and 50ml distillation.Mixture adds hot reflux, drips the 0.7ml(0.0054 mole then) nitrite tert-butyl is dissolved in the solution among the 20mlTHF.After three hours, the reactant mixture water treatment is extracted with CHCl, washes with water and drying on magnesium sulfate.After boiling off solvent and chromatography, separable n106 compound, 131 ℃ of fusing points to 0.5 gram (yield 53%).

Example 107:2-(N, the N-diethylformamide)-3-(3, the 4-Dimethoxyphenyl) benzothiophene (method G; Compound n107).

In a round-bottomed flask, add 25 gram (0.08 mole) 3-(3, the 4-dimethoxy phenyl) benzothiophene-3-carboxylic acid (preparing) according to method D, 300ml1,2-dichloroethane, 12ml(0.16 mole) thionyl chloride and 1mlDMF.Mixture slowly is added to backflow; Solid fuses gradually, obtains a kind of solution of yellow transparent.After 4 hours, boil off solvent, obtain 24.7 grams (yield 96%), 2-(chloroformyl base)-3-(3, the 4-dimethoxy phenyl) benzothiophene.

2.5 this product of gram (0.0075 mole), immediately and 4cm ³(0.0375 mole) N, N dimethylamine is reacted in 100mlTHF, after extracting, can obtain 2.5 gram (yield 90%) 2-(N with water treatment and ethyl acetate, the N-diethylformamide)-3-(3, the 4-dimethoxy phenyl) benzothiophene, separate out crystallization with pentane development, 113 ℃ of fusing points, compound n ° 107.

Example 108:3-(3, the 4-dimethoxy phenyl)-2-ethoxy carbonyl indenone (method G):

A) 25 gram thionyl chlorides are added to 15 gram 2-(7.4-dimethoxy benzoyls) in the benzoic acid, then in 50 ℃ of heating, up to gas discharge stop till.Reaction adds some toluene after finishing, and evaporation is to remove excessive SOCl ₂The gained acyl chlorides is a kind of orange solids.

B) the enol magnesium of this acyl chlorides and excessive slightly malonic ester reacts (above-mentioned magnesium salts is made by malonic ester and magnesium ethylate) in toluene.Reaction mixture poured in the dilute acid extract with ethyl acetate.Wash with water and drying after, boil off solvent and obtain a kind of reddish oil, it can be used for the next step.

C) above gained reddish oil and 300ml5% sodium carbonate liquor added hot reflux 35 minutes.It forms a kind of red solid, and through cooling, the water-yielding stratum that inclines adds 300ml water again, reheats and refluxes 35 minutes.Filter cold back, washes drying with water, can obtain the indenone of red solid, 130 ℃ of fusing points, yield 49%(compound n ° 108).

Example 109:3-(3, the 4-dimethoxy phenyl)-2-morpholino carbonyl indenone:

0.9 gram was heated 1 hour by example 108 gained indenones and 10ml morpholine.Reactant mixture is poured in the dilute hydrochloric acid solution, extracted with ethyl acetate then, wash with water, concentrate.Obtain the product (71.5 ℃ of fusing points) of yield 98%, compound n ° 109.

Example 110:1-(3, the 4-dimethoxy phenyl)-2-morpholino carbonyl-3-hydroxyl indenes:

0.5 gram indenone of example 100 gained is with 0.05 gram NaBH ₄Reduce in 20ml methyl alcohol with 0.5 gram cerium chloride.Be reflected at end in 10 minutes, reactant mixture is poured in the water.Be adjusted to pH5 with dilute hydrochloric acid, and extract with ethyl acetate.Wash with water, boil off solvent, obtain 0.49 gram indenols, 134 ℃ of (yield 99%) compound n of fusing point ° 110).

Example 111:2-morpholino carbonyl-3-(3, the 4-dimethoxy phenyl)-6-methoxyl group indenes (method H):

A) make 0.8 gram sodium metal and the reaction of 100ml absolute ethyl alcohol in a reactor, add 10 grams 3 then, 4-dimethoxy benzoyl acetyl morphine also stirred 15 minutes.Yet add 0.3 gram 3-methoxyl group Bian chlorine.Refluxed 1.5 hours, and concentrated reaction mixture under reduced pressure.Water and dilute hydrochloric acid are handled, and extract with ethyl acetate, obtain an orange oil.

B) 53 gram polyphosphoric acid are added in the above-mentioned 5.1 gram oil, and 70 ℃ of heating 6 hours.Water is added in the reaction mixture, stirs, extract with ethyl acetate then until dissolving.By chromatographic purifying (eluant, eluent: ethyl acetate).Yield 25%, 115 ℃ of fusing points (compound n ° 111).

Example 112:2-morpholino carbonyl-3-(3, the 4-dimethoxy phenyl)-5,6-methoxyl group indenes (method I):

A) with 3,4-(dimethoxy benzoyl)-acetyl morphine and veratraldehyde carry out condensation in the presence of piperidines and aceticanhydride in acetum.Be heated to 100 ℃, pour in the water, extract, wash organic facies with saturated potassium carbonate with Methane Carboxylic Acid.By the silicic acid chromatographic purifying, eluant, eluent is 10/90 mixture of pentane/ethyl acetate, obtains a kind of fusing point and be 150 ℃ red solid.

B) yet, Acetolon reduces in methyl alcohol in the presence of cerium chloride with NaBH.Thereby obtain the allyl alcohol (110 ℃ of fusing points) of 83% yield.

C) in 80ml toluene, put into 2.2 allyl alcohols that obtain previously of gram and the p-methyl benzenesulfonic acid of catalytic amount, added hot reflux 5 hours, remove the water that in reaction, generates simultaneously.Pour in the water.Inclining, and with the washing of rare saleratus, washes with water again, can obtain the shallow maroon powder of 1.9 grams (compound n ° 112).

Following compound is to utilize one of aforesaid method to prepare.Their structure and physicochemical property and preparation method are all indicated in the following table I.

In addition, this form is also classified the structure and the character of the product of example 101-112.These compounds have formula (II) structure, wherein R ₁₅Be H, NR ₁₁R ₁₂It is a 4-morpholino.

The K of passing type (62) ₁₁₀, R ₁₃, R ₁₄, R ₁₆, R ₁₇, R ₁₈And R ₁₉In following table, provide structure.(the table I is seen the literary composition back)

In addition, the table II is also sorted out the structure and the physicochemical property of formula II compound, wherein K ₁₁₀Be a sulphur atom, R ₁₃And R ₁₄Be methoxyl group, R ₁₅, R ₁₆, R ₁₈And R ₁₉Be a hydrogen atom, R ₁₇And NR ₁₁R ₁₂As show as indicated in the II.These compounds prepare according to method G.(the table II is seen the literary composition back)

Example 171-184:2-chloro-3 ', 4 '-dimethoxy-5-nitro-benzophenone [is the intermediate of preparation formula (II) product, wherein K ₁₁₀Be O, S or W(R ₁₁₀)].

In a round-bottomed flask, add 11g(0.05 gram mole in succession) 2-chloro-5-nitro-chlorobenzoyl chloride, 20ml(0.15 restrains mole) 1,2-dimethoxy benzene and 0.5g anhydrous ferric chloride.Reactant mixture is heated to 150 ℃ gradually, keeps 1 hour.After cooling, reactant mixture is poured among the 200ml1NHCl, use 3 * 200ml carrene to extract then.After the sodium bicarbonate washing, organic facies is at MgSO ₄Last dry, concentrating under reduced pressure obtains brown oil then.Separable with 300ml pentane development back to 12.5g(yield 78%) 2-chloro-3 ', 4 '-dimethoxy-5-nitro-benzophenone, be beige solid, fusing point is 138 ℃ (compound n ° 171).

Other compounds can obtain under conditions of similarity: during their structures and physicochemical property institute show afterwards.These compounds are formula (XII ') product, wherein R ₁₅Be H, R ₁₄Be methoxyl group, and A ₁, R ₁₃, R ₁₆, R ₁₇, R ₁₈And R ₁₉Have and implication that following table (III) indicates.

* example 201-253 relates to the subclass derivative of formula (III).

Example 201:2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl)-1-morpholino carbonyl benzene:

In the 100ml round-bottomed flask, add the 1.6g(0.00454 mole) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) benzoic acid (compound 204), 50ml oxolane and 0.92g(0.0057 mole) diimidazole base phosphinylidyne.Stirred 2 hours at 20 ℃, add the 1ml(0.013 mole then) morpholine, stir maintenance down 6 hours.To 150ml distilled water, will separate out solid filtering, use the 100ml water washing, then the air drying to reactant mixture.So obtain 1.3g(yield 68.4%) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl)-1-morpholino carbonyl benzene, be white solid, 153 ℃ of fusing points (compound 201).

With obtain compound 201-231 with quadrat method.These compounds are formula (III) structure, wherein R ₂₃And R ₂₄Be methoxyl group, R ₂₅, R ₂₈And R ₂₉Be hydrogen atom, R ₂₆, R ₂₇And Z ₂Have with the implication of showing (IV), (IV ') expression later on.

Other subclass products have formula (III) structure, wherein R ₂₃And R ₂₄The common methylene-dioxy of forming a divalence, R ₂₅, R ₂₆, R ₂₈And R ₂₉Be hydrogen atom, and R ₂₇And Z ₂Have with showing the implication that (V) provides later on.(table III, IV, V are seen the literary composition back)

Example 232:2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl)-benzoic acid (compound 232):

In a 100ml round-bottomed flask, add the 2.8g(0.074 mole) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) ethyl benzoate, 50ml absolute ethyl alcohol and 2ml10N soda.Mixture refluxed 2 hours, poured into then in the 150ml1N hydrochloric acid.To separate out solid and filter by sand core funnel, and wash with water, then the air drying can obtain 2.1g(yield 80%) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) benzoic acid, be white solid, 210 ℃ of fusing points.

Example 233:2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) ethyl benzoate (compound 233):

In the 250ml three-neck flask, add 30ml 1 of argon-degassed, the 2-dimethoxy-ethane, add the 3.65g(0.010 mole again) 4-bromo-2-(3, the 4-dimethoxy phenyl)-ethyl benzoate (compound 209), 0.1g four [triphenyl phasphines] close palladium, the 1.7g(0.012 mole) 4-fluorophenyl-boric acid and 20ml2M sodium carbonate.After refluxing in 8 hours, reactant mixture is poured in the 100ml distilled water.Use 2 * 100ml carrene to extract then, with the 100ml water washing once, dry on magnesium sulfate, and, boil off solvent by the separation of silicic acid layer, and obtain 3.4g(yield 89.5%) 2-(3, the 4-dimethoxy phenyl)-and the 4-(4-fluorophenyl) ethyl benzoate, 127 ℃ of fusing points (compound 233).With with quadrat method preparation formula (III) compound, wherein R ₂₃And R ₂₄Be methoxyl group, and R ₂₅, R ₂₆, R ₂₈, R ₂₉It is hydrogen atom; R ₂₇And Z ₂Has the implication that shows as later table (VI).(the table VI is seen the literary composition back)

Can make formula (III) compound equally, wherein R ₂₃And R ₂₄A common divalent group methylene-dioxy, the R of forming ₂₅, R ₂₆, R ₂₈And R ₂₉Be hydrogen atom, and R ₂₇And Z ₂Has the implication that shows as the following table VII.(the table VII is seen the literary composition back)

Example 250:4-bromo-2-(3,4-dimethoxy phenyl) ethyl benzoate (compound n ° 250):

In the 100ml three-neck flask, add the 20.0g(0.066 mole) 4-amino-2-(3, the 4-dimethoxy phenyl)-ethyl benzoate (compound 252) and 200ml acetate.After dissolving, add 60ml47% bromine hydracid, be cooled to 0 ℃, add 150ml distilled water then.Slowly adding the 4.6g10.066 mole) natrium nitrosum is dissolved in the solution of 30ml water.Stirred 1 hour at 0-5 ℃ again, then mixture is poured into a kind of cuprous bromide (0.066 mole, the 9.5g) solution in 100ml47% bromine hydracid.Reactant mixture is heated to 65 ℃, lasts 1 hour, is poured in the water then.The precipitation that leaching generates washes with water, and then the air drying can obtain 18.4g(yield 76.3%) 4-bromo-2-(3, the 4-dimethoxy phenyl) ethyl benzoate, 53 ℃ of fusing points (compound 350).

Availablely be equipped with formula (III) compound, wherein R with the quadrat method manufacturing ₂₃, R ₂₄Be methoxyl group, R ₂₅, R ₂₆, R ₂₈, R ₂₉It is hydrogen atom; Z ₂Has implication described later, R ₂₇It is bromine atoms.

Compound N ° Z ₂R ₂₇Fusing point ℃

250 OC ₂H ₅Br 53

251 OH Br 181.5

Example 252:4-amino-2-(3, the 4-dimethoxy phenyl) ethyl benzoate (compound 252):

In the 500ml round-bottomed flask, add 200ml1,2-dimethoxy-1,2-ethane, 17g(0.07 mole) 4-amino-2-bromo-ethyl benzoate (compound 218), 0.3g four [triphenyl phasphines] closes palladium and 100ml2M sodium carbonate.After refluxing boiling in 8 hours, reactant mixture is poured in the 600ml water.Filter, wash with water, the air drying obtains solid, again with obtaining 20.0g(yield 95% after the washing of 50ml pentane) 4-amino-2-(3, the 4-dimethoxy phenyl) ethyl benzoate, fusing point is 127 ℃ (compounds 252).

With obtaining (III) product, wherein R with quadrat method ₂₃, R ₂₄Be methoxyl group, R ₂₅, R ₂₈And R ₂₉It is hydrogen atom; Z ₂, R ₂₇And R ₂₆Have implication as shown in the table:

Compound N ° Z ₂R ₂₇R ₂₆Fusing point ℃

252 OC ₂H ₅NH ₂H 127

253 OH H NO ₂182

Example 254:4-amino-2-bromo-ethyl benzoate (compound 254):

In the 1000ml round-bottomed flask, add the 46g(0.17 mole in succession) 2-bromo-4-nitro-ethyl benzoate, 250ml ethanol, 28g(0.5 mole) iron powder and 20ml concentrated hydrochloric acid.This mixture refluxed 4 hours.After cooling, the Sodium bicarbonate saturated solution of reactant mixture 500ml is handled, and extracts with 5 * 300ml ethyl acetate.After drying on the magnesium sulfate, filter and boil off solvent, separable to 35.2g(yield 86%) 4-amino-2-bromo-ethyl benzoate, 93 ℃ of fusing points (compound n ° 254).

Example 301-399 and 3100-3119 be the preparation of Ming Dynasty style (IV) compound specifically.

Example 301:N-(2-(3, the 4-dimethoxy phenyl)-6-phenyl nicotinoyl base)-morpholine (compound 301) (method b):

At 25-30 ℃, dropwise with the 1.8g(0.002 mole) morpholine is added to a kind of 0.9g(0.005 mole) 2-(3, the 4-dimethoxy phenyl)-solution of 6-phenyl-nicotinoyl chlorine (compound 2) in 60mlTHF.When dripping at the beginning, promptly separate out hydrochloride.After adding, stirred again 10 minutes, with 200ml ethyl acetate dilute reaction solution.With this reactant liquor of 2 * 100ml water washing.This solution is dry on anhydrous magnesium sulfate, under reduced pressure concentrates then, obtains a kind of oil, and it separates out crystallization in ether.After filtration and drying, obtain 1.9g cream-coloured powder (yield 95%), 185.5 ℃ of fusing points.

Example 304-308:2-(3, the 4-dimethoxy phenyl)-6-phenyl-nicotinoyl chlorine (compound 302):

With the 1.8g(0.0054 mole) 2-(3, the 4-dimethoxy phenyl)-the mixture ebuillition of heated of 6-phenyl-nicotinic acid (compound 303) and 20ml thionyl chloride refluxed 1 hour.Concentrating under reduced pressure obtains 1.9g(yield 100%) yellow sweet shape thing.

So operation can obtain the nicotinoyl chlorine derivative of formula (IV " '), wherein Z ₃Be the chlorine atom, R ₂₇₁Has the following implication that shows.

Compound N ° R ₃₇₁PF ℃

304 H honey shape

305 Cl 114

306 F 114

307 Br 106

308 CN 160

Example 303 and 310-313:2-(3,4-dimethoxy phenyl)-6-phenyl-nicotinic acid (compound n ° 303).

The 2ml30% soda is added to a kind of 3.6g(0.01 mole) 2-(3, the 4-dimethoxy phenyl)-solution of 6-phenyl-ethyl nicotinate (compound 309) in 100ml95% ethanol.This medium was heated 2 hours at 60-70 ℃.Behind the concentrating under reduced pressure residue is dissolved in the 100ml water.With this medium of 2ml concentrated hydrochloric acid acidifying: jelly is separated out.Extract with the 100ml ethyl acetate.This solution is with 2 * 100ml water washing, and dry on anhydrous magnesium sulfate, the dope that reduces pressure then can obtain a kind of meringue shape thing, can separate out crystallization with the development of 50ml ether.After filtration, drying can get 2.5g(yield 75%) cream-coloured powdered product, 178 ℃ of fusing points.With with the quadrat method operation, can get formula (IV ' ") compound, wherein Z ₃Be hydroxyl, R ₃₆₁Has the following implication that shows.

Compound N ° R ₃₇₁Fusing point ℃

303 H 178

310 Cl 145

311 F 170

312 Br 162

313 CN 163

Example 309 and 315-317:2-(3, the 4-dimethoxy phenyl)-6-phenyl-ethyl nicotinate (compound 309): method a ':

With a kind of 7.7g(0.02 mole) 2-(3,4-dimethoxy benzoyl)-5-oxo group-5-phenyl-pentanoic acid ethyl ester (compound 314), 3.1g(0.04 mole) mixture of ammonium acetate and 30ml acetic acid added hot reflux 4 hours.Reactant liquor is poured in the 300ml water: a kind of oil becomes granular solids.This thing extracts with the 200ml ethyl acetate.Organic solution is with 3 * 100ml water washing, and dry on anhydrous magnesium sulfate then, concentrating under reduced pressure obtains 4.5g shallow brown oil (yield 62%), is 2-(3, the 4-dimethoxy phenyl)-6-phenyl-ethyl nicotinate.

With getting formula (IV ' " with the quadrat method operation) compound, wherein Z ₃Be ethyoxyl, and R ₃₇₁Have following implication:

Compound N ° R ₃₇₁Physical characteristic

315 phenyl honey shape

316 4-chlorphenyls honey shape

317 4-fluorophenyls honey shape index of refraction 1.611

Example 318-320:

Operate according to as above routine method,, can obtain with following formula (IV " ') compound, wherein Z by means of the corresponding intermediate of suitable replacement ₃=ethyoxyl:

Compound N ° R physical characteristic

318 4-bromophenyls honey shape

118 ℃ of 319 4-hydrogen base phenyl fusing points

320 4-thienyls honey shape

Example 321-344:2-(3,4-dimethoxy benzoyl)-5-oxo group-5-phenyl-pentanoic acid ethyl ester (compound 314):

The 8.4g(0.05 mole) 3-chloro-phenyl ethyl ketone is added to a kind of 13.7g(0.05 mole) in the sodium salt of (3,4-dimethoxy benzoyl)-ethyl acetate: reaction is heat release, and medium temperature slowly is elevated to 35 ℃ from 24 ℃.Under agitation react 3/4 hour (about room temperature).Reactant liquor is poured in the 400ml water; Product is separated out agglutination, this thing 300ml chloroform extraction.

Chloroformic solution is with 5 * 200ml water washing, and is dry on anhydrous magnesium sulfate then, concentrates under the decompression, obtains the brown sweet shape thing of 19.5g.After in being dissolved in 100ml ether, product is separated out crystallization.After sediment filtration and filtration cakes torrefaction, obtain 15g(yield 77%) cream-coloured powdered product, 70 ℃ of fusing points are 2-(3,4-dimethoxy benzoyl)-5-oxo group-5-phenyl-pentanoic acid ethyl ester.

With with the quadrat method operation, can obtain similar compound: (3, the 4-dimethoxy phenyl) as structural formula in the following table

(the table VIII is seen the literary composition back)

Example 345:N-[5-(4-chlorophenyl)-and 2-(3,4-dimethoxy benzoyl)-5-nicotinoyl base] morpholine (for compound 345) (method a):

With the 46g(0.1 mole) the N-[5-(4-chlorophenyl)-2-(3,4-dimethoxy benzoyl)-5-oxo group-valeryl] morpholine (compound 346) and 15.4g(0.2 mole) ammonium acetate is dissolved in the 150ml acetic acid.Ebuillition of heated refluxed 4 hours, simultaneously bubbling bubbling air stream in reactant liquor.Cool to room temperature, reactant liquor is poured in 0.5 premium on currency: a kind of colloid is separated out.Extract with the 200ml carrene, wash this dichloromethane solution with water, use this solution of charcoal treatment then.Obtain a kind of brown sweet shape thing after concentrating, development makes it separate out crystallization in the 200ml ether, filters, and washs this filter cake with ether, and drying under reduced pressure can get the 21.2g cream-coloured powder then, 152 ℃ of yields 48% of fusing point).

Example 345-394:

With with example 345(method a) and 301(method b) one of the method for operating of method, initial from suitable replacement intermediate, can obtain formula (IV " ") derivative, its substituting group is shown in method therefor and physical constant can see the following form.

The morpholino group that replaces is by the oxygen atom Base Serial Number, free valency chain azine atom.Asterisk represents that this compound is a kind of synthetic intermediate.(the table IX is seen the literary composition back)

Example 3110-3119:

According to the method for operating of example 345 (method a), initial by the intermediate of suitable replacement, can obtain formula (IV ') derivative, wherein NR ₃₁R ₃₂Be a morpholino, R ₃₁Implication with and the normal thing of physics of product all see the following form: (the table X is seen the literary composition back)

Example 401-458 is the preparation of Ming Dynasty style (V) compound and derivative thereof specifically.

Example 401:3-(3, the 4-dimethoxy phenyl)-3-bridging oxygen-2-(dimethylamino methylene)-ethyl propionate (compound 401):

In reactor, add 20g3,4-dimethoxy benzoyl-ethyl acetate, 80ml toluene and 20g dimethyl formamide-dimethylacetal.Added hot reflux 2 hours, room temperature is placed and is spent the night.Boil off solvent and excessive reagent.Product is by purification by silica gel column chromatography (eluant, eluent: ethyl acetate), obtain the yellow sweet shape thing of 74% yield.

Example 402:1-(3, the 4-dimethoxy phenyl)-3-dimethylamino-2-morpholino carbonyl-propenone (compound 402):

In reactor, put into 20g3,4-dimethoxy benzoyl-acetate morpholine, 28g dimethyl formamide-dimethylacetal and 20ml dimethyl formamide.60 ℃ of heating 7 hours, room temperature was placed and is spent the night.Reactant liquor to water, is filtered the solid of being separated out and can obtain a kind of yellow solid, 156.8 ℃ of fusing points, yield 84%.

Example 403: with method in the example 401 and 402, but initial, can obtain the derivative of formula (X V '), wherein Ar with the centre of suitable replacement ₄Have as aforementioned implication, and R wherein ₄₃And R ₄₄Be methoxyl group, R ₄₅And R ₄₉Be hydrogen atom, X ₄And Z ₄As shown in the table:

Compound N ° X ₄Z ₄Feature

403 NMe ₂NMe honey shape

404 NMe ₂NEt ₂The honey shape

Example 405:5-carbethoxyl group-2(4-chloro-phenyl)-and 4-(3, the 4-dimethoxy phenyl)-pyrimidine (compound 405):

In reactor, put into 20ml absolute ethyl alcohol and 0.3g sodium.After dissolving, add the iodine hydrohalogenic acid salt of 3.7g4-chloro-benzenecarboximidamide, added hot reflux 1 hour, add enamine ketone 4.06g synthetic in the example 401 again, added hot reflux again 2.5 hours.Boil off solvent, wash the precipitation of gained with water, drying can get the 4.2g white solid, 115.4 ℃ of fusing points.

Example 406:5-carboxyl-2-(4-chlorophenyl)-and 2-(3, the 4-dimethoxy phenyl)-pyrimidine (compound N ° 406):

Product (3.3g) by example 404 gained is dissolved in the 100ml ethanol, handles with the 2ml10N soda again, heats these mixtures 1 hour at 80 ℃, boils off solvent, and the water dissolved residue is used the HCl acidifying again.Obtain yellow mercury oxide, filter, wash yield 95%, 258.1 ℃ of fusing points with water.

Example 407:2-(4-chlorphenyl)-and 4-(3, the 4-dimethoxy phenyl)-5-morpholino carbonyl-pyrimidine (compound N ° 407):

The acid and the 35ml thionyl chloride of 1.5g gained in example 406 were heated 1.5 hours in 75 ℃.Concentrate, add carrene again, and boil off solvent (, so can obtain orange solids) again to remove excess reagent fully.

Above-mentioned acyl chlorides is dissolved in the 100ml ether, is cooled to 0 ℃, drip 0.9g morpholine and the solution of 0.4g pyridine in the 40ml ether.After adding, at room temperature stirred 1.5 hours.Reactant liquor to water, is used extracted by ether, dry on magnesium sulfate, concentrate.After with the ether recrystallization, can get the 1g solid, 168 ℃ of fusing points (yield 48%).

Example 408:2-(3, the 4-dichlorophenyl)-4-(3, the 4-dimethoxy phenyl)-5-morpholino carbonyl-pyrimidine (compound 408):

In reactor, put into 10ml absolute ethyl alcohol and 0.1g sodium, be stirred to dissolving, add 1.35g3 again, the benzene sulfonate of 4-two chloro-benzenecarboximidamides.60 ℃ of heating 30 minutes, be added in the enamine ketone and the 15ml absolute ethyl alcohol of preparation in the example 402 again.Added hot reflux 5 hours.Filter, wash the gained solid with cold ethanol with pentane, drying can get the solid (83% yield) of 181 ℃ of a kind of fusing points.

Press the operation of example 405-408 respectively, but initial by the suitable replacement intermediate of difference, can get formula (V) derivative, wherein R ₄₃-R ₄₄Be methoxyl group, R ₄₅And R ₄₉It is hydrogen atom; Z ₄And R ₄₇Has implication as shown in the table.(the table XI is seen the literary composition back)

Example 423:4-(3, the 4-Dimethoxyphenyl)-2-methyl mercapto-5-morpholino carbonyl-pyrimidine (compound 423):

In reactor, get 6.6gKOH and be dissolved in 60ml water, add the sulphate of 16.3gS-methyl isothiourea again, add the enamine ketone that 13.6g synthesizes then immediately in example 402.Refluxing after 1.5 hours forms precipitation, and leaching washes with water, and drying can get the solid of 58% yield, 151 ℃ of fusing points.

Example 432:4-(3, the 4-Dimethoxyphenyl)-2-methylsulfonyl-5-morpholino carbonyl-pyrimidine (compound 432):

In the 10ml carrene, dissolving 9.5g adds the 11g metachloroperbenzoic acid by the pyrimidine of example 432 gained in 0 ℃ of gradation.At room temperature stirred 2.5 hours.Destroy excessive peracid with bisulfites, again with the bicarbonate solution washing, detergent with dried over mgso after, boil off solvent, obtain the 9.9g white solid, 77 ℃ of fusing points.

Example 433:4-(3, the 4-Dimethoxyphenyl)-2-(4-methyl-phenoxy group)-5-morpholino carbonyl-pyrimidine (compound 433):

In reactor, put into the 10ml acetonitrile, 0.5g potash, the pyrimidine of 2.7g paracresol and 1g gained in example 432, and three TDA-1[three (3, the 6-dioxaheptyl) amine] as catalyzer.Heated 1 hour down at 65 ℃, boil off solvent.Again add water, extract with ether, dry on magnesium sulfate, boil off solvent, can get white solid, yield 75%, 152 ℃ of fusing points.

Adopt the method for operating of example 423,432 and 433 respectively, but utilize the intermediate of suitable replacement, can make formula (V) derivative, wherein R ₄₃-R ₄₄Be methoxyl group, R ₄₅And R ₄₇Be hydrogen atom, Z ₁And R ₄₇Has implication such shown in the following table.

(the table XII is seen the literary composition back)

Example 501:2-acetyl group-3-(3,4-dimethoxy phenyl)-preparation of 5-phenyl-5-oxo group-ethyl valerate (compound 501).

With the 26.8g(0.1 mole) 3,4-dimethoxy-chalcone (m, p-(CH ₃O) C ₆H ₃-CH=CHCO-C ₆H ₅) and the 13.09(0.1 mole) ethyl acetoacetate is dissolved in the 300ml ethanol, adds 1g active oxidation barium, stirred 20 hours down at 20 ℃.Leaching oxidation valerate precipitation is used washing with alcohol, drying, can get 27g(receive 68%) compound 501,135 ℃ of fusing points.

Example 502:4-(3, the 4-dimethoxy phenyl)-2-methyl-6-phenyl-ethyl nicotinate (compound 502):

With the 20g(0.05 mole) compound 501, the 7.7g(0.1 mole) the mixture ebuillition of heated of ammonium acetate and 80ml acetic acid refluxed 5 hours.Boil off solvent, residue is dissolved in the 200ml carrene again,, wash with water again with the sodium bicarbonate aqueous solution washing.Concentrate, drying is used the silica gel column chromatography purifying, can get the 8.5g beige solid, 82 ℃ of fusing points (yield 45%, compound 502).

Example 503:4-(3,4-dimethoxy phenyl)-preparation (compound 503) of 2-methyl-6-phenyl-nicotinic acid:

With the 10ml10N soda aqueous solution and a kind of 8.4g(0.022 mole) the mixture ebuillition of heated of the solution of n ° of 502 compounds in 100ml ethanol refluxed 30 hours.Concentrate back water dissolving, acidifying is extracted with ethyl acetate, and drying concentrates, and can get 4.7g(yield 61%) n ° 503 compounds, 208 ℃ of fusing points.

Example 504:4-(3,4-dimethoxy phenyl)-preparation of 2-methyl-6-phenyl-nicotinoyl chlorine (compound 504)

With the 3.5g(0.01 mole) n ° 503 compounds and 20ml thionyl chloride mix the back ebuillition of heated and refluxed 1 hour.Concentrate.N ° 504, product, be orange red crystallization, yield 100%, fusing point: 140 ℃.

Example 505:N-[4-(3, the 4-dimethoxy phenyl)-2-methyl-6-phenyl-nicotinoyl base] morpholine (compound 505)

This relates to formula (VI) product, wherein R ₅₉=methyl, Z ₅=morpholino, R ₅₃=R ₅₄=methoxyl group, R ₅₅=R ₅₆=H, R ₅₇=C ₆H ₅

At a kind of 1.2g(0.033 mole) n ° 503 compounds put and add the 2ml morpholine in the solution in the 50ml chloroform.In 20 ℃ of stirrings 3 hours, wash with water, concentrate; Make it separate out crystallization with ether, heavy getting, drying can get 0.9gn ° of 505 compounds (white powder; Yield 65%), 176 ℃ of fusing points, logP=3.8

Example 506-507: compound 506 and 507 is to prepare by example 505, and just morpholine is respectively by CH ₃-NH-C ₂H ₅And CH ₃-NH-CH ₂-CH ₂-OCH ₃Replace.The fusing point of compound 506 is 76 ℃ (logP=4.2), and compound 507 is a kind of sweet shape things (logP=4.0).

Example 601:2-(3,4-dimethoxy phenyl)-preparation of 5-phenyl-3-furancarboxylic acid ethyl ester:

With the 10g(0.027 mole)-2(3,4-dimethylbenzoyl-4-phenyl)-4-oxo group-ethyl butyrate and 2.75g(0.027 mole) aceticanhydride, the mixture of 2 concentrated sulfuric acids and 50ml acetic acid added hot reflux 12 hours.Reactant liquor is poured in the 500ml water, extract product with the 300ml ethyl acetate, with potassium-containing hydrogen salt solution washing organic facies, with the pure water washing, dry on anhydrous magnesium sulfate then.Concentrating under reduced pressure can get a jelly, can separate out crystallization when it is developed with the 50ml heptane.Leaching, drying can get 6.5g(yield 68%) the expection product, be cream-coloured powder.68 ℃ of fusing points (compound n ° 601).

Example 602:2-(3, the 4-dimethoxy phenyl)-6-phenyl-3-furancarboxylic acid:

To contain the 5g(0.0142 mole) compound of example 601, the mixture of 6ml10N soda and 100ml ethanol added hot reflux 1 hour.The concentrating under reduced pressure reactant liquor is dissolved in residue in the 100ml water, is acidified to pH=4 with the concentrated hydrochloric acid adding and separates out white solid.The leaching precipitation washes with water, in decompression down, and at dehydrating agent P ₂O ₅There is down dry this product.Obtain 4.3g(yield 93%) the expection product, be white powder, 177 ℃ of fusing points (compound n ° 602).

Example 603:2-(3, the 4-dimethoxy phenyl)-6-phenyl-3-furoyl chloride;

The product of 2.8g example 2 and the mixture of 20ml thionyl chloride were added hot reflux 45 minutes, the concentrating under reduced pressure reactant liquor: green solid method crystallization, the 3g(quantitative yield) product, 14 ℃ of fusing points (compound n ° 603).

Example 604:2-(3, the 4-dimethoxy phenyl)-5-phenyl-N-ethyl-N-methyl-3-furoylamide:

With the 1.51g(4.4 mM) example 603 gained acyl chlorides are dissolved among the 20mlTHF, stir to add the 0.59g(10 mM down) Methylethyl amine: the hydrochloride of separating out amine immediately.Stirred 1/4 hour down in normal temperature, this hydrochloride of leaching, filtrate concentrates.Sweet shape residue 100ml chloroform extraction.Wash this chloroformic solution with water, make product crystallization in the mixed solvent of diisopropyl ether and heptane after concentrating.In the leaching crystallization, after the drying, can obtain 0.6g(yield 37%) expecting compound, be cream-coloured powder, 74 ℃ of fusing points (compound 604).

Example 605:N-[4-(3, the 4-dimethoxy phenyl)-the 6-(4-fluorophenyl)-the 3-furoyl] morpholine:

To contain the 1g(2.3 mM) N-[2-(3, the 4-dimethylbenzoyl)-the 4-(4-fluorophenyl)-4-oxo group-bytyry] morpholine, the mixture of 20ml ethanol and 1ml concentrated hydrochloric acid added hot reflux 30 hours.Reactant liquor is poured in the 200ml water, used the 150ml chloroform extraction, wash chloroform layer solution with water, concentrate chloroformic solution, make product separate out crystallization with 20ml ether development residue.After leaching and drying, can get 0.8g(yield 83%) the expection product, be white powder, 168 ℃ of fusing points (compound 605).

Example 606:2-(3,4-dimethoxy phenyl)-the 5-(4-fluorophenyl)-the 3-(morpholino carbonyl)-preparation of pyridine:

With the 5g(11.6 mM)-N-[2-(3; 4-dimethoxy benzoyl)-the 4(4-fluorophenyl)-4-oxo group-bytyry] morpholine, 1.8g(23.2 mM) mixture of ammonium acetate and 30ml acetic acid added hot reflux 12 hours; reactant liquor is poured in the 30ml water; extract product with the 200ml ethyl acetate; with potassium-containing hydrogen salt solution washing organic facies; the back is with the pure water washing, and is dry on anhydrous magnesium sulfate.Concentrate the back and residue (product) be recrystallized, can get 1.4g(yield 28% with 300ml toluene) the expection product, be yellow powder, 190 ℃ of fusing points (compound 606).

Example 607:5-(4-fluorophenyl)-and 2-(3, the 4-dimethoxy phenyl)-1-methyl-3-(morpholino carbonyl)-pyrroles:

With the 0.72g(0.023 mole) single methylamine; 5g(0.00115 N-[2-(3 mole); 4-dimethoxy phenyl benzoyl)-the 4-(4-phenyl)-4-oxo group-bytyry] morpholine is dissolved in the 30ml acetate, and reactant liquor added hot reflux 10 hours, poured into then in the 300ml water.Product extracts with the 200ml ethyl acetate.Organic solution earlier with bicarbonate, after wash with water.Dry on magnesium sulfate then, concentrate again: can get a kind of maroon solid, in ether, behind the recrystallization, obtain 1.3g expection product (yield 26%), 148 ℃ of fusing points (compound 607).

Example 608:2-(4-chlorophenyl)-and 3(3, the 4-Dimethoxyphenyl)-4-(morpholino phenyl)-pyrazoles:

In reactor, add 2.5g1-(3, the 4-dimethoxy phenyl)-the 3-(dimethylamino)-2-morpholino carbonyl-propenone (example 402), 2.1g4-chlorphenyl hydrazonium salt hydrochlorate, 1.2g triethylamine and 100ml ethanol added hot reflux 8 hours 30 minutes.Boil off solvent, residue is poured in the water, after extracting with ethyl acetate, dry on sodium sulphate, concentrate, in that (eluant, eluent is ethyl acetate/heptane: 90/10) after filtered through silica gel, can obtain the 2.1g yellow solid, 125 ℃ of (yield 60%) (compounds 608) of fusing point:

Example 609:4-carbethoxyl group-2-(4-oxygen phenyl)-and 3-(3, the 4-dimethoxy phenyl)-pyrazoles:

In reactor, put into 2.5g3-(3, the 4-dimethoxy phenyl)-3-oxo group-2-(dimethylaminomethylene)-ethyl propionate (example 401), 1.49g4-chlorphenyl hydrazonium salt hydrochlorate, 0.82g triethylamine and 100ml ethanol added hot reflux 8 hours.After boiling off solvent residue is poured in the water, extracted with ethyl acetate, boil off solvent after drying on the sodium sulphate, can get 3g maroon solid (yield 95%) (compound 609), it can be not purified directly by being used for the next step.

Example 610:4-carboxyl-2-(4-chlorphenyl)-and 3-(3, the 4-Dimethoxyphenyl)-pyrazoles:

The ester of gained is placed in the reactor that contains 150ml ethanol in example 609, handles with 1.01g86% particle potash, adds hot reflux 4 hours, boils off solvent, and residue is poured in the water, is acidified to pH=1 with the 1N hydrochloric acid solution.The precipitation of solvent is washed with water by leaching, uses heptane wash then, can get 2.6g maroon powder (93.5%) (compound 610), can not purifiedly be directly used in the next step.

Example 611:4-(N-methyl-N-ethyl-amino carbonyl)-the 2-(4-chlorphenyl)-3-(3, the 4-dimethoxy phenyl)-pyrazoles:

Sour 2.6g and 50ml75% thionyl chloride that example 610 is made heated 8 hours.Extract with carrene again, concentrate.Gained oil (1.4g) is dissolved in the 30ml carrene, is cooled to 3 ℃, adds 0.54gN-methyl-N-ethylamine and 0.3g pyridine, the 30ml carrene, and holding temperature is lower than 5 ℃.At room temperature stirred 6 hours 20 minutes.Reactant liquor is poured in the water, extracted with carrene, dry back concentrates on sodium sulphate, can get the orange sediment of 1.2g, 110 ℃ of (yield 82.2%) (compounds 611) of fusing point.

Example 612:4-(N, N-diethylamino carbonyl)-2-(4-chlorination phenyl)-3-(3, the 4-Dimethoxyphenyl) pyrazoles:

The method of operating of utilizing example 611 to introduce, and utilize diethylamine and get.Yield 80% gets a kind of orange sweet shape thing (compound 612).

Example 613:1-benzyl 3-(3, the 4-dimethoxy phenyl)-the 4-morpholino carbonyl)-pyrazoles:

Utilize same operation method in the example 608, adopt the benzyl hydrazine hydrochloride to prepare, obtain the yellow oil (compound n ° 613) of 22.8% yield, obtain normal desired isomer (45.7%) in addition.

Example 614:1-(4-bromobenzyl)-and 3-(3, the 4-dimethoxy phenyl)-the 4-(morpholino carbonyl)-pyrazoles:

In reactor, put into 0.9g3-(3, the 4-dimethoxy phenyl)-the 4-(morpholino carbonyl)-pyrazoles (utilize the method for operating of example 608, adopt hydrazine hydrate to make), 0.7g4-bromobenzyl 0.4g potash and 70mlDMF(dimethyl formamide), this mixture was heated 5.5 hours in 75 ℃, after answer liquid to pour in the water, extract drying with ethyl acetate, concentrate, after silicic acid filters, separable to 0.6g(yield 43.5%) sediment, 122 ℃ of fusing points (compound 614).

Utilize example 601-614 to operate like that respectively, but initial, can obtain the derivative of formula (VII), wherein R by the intermediate of suitable replacement ₆₁₀Be-CH=R ₆₃And R ₆₄Be methoxyl group, R ₆₅Be hydrogen atom, NR ₆₁R ₆₂, K ₆₆And K ₆₇Have as the indicated implication of following table.(table X III is seen the literary composition back)

Biological Examples

The following example has shown the character of the good fungicide of The compounds of this invention.

Embodiment B 1: the processing of tomato mildew (phytophthora infestans):

Tomato Lyeopersicon esculentum with the Marmande kind) plant culture is in alms bowl.(5 to 6 blade periods when these plant grow to a monthly age, height is 12 to 15 centimetres), by with the sprinkling of the suspension of test material or the aqueous solution plant being handled, this suspension or the aqueous solution have required concentration and contain the surfactant of the condensation product of dehydration sorb (sugar) alcohol-oleic acid and 20 moles of ethylene oxide.This surfactant concentrations equals half concentration of active substance.Each tomato plant obtains 5 ml solns or dispersion approximately.Use the various concentration of test material that two plant are handled.With the plant that compares with not containing active substance but the solution that contains the similar face activating agent of same concentrations handle.

After dry 24 hours, aqueous suspension with phytophthora infestans (Phytophthorainfestans) spore sprays, making every plant be infected (the phytophthora infestans spore can cause the tomato mildew) sprays with the consumption of about 5 milliliters/plant (promptly about 50,000 spores of each plant).

After infecting specifically, tomato plant saturated atmosphere press and about 15 ℃ down hatching cultivated one day, under about 17 ℃ and 70% to 90% relative moisture, cultivated five days then.

Infected back seven days, will compare with the result who uses gained in the plant that compares with the result who was handled gained in the plant by the test active substance.

In these cases, can be observed, dosage is 1, the 000ppm(1 grams per liter) compound 104,110,111,112,113,117,118,129,133,148,149,150,164,166,167,169,201 to 203,205,206,208,209,211,212,214,222,223,235,236,237,238,301,345,347,349,350,353,356,359,364,369,370,379,381,382,384 to 386,388,391 and 393,396,3113,3118,3119,407,414 to 416,433,434,435,440,445,458,505 to 507,607,619,621,608 and 6081 cause can suppressing 80% at least to the mould growth.

Embodiment B 2: the processing of downy mildew of garpe (it is mould that grape is given birth to single shaft):

Vine shoot (Vitisvinifera) cutting of Chardonnay kind is cultivated in alms bowl.(8 to 10 blade period, height is 20 to 30 centimetres) are used with Embodiment B 1 similar methods they are handled when these plant grow to 2 monthly ages.

After dry 24 hours, grape is given birth to single shaft mould (Flasmopara vcticola) aqueous spore suspension to be sprayed to and to make it be infected that (grape is given birth to the mould spore of single shaft can cause downy mildew of garpe on each plant, with about 5 milliliters/plant (being about 100,000 spores of each plant) when consumption sprays.

After infecting specifically, depress 18 ℃ and saturated atmosphere grapevine seedling was cultivated two days, cultivation five days under about 20-22 ℃ and 90-100 ℃ of relative temperature then.

Infected back eight days, and will compare with the result who uses gained in the plant that compares with the result of gained in the plant of being handled by the test active substance.

Can be observed the 300ppm(0.33 grams per liter in these cases) compound 101,104,105,107,110 to 118 of dosage, 121 to 125,127 to 134,136,137,141,148 to 150,152 to 160,162 to 164,166 to 170,201 to 203,204,205,206,208,209,210,211,212,213,214,215,217,222,223,229,234 to 239,301,345,347,349 to 351,353 to 356,358,359,361 to 370,373 to 380,382 to 391,393 to 394,396,397,399,3100,3112 to 3119,407,414 to 416,420,421,433 to 442,445,450,458,505 to 507,616,607,608,612,613,619,621,623, reach 626 and cause can suppressing 80% at least the mould growth.

Embodiment B 3: to the effect of the soil fungi of phytopathogen:

Compound of the present invention has effect to following fungi:

Phytophthora brown rot of citrus (Phylophthora citrophthora), the parasite of the citrus fruit root of expressing by the distortion of mycosis and gas first portion.

Carry out each experiment with following method: make nutrition base add to one group of Petri dish (20 milliliters of processes of every ware are sterilized) under the supercooled state in 120 ℃ of following autoclave sterilizers based on the potato extract that solidifies with agar.

In the filling ware, the acetone soln of active substance was injected in the cold medium to obtain required ultimate density.

In contrast, adopt Petri dish similar to the above, to the nutrition base of wherein pouring the equal number that does not contain active substance into.

After the curing, the seedling filament fragment that inoculation goes into to obtain from the identical fungal cultures in front in each ware.

These wares were preserved 5 days down at 22 ℃, and the breeding that will contain fungi in the ware of underproof active substance then compares with usefulness that the breeding of identical fungi compares in the ware.

In these cases, 30ppm(ppm be 1,000,000/) following compounds of dosage can suppress 80%:101,102,104,105,107 at least to the growth of fungi, 110 to 118,121 to 129,131 to 137,141,149 to 150,153 to 158,162 to 164,166,167,169,201 to 203,204,205,206,208,209,210,211,212,213,214,215,216,217,222,223,224,228,229,230,231,234 to 239,301,345,347,349,350,353,354,355,356,358 to 360,363 to 370,373,376 to 386,388 to 397,3110 to 3119,407,414 to 416,420,425 to 430,433 to 422,445,447,449,450,458,505 to 507,607,608,619 and 621.

The purposes of The compounds of this invention:

The compounds of this invention can be used as active fungicidal substance, especially can resist the fungal disease of plant, particularly by the oomycetes kind of pathomycete especially Phytophthora (Phytophthora sp) type, phytophthora infestans (Phytophthora infestans) (potato or tomato mildew) for example, phytophthora brown rot of citrus (Phytophthoracitropthora,) Phytophthora capsici (Phytophthora capsici), inferior epidemic disease mould (Phytophthora cactorum), palm mould (phytophthora palmivora), camphor tree epidemic disease mould (Phytophthora cinnamoni), big male epidemic disease mould (Phytophthora meqasperma), phytophthora parasitica (Phytophthora parasitica), Peronospora (Phytophthora sp, (especially to the tobacco mildew), Plasmopara (Plasmopara sp.) particularly grape is given birth to single shaft mould (plasmopara viticola) (downy mildew of garpe) and this single shaft of Hall mould (Plasmopara halstedei) (heronsbill mildew), false Peronospora (Pseudoperonospora sp.) (particularly cucurbit mildew and hops mildew), Bremia (Bremia lactucae) (lettuce mildew) and soil fungi, caused plant mycosis.

It is 0.01 to 5 kilogram/hectare that these compounds use effective dosage, and 0.02 to 1.5 kilogram/hectare more preferred.Use for reality, compound of the present invention uses seldom separately.They mostly are the part of composition greatly.These compositions can protect vegetables to resist mycosis; these compositions or in the composition of plant growth regulating; contain at least a above-mentioned The compounds of this invention, be aided with that agricultural goes up acceptable solid or liquid inertia Zhi Zaiti and/or compatible and also be that agricultural goes up acceptable surfactant with active substance as active substance.Specifically, can adopt common inert carrier and common surfactant.

In this patent, term " carrier " refers in particular to a kind of natural materials or synthetic of organic or inorganic: it can combine with active substance is convenient to it and uses on plant, seed or soil.This carrier thereby often be inertia, and must be acceptable on agricultural, be acceptable especially in plant treatment.Carrier can be solid (clay, natural or synthetic silicate, silica gel, resin, wax, solid fertilizer or the like) or for liquid (water, alcohol, ketone, petroleum distillate, aromatic hydrocarbons or alkane or chlorohydrocarbon) or be a kind of gas.

The present composition (selling or directly use under diluted state with enrichment stage) generally includes 0.0001 to 95%, better contains 0.0005 to 90% active substance, and 0 to 20%, be preferably 0.5 to 15% surfactant.The composition that concentrates of planning to sell contains 0.1 to 95% usually, is preferably 0.5 to 90% active substance.

Surfactant can be emulsifier, dispersant or is ionic or non-ionic wetting agent.For example, can mention polyacrylate, lignosulphonates, phenolsulfonate or naphthalene sulfonate, oxirane and fatty alcohol or with fatty acid or with salt, taurine derivatives (particularly taurine alkyl salt) and the phosphate of polyoxyethylenated alcohol or the phosphate of phenol of the bunching thing of fatty amine, substituted phenol (particularly alkyl phenol or aryl phenol), esters of sulfosuccinic acids.When active substance and/or inert carrier is water insoluble and water is to use carrier, must there be at least a surfactant usually.

The composition of Shi Yonging can be different forms in the present invention: fluid, liquid or solid.

Form as fluid composition or fluid composition, can mention emulsible concentrate, emulsion, concentrated aqueous suspension agent, paste, the solution of containing especially, especially water-soluble concentrate, the solution (the ultralow volume solution of UL.V=) and the aerosol that concentrate in organic media.

Emulsible or soluble concentrate often contains 10 to 80% active substance.Emulsion or the solution preparing to use contain 0.001 to 20% active substance.Except active substance and solvent, when needing, emulsible concentrate also comprises the proper additive of suitable cosolvent and 2 to 20%, such as stabilizing agent, bleeding agent, corrosion inhibitor, colouring agent and adhesive.

From these concentrates, can obtain the emulsion of any desired concn by dilute with water, this is particularly suitable for the use in ploughing.For example, be the composition of some emulsifiable concentrates here.

Embodiment C EI

-active substance (compound No. 101 or No. 202 or No. 301) 250 grams per liters

-epoxidized vegetable oil 25 grams per liters

-alkyl aryl sulfonate and poly-second two

Mixture 100 grams per liters of-alcohol ether and fatty alcohol

-dimethyl formamide 50 grams per liters

-dimethylbenzene 575 grams per liters

Embodiment C E2

-active substance (compound No. 105 or No. 206 or No. 345) 400 grams per liters

-DBSA alkali metal salt 24 grams per liters

-with 10 moles of ethylene oxide polycondensations

-nonyl phenol 16 grams per liters

-cyclohexanone 200 grams per liters

1 liter of-aromatic solvent

Can obtain the emulsion of any desired concn by dilute with water from these concentrates, it especially is fit to leaf is used.

The suspending agent that concentrates also can spray use, it is a kind of stable fluid product that obtains through the preparation result, it does not precipitate and separates out, usually contain 10 to 74% active substance, 0.5 to 15% surfactant, 0.1 to 10% thixotropic agent and 0 to 10% proper additive, such as antifoaming agent, erosion inhibitor, stabilizing agent, bleeding agent and adhesive, and as water or a kind of organic liquid of carrier, active substance is slightly soluble or insoluble therein; Some solid organic matter or mineral salt can be dissolved in carrier separates out to stop precipitation, or helps the water anti-freeze.

For example, be the composition that contains aqueous suspension agent that concentrates according to more of the present invention here:

Embodiment SAC1:

-active substance (compound No. 106 or No. 206 or No. 350) 100 grams per liters

The same alkylphenol of-wetting agent oxirane

-condensation polymer 5 grams per liters

-dispersant (sodium naphthasulfonate) 10 grams per liters

-antifreezing agent (propane diols) 100 grams per liters

-thickener (glycan) 3 grams per liters

-biocide (formaldehyde) 1 grams per liter

-water adds to 1 liter

Embodiment SAC2:

Prepare a kind of aqueous suspension agent that contains, comprising:

-active substance (compound No. 108 or No. 208 or No. 301) 250 grams per liters

(oxirane and CB close-wetting agent

The condensation polymer of-one-tenth alcohol) 10 grams per liters

-dispersant (lignosulphonic acid acid sodium) 15 grams per liters

-antifreezing agent (urea) 50 grams per liters

-thickener (glycan) 2.5 grams per liters

-biocide (formaldehyde) 1 grams per liter

-water adds to 1 liter

Embodiment SAC3:

Prepare a kind of aqueous suspension agent that contains, comprising:

-active substance (compound No. 109 or No. 209 or 345

Number) 500 grams per liters

-wetting agent (oxirane and C synthol

-condensation polymer) 10 grams per liters

(oxirane becomes with poly-aryl phenol phosphate-dispersant

Salt composite)

50 grams per liters

-antifreeze (propane diols) 100 grams per liters

-thickener (glycan) 1.6 grams per liters

-biocide (4-methyl hydroxy benzenes

-sodium formate) 3.3 grams per liters

-water adds to 1 liter

Form as solid composite; can mention pulvis (content of active substance can reach 100%) and the granule used as dusting, particularly by extruding, by compress, dipping by the granulating carrier or from powder resulting these the particle systems (content of formula (I) compound these granules is between 0.5 and 80% for these examples of back) of granulating.

It is that they contain 10 to 95% active substance that wetting powder (or as the pulvis that sprays) usually makes like this, they are usually except that containing solid carrier in addition, also contain 0 to 5% wetting agent, 3 to 10% dispersant and, when needing, contain 0 to 10% one or more stabilizing agent and/or other additive, such as bleeding agent, adhesive or anti-caking agent, colouring agent or the like.

For example be the composition of some wetting powders here.

Embodiment PMI

-active substance (compound No. 111 or No. 211 or 350

Number) 10%

The C that-branched chain type is synthetic ₁₃Contain oxygen alcohol with 8 to 10

The condensation product of-individual oxirane (wetting agent) 0.75%

-neutral Calcium Lignosulphonate 99.99 min (dispersant) 12%

-calcium carbonate (inertia filler) adds to 100%

Embodiment PM2:

-active substance (No. 102, compound of the present invention or 202

Number or No. 301) 50%

The condensation product of-oxirane and fatty alcohol

-(wetting agent) 2.5%

Contracting of-oxirane and styryl phenol

-compound (dispersant) 5%

-chalk (inert carrier) 42.5%

Embodiment PM3: contain the composition identical, have following proportioning with front embodiment

-active substance (compound No. 105 or No. 206 or 345

Number) 75%

-wetting agent 1.5%

-dispersant 8%

-calcium carbonate (inert filler) adds to 100%

Embodiment PM4:

-active substance (compound No. 106 or No. 206 or 350

Number) 90%

The condensation of-oxirane and fatty alcohol

-thing (wetting agent) 4%

-oxirane and styryl phenol

-condensation product (dispersant) 6%

Spray pulvis or wetting powder in order to obtain these, active substance is closely mixed with the interpolation material in suitable blender, mixture grinds with mill mortar or other suitable grinder.Can obtain the pulvis that can spray in this way, its wettable and suspendability are good; They can be suspended in the water by any desired concn, and this suspending agent can be used effectively, can be applied to effectively on the leaf of plant especially.

Formula (I) compound can use for dusting powder with powder type in addition; Also can use the composition that contains active substance (50 gram) and talcum powder (950 gram); Also can use and contain active substance (20 gram), segment broken silica (10 gram) and talcum powder (970 gram); With these combined hybrid and grinding, mixture can be used by removing the powder method.

Its size of granule of using for dusting can prepare by cohesion or dipping between 0.1 and 2 millimeter.Usually, granule is contained in 0.5 to 25% active substance, and 0 to 10% such as additives such as stabilizing agent, slowly-releasing modifier, binding agent and solvents.

Here be the embodiment of two kinds of granule composites:

Embodiment G1 and G2

-active substance (compound No. 108 or No. 208 or 301

Number) 50 grams, 200 grams

-propane diols 50 grams 50 grams

-hexadecane and polyglycol ether 2.5 grams 2.5 grams

-polyethylene glycol 35 grams 35 grams

-kaolin

(particle size: 0.3 to 0.8 millimeter) 910 grams 760 grams

Compound of the present invention can be mixed with the granule form that can be dispersed in the water effectively, and these are included in the scope of the present invention.

These dispersible granules agent, its apparent density are usually about 0.3 to 0.6, and its granule size is usually between about 150 and 2,000 microns, preferably between 300 and 1500 microns.

The content of active substance of these granules between about 1% and 90%, is between 25% and 90% usually preferably.

The residual fraction of granule mainly comprises a kind of solid filler, and comprises also that at random containing surfactant additive makes particle have dispersant in water.Whether water-soluble according to filler, these granules can be divided into two kinds.For water soluble filler, it can be inorganic, but is organic filler preferably.Can obtain excellent results with urea.For water solvent filler not, it is inorganic preferably, such as, kaolin or bentonite.Be accompanied by then and add surfactant (accounting for 2 to 20% ratio of granule weight), surfactant additive must surpass half of at least a dispersant, this dispersant is necessary for anionic, such as a kind of poly-(naphthalene sulfonic acids) alkali metal salt or poly-(naphthalene sulfonic acids) alkali salt or a kind of lignosulphonic acid alkali metal salt or lignosulphonic acid alkali salt.Remaining part comprises such as the nonionic of alkyl naphthalene sulfonic acid alkali metal salt or alkali salt or anionic wetting agent.

In addition, though dispensable, also can add other assistant agent such as antifoaming agent.

By essential composition is mixed, adopt some original known technology (spherical granulating machine, stream are stopped bed, atomizer, extruder or the like) granulation to prepare then according to granule of the present invention.Pulverize the back by sieving the particle of selecting granule size in the above-mentioned limit, this process promptly comes to an end.

Preferably, granule of the present invention can obtain by extruding.But shown following dispersible granule preparation of compositions in the following example.

Embodiment GC1:

Place blender to mix active substance [No. 111, compound or No. 211 90%(weight)] and urea pearl (10%).Mixture is pulverized in rod-toothed crusher.The wet powder that obtains is extruded in porous roll-type extruder.Obtain particle after the drying, broken then and sieve, the result has only kept the particle of particle size between 150 and 2000 microns respectively time.

Embodiment GD2:

Place blender to mix following composition

-active substance (compound No. 105 or No. 202 or 345

Number) 75%

-wetting agent (Negel) 2%

-dispersant (poly-sodium naphthalene sulfonate) 8%

-water-insoluble inert filler (kaolin) 15%

Embodiment GD3:

-active substance (compound No. 105 or No. 206 or 350

Number) 20%

-Negel 2%

-methylene-two-sodium naphthalene sulfonate 8%

-kaolin 70%

The granulation in fluid bed in the presence of water of this mixture, dry then, the broken and result that sieves obtains the particle of size between 0.16 and 0.40 millimeter.

These granules can be used separately with in solution or a kind of like this method that is dispersed in the water obtain required dosage.They also can be used for preparation and other active substance, and especially with back dose of fungicide, these latter are in wetting powder form or granule form or contain the aqueous suspension agent form.

Compound of the present invention also can be mixed with organic solution agent form, and they can be formed the polymer wall film, for example based on polyamide, polyureas or polyamide urea by special in interfacial polymerization in the encapsulate.These capsules are concentrated aqueous dispersion state, and it can dilutedly obtain a kind of slurry in use and be used for spraying.

As having addressed, contain water dispersant and emulsion,, be in the total size of the spendable composition of the present invention for example by dilute with water wettable powder of the present invention or missible oil resultant composition.Emulsion can be water-in-oil type or oil-in-water type, and they have the thick denseness that resembles " mayonnaise ".

The present invention relates in addition improvement by the caused disease of fungi of plant pathogenic bacteria, particularly to by phytophora sp, the oomycetes section of (Phytophthora) type, phytophthora infestans (potato or tomato mildew) for example, phytophthora brown rot of citrus, Phytophthora capsici, Phytophthora cactorum, palm mould, the camphor tree epidemic disease is mould, big male epidemic disease is mould, phytophthora parasitica, Peronospora (especially tobacco mildew), Plasmopara, particularly grape is given birth to Plasmopara (grape mildew) and this single shaft of Hall mould (heronsbill mildew), false Peronospora (particularly cucurbit mildew and hops mildew), the improvement of the fungal disease of dish stalk mould (lettuce mildew) and the caused plant pathogenic bacteria of soil fungi.

This method comprises the composition of these plants being used effective dose, and composition contains formula of the present invention (I) compound as active substance." effective dose " means is enough to control and eliminate the fungi that is present in these plants.But the compound of the fungi that the dosage of use then can be killed according to need, kind, weather conditions and the use of crop is different and change in broad range.

The actual dosage that uses from 1 gram/hectolitre to 500 restrain/hectolitre do not wait, the approximate dosage that is equivalent to active substance to 5000 gram/hectares, can obtain good result at 10 gram/hectares.

As the example of spendable processing method, can mention that the fusion that leaf or soil are sprayed, remove powder, immersion, granule, pulvis or paste goes in soil pouring, the injection in-tree, brushes and to seed treatment.

The table II

Compound N ° R ₁₇NR ₁₁R ₁₂PF LogP

150 H N-Methylethyls amino 95 3.6

151 H two (methoxy ethyl) amino 90 3.7

107 H N-diethylaminos 113 4.1

152 H 2, the 6-thebaine is for 150 4.2

153 H piperidyls 110 4.3

154 H pyrrolidinyls 119 3.7

155 H N-dimethylaminos 128 3.1

156 H N-methyl carboxy ethyls amino 84 2.8

157 H 2-carboxyl methyl-piperidyls 60 3.8

The amino sweet shape 3.4 of 158 H N-methyl-methoxyethyl

159 H 2-methoxy piperidyls 123 4.5

160 H 2-carboxyl methylpyrrole alkyl 74 3.3

161 H 4-carboxyl piperidyls 166 2.2

162 H 4-oxo group piperidyls 148 3.0

163 H 2-methoxy pyrrolidinyls 60 3.9

164 H 3-carboxyl piperidyls 90 3.1

165 H 4-methoxyl group piperidyls 139 2.8

166 H 3-methoxyl group piperidyls 60 3.8

167 F N-Methylethyls amino 103 3.8

168 F 2, the 6-thebaine is for 134 4.4

The amino sweet shape 3.6 of 169 F N-methyl methoxy base ethoxies

170 F two (dimethoxy ethoxy) amino 99 3.9

The table IV

N ° of Z ₂R ₂₇Fusing point ℃ logP

201 morpholino 4-fluorophenyls 153 4.1

202 morpholino phenyl 130 4.0

203 morpholino 4-aminomethyl phenyls 129 4.6

204 N(CH ₃) CH ₂CH ₂OCH ₃Br honey shape 3.2

205 N（C ₂H ₅） ₂Br 82 4.0

206 N（CH ₃）C ₂H ₅Br 85 3.4

207 pyrrolidinyl Br 76 3.5

208 morpholino Cl 108 2.9

209 N（CH ₃）C ₂H ₅Cl 68 3.3

210 N(CH ₃) CH ₂CH ₂OCH ₃Cl honey shape 3.1

211 N（C ₂H ₅） ₂Cl 54 3.8

212 N(CH ₃) C ₂H ₅Propylene-2-base 98 3.6

213 N(CH ₃) CH ₂CH ₂OCH ₃Propylene-2-base 78 3.4

214 N(C ₂H ₅) ₂Propylene-2-base 68 4.1

215 N(CH ₃) C ₂H ₅Right-tolyl 130 5.0

216 N(CH ₃) CH ₂CH ₂OH is right-tolyl 130 4.2

217 N(CH ₃) ₂Right-tolyl 109 4.5

218 N（CH ₃）C ₂H ₅CH ₃110 3.2

219 N（C ₂H ₅） ₂CH ₃73 3.7

220 morpholino CH ₃132 2.8

221 N（CH ₃）CH ₂CH ₂OCH ₃CH ₃63 3.0

222 morpholino Br 123 3.0

Table (IV ')

N ° of Z ₂R ₁₆Fusing point ℃ logP

223 morpholino Br 55 3.0

Table (V)

N ° of Z ₂R fusing point ℃ logP

145 ℃ 2.9 of 224 morpholino Br

225 N(CH ₃) C ₂H ₅Br honey shape 3.4

226 N(CH ₃) CH ₂CH ₂OCH ₃Br honey shape 3.2

227 N(C ₂H ₅) ₂Br honey shape 3.9

228 N(CH ₃) C ₂H ₅98 ℃ 4.5 of 4-fluorophenyl

170 ℃ 4.0 of 229 morpholino 4-fluorophenyl

230 N(CH ₃) C ₂H ₅Right-148 ℃ 5.0 of tolyl

231 morpholinoes are right-137 ℃ 4.5 of tolyl

The table VI

Compound N ° Z ₂R ₂₇Fusing point ℃ LogP

233 OC ₂H ₅4-F-phenyl 127 *

234 morpholinoes 3,4-dimethoxy phenyl 189 3.4

235 morpholino (CH ₂) ₃C=CH-97 3.8

236 morpholino H ₂C=C(CH ₃)-128 3.2

237 morpholino 4-chlorphenyls 144 4.7

238 morpholino 3-thienyls 151.5 3.6

239 morpholino 4-(methylenedioxy) benzyls 138 3.4

240 OC ₂H ₅4-anisyl 125 *

241 OH are right-tolyl 215 *

242 OC ₂H ₅Right-tolyl 84 *

243 OH 4-anisyls, 202 *

The table VII

N ° of Z R fusing point ℃

244 OH Br 194

245 OC ₂H ₅4-fluorophenyl 72

246 OC ₂H ₅Right-tolyl 98

247 OH 4-fluorophenyls 177

248 OH are right-tolyl 180

249 OH phenyl 177

Examples of compounds N ° of R ₄₇Z ₄Feature LogP

Method in N °

409 405 3-nitro-phenyl OC ₂H ₅Fusing point=141 ℃ *

410 406 3-nitro-phenyl OH fusing point=226 ℃ of *

412 405 phenyl OC ₂H ₅Fusing point=98 ℃ *

413 406 phenyl OH fusing points=215 ℃ of *

414 407 phenylmorpholines are for fusing point=172 ℃ 2.3

415 407 phenyl N(CH ₃) (CH ₃) fusing point=100 ℃ 2.7

416 407 phenyl N(CH ₃) (CH ₃OC ₂H ₄) orange oil 2.5

405 405 4-chloro-phenyl OC ₂H ₅Fusing point=115 ℃ *

407 407 4-chloro-phenylmorpholines are for fusing point=168 ℃ 3.0

417 405 3,4-dichlorophenyl OC ₂H ₅Fusing point=74 ℃ *

418 406 3,4-dichlorophenyl OH fusing point=267 ℃ of *

408 408 3,4-dichlorophenyl morpholino fusing point=181 ℃ 3.7

420 407 3,4-dichlorophenyl N(C ₂H ₅) ₂Fusing point=122 ℃ 3.6

421 407 3,4-dichlorophenyl N(CH ₃) (C ₂H ₅) fusing point=146 ℃ 4.1

422 405ou423 methyl mercapto OC ₂H ₅Fusing point=81 ℃ *

423 407 methyl mercapto morpholino fusing points=151 ℃ of *

424 405 3-CF base phenyl OC ₂H ₅Oil *

425 408 3-CF base phenylmorpholine is for fusing point=149 ℃ 3.2

426 406 3-CF phenyl OH fusing point=162 ℃ of *

427 408 4-bromo-phenylmorpholine base fusing point=169 ℃ 3.2

428 407 3-CF ₃-phenyl N(CH ₃) (C ₂H ₅) sweet shape 3.6

429 407 3-CF ₃Phenyl N(C ₂H ₅) ₂Fusing point=98 ℃ 4.1

430 408 4-bromo-phenyl N(C ₂H ₅) ₂Honey shape 4.1

431 408 4-chloro-benzyl morpholino fusing points=116 ℃ 3.2

Examples of compounds N ° of R ₄₇Z ₄Fusing point logP

Method in N °

434 423 benzylthio morpholinoes 53 2.9

435 423 4-benzyl chloride sulfenyl morpholinoes 134 3.9

436 423 4-chlorobenzene sulfenyl morpholinoes 147 3.7

437 4-chloryl morpholinoes 174 3.7

438 422+432+433 4-bromo-phenoxy group morpholinoes 170 3.9

439 422+432+433 4-fluoro-phenoxy group morpholinoes 189 3.1

440 422+432+433 2-methyl-phenoxy group morpholinoes 136 3.6

441 422+432+433 4-chloro-3-methyl-phenoxy group morpholinoes 176 4.3

433 422+432+433 4-methyl-phenoxy group morpholinoes 152 3.6

442 422+432+433 4-CF-phenoxy group morpholinoes 54 3.9

444 422+432+433 2-chloro-thiophenyl morpholinoes 179 3.1

445 422+432+433 3-chloro-thiophenyl morpholinoes 58 3.6

446 422+432+433 2-bromo-thiophenyl morpholinoes 169 3.8

447 422+432+433 4-bromo-thiophenyl morpholinoes 158 3.8

448 422+432+433 3-fluoro-thiophenyl morpholinoes 67 3.1

449 422+432+433 4-fluoro-thiophenyl morpholinoes 116 3.1

450 42,2+4,32+,433 3,4-dichloro-benzenes sulfenyl morpholino 135 3.1

451 42,2+4,32+,433 2,6-dichloro-benzenes sulfenyl morpholino 187 3.2

453 422+432+433 anilino-morpholinoes 210 3.2

454 422+432+432 4-chloro-anilino-morpholinoes 184 3.3

455 42,2+4,32+,432 3,4-dichloro-benzenes amido morpholino 152 4.6

456 422+432+432 2-chloro-4-bromo-anilino-morpholinoes 122 4.8

457 422+432+432 3-chloro-4-fluoro-anilino-morpholinoes 178 4.1

458 422+432+432 piperazine purine base morpholinoes 150.6 2.6

Compound is at example K ₆₆K ₆₇NR ₆₁R ₆₂Fusing point logP

N ° of N ° of intermediary ℃

Method continues

615 604 O-C(4-chlorphenyl)=NCH) CH 102 4.7

616 605 O-C(4-chlorphenyl)=morpholino 139 4.3

617 605 O-C(phenyl)=morpholino 177 3.6

604 604 O-C(phenyl)=NCH) CH 74 4.0

605 605 O-C(4-fluorophenyl)=morpholino 168 3.7

606 606-NH--C(4-fluorophenyl)=morpholino 190 3.1

607 607-N(CH ₃The C(4-of)--fluorophenyl)=morpholino 148 3.9

618 606-NH--C(4-fluorophenyl)=morpholino 225 3.7

619 607-N(CH ₃The C(4-of)--fluorophenyl)=morpholino 155 4.5

620 606-N(H)--the C(phenyl)=morpholino 160 3.0

621 607-N(CH ₃The C(of)--phenyl)=morpholino 173 3.8

622 606-N(H)--the C(4-tert-butyl-phenyl)=morpholino 156 4.9

623 608-N(C ₆H ₅The N=of)--morpholino 110 2.5

624 611-N(C ₆H ₅The N=NCH of)--) CH honey shape 2.9

625 612 -N（C ₆H ₅）- -N＝ -NCH） 111 3.4

608 608-N(4-chlorphenyl)-N=morpholino 125 3.2

611 611-N(4-chlorphenyl)-CH 110 3.6 of N=-NCH)

612 612-N(4-chlorphenyl)-the sweet shape 4.0 of N=-NCH)

626 608-N-benzyl-N=morpholino honey shape 2.5

The CH 105 2.9 of 627 611-N-benzyl-N=-NCH)

628 612-N-benzyl-N=-NCH)-sweet shape 3.3

619 613-N=-N-(phenyl) morpholino honey shape 2.5

614 614-N=-N(4-bromobenzyl) morpholino 122 3.4

Claims (17)

1, a kind of fungicide composite is characterized in that it comprises following formula (III) compound of antifungal effective dose is gone up acceptable diluent or carrier as active component and agricultural:

Wherein: Z ₂Represent NR ₂₁R ₂₂Group,

R ₂₁And R ₂₂Identical or different, represent C respectively ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl, perhaps R ₂₁And R ₂₂Be joined together to form morpholino group, thiomorpholine for group or pyrrolidinyl by the N atom;

R ₂₃And R ₂₄Identical or different, represent C separately ₁-C ₄Alkoxyl, perhaps R ₂₃And R ₂₄Common methylene-dioxy or the dioxo methylene that forms divalence;

R ₂₅Be hydrogen;

R ₂₆Be hydrogen, NO ₂Or halogen;

R ₂₇Represent hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl, C ₁-C ₄Alkylthio, halogen, C ₁-C ₄Thiazolinyl, C ₁-C ₄Alkylthio, C ₁-C ₄Haloalkyl, amino, randomly by halogen, C ₁-C ₄Alkyl or C ₁-C ₄The phenyl that alkoxyl replaced;

R ₂₈And R ₂₉Represent hydrogen.

2, composition according to claim 1 is characterized in that, in described general formula (III) compound,

Z ₂Represent NR ₂₁R ₂₂, R wherein ₂₁And R ₂₂Identical or different, represent C separately ₁-C ₄Alkyl, perhaps R ₂₁And R ₂₈Be joined together to form morpholino group or thiomorpholine for group with the N atom;

R ₂₃And R ₂₄Identical or different, represent C ₁-C ₄Alkoxyl;

R ₂₅Be hydrogen;

R ₂₆Be hydrogen or halogen;

R ₂₇Represent C ₁-C ₄Alkyl, halogen, C ₁-C ₄Haloalkyl is by halogen, C ₁-C ₄Alkyl, C ₁-C ₄The phenyl that alkoxyl replaced.

3, composition according to claim 1 is characterized in that in wherein said general formula (III) compound,

Z ₂Be morpholino, thiomorpholine generation, N-methyl-N-ethylamino or N, N-diethylamino;

R ₂₃And R ₂₄Representation methoxy;

R ₂₅Be hydrogen;

R ₂₆Be hydrogen or halogen;

R ₂₇Represent C ₁-C ₄Alkyl, halogen, C ₁-C ₄Haloalkyl.

4,, it is characterized in that it further comprises surfactant according to claim 1,2 or 3 described compositions.

5,, it is characterized in that it contains 0.0001 to 95% active substance according to claim 1,2 or 3 described compositions.

6, composition according to claim 4 is characterized in that surface-active contents wherein is 0-20%.

7,, it is characterized in that it comprises active substance between 0.0005 and 90% according to claim 1,2 or 3 described compositions.

8,, it is characterized in that it comprises active substance between 0.1 and 95% according to claim 1,2 or 3 described compositions.

9,, it is characterized in that it comprises active substance between 0.5 and 90% according to claim 1,2 or 3 described compositions.

10, composition according to claim 6 is characterized in that it comprises surfactant between 5 and 15%.

11,, it is characterized in that it is the state of emulsification concentrate, comprises 10 to 80% active substance according to claim 1,2 or 3 described compositions.

12, according to claim 1,2 or 3 described compositions, it is characterized in that it be contract contain the aqueous suspension agent form, comprise 10 to 75% active substance.

13,, it is characterized in that it is the wetting powder form that contracts, and comprises 10 to 95% active substance according to claim 1,2 or 3 described compositions.

14,, it is characterized in that it is the granula form, comprises 0.5 to 25% active substance according to claim 1,2 or 3 described compositions.

15,, it is characterized in that it is the dispersible granule form, comprises 1 to 90% active substance according to claim 1,2 or 3 described compositions.

16, a kind of application of claim 1 composition is characterized in that 0.01 to 5 kilogram/hectare amount of substance is used, to administer by mould germ crop that infect or that be easy to infect.

17, method according to claim 17 is characterized in that active substance uses with 0.02 to 1.5 kilogram of/hectare consumption.