CN1015626B - Process for preparing new derivatives of pyrrole - Google Patents

Process for preparing new derivatives of pyrrole

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Publication number
CN1015626B
CN1015626B CN85106411A CN85106411A CN1015626B CN 1015626 B CN1015626 B CN 1015626B CN 85106411 A CN85106411 A CN 85106411A CN 85106411 A CN85106411 A CN 85106411A CN 1015626 B CN1015626 B CN 1015626B
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China
Prior art keywords
formula
base
represent
pyrroles
proyl
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CN85106411A
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Chinese (zh)
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CN85106411A (en
Inventor
琼·特斯尔
琼-皮埃尔·德穆特
布伦特·塔利安尼
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Sanofi Aventis France
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Roussel Uclaf SA
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Priority claimed from FR8506134A external-priority patent/FR2580637B2/en
Application filed by Roussel Uclaf SA filed Critical Roussel Uclaf SA
Publication of CN85106411A publication Critical patent/CN85106411A/en
Priority to CN91111112A priority Critical patent/CN1062071A/en
Publication of CN1015626B publication Critical patent/CN1015626B/en
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  • Pyrrole Compounds (AREA)

Abstract

Novel pyrrole derivatives of the formula I wherein one of R2 and R3 is and the other of R2 and R3 as well as R4 and R5 are individually selected from the group consisting of hydrogen, halogen, alkyl of 1 to 18 carbon atoms, aryl of 6 to 14 carbon atoms, aralkyl of 7 to 18 carbon atoms, -CN, -CF3, -NO2, -COOAlk and Alk is alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, n is 0, 1 or 2, R', R1' and R2' are alkyl of 1 to 8 carbon atoms and R4 and R5 taken together with the carbon atoms to which they are attached may form an optionally further unsaturated carbon homocycle of up to 8 carbon atoms, Z is selected from the group consisting of hydrogen, -CN, -C 3BOND CH, -CF3 and alkyl of 1 to 3 carbon atoms, A is the residue of a pyrethrinoid acid, R1 is selected from the group consisting of +TR X', X, Y, Y' and Y'' are individually selected from the group consisting of hydrogen, halogen, alkyl of 1 to 8 carbon atoms and aryl of 6 to 14 carbon atoms, the dotted line indicating an optional double bond, r' is selected from the group consisting of hydrogen, alkyl of 1 to 18 carbon atoms, aryl of 6 to 14 carbon atoms, aralkyl of 7 to 18 carbon atoms, -CF3, -COOAlk and alkoxy of 1 to 8 carbon atoms and Alk has the above definition, R'' and R''' are individually selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl of 6 to 14 carbon atoms, aralkyl of 6 to 18 carbon atoms, -CF3, -COOAlk' and alkoxy of 1 to 8 carbon atoms and Alk' is alkyl of 1 to 8 carbon atoms having pesticidal properties and novel intermediates.

Description

Process for preparing new derivatives of pyrrole
The purpose of this invention is to provide the method for preparing new pyrrole derivative.The general formula of this derivative is:
Figure 85106411_IMG21
Wherein:
-R 2Or R 3One of represent group
Figure 85106411_IMG22
(wherein A is analogy chrysanthemic acid (pyrethrinoid acid) ACO 2The residue of H, Z are represented H, C ≡ N, C ≡ CH, CF 3, or the alkyl of 1-3 carbon.Not)-another does not represent the R of above-mentioned group 2Or R 3, and R 4And R 5(being same to each other or different to each other) but hydrogen atom, halogen atom, up to the alkyl of 18 carbon, up to the aryl of 14 carbon, up to the aralkyl of 18 carbon, cyano group, CF 3, up to 8 CO 2-alkyl, NO 2, up to the alkoxyl group of 8 carbon, and group
Figure 85106411_IMG23
(n=0 wherein, 1 or 2, R ' R 1', R 2' represent the alkyl of 1-8 carbon atom), R 4And R 5Can form saturated or undersaturated, up to the carbocyclic ring of 8 carbon atoms.
-R 1Representative:
-
Figure 85106411_IMG24
-C ≡ C-Y wherein X and Y(is same to each other or different to each other) represent hydrogen atom, halogen atom, the alkyl of 1-8 carbon atom, or up to the aryl of 14 carbon;
-or
Figure 85106411_IMG25
Wherein " (being same to each other or different to each other) represents a group in top X and the Y definition, and dotted line is illustrated in two keys that may form between 1 carbon and 2 carbon for X ', Y ', Y;
-or
Figure 85106411_IMG26
The wherein definition of γ ' and top R 4And R 5The definition unanimity, but do not comprise halogen, cyano group, NO 2,
Figure 85106411_IMG27
(n=1 or 2), and
Figure 85106411_IMG28
Group;
-or
Figure 85106411_IMG29
Wherein R " and R ' " (identical or different) represents hydrogen atom, and the alkyl of 1-18 carbon is up to the aryl of 14 carbon, up to the aralkyl of 18 carbon, CF 3, up to the CO of 8 carbon 2-alkyl is up to the alkoxyl group of 8 carbon.
Said analogy chrysanthemic acid (pyrethrinoid acid) promptly is ACO 2H can be used as the intermediate of pyrethroid (pyrethrinoid) derivative of preparation biologically active.
When Z represents alkyl, methyl preferably.
When a substituting group of mentioning in general formula (1) definition is alkyl, preferably methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-or n-pentyl.
When a substituting group of mentioning in general formula (1) definition is represented halogen atom, preferably fluorine, bromine or chlorine atom.
When a substituting group of mentioning in general formula (1) definition was represented aryl, it is phenyl preferably, and this aryl can be substituted, particularly by the alkyl of 1-8 carbon or alkoxyl group, NO 2, CF 3, OH, halogen, the amino replacement.
When a substituting group of mentioning in general formula (1) definition is represented aralkyl, benzyl preferably.
A substituting group of mentioning in logical formula I definition is represented CO 2When-alkyl or alkoxyl group, " alkyl " be methyl preferably, ethyl, propyl group or sec.-propyl; " alkoxyl group " be methoxyl group, oxyethyl group, propoxy-or isopropoxy preferably.
Work as R 4And R 5When forming carbocyclic ring, the ring of 4 or 5 carbon atoms is arranged preferably.
The present invention provides preparation to have R in logical formula I and (I) especially 1Representative-CH 2The method of the compound of-C ≡ CH group.
In the compound according to qualifications that obtains by the inventive method, can list group:
Figure 85106411_IMG30
Middle substituting group Z is those compounds of hydrogen atom or cyano group.
Those substituent R 2For
Figure 85106411_IMG31
The compound of group also can be classified the compound according to qualifications that obtains by the inventive method as.
The present invention also provides preparation to have logical formula I especially, and substituent R in (I) 2, R 4, and R 5Respectively be the compound of hydrogen atom, and R 2, R 4And R 5Method for the compound of nitro or trifluoromethyl.
The present invention especially provides preparation to have the method for the compound of logical formula I, it is characterized in that:
-A represents group:
Figure 85106411_IMG32
Wherein:
-Z 1And Z 2Be respectively methyl,
-or Z 1Be hydrogen atom, and
-Z 2Represent group
Figure 85106411_IMG33
Z wherein 3Be hydrogen or halogen atom, T 1And T 2(identical or different) represents the alkoxyl group or the alkyl of hydrogen atom, halogen atom, a 1-8 carbon, CF 3, or CN, or the phenyl ring that can be replaced by halogen, perhaps T 1And T 2Form the cycloalkyl of 3-6 carbon, or group:
Wherein B is oxygen or sulphur atom;
-or Z 2Represent group
Figure 85106411_IMG35
A wherein, b, c, d, (identical or different) respectively is halogen atom;
-or Z 2Represent group
Wherein D represents hydrogen or halogen atom, the alkoxyl group of 1-8 carbon; G is oxygen or sulphur atom; J or be 1-8 the saturated or unsaturated alkyl of carbon straight chain, side chain or cyclic, this alkyl can be replaced by one or more identical or different functional groups; Or be aryl 6-14 carbon, that can be replaced by one or more identical or different functional groups; Or be can be by the heterocyclic radical of one or more identical or different functional groups replacement;
-or A represent group
Wherein U can represent halogen atom, the alkyl of 1-8 carbon or alkoxyl group, m=0,1 or 2 on any position of phenyl ring.
Work as T 1, T 2, Z 3When being halogen atom, preferably fluorine, chlorine, bromine atoms.
Work as T 1Or T 2When expression alkyl or alkoxyl group, preferably methyl, ethyl, n-propyl, methoxyl group, oxyethyl group or positive propoxy.
A, b, c, d, be preferably the chlorine or bromine atom.
When D represents halogen atom, preferably fluorine, chlorine or bromine atom.
When alkyl that J represents to be replaced by one or more functional groups, alkyl is the alkyl of 1-8 carbon preferably, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, or tertiary butyl.A kind of functional group that functional group lists in disclosed european patent application (No. 50534).
J also can represent by aryl, especially the alkyl that may be replaced by phenyl.
When alkyl that J represents to be replaced by one or more functional groups, following groups is the best substituted alkyl of J:
--(CH 2) N1-CHal 3N wherein 1Be the integer of 1-8, Hal is a halogen atom, as :-CH 2-Ccl 3,-CH 2-CF 3,-CH 2-CH 2-Ccl 3, or-CH 2-CH 2-CF 3;
--(CH 2) N2-CHHal 3Wherein the Hal definition is the same, n 2Be the integer of 0-8, as :-CH 2-CHcl ,-CH 2-CHF 2, or-CHF 2;
--(CH 2) N1-CH 2Hal is n wherein 1The same with the Hal definition, as :-CH 2-CH 2Cl, or-CH 2-CH 2F;
--C-(CHal 3) 3, wherein the Hal definition is the same, as :-C-(CF 3) 3,
Figure 85106411_IMG38
-(CH 2) n 1-ORa, wherein n 1Define the samely, Ra represents hydrogen atom, or 1-8 carbon straight or branched alkyl, as :-CH 2-OCH 3,-CH 2-CH 2-O-CH 3,-CH 2-CH 2-O-CH 2-CH 3, or-CH 2-CH 2-OH;
-
Figure 85106411_IMG39
When J representative-can substituted aryl, preferably can substituted phenyl.
When J represents heterocyclic radical, pyridyl preferably, furyl, thienyl, oxazolyl or thiazolyl.
In the according to qualifications compound that obtains with the inventive method, can list A and represent group
Figure 85106411_IMG41
Compound, Hal represents halogen atom in the formula, as chlorine, or bromine atoms.
Also can list A and represent group
Figure 85106411_IMG42
Compound, J represents straight chain, side chain or the cyclic alkyl of 1-8 carbon in the formula, two key geometric configurations are cis (Z).In these compounds, the best represent methylidene of J, ethyl, n-propyl, sec.-propyl or the tertiary butyl.
Also can enumerate and have logical formula I, and A represents group
Figure 85106411_IMG43
Compound.Hal represents halogen atom in this formula, and J represents the alkyl of 1-8 carbon, and two key geometric configurations are trans (E).
In these compounds, the best represent methylidene of J, ethyl, n-propyl, sec.-propyl or the tertiary butyl.
The present invention provides especially that A represents group in the preparation general formula
Figure 85106411_IMG44
The method of compound, in the compound according to qualifications that obtains by the inventive method, can list general formula with following title compound for (I):
-1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters;
-1R, along (△ Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters;
-1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-Trifluoromethyl-1 H-pyrroles-3-yl) methyl esters;
-1R, along (△ E) 2,2-dimethyl-uncle 3-(3--butoxy-3-oxo-2-fluoro-1-propenyl)-cyclopropane-carboxylic acid (1-(2-proyl)-2-Trifluoromethyl-1 H-pyrroles-3-yl) methyl esters.
General formula is the preparation method of the compound of (I), it is characterized in that general formula is (II)
Alcohol be subjected to general formula and be Acid of (III) (definition of A is consistent with the front) or functional group derivant's that should acid effect.In logical formula II, R 2" and R 3" one of represent group
Figure 85106411_IMG47
Wherein the definition of Z is consistent with the front, another R 2" or R 3" and R 4And R 5Keep the front and give a definition R 1Definition and front consistent.
The most handy chloride of acid of functional group derivant of acid.
When general formula is the acid and when reaction alcohol of (III), is preferably in dicyclohexyl carbodiimide and carries out under existing.
R in the logical formula I of preparation 1The method that comprises the compound of carbon-carbon double bond is characterized in that handling the corresponding derivative contain three key-carry out as carrying in the presence of palladium barium sulfate and the quinoline at catalyzer with a moles of hydrogen.
Product with logical formula II is a novel substance.R in the formula 1, R 2",
R 3", R 4And R 5Keep former definition.On pyrrole ring, introduce one or more groups, or all synthetic this heterocycle, on the synthetic pyrrole ring, introduce one or more functional groups subsequently, can obtain the product of general formula for (II).
Having described the general formula that obtains by following synthetic route in an embodiment is the various products of (II).
Figure 85106411_IMG49
Figure 85106411_IMG50
Figure 85106411_IMG51
Figure 85106411_IMG52
Figure 85106411_IMG54
Figure 85106411_IMG55
Compound with logical formula II can adopt the method for as above signal to produce, and is also available similar, is that conspicuous method obtains to the professional and technical personnel.
The product that has logical formula II described in the embodiment obviously all is the compound of selecting the superior.
Produce if desired and have logical formula I, and the Z in (I) is-compound of CN base also can adopt the existing method of different so-called phase transfer methods, method described in belgian patent 851900.Phase transfer method comprises that order and corresponding aldehyde of the alcohol of logical formula II and general formula react in the presence of water for the acid of (III), and alkaline cyanide is eluted in the water, adopts the aprotonic solvent and the phase-transfer catalyst that are immiscible in water to a certain extent.
Produce if desired and have logical formula II, and substituent R in (II) 2" or R 3", R 4, R 5In three the expression hydrogen atoms alcohol, preferably according to R 3" or R 2" expression group , and employing is corresponding to the method for synthetic route 1 or 2.
Have-alcohol of CN group if produce to have on two of pyrrole rings in logical formula II and (II), according to-CN and methylol position separately, preferably select method for use corresponding to synthetic route 3 or 4.
Have pyrrole ring two bit strip NO in logical formula II and (II) as producing 2The alcohol of group is preferably selected synthetic route 5 for use.
Have pyrrole ring three bit strip NO in logical formula II and (II) as producing 2The alcohol of group is preferably selected synthetic route 6 for use.
Have pyrrole ring two bit strip CF in logical formula II and (II) as producing 2The alcohol of base is preferably selected the method corresponding to synthetic route 7 for use.
General formula has some key property for the compound of (I), therefore can be used to eliminate parasite, as the parasite on killing off plant, the indoor and warm-blooded animal.Based on this effect, product of the present invention can be used to killing off plant and animal insect, nematode on one's body, and parasitic mite.
Product with logical formula I is used in particular for eliminating Agricultural pests, as Lice, lepidopteran and the Coleoptera larva of a tapeworm or the cercaria of a schistosome.The consumption of per hectare active constituent is 10～300g.
Product with logical formula I also can be used to eliminate insect, especially fly, mosquito and the cockroach in the house.
Compound insecticidal properties among the embodiment 1,2,15,40 is very remarkable, and the fabulous performance of knocking down is especially arranged.
Product with logical formula I also can be used to post the worm mite on the killing off plant.
Compound acaricidal properties among the embodiment 40 is especially remarkable, and the result is as follows for its biological test.
Compound with logical formula I also can be used to the parasitic nematode of killing off plant.
Compound with logical formula I also can be used to eliminate the parasitic mite on the animal body, as various ticks, particularly in the tick that belongs to kind of tick, the tick that glass eye tick belongs to kind, the tick of Amblyomma kind, and the tick of Rh.Or various mite classes, particularly itch mite, itch mite and skin mite.
Can be mixed with composition with the compound that leads to formula I as effective ingredient, eliminate the warm-blooded animal body with these compositions again, in the dwelling house and the parasite on the plant.
Compound with logical formula I is particularly useful for preparing insecticides.
The preparation of composition is according to the universal method in agrochemical industry, animal doctor's industry or the industry of animal foodstuff among the present invention.
Composition can be made into pulvis, particle, suspension, emulsion, solution, aerosol solution, inflammable band, bait or other compound methods of using these compounds to adopt usually.
Except that effective ingredient, generally will add vehicle and/or tensio-active agent in these compositions, but to require be non-ionic type, make each material of composition mixture can homodisperse.But vehicle liquid such as water, alcohol, hydrocarbons or other organic solvents, mineral, animal or plant oil, powdery such as talcum, clay, silicate, diatomite or inflammable solid.
The active constituent that preferably contains 0.005～10Wt% in the insecticides of the present invention.
For ease of using in the house, the present composition can be mixed with stifling composition.
Consider non-active portion, the present composition can be made into inflammable spiral sterilant, also can be made of non-combustible fibrous matrix.Under latter event, the fumigant for preparing with active constituent can be placed on heating unit such as the electric mosquito killer.
If use the volution sterilant, inert support can be by the pyrethrum residue, Tabu powder (or Machilus Thumbergii leaf powder), pyrethrum stem powder, cedar leaf powder, wood powder (as pine powder), formations such as starch and coconut shell powder.The consumption of active constituent is 0.03～1Wt%.
As to use non-combustible fibrous carrier, active constituent consumption be 0.03～95wt%.
As using in doors, composition of the present invention can be made into the diffusible oil based on active constituent, with this oil immersion bubble wick, makes its burning again.
The concentration of active constituent is preferably 0.03～95wt% in the oil.
Compound with logical formula I also can be prepared miticide composition.
Have in the product of logical formula I structure, the product among the embodiment 38 and 40 is particularly suited for doing miticide.
Compound with logical formula I also can be prepared nematicidal agent composition.
All can add one or more other sterilant in insecticides of the present invention and miticide and the nematicidal agent composition.Miticide and nematicidal agent composition can be made pulvis, particle, suspension, emulsion and solution especially.
Do the miticide time spent, the most handy wettable powder carries out foliage spray, includes the active constituent of 1-80%.Also available every liter of liquid that contains 1～500g active constituent carries out foliage spray, and the also available pulvis that contains 0.05～3% active constituent carries out foliage spray.
Do the nematocides time spent, the most handy liquid treatment soil that contains the 300-500g/l effective ingredient.
The consumption of miticide and nematocides compound per hectare 1-100 gram active constituent preferably among the present invention.
Compound with logical formula I also can be prepared the parasitic acariasis that is used for eliminating on the warm-blooded animal body, particularly eliminates the miticide composition of tick class.
In order to improve the biological activity of the product that obtains with the inventive method, can add synergistic agent general under the analogue, as: 1-(2,5,8-trioxa dodecyl)-2-propyl group-4,5-(methylenedioxy) benzene (or piperonyl butoxide) or N-(2-ethyl heptyl) two rings (2,2-1)-5-heptene-2,3-two carbimides, or 3,4-(methylenedioxy) benzyl-two-2-(2 '-n-butoxy oxyethyl group) ethyl acetal (or tropi-tal)
If be used for eliminating parasitic mite class on the animal body, the nutrition dubbed feed mixture that product is often used among the present invention in the animal foodstuff.Nutrition apparent motion species is different and different, can comprise cereal, sugar and grain, soybean, peanut, Sunflower Receptacle cake, animal meat, as the flesh of fish, and synthesizing amino acid, inorganic salt, VITAMIN and oxidation inhibitor.
So the compound with logical formula I also can be used to the preparing animal fodder mixture.
Product also can be used as biocide or growth regulator among the present invention.
Compound with logical formula I can be used to preparation and has the active composition of sterilant, miticide and nematocides, it is characterized in that, active constituent in the composition, promptly comprise the compound of at least a general formula, comprise at least a pyrethroid (pyrethrinoicl) compound of from one group of ester that following ester constitutes, selecting again for (I).These compounds are: by Pynamin alcohol ketone, 3,4,5, the ester that 6-tetrahydrochysene phthaloyl imino methyl alcohol, 5-benzyl-3-furyl alcohol, 3-phenoxy group benzylalcohol, α-Qing Ji-3-Ben Yangjibianchun class and chrysanthemumic acid class form; 5-benzyl-3-furyl alcohol and 2,2-dimethyl-3-(2-oxo-3-tetrahydrochysene sulfo-phenylidene methyl) ester that forms of cyclopropane-1-carboxylic-acid; 3-phenoxy group benzylalcohol and α-Qing Ji-3-Ben Yangjibianchun class and 2,2-dimethyl-3-(2,2-dichloroethylene) ester that forms of cyclopropane-1-carboxylic-acid; α-Qing Ji-3-Ben Yangjibianchun class and 2,2-dimethyl-3-(2,2-dibromo vinyl) ester that forms of cyclopropane-1-carboxylic-acid; The ester that 3-phenoxy group benzylalcohol and 2-rubigan-2-sec.-propyl acetate class forms; Pynamin alcohol ketone, 3,4,5,6-tetrahydrochysene phthaloyl imino methyl alcohol, 5-benzyl-3-furyl alcohol, 3-phenoxy group benzylalcohol, α-Qing Ji-3-Ben Yangjibianchun class and 2,2-dimethyl-3-(1,2,2,2-four haloethyls) ester of cyclopropane-1-carboxylic-acid formation, (wherein " halogen " expression fluorine, chlorine or bromine atom).The compound of logical formula I can its various possible stereoisomeric forms in any ratio exist, and also can be the acid of above-mentioned pyrethroid compound, pure link (oopulas).
The outstanding advantage of above-mentioned composition of the present invention is: by its multiple action, can eliminate the parasitosis of wide range, in addition, show synergism in some aspects.
According to the present invention, also can add the pyrethroid synergistic agent in the different insecticides.
Following compounds is the conventional synergistic agent of selecting for use under the analogue: 1-(2,5,8-trioxa dodecyl)-2-propyl group-4,5-(methylenedioxy) benzene (or pepper butyl ether), or N-(2-ethyl heptyl) two ring (2,2-1)-5-heptene-2,3-two carbimides, or 3,4-(methylenedioxy) benzyl-two-2-(2 '-n-butoxy oxyethyl group) ethyl acetal (or tropital).
Following embodiment illustrates the present invention, but does not limit the present invention.
Embodiment 1:
1R is along (△ Z) 3-(3-methoxyl group-3-oxo-1-propenyl)-2,2-dinethyl cyclopropane carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
The 542mg3-(1-(2-proyl) pyrryl) methyl alcohol is dissolved in 10cm 3In the methylene dichloride, be cooled to 0 °-5 ℃ then, add 795mg(1R, suitable) 2,2-dimethyl-3-(3-oxo-3-methoxyl group-1(△ Z) propenyl) cyclopropane-carboxylic acid, stirred 10 minutes.At 7 ℃, one after another drop of splashing into contained 8cm 3Methylene dichloride, the solution of 835 milligrams of dicyclohexyl carbodiimides and 5 milligrams of dimethylamino pyridines.After above-mentioned being added dropwise to complete, allowing the mixture of reaction return to room temperature and stirred 16 hours.Filter then, filtrate is concentrated into dried; Resistates dissolves with ether and filters to remove insoluble substance.Concentrated filtrate obtains the 1.112g coarse products, and the product that obtains is done used in chromatograph hexane isopropyl ether (55-45) and 2% triethylamine mixture elution in silicagel column.The product that obtains so just obtains 700 milligrams of desired products with isopropyl ether purifying once more.
(a) D=+23 °+2 ° (C=0.3% toluene)
According to the operation steps among the embodiment 1, and, obtain following product according to the specified synthetic route in back.
Embodiment 2:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1 propenyl)-cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 3:1R, along (△ Z) 2,2-dimethyl 3-(3-tert.-butoxy-3-oxo-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 4:1R, along (△ E) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 5:1R, along (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 6:1R, along 2,2-dimethyl-3-(dibromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 7:1R, along (△ Z) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 8:1R, trans 2,2-dimethyl-3-(2,2-difluoroethylene base) cyclopropane-carboxylic acid 1-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 9:1R, along 2,2-dimethyl-3-(2,2-difluoroethylene base) cyclopropane-carboxylic acid 1-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 10:2,2-dimethyl-3,3-dimethyl-cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 11: methyl esters (2S) 2-(4-difluoro-methoxy phenyl-3 Methylbutanoic acid (1-(2-proyl)-1H-pyrroles-3-yl).
Embodiment 12:1R, trans (△ Z) and △ E2,2-dimethyl-3-(3,3,3-three fluoro-2-chloro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Figure 85106411_IMG58
Figure 85106411_IMG59
Figure 85106411_IMG60
Figure 85106411_IMG61
Embodiment 12:
Figure 85106411_IMG63
α D=+6,5 ° ± 4 ° (C=0,3% toluene)
Preparation 1: the raw material 1-(2-proyl that is used for producing product 1～12)-preparation method of 1H-pyrroles-3-methyl alcohol is as follows:
Steps A: the 1-(2-proyl)-1H-pyrroles-3-carboxylic formaldehyde.
2.924 gram pyrroles-3-carboxylic formaldehyde (J.ORG.CHEM.1981,46,839) is dissolved in 45cm 3In the tetrahydrofuran (THF), the 1.488 gram sodium hydrides of adding 50% in oil stirred 10 minutes, at room temperature cooled off then 40 minutes.After the cooling, add 2.5cm 3Propargyl bromide, stirred 1 hour 30 minutes at 5 ℃, add 2 milliliters of propargyl bromides again, stirred 1 hour at 5 ℃, all pour in the water then and use dichloromethane extraction, at normal pressure solvent is distilled.In silicagel column, purify,, obtain the desired product of 2.868g like this with the elution of hexane-vinyl acetic monomer (65-35) mixture with stratography.
Step B:1-(2-proyl)-1H-pyrroles-3-methyl alcohol.
3.1 gram products in A step preparation are dissolved in 90cm 3Tetrahydrofuran (THF) and 19cm 3In the solution of water, this solution at room temperature stirred 15 minutes, added 2.517 gram potassium borohydrids then, at room temperature, stirred and after 5 hours 30 minutes reaction mixture was poured in the saturated sodium chloride aqueous solution, extracted with methyl chloride then.Extract is dry and concentrated dried at 20 ℃.Obtain the coarse products that 3.4 grams can be used.
According to the step operation of embodiment 1, and, obtain following product according to indicated synthetic route.
Embodiment 13:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters, be separated into two isomer A and B.
Embodiment 14:1R, along (△ Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 15:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2 fluoro-1-propenyl)-2,2-dinethyl cyclopropane carboxylic acid cyano group-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters, (A and B are isomer).
Embodiment 16: and sec.-propyl-4-chloro-phenyl-acetic acid (R, S)-cyano group-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 13:
Figure 85106411_IMG65
Figure 85106411_IMG66
Preparation 2: as the Alpha-hydroxy-1-(2-proyl of the raw material of embodiment 12 to 16)-1H-pyrroles-3-acetonitrile is prepared as follows:
With 0.44cm 3Acetate add the product contain B step preparation in the 510mg preparation 1,7cm 3Methyl alcohol and 2cm 3The solution of water in.Add 0.44cm again 3Acetate, and complete soln is cooled to 20 ℃.Then, add the sodium cyanide of 2.82mg, mixture was stirred 1 hour 30 minutes, be cooled to then+10 ℃ at 20 ℃.The sodium cyanide and the 2.2cm that add 1.4g again 3Acetate.Stir after 4 hours, with in the reaction mixture impouring water and use ethyl acetate extraction.Wash organic phase with water, dry again, be concentrated into dried then.Obtain the expectation product of 590mg.
With the operation steps among the embodiment 1,, obtain following product according to the synthetic route of pointing out:
(1R, suitable) 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-2-yl) methyl esters.
Embodiment 17:
Figure 85106411_IMG67
(α) D=-12 ° ± 1 ° (C=1% toluene)
Preparation 3: as raw material 2-(1-(2-proyl)-pyrryl of embodiment 17) being prepared as follows of methyl alcohol:
Steps A: 1, the 2-propynyl pyrroles
10.32g propargyl amine and 24.76g2,5-dimethoxy hydrogenation furans is at 38cm 3Be mixed together in the acetate, be warming up to 110 ℃, continue to stir for 3 quarters with heating bath.Mixture is poured 250cm into 3In the water, and add 345cm 32N sodium hydroxide, after extracted with diethyl ether, drying also is concentrated into the dried 15g of obtaining product, carries out chromatographic separation in silicagel column, with the mixture wash-out of hexane-ethyl acetate (8～2), concentrating under reduced pressure in the time of 30 ℃, obtains the expectation product of 10g.
Step B:2-(1-(2-proyl) formaldehyde pyrryl).
The 16g phosphoryl chloride is added in the dimethyl formamide of 7.64g, add 50cm again 3Methylene dichloride stirs half an hour at 0 ℃, will contain the 11g1-(2-proyl at 0 ℃ then) 40cm of pyrrole aldehyde 3Dichloromethane solution add wherein, reaction mixture refluxed half an hour be cooled to 20 ℃ then, and the aqueous solution that adds sodium acetate is (at 117cm 3The 58.6g sodium acetate is arranged) in the water.Complete soln refluxes a quarter under fully stirring again.With washing with water behind the dichloromethane extraction, dry and concentrated, obtain product and carry out chromatographic separation with silicagel column, with hexane-ethyl acetate (6～4) mixture wash-out, obtain the expectation product of 9.3g.
Step C:2-(1-(2-proyl)-pyrryl) methyl alcohol.
Prepared product in containing 1.75g step B, 50cm 3Tetrahydrofuran (THF) and 10cm 3The solution of water in add the potassium borohydrid of 0.7g.After 1 hour, add the 0.35g potassium borohydrid 20 ℃ of stirrings again, and continue to stir 30 minutes at 20 ℃.This solution is saturated with sodium-chlor then, and uses ethyl acetate extraction.Organic phase is merged dry.Under reduced pressure, make the expectation product of isolating 1.78g 40 ℃ of solvent evaporated.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below:
Embodiment 18:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid 2-cyano group (1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 19:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid 2-cyano group (1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 20:1R, along 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl)-2,2-dinethyl cyclopropane carboxylic acid 2-cyano group (1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 21:1R, along (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid 2-cyano group (1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Figure 85106411_IMG68
Figure 85106411_IMG69
Figure 85106411_IMG70
α D=+35 ° ± 2 ° (C=0.5% toluene)
Preparation 4: as the 4-methylol-1-(2-proyl of raw material)-1H-pyrroles-2-nitrile is prepared as follows:
Steps A: the 1-(2-proyl)-1H-pyrroles-2-nitrile.
The 2-cyanopyrrole of 51.57g (it prepares according to the chemical engineering magazine of Canada (Can.J.chem) 59, the method for pointing out in 2763(1981)), the triphenyl phosphine of 146.9g and the propargyl alcohol of 43.95g mix, and add 420cm 3Tetrahydrofuran (THF), complete soln be cooled to+and 5 ℃, in the time of 0～5 ℃, in half an hour, add the azo connection carboxylic acid, ethyl ester of 97.5g.Make temperature be raised to room temperature, continue to stir 18 hours.Vapourisation under reduced pressure falls solvent, obtains the crystalline residue and also filters with ether dissolution.After filtrate concentrates, obtain a kind of oily matter, separate in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, with hexane-ethyl acetate (7～3) mixture wash-out, obtain 34g expectation product.
Step B:4-formyl-((2-propynyl)-1H-pyrroles-2-nitrile.
At 6cm 3Anhydrous methylene chloride in contain 2.36g aluminum chloride mixture be cooled to-78 ℃.In this mixture, be added in 8cm 3The solution and the 0.5cm of the product for preparing in the 1.3g steps A in the methylene dichloride 3Nitromethane 99Min..Be dissolved in 15cm-55 ℃ of addings then 3The 1.49g dichlormetbylether of methylene dichloride.Reaction mixture was kept 1 hour at-60 ℃, made it be warmed up to 20 ℃ then, kept 18 hours in this temperature.Then reaction mixture is poured in the water, stirred, use 33cm 3The 2N sodium hydroxide pH value that neutralizes is 7.Use dichloromethane extraction; Extraction liquid is with the potassium bicarbonate solution washing of 1M, and is dry then.Be concentrated into dried.Obtain the product of 1.5g, with dupentane washing, drying.Obtain the expectation product of 1.1g, fusing point is 97 ℃.
Step C:4-(methylol)-the 1-(2-proyl)-1H-pyrroles-2-nitrile.
The potassium borohydrid of 372mg is added at 40cm 3Tetrahydrofuran (THF) and 5.5cm 3Water contains in the solution of the 546mg product for preparing among the B in steps.At room temperature continue to stir after 15 minutes, add 50cm 3Saturated aqueous sodium chloride.Use ethyl acetate extraction, drying, concentrated extract obtains the expectation product of 600mg to doing.
Embodiment 22:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group-(2-cyano group-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
The 4-of 447mg formyl-1-(2-proyl)-1H-pyrroles-2-nitrile pours 13cm into 3Toluene in, add then: the sodium cyanide of 173mg, the bromination tetrabutylammonium of 38mg, the 1R of 894mg, cis 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropanecarbonyl chloride and 0.13cm 3Water.After stirring 18 hours under 20 ℃, add 100cm 3Benzene, dry and be concentrated into dried complete soln thereafter.Obtain the expectation product of 1017mg.
(α) D=+9 ° ± 2 ° (C=0.3% toluene)
With the operation steps of embodiment 1, and, obtain following product according to the following synthetic route of pointing out:
Embodiment 23:1R, along (△ Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid cyano group-(2-cyano group-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 24:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid cyano group-(2-cyano group-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 25:1R, along (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid cyano group-(2-cyano group-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Figure 85106411_IMG71
α D=+39 ° ± 1 ° (C=1% toluene)
With the operation of embodiment 1,, obtain following product according to the synthetic route of pointing out below:
Embodiment 26:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 26:
Figure 85106411_IMG73
α D=-5.5 ° ± 1 ° (C=1% toluene)
Preparation 5: the 3-methylol-1-(2-proyl that in embodiment 25 to 28, is used as raw material)-1H-pyrroles-2-nitrile is prepared as follows:
Steps A: 2-formyl-1-(2-proyl)-1H-pyrroles-3-methyl-formiate.
1 of 7.05g, the propargyl amine of 1-dimethoxy-2-oxo-methyl-butyrate and 4.4g is at 20cm 3Solution in the water is cooled to 20 ℃, stirs 10 minutes.Acetate 1.2-two bromo-ethyl esters with 0.9 gram dropwise add then, keep stirring at 20 ℃ reaching 24 hours.Then complete reaction mixture is poured in the water, used ethyl acetate extraction, extraction liquid washs with sodium hydrogen carbonate solution, drying, and be concentrated into dried.Obtain the 10g product, carry out chromatographic separation in the silicon post, with hexanaphthene-ethyl acetate (75～25) mixture wash-out, obtain the expectation product of 1.9g, its fusing point is 76 ℃.
Step B:1-(2-proyl)-2-oximido methyl-3-pyrrole methyl formate.
The product 2g of steps A preparation, hydroxyl hydrochloride 725mg and 11cm 3Anhydrous pyridine at room temperature stirred 3 hours.Under reduced pressure concentrate pyridine.Resistates is with acetic acid ethyl dissolution and wash with water, and is dry then and concentrate.Obtain 2.3g expectation product, its fusing point is 88～98 ℃.
Step C:2-cyano group-1-(2-proyl)-1H-pyrroles-3-methyl-formiate.
To be dissolved in 2cm 33.54g thionyl chloride in the methylene dichloride and be dissolved in 15cm 3The 2.2g product that previous step in the methylene dichloride obtains mixes, the solution that obtains is cooled to 20 ℃, at room temperature stirred reaction mixture is 24 hours, concentrate then, thereby obtain the 1.8g product, it is carried out chromatographic separation in silicagel column, and with hexanaphthene-ethyl acetate (7～3) mixture wash-out.Obtain 1.430g expectation product, fusing point is 112 ℃.
Step D:3-(methylol)-the 1-(2-proyl)-1H-pyrroles-2-nitrile.
The product 830mg that contains the previous step preparation, 8cm 3Tetrahydrofuran (THF) and 2cm 3The mixture of water stirred 24 hours at 20 ℃, added the 280mg lithium borohydride then, was adding 30cm 3Ethyl acetate after, dry and be concentrated into driedly, obtain the product of 750mg, it is carried out chromatographic separation in the silicon post, and, obtains the expectation product of 138mg by the mixture wash-out of hexanaphthene and ethyl acetate (6-4), fusing point is 65 ℃.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below:
Embodiment 27:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 28:1R, along 2,2-dimethyl 3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-nitro-1H-pyrroles-4-yl) methyl esters.
Embodiment 29:1R, along (△ Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid [2-nitro-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 30:1R, along (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid [2-nitro-1-(2-propynyl)-1H-pyrroles-4-yl) methyl esters.
Figure 85106411_IMG74
Figure 85106411_IMG75
Preparation 6: as the 2-nitro-1-(2-proyl of the raw material among the embodiment 29 to 32)-1H-pyrroles-4-methyl alcohol is prepared as follows:
The A step: 2-nitro-1-(2-proyl)-1H-pyrroles-4-formaldehyde.
In the time of+5 ℃, the oil that contains the 310mg sodium hydride with 50% is added to the 15Cm of the 2-nitro-1H-pyrroles-4-formaldehyde that contains 0.9g 3The solution of tetrahydrofuran (THF) in.2-nitro-1H-pyrroles-4-formaldehyde wherein is that (Bull.Soc.Chim France) goes up described method preparation for (1972) the 283rd～291 pages according to France's " chemical association circular ".After making temperature of charge rise to room temperature, add 0.53Cm 3Propargyl bromide.At 60 ℃ reaction mixture was stirred 6 hours, then, stirred 18 hours at 20 ℃.After filtration, be concentrated into do after, obtain the product of 1g.This product carries out chromatographic separation in silicagel column, with the mixed solution wash-out of heptane and ethyl acetate (1-1), obtain the expection product of 450mg.
Fusing point: 128 ℃
The B step: 2-nitro-1-(2-proyl)-1H-pyrroles-4-methyl alcohol.
The 270mg POTASSIUM BOROHYDRIDE is added to the product that is prepared by the 450mgA step, 30Cm 3Tetrahydrofuran (THF) and 4Cm 3In the solution that water is formed, continue to stir after 15 minutes, in the saturated solution with total overall reaction thing impouring sodium-chlor, use ethyl acetate extraction, the extract drying is also concentrated, obtain the expection product of 455mg.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below.
Embodiment 31:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group-(2-nitro-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 32:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (R, S)-cyano group-(2-nitro-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Figure 85106411_IMG77
Preparation 7: the Alpha-hydroxy-1-(2 proyl that is used as raw material among the embodiment in front)-1H-pyrroles-5-nitro-3-acetonitrile is prepared as follows:
2-nitro-1-(2-proyl with 801mg)-and 1H-pyrroles-4-formaldehyde, 15Cm 3Methyl alcohol and 3Cm 3Water mix, add 3.6Cm then 3Acetate, the total overall reaction thing is cooled to+5 ℃, add the sodium cyanide of 2.2g, allow temperature rise to 20 ℃, kept 4 hours, with in the reaction mixture impouring frozen water, use extracted with diethyl ether then, ether washes with water mutually, drying, concentrated after, obtain the expection product of 920mg.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below.
Embodiment 33:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (3-nitro-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 33:
Figure 85106411_IMG78
α D=-26.5 ° ± 2 ° (toluene of C=0.5%)
Preparation 8: as the 3-nitro-2-(2-proyl of raw material)-1H-pyrroles-4-methyl alcohol is prepared as follows:
The A step: 3-nitro-1-(2-proyl)-1H-pyrroles-4-formaldehyde.
Pour 3-nitro-1H-pyrroles-4-formaldehyde of 826mg (according to " chemical association circular " (Bull.Soc.Chim) the method preparation in (1972) the 283rd～291 pages) into 40Cm 3Tetrahydrofuran (THF) in, then at+5 ℃, add 50% the oil that contains the 280mg sodium hydride, with temperature 20 ℃ keep 1 hour after, add the propargyl bromide of 1.19g.Reactant was stirred 18 hours at 20 ℃, filter then, concentrate, in silicagel column, carry out chromatographic separation,, obtain the product of 800mg, fusing point: 120 ℃ with the mixed solution wash-out of hexane and ethyl acetate (1-1).
The B step: 3-nitro-1-(2-proyl)-1H-pyrroles-4-methyl alcohol.
At 20 ℃, the POTASSIUM BOROHYDRIDE of 242mg is added to product by the preparation of 400mgA step, 30Cm 3Tetrahydrofuran (THF) and 4Cm 3In the solution that water is formed, at room temperature, mixture was stirred 15 minutes, in the time of 20 ℃, add 10Cm 3The saturated solution of sodium-chlor also stirred 5 minutes, and is dry, concentrated behind ethyl acetate extraction, obtains the expection product of 410mg.Fusing point: 60 ℃.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below.
Embodiment 34:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group-(3-nitro-1-(2-proyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 34:
Figure 85106411_IMG79
Figure 85106411_IMG80
α D=-28.5 ° ± 1 ° (toluene of C=1.3%)
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below.
Embodiment 35:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid ((1-propadiene base-1H-pyrroles-3-yl) methyl esters.
Embodiment 36:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid ((1-propadiene base)-1H-pyrroles-3-yl) methyl esters.
Embodiment 35:
Figure 85106411_IMG81
α D=+17 ° ± 1 ° (toluene of C=0.8%)
Embodiment 36:
Figure 85106411_IMG82
α D=-13.5 ° ± 1 ° (toluene of C=1%)
Preparation 9: as the 3-(1-(propadiene base of raw material) pyrryl) methyl alcohol is prepared as follows:
A step: 1-propadiene base-1H-pyrroles-3-formaldehyde.
1g pyrroles-3-formaldehyde is dissolved in 25Cm 3Tetrahydrofuran (THF) in, at room temperature stirred 15 minutes, be cooled to 0 °～5 ℃ then, add 50% the oil that contains the 528mg sodium hydride, and under cooling, stirred 10 minutes, make temperature rise to room temperature then, restir is 40 minutes under nitrogen, adds 1Cm 3Propargyl bromide, stirred 2 hours at 40 °～50 ℃, then with reaction mixture impouring 15Cm 3In the water, use dichloromethane extraction.With the extraction liquid drying, desolventize concentratedly by steaming, in silicagel column, carry out chromatographic separation, with the mixed solution wash-out of hexane and ethyl acetate (7-3), obtain the expection product of 1.166g.
B step: methyl alcohol pyrryl 3-(1-(propadiene base)).
The product of the A step of 1.009g preparation is dissolved in 35Cm 3Tetrahydrofuran (THF) and 6.7Cm 3The solution of water in, 20 ℃ stir 15 minutes after, add the POTASSIUM BOROHYDRIDE of 523mg, and stirred 2 hours 15 minutes at 20 ℃.Then, in the saturated aqueous solution with complete reaction mixture impouring sodium-chlor, use dichloromethane extraction, drying, concentrate after, obtain the product of 0.899g, this product directly uses.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below.
Embodiment 37:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-Trifluoromethyl-1 H-pyrroles-3-yl) methyl esters.
Embodiment 38:1R, along (△ E) 2,2-dimethyl-3-(3-oxyethyl group-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-Trifluoromethyl-1 H-pyrroles-3-yl) methyl esters.
Figure 85106411_IMG83
Figure 85106411_IMG84
α D=+1 ° ± 1 ° (toluene of C=0.5%)
Preparation 10:1-(2-proyl)-2-trifluoromethyl-3-pyrroles's methyl alcohol.
The A step: the 1-(2-proyl)-2-trifluoromethyl-3-minaline ethyl ester.
At 10 ℃, with 1.8Cm 33-oxo-4,4,4-trifluoroacetic acid ethyl ester adds 3.15Cm 32-propargylamine and 10Cm 3In the solution of water, stirred 10 minutes, add 1.65Cm then 3Acetate 1,2-dibromo ethyl ester.Mixture heating up to 70 ℃ continues 45 minutes, uses ethyl acetate extraction then, after the extraction liquid drying concentrates, obtains the oily matter of 6g, and this oily matter carries out chromatographic separation in silicagel column, obtain the expection product of 360mg.
The B step: the 1-(2-proyl)-2-trifluoromethyl-3-pyrroles's methyl alcohol.
At 5 ℃, will contain the 10Cm of product of the A step preparation of 1.74g 3The lithium aluminum hydride of tetrahydrofuran solution and 270mg mixes, and this mixture at room temperature stirred 3 hours.Cooling then adds 10Cm 3Ethyl acetate, the saturated solution of several Seignette salts is wherein arranged.
Separate and concentrated postcooling, obtain the oily matter of 2.4g, this oily matter carries out chromatographic separation in silicagel column, with the mixture wash-out of hexanaphthene-ethyl acetate (8-2), obtains the expection product of 40mg, fusing point: 63 ℃.
According to the operation steps of front, can prepare following product.
Embodiment 39:
Figure 85106411_IMG85
Embodiment 40:1R, along (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluorine propenyl)-cyclopropane-carboxylic acid (2-Trifluoromethyl-1-(2-propynyl)-1H-pyrroles-3-yl) methyl esters.
With the dicyclohexylcarbodiimide of 455mg, the Dimethylamino pyridine of 3mg and 5Cm 3The solution formed of anhydrous methylene chloride dropwise join in ice bath in the refrigerative mixture, this mixture contains the 1-(2-proyl of 450mg)-2-trifluoromethyl-3-pyrroles's methyl alcohol, the 1R of 570mg, along (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid and 4Cm 3Anhydrous methylene chloride, allow the temperature of reaction mixture rise to room temperature and stirred 5 hours, remove by filter the precipitation of generation.Dissolve filtrate with isopropyl ether, concentrate, then insoluble material is removed by filter, filtrate is carried out chromatographic separation after concentrating in silicagel column, with the mixed solution wash-out of hexane and ethyl acetate (9-1), obtains the expection product of 518mg.
Embodiment 41:1R, along 2,2-dimethyl-3-vinyl cyclopropane-carboxylic acid (2-Trifluoromethyl-1-(2-propynyl)-1H-pyrroles-3-yl) methyl esters.
According to the operation steps of embodiment 1,,, the 1-(2-proyl of 2-dimethyl-3-vinyl cyclopropane-carboxylic acid and 800mg) along 2 with the 1R of 610mg-2-trifluoromethyl-3-pyrroles's methyl alcohol makes raw material, obtains the expection product of 1.28g.
(α) D=+9 ° (0.2% toluene)
Embodiment 42:1R, along () 2,2-dimethyl-3-(3-methoxyl group-(3-oxo-1-propenyl)) cyclopropane-carboxylic acid (2-Trifluoromethyl-1-(2-propynyl)-1H-pyrroles-3-yl) methyl esters.
Operation steps according to embodiment 1,1R with 860mg, along (△ Z) 2,2-dimethyl-3-(3-methoxyl group)-the 3-oxo)-the 1-(2-proyl of 1-propenyl cyclopropane-carboxylic acid and 800mg)-2-trifluoromethyl-3-pyrroles's methyl alcohol makes raw material, obtains the expection product of 1.18g.
(α) D=+17.5 ° (0.7% toluene)
Embodiment 43:1R, along (Z) 2,2-dimethyl-3-((2-chloro-3,3,3-trifluoro)-1-propenyl) cyclopropane-carboxylic acid (2-cyano group-1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
(2-cyano group-1-(2-proyl)-1H-pyrroles with 430mg)-and the 1R of 3-methyl alcohol and 600mg, along (Z) 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro)-1-propenyl) cyclopropane-carboxylic acid adds 12Cm 3Methylene dichloride in, at 0 ℃, the Dimethylamino pyridine that dropwise adds the dicyclohexylcarbodiimide of 509mg and 3mg in the solution that obtains is in 2Cm 3The solution that forms in the methylene dichloride.In the time of 20 ℃, reactant was stirred 5 hours, filter then, filtrate is concentrated into drying, adds isopropyl ether, removes by filter insoluble by product, filtrate is concentrated into drying, add the mixed solution of hexane and isopropyl ether (1-1), refilter, and filtrate is concentrated into drying, resistates carries out chromatographic separation in silicagel column, mixed solution wash-out with hexane and isopropyl ether (1-1) still contains a spot of urea in the product that obtains, to wherein adding 2Cm 3Isopropyl ether, by removing by filter the insoluble substance of generation, under reduced pressure distill then filtrate be concentrated into drying, obtain the expection product of 896mg.
(α) D=+7 ° (toluene of C=0.4%)
Ultimate analysis: C 18H 16ClF 3N 2O 2: 884.789
Calculated value: C%56.19 H%4.19 cl%9.21 F%14.8 N%7.28
Enforcement value: 56.3 4.4 9.0 14.9 7.2
Embodiment 44:1R, along (E) 2,2-dimethyl-3-(3-oxyethyl group-2-fluoro-3-oxo-1-propenyl) cyclopropane-carboxylic acid cyano group-(1-(2-proyl)-1H-pyrroles-3-yl) methyl esters.
With (R, S) alpha-cyano (2-cyano group-1-(2-proyl)-1H-pyrroles-3-yl)-4-methyl alcohol of 2g and the 1R of 2.48g, along (E) 2,2-dimethyl-3-(3-oxyethyl group-2-fluoro-3-oxo-1-propenyl) cyclopropane-carboxylic acid is dissolved in 30Cm 3Methylene dichloride in, then under 10 ℃, in about 30 minutes, add the dicyclohexylcarbodiimide of 2.22g and the 4-Dimethylamino pyridine of 13mg be dissolved in 30Cm 3Methylene dichloride in solution.Stirred 18 hours at 20 ℃, be concentrated into drying after the filtration.Add ether, refilter, be concentrated into drying.The product that obtains at last carries out chromatographic separation in silicagel column, with the mixed solution wash-out of hexane and ethyl acetate (7-3), obtain the acid of 3.14g expection.
(α) D=+40 ° (C=1% toluene)
Ultimate analysis: C 21H 20FN 3O 4: 397.409
Calculated value: C%63.47 H%5.07 F%4.78 N%10.57
Experimental value: 63.4 5.1 4.8 10.3
Preparation 11: the used 4-hydroxyl-1-(2-proyl of raw material in embodiment 44)-1H-pyrroles-5-cyano group-3-acetonitrile can be prepared as follows:
1-(2-proyl with 6g)-and 1H-pyrroles-2-nitrile, 125Cm 3Methyl alcohol and 25Cm 3Water mix, be cooled to then+5 ℃, and add 15.2Cm 3Acetate, then the sodium cyanide with 9.3g divides several parts of addings, in 4 hours, the temperature of reactant is risen to 20 ℃, in the water with 1 liter of complete reaction mixture impouring, use extracted with diethyl ether then, with the organic phase drying, and be concentrated into drying, obtain the expection product of 7g.Fusing point: 60 ℃.
Embodiment 45:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxo-3-tert.-butoxy-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-3-trifluoromethyl)-1H-pyrroles-4-yl) methyl esters.
With the 1g1-(2-propenyl)-3-Trifluoromethyl-1 H-pyrroles-4-methyl alcohol and 1.5g1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxo-3-tert.-butoxy-propenyl) cyclopropane-carboxylic acid is dissolved in 25Cm 3Methylene dichloride in, then,, little by little add, and stirred 15 minutes at 0 ℃ by the dicyclohexylcarbodiimide of 1.3g and the mixture of 4-Dimethylamino pyridine in methylene dichloride of 150mg at 0 ℃, in the time of 20 ℃, stirred 2 hours then.Reaction mixture is filtered, and filtrate is concentrated into dried.Add isopropyl ether, its temperature is fallen 0 ℃, and then filter, under reduced pressure distillation is concentrated into filtrate dried.The product that obtains carries out chromatographic separation twice in silicagel column, with the mixed solution wash-out of hexane and ethyl acetate (35～15), obtain the expection product of 1.7g.
(α) D=40.5 ° (C=0.7% chloroform)
Ultimate analysis: C 22H 25F 4NO 4: 443.443
Calculated value: C%59.6 H%5.68 F%17.14 N%3.16
Experimental value: 59.2 5.7 17.1 3.2
Preparation 12: as at the 1-(2-proyl of embodiment 45 raw materials)-3-Trifluoromethyl-1 H-pyrroles-4-methyl alcohol can prepare with following method:
A step: 3-Trifluoromethyl-1 H-pyrroles-4-ethyl formate.
With 7.4g4,4,4-three fluoro-(E)-butenoic acid ethyl (E.T.McBEE, " U.S. association magazine " be the 76th volume (J.Am.Soc), 3724 pages (1954)) and 8.6g tosyl group methyl carbylamine are added to 200Cm 3Methyl-sulphoxide and ether (1-2) mixture in, little by little add 50% the vaseline oil that contains the 2.9g sodium hydride then, have hydrogen to generate, in the time of 20 ℃, stir after 30 minutes, add several acetate.Then, in complete reaction mixture impouring frozen water, use extracted with diethyl ether.Extract is concentrated into dried by distillation under reduced pressure.Residuum carries out chromatographic separation in silicagel column, with the mixed solution wash-out of hexane and ethyl acetate (7-3), obtain the expection product of 6.6g.Fusing point: 165 ℃.
Ultimate analysis: C 8H 8F 3NO 2: 207.154
Calculated value: C%46.39 H%3.85 F%27.51 N%6.76
Experimental value: 46.5 3.9 27.1 6.8
The B step: the 1-(2-proyl)-3-Trifluoromethyl-1 H-pyrroles-4-ethyl formate.
3-Trifluoromethyl-1 H-pyrroles-4-ethyl formate that 1g is obtained in the A step is added to 10Cm 3Tetrahydrofuran (THF) in, in the time of 0 ℃, little by little add 50% the vaseline oil that contains the 240mg sodium hydride, in the time of 20 ℃, stir after 30 minutes, be cooled to 0 ℃, with 0.45Cm 3Propargyl bromide be dissolved in 1Cm 3The solution of tetrahydrofuran (THF) be added in the reactant, stirred 30 minutes at 0 ℃, stirred 1 hour at 20 ℃ then, be cooled to 0 ℃ again, add some sodium hydrides, under this temperature, stirring adding 0.45Cm 3Propargyl bromide be dissolved in 1Cm 3The solution of tetrahydrofuran (THF).With in the whole impouring water of reactant, use dichloromethane extraction then, under reduced pressure distillation is concentrated into extraction liquid dried.Residuum carries out chromatographic separation in silicagel column, with the mixed solution wash-out of hexane and ethyl acetate (8-2), obtain the expection product of 0.950mg.Fusing point=58 ℃.
The C step: the 1-(2-proyl)-3-Trifluoromethyl-1 H-pyrroles-4-methyl alcohol.
At 0 ℃, the lithium aluminum hydride of 1.95g little by little is added to the 1-(2-proyl that 12.6g is obtained by the B step)-3-Trifluoromethyl-1 H-pyrroles-4-ethyl formate is in 65Cm 3The solution of tetrahydrofuran (THF) in, stirred 2 hours at 20 ℃, add 10Cm 3Ethyl acetate with remove may be excessive hydride, then in the saturated solution with reaction mixture impouring Seignette salt, behind ethyl acetate extraction, under reduced pressure distill extraction liquid is concentrated into dried.Residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, with the mixed solution wash-out of hexane and ethyl acetate (7～3), obtains the expection product of 5.7g.Fusing point=45 ℃.
With the operation steps of embodiment 43, or method (II) or (III), according to the synthetic route of pointing out below, obtain following product.
Embodiment 46:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group ((1-benzoyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 47:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl-2-methoxyl group-2-oxo-1H-pyrroles-3-yl) methyl esters.
Embodiment 48:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R or S)-cyano group-(1-(2-proyl-2-methoxycarbonyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 49:1R, anti-(E, 1/3) (Z, 2/3), 2,2-dimethyl-3-(2-chloro-2-trifluoromethyl vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 50:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group (1 ,-(2-propenyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 51:1R, along 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 52:1R, along 2,2-dimethyl-3-(2-fluoro-2-oxygen base-2-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-cyano group-1H-pyrroles-3-yl) methyl esters.
Figure 85106411_IMG86
Figure 85106411_IMG87
(α) D=-6 ° (C=0.9% toluene)
Preparation 13:
Embodiment 46 used raw material alpha-cyano-3 ((1-benzoyl)-pyrroles) methyl alcohol can be made by following method.
Steps A: 1-benzoyl-3-formyl radical pyrroles,
500mg3-formyl radical pyrroles is dissolved in 10Cm 3Tetrahydrofuran (THF) in, then at 20 ℃, disposable adding is dispersed in sodium hydride 227mg in the vaseline oil with 55% amount.Have gas to emit this moment, after stirring 15 minutes, at 5 ℃, dropwise adds 0.58Cm 3Benzoyl chloride is at 2Cm 3Solution in the tetrahydrofuran (THF) stirred 2 hours at 20 ℃, and dilute with water is used extracted with diethyl ether, and underpressure distillation is concentrated into drying, and residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 7: 3 hexanes and ethyl acetate mixture wash-out, obtains 558mg purpose product.
Nuclear magnetic resonance spectrum (tri-chlorination deuterium)
Represent hydrogen on 4 of the pyrroles with 6.8 to 6.9ppm peak.
Represent the hydrogen on 5 of the pyrroles at the peak at 7.4ppm place.
The hydrogen on the phenyl is represented at from 7.5 to 8.0 peak.
Represent the hydrogen on 2 of the pyrroles at the peak at 7.93ppm place.
Represent the hydrogen on the formyl at the peak at 10.0ppm place.
Step B: alpha-cyano-3-((1-benzoyl)-1-pyrroles) methyl alcohol.
1-benzoyl-3-formyl radical pyrroles and 12Cm with 0.9g 3Methyl alcohol, 4Cm 3Water, 1Cm 3Acetate and 0.47g sodium cyanide mix, stirred 4 hours down at 20 ℃, reaction mixture is poured in the icy salt solution, use ethyl acetate extraction, extraction liquid is concentrated into dried with underpressure distillation, residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtains 0.57g purpose product with 1: 1 hexane and eluent ethyl acetate, fusing point: 85 ℃.
Nuclear magnetic resonance spectrum (tri-chlorination deuterium)
Peak at the 5.5ppm place is represented
Figure 85106411_IMG88
Hydrogen
Represent the hydrogen on 4 of the pyrroles at the peak at 6.5ppm place.
The hydrogen of having represented phenyl from 7.3 to 7.9ppm peak.
Embodiment 48:
Figure 85106411_IMG89
(α) D=-36.5 ° (C=0.4% toluene).
Preparation 14:
Be used as the 4-(hydroxymethyl of the raw material of embodiment 47)-the 1-(2-propenyl)-1H-pyrroles-2-methyl-formiate can be prepared as follows.
Steps A: 1H-pyrroles-2-methyl-formiate
With cold concentration be 45nmoles/l 2-chloroformyl-the solution 40Cm of 1H-pyrroles in methylene dichloride 3Under cooling, dropwise join 4.3Cm 3Pyridine and 3.5Cm 3In the methanol mixture, reaction mixture is water and 6Cm successively 3Dichloromethane extraction is used in the sodium hydroxide washing of 1N.Organic phase is carried out drying, is concentrated into driedly, and residuum separates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum.With the mixture wash-out of 8: 2 hexanes and ethyl acetate, obtain the expection product of 4.014g, 74 ℃ of fusing point: ≌.
Step B:
The 1-(2-proyl)-1H-pyrroles-2-methyl-formiate.
With 3.302g1H-pyrroles-2-methyl-formiate, be dissolved in 40Cm 3Tetrahydrofuran (THF) in, be dispersed in sodium hydride suspension 1.422g in the vaseline oil 0 ℃ of adding with 50% amount then, stirred 1 hour down at 20 ℃, dropwise add 2Cm 3Propargyl bromide at 10Cm 3Solution in the tetrahydrofuran (THF) stirred 1 hour down at 50 ℃, was adding 5Cm 3Propargyl bromide after, reaction mixture is poured in the water, and uses dichloromethane extraction, the extraction liquid underpressure distillation is concentrated into dried.Residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtains 2.993g purpose product with 9: 1 hexanes and ethyl acetate mixture wash-out.
Nuclear magnetic resonance spectrum (tri-chlorination deuterium)
Peak at the 2.37-2.42-2.46ppm place represents-hydrogen of H-C ≡ CH.
Peak at 3.8ppm is represented-OCH 3Hydrogen.
Peak at the 5.16-5.20ppm place is represented-CH 2The hydrogen of-C ≡ CH-C.
Represent the hydrogen on 4 of the pyrroles from 6.1 to 6.2ppm peak.
Represent the hydrogen on 3 and 5 of the pyrroles from 6.9 to 7.0ppm and 7.1 to 7.2ppm peak.
Step C:4-formyl radical-1-(2-proyl)-1H-pyrroles-2-methyl-formiate.
1-(2-proyl with 2.981g)-1H-pyrroles-2-methyl-formiate is at 11Cm 3Solution in the methylene dichloride and 1Cm 3Nitromethane 99Min. is at 4Cm 3Solution in the methylene dichloride mix solution A.The aluminum chloride of 4.312g is suspended in 11Cm 3In the methylene dichloride, suspension is cooled to-62 ℃, dropwise adds solution A, adds then and contains 2.3Cm 3Dichloromethyl ether and 19Cm 3The solution of methylene dichloride.Stirred 2 hours down at-60 ℃, stirred at ambient temperature again 1 hour.Add 200Cm 3Methylene dichloride and 300Cm 3Water, using 11Cm 310N sodium hydroxide in and after, stir and decant, organic phase is washed with potassium bicarbonate solution, and is dry and be concentrated into driedly, residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 7: 3 hexanes and ethyl acetate elution, obtains 2.734g and expects product.
Step D:4-(hydroxymethyl)-the 1-(2-proyl)-1H-pyrroles-2-methyl-formiate.
With 747mg4-formyl radical-1-(2-proyl)-1H-pyrroles-2-methyl-formiate is dissolved in 12Cm 3Tetrahydrofuran (THF) and 3.3Cm 3Water in, add the potassium borohydrid of 426mg, stirred 5 hours down at 20 ℃.Reactant is poured in the saturated sodium chloride aqueous solution, uses dichloromethane extraction, and extraction liquid is concentrated into dried with underpressure distillation, obtains the purpose product of 758mg, fusing point: 77 ℃.
Infrared spectra (chloroform)
At 3609Cm -1The place absorbs expression-OH.
At 3307Cm -1The place absorbs expression-C ≡ CH.
At 2110Cm -1The place absorbs expression-C ≡ C
At 1702Cm -1The place absorbs expression-C=O
At 1445Cm -1The place absorbs expression-CH 3
1564,1476Cm -1The place absorbs the expression heterocycle.
Figure 85106411_IMG90
Embodiment 50:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group (1-(2-propenyl)-1H-pyrroles-3-yl) methyl esters.
With 1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group (1-(2-proyl)-1H-pyrroles-3-yl) methyl esters, 682mg and 25Cm 3The De diox mixes in hydrogenation unit, adds then with 5% amount to be attached to palladium 167mg and 1/10Cm on the barium sulfate 3Quinoline.After the hydrogen cleaning and stirring, when having absorbed 35Cm 3During hydrogen, stop hydrogenation.Reactant filters, and the filtrate decompression distillation is concentrated into dried, and residuum with the mixture of 85: 15 hexanes and ethyl acetate and 2% triethylamine wash-out, obtains the purpose product of 535mg, 60 ℃ of fusing points after the enterprising circumstances in which people get things ready for a trip spectrum of silica gel is separated.(α) D=-54 ° (C=0.6% toluene).
Embodiment 52:
Figure 85106411_IMG92
(α) D=+18 ° (C=0.4% toluene)
According to the step of embodiment 43 or according to process (II), the synthetic route that (III) or (IV) pointed out below can obtain following product:
Embodiment 53:1R, suitable, (E) 2,2-dimethyl-3-(2-fluoro-2-oxyethyl group-2-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-propenyl)-2-cyano group-1H-pyrroles-4-yl) methyl esters.
Embodiment 54:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (1-(2-propenyl)-2-cyano group-1H-pyrroles-4-yl) methyl esters.
Embodiment 55:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-propenyl)-2-cyano group-1H-pyrroles-4-yl) methyl esters.
Embodiment 56:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-propenyl)-1H-pyrroles-3-yl) methyl esters.
Embodiment 57:1R, along (E), 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid 1-(1-(2-proyl)-2-cyano group-1H-pyrroles-4-yl) propine-2-ester.
Embodiment 58:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (R.S)-cyano group-(1-(2-propenyl)-2-cyano group-1H-pyrroles-4-yl) methyl esters.
Embodiment 59:1R, along 2,2-dimethyl-3-(2, the rare base of 2-two bromo second) cyclopropane-carboxylic acid (1-(2-proyl)-2-cyano group-1H-pyrroles-4-yl)-the 1-ethyl ester.
(α) D=25 ° (C=0.7% toluene)
Preparation 15:
(2-cyano group-1-(2-propenyl)-1H-pyrroles-4-methyl alcohol as embodiment 53 raw materials) can be prepared as follows:
Steps A: 2-cyano group-1-(2-propenyl)-1H-pyrroles-4-formaldehyde.
At 20g2-cyano group-4-formyl radical-1H-pyrroles and 250Cm 3Be suspended in suspension in the vaseline oil bit by bit to add the 8.01g50% sodium hydride in the mixture of tetrahydrofuran (THF), add 14Cm down at 20 ℃ then 3Allyl bromide 98 and 20Cm 3The mixture of tetrahydrofuran (THF) stirred 2 hours at 60 ℃, and then added 14Cm 3Chlorallylene, 60 ℃ of restir 2 hours.Then reactant is poured into and used dichloromethane extraction in the water, this extraction liquid underpressure distillation is concentrated into dried, and residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtains 24.1g purpose product with 6: 4 hexanes and eluent ethyl acetate.
Step B: (2-cyano group-1-(2-propenyl)-1H-pyrroles-4-methyl alcohol).
With 14.1g4-formyl radical-2-cyano group-1-(2-propenyl)-1H-pyrroles, 160Cm 3Tetrahydrofuran (THF) and 43Cm 3Water mixes, and adds the 481mg lithium borohydride, stirs 30 minutes down at 20 ℃.Add the 493mg lithium borohydride again, 20 ℃ of restir 20 minutes, add ethyl acetate then, use ethyl acetate extraction after it is poured into saturated sodium chloride aqueous solution, underpressure distillation is concentrated into dried, residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 55: 45 hexanes and ethyl acetate mixture elution, obtains 13.882g purpose product.
Nuclear magnetic resonance spectrum (tri-chlorination deuterium)
Peak at the 1.97ppm place represents-hydrogen of OH
Peak at the 4.5ppm place is represented-CH 2The hydrogen of O
Peak at the 4.5-4.7ppm place is represented-N=CH 2Hydrogen
Peak at 5.0～5.4ppm place is represented=CH 2Hydrogen
Represent from the peak of 5.7-6.2ppm-hydrogen of CH=
The hydrogen of representing aromatics at the peak at 6.8-6.9ppm place
Embodiment 54:
Figure 85106411_IMG94
Embodiment 56:
Figure 85106411_IMG95
(α) D=+15.5 ° (C=0.4% toluene)
Preparation 16:
Be used as Alpha-hydroxy-(the 2-cyano group-1-(2-propenyl) of embodiment 55 raw materials)-1H-pyrroles-4-acetonitrile can be prepared as follows:
With 1.072g2-cyano group-1-(2-propenyl)-1H-pyrroles-4-formaldehyde, 15Cm 3Methyl alcohol, 4.5Cm 3Water and 2.5Cm 3Acetate mixes, and then, adds the 2g sodium cyanide at 0 ℃, stirs 4 hours 30 minutes at 20 ℃, and then adds 3Cm 3Acetate and 3g sodium cyanide stirred 2 hours at 20 ℃, after washing with water, used dichloromethane extraction again, and underpressure distillation is concentrated into dried, obtains 1.25g purpose product.
Embodiment 56:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-ethoxy carbonyl-1-propenyl) cyclopropane-carboxylic acid 1-(2-propenyl-1H-pyrroles-3-yl) methyl esters.
With 700mg1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-ethoxycarbonyl-1-propenyl) cyclopropane-carboxylic acid 1-(2-proyl-1H-pyrroles-3-yl) methyl esters.0.14Cm 3Quinoline and 200mg are attached to palladium on the barium sulfate with 5% amount and send in the hydrogenation unit together and feed hydrogen and stir, when absorption of hydrogen to 45Cm 3The time stopped reaction, after reactant filtered, underpressure distillation is concentrated into did this filtrate, chromatographic separation residuum on silica gel washs with the triethylamine of 7: 3 hexanes and ethyl acetate and 2%, obtains the purpose product of 482mg.
(α) D=+15.5 ° (C=0.4% toluene)
Embodiment 57:
Figure 85106411_IMG96
(α) D=+19 ° ± 2 ° (C=0.5% toluene)
Preparation 17:
Be used as the 1(R of raw material among the embodiment 57, S) hydroxyl-(2-cyano group-1-(2-proyl)-1H-pyrroles-4-yl)-the 2-propine can be prepared as follows:
At 20 ℃ with the 3g1-(2-proyl)-2-cyano group-4-formyl radical-1H-pyrroles is dissolved in 20Cm 3In the tetrahydrofuran (THF), poured this solution into 70Cm that titration concentration is 0.82mmole/l with 10 minutes 3In the tetrahydrofuran solution of ethynyl bromination magnesium.Stir after 3 hours 30 minutes, reactant is poured in the saturated biphosphate sodium water solution, and use extracted with diethyl ether, the extraction liquid underpressure distillation is concentrated into dried, residuum is used chromatographic purification on silica gel, obtain 2.897g purpose product with 1: 1 hexane and ethyl acetate mixture wash-out, fusing point=66 ℃.
Nuclear magnetic resonance spectrum (tri-chlorination deuterium)
The hydrogen of representing hydroxyl at the peak at 2.3-2.4ppm place
Represent at the peak at 2.51-2.55-2.59ppm place on the proyl-hydrogen of C ≡ CH
Peak at the 2.61-2.65ppm place is represented Hydrogen
Peak at the 4.74-4.82ppm place is represented-CH 2The hydrogen of methylene radical on the-C ≡ CH
Peak at the 5.40ppm place is represented
Figure 85106411_IMG98
Hydrogen
Represent each hydrogen on 3 and 5 of pyrrole at the peak at 6.90-6.93ppm place.
Embodiment 58:
Figure 85106411_IMG99
(α) D=+39.5 ° (C=0.4% toluene)
Embodiment 59:
Figure 85106411_IMG101
(α) D=-6.5 ° ± 2 ° (C=6% toluene)
Preparation 18:
Raw materials used 2-cyano group-4 (1(R.S) hydroxyethyl-1-(2-proyl among the embodiment 59))-1H-pyrroles can be with the preparation of following method:
To contain the 4g1-(2-proyl)-2-cyano group-4-formyl radical-1H-pyrroles's 45Cm 3Tetrahydrofuran solution slowly joins 50Cm under 10 ℃ 3Contain in the tetrahydrofuran (THF) mixed solution (titration concentration 1.7mmol/l) of methyl magnesium iodide.Stirring is after 4 hours down at 20 ℃, and reaction mixture is poured in the biphosphate saturated aqueous solution of sodium, and uses extracted with diethyl ether.With the extraction liquid underpressure distillation: be concentrated into drying, residuum separates at the enterprising circumstances in which people get things ready for a trip layer of silicon-dioxide, with hexane and ethyl acetate mixed solution (1-1) wash-out, obtains the required product of 2.855g.Fusing point is lower than 50 ℃.
Nuclear magnetic resonance spectrum (CDCl 3)
1.4-1.5ppm between the peak represent hydrogen in the methyl
2.50-2.54-2.58ppm between the peak represent-hydrogen among the C ≡ C-H
4.68-4.80 and the peak between the 4.90-5.03ppm is represented
Figure 85106411_IMG102
4.76-4.80ppm between the peak represent CH 2Hydrogen on the methylene radical among the-C ≡ C-H
6.80-6.83ppm and 4.91 and 5.03ppm between the peak represent last 3 and 5 s' of pyrroles hydrogen
With the operation steps of embodiment 43, or, obtain following product according to the method (I) of the synthetic route of pointing out below:
Embodiment 60:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-proyl) cyclopropane-carboxylic acid (1-(2-proyl)-2-cyano group-1H-pyrroles-4-yl) ethyl ester.
Embodiment 61:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid 1R, the S/1-(2-proyl)-2-cyano group-1H-pyrroles-4-base/propine-2 ester.
Embodiment 62:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (1-(2-proyl)-4-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 63:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-4-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 64:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-proyl)-4-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 65:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxygenate-1-propenyl) cyclopropane-carboxylic acid (2-cyano group-(1-(3-chloro-2-(Z)-propenyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 66:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (2-cyano group-(1-(3-chloro-2-(E)-propenyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 67:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-proyl)-2-cyano group-1H-pyrroles-3-yl) methyl esters.
Embodiment 60:
Figure 85106411_IMG103
Figure 85106411_IMG104
Figure 85106411_IMG106
(α) D=-15.5 ° (C=0.5% toluene)
Preparation 19:
Raw material 4-((R, S) alpha-cyano methanol-based)-1-(2-proyl)-1H-pyrroles-3-nitrile used among the embodiment 64 can prepare with following method:
Steps A: 1,3-butadiene (1, two (the dimethylin)-2-cyano group of 4--3-methyl-formiate.
With 23g alpha-cyano methyl propionate and 126Cm 3Two (dimethylin) methane blended of tert-butoxy, placed 5 hours down at 170 ℃.Isopropylcarbinol at first steams.Reaction mixture temperature is reduced to 50 ℃, then vacuum (0.1 mmhg), 110 ℃ of following placements 1 hour.Mixture is after the silicon-dioxide chromatogram is purified, and mixed solution (1-9) elution with hexane and ethyl acetate obtains the required product of 15.9g, and fusing point is 106 ℃.
Step B:3-cyano group-1-(2-proyl)-1H-pyrroles-4-methyl-formiate.
With 14.5g1,3-divinyl 1, two (the dimethylin)-2-cyano group of 4--3-methyl-formiate, 400Cm 3Ethanol and 4.2Cm 3Single propargylamine mix, refluxed 5 hours.With the reaction mixture cooling, pour in the saturated aqueous sodium chloride subsequently, use dichloromethane extraction.The underpressure distillation extract is concentrated into drying.Residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silicon-dioxide, and mixed solution (65-35) elution with hexane and ethyl acetate obtains the required product of 3.75g, and fusing point is 134 ℃.
Step C:4-methylol-1-(2-proyl)-1H-pyrroles-3-nitrile.
With 3.90g3-cyano group-1-(2-proyl)-1H-pyrroles-4-methyl-formiate, 35Cm 3Tetrahydrofuran (THF), 11Cm 3Water and 1.556g lithium borohydride mix, and 20 ℃ were stirred 3 hours 30 minutes down.Reaction mixture is poured in the saturated aqueous sodium chloride, stirred, use ethyl acetate extraction.The underpressure distillation extraction liquid is concentrated into drying.Residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silicon-dioxide, and mixed solution (4-6) elution with hexane and ethyl acetate obtains the required product of 1.33g, and fusing point is 95 ℃.
Step D:4-formyl radical-1-(2-proyl)-1H-pyrroles-3-nitrile.
With 18Cm 3The dichloromethane solution of 1M dimethyl sulfoxide (DMSO) dropwise drips to 9.5Cm under-60 ℃ 3In the dichloromethane solution of 1M oxalyl chloride, stirred 5 minutes down at-60 ℃.Under-60 ℃, dropwise splash into 724g4-methylol-1-(2-proyl)-1H-pyrroles-3-nitrile solution, under same temperature, stirred 5 hours.Subsequently, in 30 minutes, dropwise add 25Cm while stirring under-60 ℃ 3The dichloromethane solution of 1M triethylamine.The question response mixture temperature reaches envrionment temperature, adds water, stirs.Clarification then.Wash organic phase with saturated aqueous sodium chloride, underpressure distillation is concentrated into drying.Residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silicon-dioxide, and mixture (1-1) elution with hexane and ethyl acetate obtains the required product of 702mg, and fusing point is 114 ℃.
Step e: 4-((R, S) alpha-cyano methanol-based)-1-(2-proyl)-1H-pyrroles-3-nitrile.
With 495mg4-formyl radical-1-(2-proyl)-1H-pyrroles-3-nitrile, 15Cm 3Methyl alcohol, 2.1Cm 3Water, 1.2Cm 3Acetate and 900mg sodium cyanide mix.When temperature reaches 20 ℃, stirred 15 minutes down at 20 ℃.Wash reaction mixture with water, use ethyl acetate extraction, and distillation under reduced pressure, concentrated extract obtains being used for the required crude product of embodiment 46 to dry.
Figure 85106411_IMG107
Embodiment 65:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (2-cyano group-1-(3-chloro-2-(Z)-propenyl)-1H-pyrroles-4-yl) methyl esters.
With 1.55g (2-cyano group-1-(3-chloro-2-(Z+E)-propenyl)-1H-pyrroles-4-yl)-methyl alcohol, 1.8glR, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid and 20Cm 3Methylene dichloride mixes, and then, under+5 ℃, adds 1.625 gram dicyclohexyl carbodiimides gradually, 10Cm 3The mixture of methylene dichloride and 29mg4-dimethylamino pyridine, and under 20 ℃, stirred 20 hours.After the filtration, underpressure distillation filtrate is concentrated into drying.Separate in the enterprising circumstances in which people get things ready for a trip spectrum of silicon-dioxide,, obtain the required product of 0.83g with 7-3 and the hexane of 9-1 ratio and the mixed solution elution successively of ethyl acetate.
(α) D=+32.5 ° (C=0.8% toluene)
Embodiment 66:lR, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (2-cyano group-1-(3-chloro-2-(E)-propenyl)-1H-pyrroles-4-yl) methyl esters.
From the follow-up overhead product of embodiment 65 chromatographic separation, can obtain the required product of 0.32g.
(α) D=+28 ° (C=0.5% toluene)
Preparation 20: the raw material 4-methylol among the embodiment 65 and 66-2-cyano group-1-(3-chloro-2-propenyl)-the available following method preparation of 1H-pyrroles's (suitable, anti-):
Steps A: 4-formyl radical-2-cyano group-1-(3-chloro-2-propenyl)-1H-pyrroles's (suitable, anti-)
4.15g2-cyano group-4-formyl radical-1H-pyrroles is added to 20Cm 3In the dimethyl formamide, be cooled to+10 ℃ after, bit by bit add and contain 1.563g55% and be dispersed in sodium hydride in the oil, then stirred 30 minutes down at+15 ℃.Be cooled to+5 ℃ after, in 20 minutes, add 32Cm 31, the 3-dichloropropylene ,+15 ℃ were stirred 2 hours down.Reaction mixture is poured in the water, used extracted with diethyl ether.Drying concentrates the ether phase, and chromatographic separation residuum on silicon-dioxide with mixed solution (1-1) elution of hexane and ethyl acetate, obtains 6.4g expection product.
Step B:4-methylol-2-cyano group-1-(3-chloro-2-propenyl)-1H-pyrroles's (suitable, anti-).
With the 4g product that obtains in the steps A, 100Cm 3Tetrahydrofuran (THF), 22Cm 3Distilled water and 4.4g POTASSIUM BOROHYDRIDE are mixed, and stir 45 minutes, add ether, restir 2 hours.By the solution clarification, the extraction that adds diethyl ether again, the method for dry organic phase obtains required product.
Embodiment 67:
(α) D=+21 ° (C=0.5% toluene)
Preparation 21:
Used raw material 2-hydroxyl among the embodiment 67-(R, S)-2-cyano group-1-(2-proyl)-1H-pyrroles-3-acetonitrile can be with following method preparation:
Steps A: 3-formyl radical-2-cyano group-1-(2-proyl)-1H-pyrroles
With 27Cm 3The dichloromethane solution (1M) that contains oxalyl chloride is cooled to-60 ℃, adds 13.5Cm then 3The dichloromethane solution (1M) that contains dimethyl sulfoxide (DMSO).Stir after 5 minutes, add again and contain 1.09g3-methylol-1-(2-proyl)-20Cm of 1H-pyrroles-2-acetonitrile 3Methylene dichloride was placed 2 hours down for-60 ℃.Add 70Cm 3The dichloromethane solution (1M) that contains triethylamine ,-60 ℃ were stirred 10 minutes down, temperature are risen to 20 ℃ subsequently.Add 20Cm 3Water stirs, and clarification is concentrated into drying.Residuum separates in the enterprising circumstances in which people get things ready for a trip spectrum of silicon dichloride, and mixture (6-4) elution with hexane and ethyl acetate obtains the required product of 456mg.
Nuclear magnetic resonance spectrum (CDCl 3)
2.59-2.63-2.65ppm the peak of locating represents-proton on the C ≡ CH
6.75-6.8 and the proton on the pyrroles is represented at the peak at 7.15-7.18ppm place
4.9-4.95ppm CH in the proyl is represented at the peak of locating 2On proton
The proton on the formyl is represented at peak on the 10ppm
Step B:2-hydroxyl-(R, S)-2-cyano group-1-(2-proyl)-1H-pyrroles-3-acetonitrile.
By step e operation in the preparation 19, with 546mg3-formyl radical-2-cyano group-1-(2-proyl)-1H-pyrroles does raw material, obtains required product.
With the operation steps of embodiment 1,, obtain following product according to the synthetic route of pointing out below:
Embodiment 68:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-proyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-proyl)-3-cyano group-1H-pyrroles-4-yl) methyl esters.
Embodiment 69:1R, along (Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (R, S)-cyano group-(1-(2-proyl-2,2,2-three fluoro methyl isophthalic acid H-pyrroles-4-yl) methyl esters.
Embodiment 70:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-2,2,2-three fluoro methyl isophthalic acid H-pyrroles-4-yl) methyl esters.
Embodiment 71:1R, along (Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propylene) cyclopropane-carboxylic acid (1-(2-proyl)-3,3,3-Trifluoromethyl-1 H-pyrroles-4-yl) methyl esters.
Embodiment 72:1R, along (E) 2,2-dimethyl-3-(2-fluoro-3-oxyethyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid (1-(2-proyl)-3,3,3-Trifluoromethyl-1 H-pyrroles-4-yl) methyl esters.
Embodiment 73:1R, along 2,2-dimethyl-3-(2,2-dibromo vinyl) cyclopropane-carboxylic acid (2-cyano group-1-(3-chloro-2-(Z)-propenyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 74:1R, along 2,2-dimethyl-3-(2,2-two bromo vinyl) cyclopropane-carboxylic acid (2-cyano group-1-(3-chloro-2(E)-propenyl)-1H-pyrroles-4-yl) methyl esters.
Embodiment 68:
(α) D=+12.5 ° (C=0.6% toluene)
Figure 85106411_IMG110
Preparation 22:
Raw material 2-three fluoro methyl isophthalic acids-(2-propynyl)-1H-pyrroles-4-methyl alcohol used among the embodiment 69 and 70 can prepare with following method:
Steps A: 4-(1-(2-proyl)-2-three fluoro methyl isophthalic acid H-pyrroles) ethyl formate.
With 9g3-azepine-5-hexin-1-acid-hydrochloride 120Cm 3Toluene and 9.15Cm 3Ethyl propionate mixes, and dropwise adds 18.6Cm under+5 ℃ 3Trifluoroacetic anhydride.After reaction mixture returns 4 hours 45 minutes, be cooled to+30 ℃; Add 9.3Cm 3Trifluoroacetic anhydride, reaction mixture refluxed 5 hours also stirred 12 hours under 20 ℃, added 5.6Cm 3Acetic anhydride with reaction mixture refluxed 2 hours, after the cooling, is poured in the water, adds ether.And neutralize with saturated solution of sodium bicarbonate.Use the extracted with diethyl ether mixed solution, underpressure distillation is concentrated into drying, chromatographic separation residuum on silicon-dioxide, and mixed solution (8-2) elution with hexane and ethyl acetate obtains the required product of 3.964g.Fusing point is lower than 50 ℃.
Infrared spectra (chloroform)
-at 1712Cm -1The place absorbs, expression ester C=0
-at 3140Cm -1, 1572Cm -1, 1519Cm -1The place absorbs, expression heterocycle=CH
-at 1187Cm -1, 1162Cm -1, 1116Cm -1The place absorbs, expression CF 2
-at 3307Cm -1The absorption at place, expression C ≡ CH, ≡ CH
-at 2125Cm -1The place absorbs, expression C ≡ C
Step B:2-three fluoro methyl isophthalic acids-(2-propynyl)-1H-pyrroles-4-methyl alcohol.
With 4.785g4-(1-(2-proyl)-2-Trifluoromethyl-1 H-pyrroles) ethyl formate is dissolved in 40Cm 3In the tetrahydrofuran (THF).Bit by bit add 750 milligrams of lithium aluminum hydrides under 0 ℃ ,+7 ℃ were stirred 30 minutes down, stirred 3 hours down at 20 ℃ again, added several ethyl acetate and 10Cm then 3The sodium of disodium tartrate and the aqueous solution.Filter reaction mixture, filtrate are concentrated into drying by underpressure distillation, and residuum is chromatographic separation on silicon-dioxide, and mixed solution (6-4) elution with hexane and ethyl acetate obtains the required product of 3.45g.
Infrared spectra (chloroform)
-at 3610Cm -1The place absorbs, expression-OH
-at 3308Cm -1The place absorbs, expression-C ≡ CH
-at 1580Cm -1, 1510Cm -1The place absorbs, expression
Figure 85106411_IMG111
Embodiment 71:
Figure 85106411_IMG112
(α) D=± 41.5 ° (C=0.5% chloroform)
Embodiment 72:
Figure 85106411_IMG113
(α) D=+23.5 ° ± 3 ° (C=0.2% chloroform)
Adopt and embodiment 65 and 66 similar methods, can prepare compound in embodiment 73 and 74.
Embodiment 73:
(α) D=-6 ° (C=1% toluene)
Embodiment 74:
Figure 85106411_IMG115
(α) D=-4 ° (C=0.6% toluene)
Embodiment 75: the preparation of soluble enriched material
Uniform mixture is prepared by following material:
The product of embodiment 1 ... 0.25g
Piperonyl butoxide ... 1.00g
Tween 80 (TWeen80) ... 0.25g
Holder handkerchief Nore A(TopanolA) ... 0.1g
Water ... 98.4g
Embodiment 76: emulsifiable concentrate preparation
Following material is mixed fully:
The product of embodiment 2 ... 0.015g
Piperonyl butoxide ... 0.5g
Holder handkerchief Nore A(TopanolA) ... 0.1g
Tween 80 (Tween 80) ... 3.5g
Dimethylbenzene ... 95.885g
Embodiment 77: emulsifiable concentrate preparation
Uniform mixture is prepared by following material:
The product of embodiment 40 ... 1.5g
Tween 80 (Tween 80) ... 20.00g
Holder handkerchief Nore A(TopanolA) ... 0.1g
Dimethylbenzene ... 78.4g
Embodiment 78: stifling preparation of compositions
With following material uniform mixing:
The product of embodiment 1 ... 0.25g
The Tabu powder ... 25.00g
The cedar leaf powder ... 40.00g
Pine powder ... 33.75g
Shell is green ... 0.5g
P-NP ... 0.5g
Embodiment 79: the compound foodstuff embodiment of animal
Comprise corn, dehydrated alfalfa, straw, the foodstuff of Areca L. plant, the urea element of honey, vitaminized inorganic seasonings arranged as the basic foodstuff of equilibrated.
This foodstuff contains minimum 11% crude protein material (2.8%, from the urea element), 2.5% fatty substance, maximum 15% cellulosic materials, 6% mineral substance and 13% moisture.
The every 100Kg of foodstuff that uses is equivalent to 82 fodder unit, and every 100Kg contains vitamin A 910,000I.u, vitamins D 291,000I.u, vitamin-E 150mg, vitamins C 150mg.
Every 100Kg total eclipse material contains the compound 0.3Kg of embodiment 1 in this foodstuff.
Embodiment 80: the compound foodstuff embodiment of animal
Application is as the basic foodstuff of using in embodiment 79 of identical equilibrated.Every in the present embodiment 100Kg total eclipse material contains the compound of 0.04Kg embodiment 1.
Biological study
1) housefly is knocked down activity research
The test insect is 4 days a female housefly.This test is with acetone (5%) and IsoparL(petrolic solvent) mixture as solvent (solvent load per second 2ml), in Ji En and Ma Qi chamber (Ktans and March Chamber), undertaken by direct spraying.The each test with 50 insects.The per minute check was checked in the time of 15 minutes then once up to 10 minutes.Measure KT50 with usual method.
Obtain following result:
The KT50(branch of embodiment) the KT50(branch of embodiment)
Compound concentration 0.1g/L compound concentration 0.1g/L
1 1.3 50 3.5
2 1.6 56 4.0
3 5.8 43 2.9
4 2.4 53 2.4
5 3.2 54 4.7
6 4.7 55 8.7
15 1.8 60 1.8
26 3.5 57 4.0
40 5.6 65 3.1
44 2.2 66 7.9
48 3.7 67 3.8
51 1.9 45 6.1
52 1.5 72 3.8
49 11.0 69 4.8
70 3.9
Conclusion: product of the present invention has good knockdown effect for housefly.
2) by cockroach De Fu joint contact carrying out activity research
The male cockroach of insect (Blatella germanica) is used in test.Carry out at the end of the Petri dish of this test by certain density acetone soln being deposited on diameter 20Cm.After the drying, 20 male cockroaches of each concentration kept 1 hour on culture dish, then cockroach is transferred on the medium of health, and at 24 hours, 48 hours, the 3rd day and the 5th day check cockroach mortality ratio.
Test-results is with median lethal concentration(LC﹠-{50}) (lethal Concentration 50(LC50)) mg/m 2Expression.
Embodiment LC50
43 2.8
45 6.4
72 6.7
70 4.5
Conclusion: product of the present invention has biocidal activity for cockroach.
3) to the research of aphid (Cracivora) lethal effect
The adult of using 7 days, 10 aphids of each concentration are with contacting the method for ingesting.Handle with the Fisher atomizer on the beans leaf, the beans leaf is placed in the plastics Petri dish on the moistening paper disc.Use in test the acetone soln (every 1ml of leaf) that 2ml contains product, put insect after the leaf drying.Keep insect to contact 1 hour with leaf, then insect is placed on the leaf that does not have processing, check mortality ratio after 24 hours.
The test-results that obtains is summarised in the following table:
Embodiment LD50
The mg/ insect
49 6.5
43 7.5
Conclusion: product of the present invention has lethal effect to aphid.
4) acaricidal activity is to the lethal effect test of adult
Application has dicots bean, and leaf is handled with the Fisher atomizer with the acetone soln that contains product.After the drying, put 25 female mites (Tetranychus urticae) on the every leaf, i.e. 50 mites of each test dose of each plant.Contact testing effect after 80 hours, LD50 represents with mg/hl.
Embodiment LD50
40 32
43 342
45 264
70 2126
Conclusion: the product of the present invention particularly product of embodiment 40 has significant acaricidal action to Tetranychus urticue.

Claims (14)

1, the method for preparing the formula I compound,
Figure 85106411_IMG1
Wherein:
R 2Or R 3One of represent the base of following formula:
Figure 85106411_IMG2
A represents the base of following formula in the formula:
Z in the formula 1And Z 2Represent a methyl separately,
Or Z 1Represent H,
Z 2Represent the base of following formula:
Figure 85106411_IMG4
Z in the formula 3Represent H or fontanelle atom,
T 1And T 2Identical, represent H, halogen atom or CF 3,
Z 2Or represent the base of following formula:
D represents H or halogen atom in the formula,
G represents O,
The J representative contains the straight or branched alkyl of 1-4 carbon atom,
A or represent the base of following formula:
U in the formula on any position of benzene nucleus, represents halogen atom, contains the alkyl of 1-4 carbon atom, and m represents 0 or 1,
Z represents H, C ≡ N, C ≡ CH, CF 3Base or contain the alkyl of 1-3 carbon atom,
Do not represent
Figure 85106411_IMG7
R 2Or R 3, and R 4And R 5, identical or different each other, represent H, halogen atom, CN base, CF 3Base, contain 4 carbon nearly-CO 2Alkyl or NO 2Base,
R 1Represent a following formula base:
X and Y can be identical or different in the formula, represent H, halogen atom,
R 1Or represent a following formula base:
X ' and Y ' in the formula can be identical or different, represent the implication of above-mentioned X and Y, and Y ' represents phenyl, and dotted line is represented also can form a two key between carbon atom 1 and 2,
R 1Or represent a following formula base:
Figure 85106411_IMG10
R ' can represent above-mentioned R in the formula 4And R 5Implication, but do not represent fontanelle atom, CN and NO 2,
It is characterized in that:
Alcohol by formula II:
Figure 85106411_IMG11
R wherein " 2And R " 3A base in the base is represented the base of following formula:
Z remains with identical meanings as mentioned above, another R " 2Or R " 3Base and R 4And R 5Base remains with and above-mentioned R 4And R 5Identical meanings, R 1Remain with identical meanings as mentioned above,
React with the acid of formula III or functional derivatives that should acid
Figure 85106411_IMG13
A remains with identical meanings as mentioned above.
2,, it is characterized in that alcohol, wherein R from formula II according to the method for claim 1 1Representative-CH 2-C ≡ CH base.
3,, it is characterized in that alcohol, wherein R from formula II according to the method for claim 1 or 2 ' 2And R ' 3In a base of representing following formula:
Figure 85106411_IMG14
Z represents hydrogen atom in the formula.
4,, it is characterized in that alcohol, wherein R from formula II according to the method for claim 1 or 2 ' 2And R ' 3A base of representing following formula in the base:
Figure 85106411_IMG15
Wherein Z represents cyano group.
5,, it is characterized in that alcohol, wherein substituent R from formula II according to the method for claim 1 or 2 ' 3Represent the base of following formula:
Figure 85106411_IMG16
Z represents H, C ≡ N, C ≡ CH, CF in the formula 3Base or contain the alkyl of 1-3 carbon atom.
6,, it is characterized in that alcohol, wherein substituent R from formula II according to the method for claim 1 or 2 ' 2, R 4And R 5In one represent hydrogen atom.
7,, it is characterized in that alcohol, wherein substituent R from formula II according to the method for claim 1 or 2 ' 2, R 4And R 5In one represent nitro.
8,, it is characterized in that alcohol, wherein substituent R from formula II according to the method for claim 1 or 2 ' 2, R 4And R 5In one represent cyano group.
9,, it is characterized in that alcohol, wherein substituent R from formula II according to the method for claim 1 or 2 ' 2, R 4And R 5In one represent trifluoromethyl.
10, according to the method for claim 1, it is characterized in that acid from formula III, wherein A represents the base of following formula:
Figure 85106411_IMG17
Hal represents fontanelle atom in the formula.
11, according to the method for claim 1, it is characterized in that acid from formula III, wherein A represents the base of following formula:
Figure 85106411_IMG18
The J representative contains straight chain, side chain or the cyclic alkyl of 1-4 carbon atom in the formula, and the geometric configuration of two keys is cis (Z).
12, according to the method for claim 1, it is characterized in that acid from formula III, wherein A represents the base of following formula:
Hal represents fontanelle atom in the formula, and the J representative contains the alkyl of 1-4 carbon atom, and the geometric configuration of two keys is trans (E).
13, according to the method for claim 12, it is characterized in that acid from formula III, wherein A represents the base of following formula:
Figure 85106411_IMG20
Hal represents fluorine atom in the formula, and the J representative contains the alkyl of 1-4 carbon atom, and the geometric configuration of two keys is trans (E).
14,, it is characterized in that being from following acid and alcohol according to the method for claim 1:
1R, cis (△ E) 2,2-dimethyl-3-(3-oxyethyl group)-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid,
1R, cis (△ Z) 2,2-dimethyl-3-(3-methoxyl group-3-oxo-1-propenyl) cyclopropane-carboxylic acid,
Or 1R, cis (△ E) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-2-fluoro-1-propenyl) cyclopropane-carboxylic acid,
With the 1-(2-proyl)-1H-pyrroles-3-methyl alcohol,
Or 1-(2-proyl) 2-Trifluoromethyl-1 H-pyrroles-3-methyl alcohol.
CN85106411A 1985-04-23 1985-08-26 Process for preparing new derivatives of pyrrole Expired CN1015626B (en)

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