CN101979394B - A method to inhibit ethylene responses in plants - Google Patents

A method to inhibit ethylene responses in plants Download PDF

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CN101979394B
CN101979394B CN2010101281818A CN201010128181A CN101979394B CN 101979394 B CN101979394 B CN 101979394B CN 2010101281818 A CN2010101281818 A CN 2010101281818A CN 201010128181 A CN201010128181 A CN 201010128181A CN 101979394 B CN101979394 B CN 101979394B
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cyclopropylene
milliliters
gram
bromo
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CN101979394A (en
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R·M·雅格布森
M·J·凯利
F·L·维迈耶
K·A·埃文斯
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Rohm and Haas Co
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Abstract

The present invention generally relates to methods of inhibiting ethylene responses in plants and plant materials, and particularly relates to methods of inhibiting various ethylene responses including plant maturation and degradation, by exposing plants to cyclopropene derivatives and compositions thereof wherein: 1) at least one substituent on the cyclopropene ring contains a carbocyclic or heterocyclic ring, or 2) a substituent contains silicon, sulfur, phosphorous, or boron, or 3) least one substituent contains from one to four non-hydrogen atoms and at least one substituent contains more than four non-hydrogen atoms.

Description

A kind of method that suppresses ethylene reaction in the plant
Patent application of the present invention is that international application no is PCT/US02/06339, international filing date is on February 25th, 2002, and the application number that enters the China national stage is 02801969.5, denomination of invention is divided an application for the application for a patent for invention of " a kind of method that suppresses ethylene reaction in the plant ".
Technical field
The present invention relates generally to suppress the method for ethylene reaction in plant and the vegetable material, more specifically to by in the composition that plant is exposed to cyclopropene derivatives and they with the method for the various ethylene reactions that suppress to comprise that plant is ripe and wear out, wherein at least one substituting group on the cyclopropylene ring comprises carbocyclic ring or heterocycle.
Background technology
Well-known ethene can cause plant or plant part for example to comprise, flower, leaf, the precocious death of fruit and vegetables.Ethene also accelerates leaf flavescence and cessation of growth cessation and makes fruit early-maturing, flower and leaf drop.This activity be understood to be by with plant in specific ethylene receptor interact and to realize.Many is not that the compound of ethene is influential to these acceptors: the effect of some compound imitation ethene; Other compound can hinder the combination of ethene and offset thus its effect.For the effect of determining that these ethene are induced, very active research topic is obstruction or reduces ethene to the research of the deleterious effect of plant at present.
Be disclosed in the people's such as Sisler United States Patent (USP) U.S.5 with the method for ethene effect in diazacyclo pentadiene and derivative thereof the opposing plant, in 100,462.The people's such as Sisler United States Patent (USP) U.S.5 in 518,988, discloses cyclopropylene and derivative thereof, comprises the 1-methylcyclopropene, as the purposes of the effective blocker of ethene combination.Yet, be that they are unsettled gas typically with the subject matter of these compounds, the danger of blast will be arranged when compressed.
Although these effort are arranged, still there is demand in this area to controlling plant ripe and aging compound and composition.Preferably, novel compound can be avoided the explosion hazard of 1-methylcyclopropene, in addition, can provide other the mode that for example transmits by the liquid or solid formulation.
Summary of the invention
We have found to provide the new cyclopropene derivatives of a class of above-mentioned many advantages.These compounds and their composition provide a kind of method that suppresses the ethene effect in the plant, comprise the cyclopropene derivatives of the following formula of using ethene suppressing effect significant quantity or the step of its composition and plant contact:
Wherein:
A) R 1And R 3One of be H, and R 2, R 4With R 1And R 3In another be independently selected from the group of H and following formula:
-(L) n-Z
Wherein:
I) n is 1 to 12 integer;
Ii) L is selected from group D1 independently of one another, D2, and among E or the J one, wherein:
D1 is the group of following formula:
Figure GSA00000039172900022
D2 is the group of following formula:
Figure GSA00000039172900023
Figure GSA00000039172900031
E is the group of following formula:
Figure GSA00000039172900032
And
J is the group of following formula:
Figure GSA00000039172900033
Wherein:
A) X and Y are the group of following formula independently of one another:
-(L) m-Z；
And
B) m is 0 to 8 integer; With
C) two D2 or E group are adjacent one another are at the most, and do not have the J group adjacent one another are;
Iii) Z is selected from independently of one another:
A) hydrogen, halogen, cyano group, nitro, nitroso-group, azido-, chlorate anions, bromate, iodate, isocyanato-, isocyanide, isothiocyanato, five fluorine sulfenyls, or
B) group G, wherein G is unsubstituted or replaces; Undersaturated, fractional saturation or saturated; Monocycle, dicyclo, three rings or condense; 4 to 14 yuan of carbocyclic rings or heterocyclic systems, wherein:
1) when ring system comprises 4 yuan of heterocycles, heterocycle comprises 1 heteroatoms;
2) when ring system comprises 5 yuan or multicomponent heterocycle or encircles heterocycle more, heterocycles heterocycle or many rings comprise 1 to 4 heteroatoms;
3) each heteroatoms is independently selected from N, O and S;
4) substituent number is 0 to 5, and each substituting group is independently selected from X;
B) non-hydrogen atom in each compound adds up to 50 or still less; And
C)-(L) nHeteroatomic among the-Z adds up to 0 to 4; And
D) one of following any condition:
I) R 1Or R 3Comprise at least one group G; Or
Ii) at least one L group is the E group; Or
Iii) at least one R 1, R 2, R 3, and R 4Comprise one to four non-hydrogen atom and at least one R 1, R 2, R 3, and R 4Comprise and surpass four non-hydrogen atoms;
And enantiomorph, steric isomer, salt, and their mixture.
For purpose of the present invention, each key table opened in the structure of various L groups shows one to another L group, the key of Z group or cyclopropylene part.For example, structure
Figure DEST_PATH_GSB00000400069600011
Represent that a Sauerstoffatom is with the key to two other atoms; It does not represent the dme part.
Typical R 1, R 2, R 3And R 4Group comprises, for example: alkenyl, alkyl, alkynyl, kharophen alkenyl, kharophen alkyl, the kharophen alkynyl, alkenyloxy, alkoxyl group, alkynyloxy group, alkoxy alkoxy alkyl, alkoxy alkenyl, alkoxyalkyl, alkoxyl group alkynyl, alkoxy carbonyl alkenyl, alkoxy carbonyl alkyl, alkoxy carbonyl alkynyl, alkyl-carbonyl, alkyl-carbonyl oxygen base alkyl, alkyl (Alkoximino) alkyl, carboxyl alkenyl, carboxyalkyl, carboxyl alkynyl, dialkyl amido, the halogenated alkoxy alkenyl, halogenated alkoxy alkyl, halogenated alkoxy alkynyl, halogenated alkenyl, haloalkyl, halo alkynyl, hydroxyl alkenyl, hydroxyalkyl, the hydroxyl alkynyl, trialkylsilkl alkenyl, trialkylsilkl alkyl, the trialkylsilkl alkynyl, the dialkyl phosphine acid group closes (phosphonato), and the Acidic phosphates root closes (phosphato), and two alkylthio phosphate radicals close, dialkyl aminoalkyl, the alkyl sulphonyl alkyl, alkylthio alkenyl, alkylthio alkyl, the alkylthio alkynyl, dialkyl amino sulfonyl, halogenated alkylthio alkenyl, halogenated alkylthio alkyl, the halogenated alkylthio alkynyl, alkoxy-carbonyl oxy; Cycloalkenyl, cycloalkyl, cycloalkynyl radical, the kharophen cycloalkenyl, kharophen cycloalkyl, kharophen cycloalkynyl radical, cycloalkenoxy, cycloalkyloxy, ring alkynyloxy group, alkoxyl group alkoxyl group cycloalkyl, alkoxyl group cycloalkenyl, alkoxyl group cycloalkyl, the alkoxyl group cycloalkynyl radical, alkoxy carbonyl cycloalkenyl, alkoxy carbonyl cycloalkyl, the alkoxy carbonyl cycloalkynyl radical, naphthene base carbonyl, alkyl-carbonyl oxygen basic ring alkyl, carboxyl cycloalkenyl, the carboxyl cycloalkyl, the carboxyl cycloalkynyl radical, bicyclic alkyl amino, halo cycloalkyloxy cycloalkenyl, halo cycloalkyloxy cycloalkyl, halo cycloalkyloxy cycloalkynyl radical, halo cycloalkenyl, halogenated cycloalkyl, the halo cycloalkynyl radical, the hydroxyl cycloalkenyl, hydroxyl cycloalkyl, hydroxyl cycloalkynyl radical, the trialkylsilkl cycloalkenyl, dialkyl group silyl cycloalkyl, trialkylsilkl cycloalkynyl radical, dialkyl amido cycloalkyl, the alkyl sulphonyl cycloalkyl, naphthene base carbonyl oxygen base alkyl, naphthene sulfamide base alkyl, alkylthio cycloalkenyl, the alkylthio cycloalkyl, the alkylthio cycloalkynyl radical, bicyclic alkyl amino alkylsulfonyl, halogenated alkylthio cycloalkenyl, the halogenated alkylthio cycloalkyl, the halogenated alkylthio cycloalkynyl radical; Aryl, alkenyl aryl, alkylaryl, alkynyl aryl, the kharophen aryl, aryloxy, alkoxyl group alkoxy aryl, alkoxy aryl, the alkoxy carbonyl aryl, aryl carbonyl, alkyl-carbonyl oxygen Ji Fangji, carboxyl aryl, ammonia diaryl base, halogenated alkoxy aryl, halogenated aryl, hydroxyaryl, the trialkylsilkl aryl, dialkyl amido aryl, alkyl sulphonyl aryl, aryl sulfonyl alkyl, the alkylthio aryl, artyl sulfo alkyl, ammonia diaryl base alkylsulfonyl, halogenated alkylthio aryl; Heteroaryl, alkenyl heteroaryl, miscellaneous alkyl aryl, the alkynyl heteroaryl, kharophen heteroaryl, heteroaryl oxygen base, alkoxyl group alkoxyl group heteroaryl, alkoxyl group heteroaryl, alkoxy carbonyl heteroaryl, the heteroaryl carbonyl, alkyl-carbonyl oxygen base heteroaryl, carboxyl heteroaryl, two heteroaryl aminos, the halogenated alkoxy heteroaryl, halo heteroaryl, hydroxyl heteroaryl, the trialkylsilkl heteroaryl, the dialkyl amido heteroaryl, alkyl sulphonyl heteroaryl, heteroarylsulfonyl alkyl, the alkylthio heteroaryl, heteroaryl sulfenyl alkyl, two heteroaryl amino alkylsulfonyls, halogenated alkylthio heteroaryl; Heterocyclic radical, alkenyl heterocyclic radical (heteroycycyl), alkyl heterocyclic (heteroycycyl), alkynyl heterocyclic radical (heteroycycyl), kharophen heterocyclic radical, heterocyclyloxy base, alkoxyl group alkoxyl group heterocycle, alkoxyl group heterocyclic radical, alkoxy carbonyl heterocyclic radical, the heterocyclic radical carbonyl, alkyl-carbonyl oxygen base heterocyclic radical, the carboxyl heterocyclic radical, two heterocyclic radicals are amino, the halogenated alkoxy heterocyclic radical, the halogenated heterocyclic base, hydroxyl heterocyclic radical, trialkylsilkl heterocyclic radical, the dialkyl amido heterocyclic radical, the alkyl sulphonyl heterocyclic radical, alkylthio heterocyclic radical, heterocyclic radical sulfenyl alkyl, two heterocyclic radical amino-sulfonyls, the halogenated alkylthio heterocyclic radical; Hydrogen, fluorine, chlorine, bromine, iodine, cyano group, nitro, nitroso-group, azido-, chlorate anions close (chlorato), and bromate closes (bromato), and iodate closes (iodato), isocyanato-, isocyanide, isothiocyanato, five fluorine sulfenyls; Acetoxyl group, the carbonyl oxyethyl group, cyanate radical closes, nitroxyl, oxynitroso, the perchlorate closes, the propadiene base; The butyl sulfydryl, diethyl phosphoric acid
Figure GSA00000039172900061
The 3,5-dimethylphenyl silyl, isoquinolyl, sulfydryl, naphthyl, phenoxy group, phenyl, piperidyl, pyridyl, quinolyl, triethylsilyl, trimethyl silyl; And the analogue that replaces.
Typically the G group comprises, for example: saturated or undersaturated cycloalkyl, dicyclo, three rings, many rings, saturated or undersaturated heterocyclic radical, the phenyl that does not replace or replace, naphthyl, or the heteroaryl ring system is for example, cyclopropyl, cyclobutyl, ring penta-3-alkene-1-base, 3-methoxyl group hexamethylene-1-base, phenyl, 4-chloro-phenyl-, 4-fluorophenyl, the 4-bromophenyl, 3-nitrophenyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 4-ethylphenyl, 2-methyl-3-p-methoxy-phenyl, 2, the 4-dibromo phenyl, 3,5-difluorophenyl, 3,5-3,5-dimethylphenyl, 2,4,6-trichlorophenyl, the 4-p-methoxy-phenyl, naphthyl, 2-chloronaphthyl, methylnaphthyl, 2, the 4-Dimethoxyphenyl, 4-(trifluoromethyl) phenyl, 2-iodo-4-aminomethyl phenyl, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, pyrazinyl, pyrimidine-2-base, pyrimidine-4-yl, pyrimidine-5-base, pyridazinyl, triazol-1-yl, imidazoles-1-base, thiophene-2-base, thiene-3-yl-, furans-2-base, furans-3-base, pyrryl oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, 4-oxadiazole base, thia di azoly, quinolyl, isoquinolyl, tetrahydrofuran base, pyrrolidyl, piperidyl, THP trtrahydropyranyl, morpholinyl, piperazinyl, dioxolane base alkyl dioxin, indolinyl and 5-methyl-6-chromanyl, adamantyl, norcamphyl, and their replacement analogue is for example: 3-butyl-pyridine-2-base, 4-bromo-pyridine-2-base, 5-carbonyl oxyethyl group-pyridine-2-base, 6-methoxy ethoxy-pyridine-2-base
Preferred R 1, R 2, R 3And R 4In two be hydrogen.More preferably R 1And R 2Be hydrogen or R 3And R 4Be hydrogen.Even more preferably R 2, R 3, and R 4Be hydrogen or R 1, R 2And R 3Be hydrogen.R most preferably 2, R 3And R 4Be hydrogen.
Preferred n is 0 to 8.Most preferably n is 1 to 7.Preferred m is 0 to 4.Most preferably m is 0 to 2.
Preferably, D1 is-CXY-,-CO-, or-CS-.More preferably D1 is-CXY-.Preferably, D2 be-O-or-NX-.Preferably E is-S-,-SiXY-, or-SO 2-.Preferably, X and Y are H independently, halogen, OH, SH ,-C (O) (C 1-C 4) alkyl-,-C (O) O (C 1-C 4) alkyl-,-O-(C 1-C 4) alkyl ,-S-(C 1-C 4) alkyl, or replacement or unsubstituted (C 1-C 4) alkyl.Preferably, Z is H, halogen, or G.More preferably, Z is H or G.
Preferably, G is replacement or unsubstituted independently of one another; Five, six or seven yuan; Aryl, heteroaryl, heterocyclic radical, or cycloalkyl ring.More preferably, G is independently of one another for replacing or unsubstituted phenyl pyridyl, cyclohexyl, cyclopentyl, suberyl, pyrryl, furyl, thiophenyl, triazolyl, pyrazolyl, DOX base, or morpholinyl.More preferably, G is the phenyl that does not replace or replace, cyclopentyl, suberyl, or cyclohexyl.Most preferably, G is cyclopentyl, suberyl, and cyclohexyl, phenyl, or the phenyl that replaces, wherein substituting group is independently selected from 1 to 3 methyl, methoxyl group, and halogen.
Another aspect of the present invention is a kind of by cyclopropene derivatives from ethylene receptor blocking-up significant quantity to plant that use or the method that its composition is blocked ethylene receptor in the plant.
Also disclose the inhibition plant and naturally come off, prolonged the survival time of flower arrangement, and the method for the maturation of the fruit of inhibition harvesting or vegetables, comprise the cyclopropene derivatives from significant quantity to plant or its composition that apply.
Method described here can be carried out with various approach, for example by plant is contacted with cyclopropene derivatives or their composition, or with solid, liquid, or with the form of gas; Or the vegetables of the fruit by making plant, flower arrangement, harvesting or harvesting are exposed in the atmosphere of filling with cyclopropene derivatives or their composition.These and other suitable method of application will at length be discussed following.For realizing purpose of the present invention, " contact " is to instigate cyclopropylene and close the interosculating so that the ethylene receptor of sufficient amount is subject to the impact of cyclopropylene of plant.
The Pestcidal compositions that comprises compound of the present invention also is included in the present invention.Preferred composition comprises 0.005% to 99%, weight; Preferred 1% to 95%, weight; More preferably 2% to 90%, weight; More preferably 3% to 80%, weight; Or most preferably 4% to 70%, weight, active compound of the present invention.These compositions can comprise one or more auxiliary agent, for example, and carrier, extender, tackiness agent (binder), lubricant, tensio-active agent and/or dispersion agent, wetting agent, spreading agent, dispersion agent, tackiness agent, tackiness agent
Figure GSA00000039172900081
Defoamer, thickening material, and emulsifying agent.Common employed such auxiliary agent can find hereinafter in this area: John W.McCutcheon, Inc.publication Detergents andEmulsifiers, Annual, Allured Publishing Company, Ridgewood, New Jersey, U.S.A.
All percentage ratios are weight percentage as used herein, and all umbers are parts by weight, unless otherwise mentioned, and be comprise end value with combinative.All proportions is weight ratio, and all proportions scope be comprise end value with combinative.All molar range be comprise end value with combinative.
Can use numerous organic solvents as the carrier of active compound of the present invention, for example, hydrocarbon is hexane for example, benzene, toluene, dimethylbenzene, kerosene, diesel oil, oil fuel and petroleum naphtha, ketone is acetone for example, methyl ethyl ketone and pimelinketone, and chlorinated hydrocarbon is tetracol phenixin for example, and ester is ethyl acetate for example, amyl acetate-n and butylacetate, ether, for example, ethylene glycol monomethyl ether and methyl carbitol, alcohol for example, ethanol, methyl alcohol, Virahol, amylalcohol, ethylene glycol, propylene glycol, acetic acid butyl card must ester and glycerine.
The mixture of water and organic solvent perhaps with solution or with emulsion, also can be used as the inert support of active compound.
Can prepare solid by various ordinary methods, the liquids and gases preparation.Therefore active ingredient, if the words of solid are with finely divided form, can be with finely divided solid carrier lift-over.Perhaps, the active ingredient of liquid form comprises their mixture, solution, and dispersion, emulsion and suspension can mix with the solid carrier with finely divided form.In addition, the active ingredient of solid-state form can be mixed with liquid vehicle, forms mixture, solution, dispersion, emulsion and suspension etc.
Active compound of the present invention can be applied to plant by various suitable methods.For example, active compound can be separately with gas, liquid, or solid form is by using compound with wanting processed plant contact.In addition, active compound can be converted into the form of salt, then is applied in plant.Perhaps, can form the composition that comprises one or more active compound of the present invention.Composition can be with gas, liquid, or solid form is by using composition with wanting processed plant contact.Such composition can comprise inert support.Similarly, when with the form of gas, compound can be dispersed in the inert gas carrier so that a kind of gas solution to be provided.Also active compound can be suspended in the liquor that can be used as inert support, for example in organic solvent or the aqueous solution.The solution that comprises active compound can be heterogeneous or homogeneous phase, and can be various forms, comprises mixture, dispersion, emulsion, suspension etc.
Also cyclopropylene can be encapsulated in the molecule encapsulants.Preferred encapsulation agent comprises cyclodextrin, crown ether, polysiloxane and zeolite.Preferred encapsulation agent comprises alpha-cylodextrin, beta-cyclodextrin, and γ-cyclodextrin.Most preferred encapsulation agent will change according to the substituent size of R.Yet, will understand fully as those skilled in the art, can also use according to the present invention the mixture of any cyclodextrin or cyclodextrin, the cyclodextrin of cyclodextrin and modification.Cyclodextrin can be from Wacker Biochem Inc., Adrian, and MI or Cerestar USA, Hammond, IN, and other supplier obtains.When encapsulated, because the capacity limitation of molecule encapsulation agent, the enriched material of preferred cyclopropylene will typically be less than other composition.
The composition of active compound and they can also be used with aerosol, for example, by their are for example used pressurized gas, nitrogen, carbonic acid gas, Refrigerant 12, trichlorofluoromethane or other halon and be dispersed in the air.
The amount of the cyclopropylene that the ethene suppressing effect is required will be according to the type of specific cyclopropylene, the vegetable material that provides and quantity, employed cyclopropene compositions and the capacity that will process and is different.Usually, in processing tank the gas processing of cyclopropylene (mensuration volume/volume) concentration be about 1,000,000,000/(" ppb ") 0.1 part to 1,000,000/(" ppm ") 1000 parts enough ethene restraining effect can be provided.Similarly, the spraying of cyclopropylene process application concentration (gravimetry/weight) for about 1,000,000,000/(" ppb ") 0.01 part to 1,000,000/(" ppm ") 1000 parts enough ethene restraining effect can be provided.
Use with general significance at this term " plant ", and comprise that for example, xylophyta is tree and shrubs for example; Herbaceous plant; Vegetables, fruit and farm crop; And ornamental plant.Comprise any part of complete stool plant and they by the processed plant of method described herein, field crop for example, potted plant, seed, flower arrangement (stem and flower), and fruit and the vegetables of results.
With compound and the plant of processing by method of the present invention, preferably process with the active compound of non-plant toxicity quantity.
Can regulate various ethene effect with the present invention, for example flower, fruit and vegetables is ripe and/or old and feeble; Coming off of leaf, flower and fruit; Ornamental plant is the shortening in the survival life-span of the seedling of potted plant, flower arrangement, shrub, seed and dormancy for example; In certain plants (for example, pea) effect of inhibition growth, the effect of stimulating growth (for example paddy rice), growth hormone is active, the restraining effect of terminal growth, the control of apical dominance, the increase of branch, increase is tillered, and changes the form of plant, adjusting is to the phytopathogen susceptibility of fungi for example, change the biochemical composition (for example increasing the leaf area with respect to the stem area) of plant, termination or the restraining effect of flower and seed development, lodging effect, the hormesis of seed germination and breaking dormancy, and hormone or epinasty effect.
Active compound of the present invention has been proved to be the beyond thought establishment agent of the ethylene action of plant, fruit and vegetables, even when using with lower concentration also is.What wherein need to illustrate a bit is, the Compound Phase in compound of the present invention and the prior art is than causing insensitive to long term of ethene.Even the insensitive of this long term to ethene also may appear when using with the concentration lower than previous compound.
Another embodiment of the present invention relates to newfound cyclopropene member's compound.These compounds comprise the compound of following formula:
Figure GSA00000039172900101
Wherein:
A) R 1And R 3One of be H, and R 2, R 4With R 1And R 3In another be independently selected from the group of H and following formula:
-(L) n-Z
Wherein:
I) n is 1 to 12 integer;
Ii) L is selected from group D1 independently of one another, D2, and among E or the J one, wherein:
D1 is the group of following formula:
Figure GSA00000039172900111
D2 is the group of following formula
Figure GSA00000039172900112
E is the group of following formula:
Figure GSA00000039172900113
And
J is the group of following formula:
Figure GSA00000039172900121
Wherein:
A) X and Y are the group of following formula independently of one another:
-(L) m-Z；
And
B) m is 0 to 8 integer; With
C) two D2 or E group are adjacent one another are at the most, and do not have the J group adjacent one another are;
Iii) Z is selected from independently of one another:
A) hydrogen, halogen, cyano group, nitro, nitroso-group, azido-, chlorate anions, bromate, iodate, isocyanato-, isocyanide, isothiocyanato, five fluorine sulfenyls, or
B) group G, wherein G is unsubstituted or replaces; Undersaturated, fractional saturation or saturated; Monocycle, dicyclo, three rings or condense; 4 to 14 yuan of carbocyclic rings or heterocyclic systems, wherein:
1) when ring system comprises 4 yuan of heterocycles, heterocycle comprises 1 heteroatoms;
2) when ring system comprises 5 yuan or multicomponent heterocycle or encircles heterocycle more, heterocycles heterocycle or many rings comprise 1 to 4 heteroatoms;
3) each heteroatoms is independently selected from N, O and S;
4) substituent number is 0 to 5, and each substituting group is independently selected from X;
B) non-hydrogen atom in each compound adds up to 50 or still less; And
C)-(L) nHeteroatomic among the-Z adds up to 0 to 4; And
D) one of following any condition:
I) R 1Or R 3Comprise at least one group G; Or
Ii) at least one L group is the E group; Or
Iii) at least one R 1, R 2, R 3, and R 4Comprise one to four non-hydrogen atom and at least one R 1, R 2, R 3, and R 4Comprise and surpass four non-hydrogen atoms;
And enantiomorph, steric isomer, salt, and their mixture;
Or their composition.
Condition is:
A)-(L) n-Z is not trimethyl silyl, trimethyl silyl alkylsulfonyl or mercaptan; With
B) R 1Not benzenesulfonyl, phenyl sulphur ethyl, phenylbenzene hydroxymethyl, benzo [g] quinoline-7-alcohol-1-methyl, malonic ester derivative, the amino cyclonene of the 3-of replacement, dialkoxy benzylamino carbonyl; With
C) R 3Not 2-phenyl-vinyl, thiophenyl, (4-bromo-2-aminomethyl phenyl) carboxylamine N-carbonyl, (4-bromo-2-aminomethyl phenyl) urethanum N-carbonyl, malonic ester derivative, aryloxy, or dialkoxy benzylamino carbonyl.
Compound of the present invention can be by many method preparations.General reference is seen: Closs, G.L.Advan.Alicyclic Chem.1966,1,53-127 and AlDulayymi, A.R.; Al Dulayymi, J.R; Baird, M.S.; And Koza, G.Russian Journal of Organic Chemistry 1997,33,798-816.
Bromo alkene and dibromo carbene reaction obtain three bromo cyclopropane, can be with it with lithium methide or the as directed cyclopropylene that changes into of other organolithium compound.(see Baird, M.S.; Hussain, H.H.; Nethercott, W.J Chem.Soc.Perkin Trans.11986,1845-1854 and Baird, M.S.; Fitton, H.L.; Clegg, W; McCamley, A.J Chem.Soc.Perkin Trans.1 1993,321-326).If use lithium methide or other lithium alkylide of monovalent, will obtain the cyclopropylene of single bromo.With the lithium alkylide of two equivalents or more equivalents, (lithiated) cyclopropylene of lithiumation will be formed.Can be with its water cancellation, the cyclopropylene shown in obtaining (E=H).Alternatively, the cyclopropenyl radical lithium can react with electrophilic reagent, the cyclopropylene that obtains deriving.The example of such electrophilic reagent comprises alkylating agent, trisubstituted chlorosilane, borate, dialkyl group or diaryl disulphide, ketone, aldehyde, ester, acid amides and nitrile.
Figure GSA00000039172900141
Bromo alkene can prepare by standard method.Available chloro-alkenes substitutes bromo alkene.
Can also with the cyclopropane of three bromos with reductive agent for example diethyl phosphite change the cyclopropane of single bromo into.Can use other reductive agent.
Figure GSA00000039172900142
The dibasic alkene of 1,1-can also with the dibromo carbene reaction, obtain dibromizated intermediate.It is reduced to the cyclopropane of single bromo by zinc.The elimination of carrying out bromine with alkali obtains cyclopropylene (referring to Binger, P.Synthesis 1974,190).
Figure GSA00000039172900151
Can be with cyclopropylene with for example sodium amide deprotonation in liquefied ammonia of highly basic, and with haloalkane or the reaction of other electrophilic reagent, the cyclopropylene that obtains replacing (reference: Schipperijn, A.J.; Smael, P., Recl.Trav.Chim.Pays-Bas, 1973,92,1159).Can be with the cyclopropylene alkyl lithium reagents deprotonation that replaces, and react with electrophilic reagent.
Figure GSA00000039172900152
Can three bromo cyclopropane of alcohol or the derivative that cyclopropylene changes a kind of good leavings group (for example sulphonate) into will be comprised.Can replace leavings group to obtain the cyclopropylene of other replacement with nucleophilic reagent.
Can use the 1-trialkylsilkl that produced by vinyl trialkyl silane-2-hydroxyl cyclopropane as precursor compound (Mizojiri, the R. of cyclopropylene; Urabe, H.; Sato, F.J.Org Chem.2000,65,6217).
Figure GSA00000039172900161
Also 1-trialkylsilkl-2-halo cyclopropane can be eliminated by fluoridizing catalysis, be obtained cyclopropylene (Billups, W.E.; Lee, C-A; Arney, B.E.; Whitmire, K.H.J Am.Chem.Soc., 1991,113,7980. and Banwell, M.C.; Corbett, M.; Gulbis, J.; Mackay, M.F.; Reum, M.E.J.Chem.Soc.Perkin Trans.1,1993,945).
Another kind of method (Mueller, the P. that can be used for synthetic cyclopropylene with diazonium compound and Addition on acetylene; Cranisher, C, Helv Chim Acta 1993,76,521).
Figure GSA00000039172900162
Ester can be hydrolyzed to carboxylic acid.
Similarly, Dihalocarbene and Addition on acetylene can be obtained 1-alkyl-3,3-dihalo cyclopropylene (Bessard, Y.; Schlosser, M.; Tetrahedron, 1991,47,7323).
Compound of the present invention can also be by the preparation as follows of malonic ester derivative.
Figure GSA00000039172900171
Other method that produces cyclopropylene can find in the reference below: Duerr, H., Angew.Chem.1967,24,1104; The people such as Closs, J.Am.Chem.1963,85,3796; Baird, M.S.; Dale, C.M.; Al Dulayymi, J.R.J Chem.Soc.Perkin Trans.1,1993,1373-1374; Koster, the people such as R., Liebigs Annalen Chem.1973,1219-1235; Closs, G.L.; Closs, L.E., J.Am.Chem.Soc., 1961,83,1003-1004; Stoll, A.T.; Negishi, E., Tetrahedron Lett.1985,26,5671-5674.
Embodiment
Embodiment:
General reaction: with all cyclopropylene storage under-80 ℃.Total overall reaction is carried out under nitrogen atmosphere.The sudden strain of a muscle formula chromatography of cyclopropylene carries out under nitrogen atmosphere.The target complete compound purity is 80% or higher unless otherwise mentioned.The cyclopropylene that 1-is replaced never heats, and should notice that these compounds time at room temperature will taper to minimum level.
The preparation of embodiment 1:1-chloro-4-ring third-1-thiazolinyl methyl-benzene (compound 1)
A.1-(2-bromo allyl group)-4-chlorinated benzene
By means of using refractory pebbles valve 8 milliliters of (0.0622mol) 2 that under nitrogen atmosphere, pack into, 50 milliliters of diethyl ether solutions of 3-propylene bromide.When in ice-water bath, cooling off, add at leisure the diethyl ether solution of 62 milliliters of (0.062mol) 1M 4-chlorophenyl magnesium bromides by feed hopper.Stir be warmed up to room temperature simultaneously in 2 hours after, will react in ice bath again cooling, then add 50 milliliters of 1N hydrochloric acid by means of syringe.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Solvent is removed from filtrate in a vacuum.Resistates with cold pentane development, is obtained 12.0 gram 1-(2-bromo allyl group)-4-chlorinated benzene, be oily, it is used without further purifying.
B.2-(4-chlorophenyl methyl)-1,1,2-three bromo cyclopropane
In 20 milliliters of methenyl bromide solution of 11.4 gram (0.0494 mole) 1-(2-bromo allyl group)-4-chlorinated benzene, add 0.686 gram (0.00213 mole) Tetrabutyl amonium bromide.Be heated to 58.5 ℃ after one hour, add 10.7 milliliters of (0.0494 mole) 50% aqueous sodium hydroxide solutions.This step was repeated in two days seven times.Behind the cool to room temperature, add hexane and water.With mixture by the gravity filtration of qualitative corrugation filter paper.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Solvent is removed from filtrate in a vacuum.Resistates with hexane column chromatography purifying, is obtained 2.3 gram 2-(4-chlorophenyl methyl)-1,1,2-three bromo cyclopropane.
C.1-(4-chlorophenyl methyl)-cyclopropylene
By means of using refractory pebbles valve 1.20 gram (0.00298mol) 2-(4-chlorophenyl methyl)-1,1 that under nitrogen atmosphere, pack into, 6 milliliters of diethyl ether solutions of 2-three bromo cyclopropane.When in ice-water bath, cooling off, add at leisure the ether solution of 6.38 milliliters of (0.00893mol) Isosorbide-5-Nitrae M lithium methides by syringe.After 15 minutes, add 2 ml waters by means of syringe.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.In bathing desolventizing from filtrate under warm 20 ℃, obtain 0.430 gram 1-(4-chlorophenyl methyl)-cyclopropylene in a vacuum, be oil.
The preparation of embodiment 2:1-(2-thienyl) methyl-cyclopropylene (compound 2)
The Grignard reagent of preparation 2-bromothiophene, and by changing it into 1-(2-thienyl) methyl-cyclopropylene with the employed identical reaction sequence of the preparation of compound 1.
The preparation of embodiment 3:2-(3-ring third-1-thiazolinyl-propyl group)-[1,3] dioxane (compound 3)
Preparation 2-(2-brooethyl)-1, the Grignard reagent of 3-dioxane, and by with change it into 2-(3-ring third-1-thiazolinyl-propyl group)-[1,3] dioxane for the preparation of the identical reaction sequence of compound 1.
The preparation of embodiment 4:1-(6-(phenyl dimetylsilyl)-hexyl)-cyclopropylene (compound 4)
A.2-bromo-8-(phenyl dimetylsilyl)-Xin-1-alkene
(37 milliliters, the THF solution of 0.5M 18.5mmol) cools off in ice bath with commercially availabie pentamethylene two (magnesium bromide).Add the solution of 3.16 gram (18.5mmol) phenyldimethylchlorosilanes in 7 milliliters of THF roughly.Reaction mixture 5 ℃ of lower stirrings 15 minutes, was then at room temperature stirred 35 minutes, then be cooled to again 5 ℃.Will be in 5 milliliters of THF roughly 2, (3.7 grams 18.5mmol) join in the reaction mixture 3-propylene bromide, and it is continued 5 minutes down at 5 ℃, then are warmed up to room temperature and stir and spend the night.With the cancellation of reaction mixture water.Add ether and a small amount of 1NHCl.Separation of phases is with organic phase water and salt water washing, with magnesium chloride drying, then stripping.The column chromatography purifying obtains 1.47 gram 2-bromo-8-(phenyl dimetylsilyl)-Xin-1-alkene, water white oil.
B.N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide (phase-transfer catalyst)
To 16.5 gram (142mmol) N that stir, N, N ' adds 50.1 gram (292mmol) cylites in the 60 gram acetonitrile solutions of N '-Tetramethyl Ethylene Diamine.Mixture self heats up, and stirs 2.5 hours, and observing has a large amount of precipitations on it.Slurry is diluted with ether, filter, with ether washing and dry, obtain the N that 61.8g wants, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, white solid, fusing point 230-232 ℃.
With similar method, use N, N, N ', N '-tetraethyl-ethylene diamine obtains N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, white solid, decomposes by fusing point 190-193 ℃.
C.2-(6-(phenyl dimetylsilyl)-hexyl)-1,1,2-three bromo cyclopropane
With 1.4 gram (4.3mmol) 2-bromo-8-(phenyl dimetylsilyl)-Xin-1-alkene, 3.2 restrain 45% potassium hydroxide aqueous solution (25.6mmol), 0.2 gram N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, and the mixture of 7.5 milliliters of methylene dichloride is processed with 1.1 milliliters of methenyl bromides (12.6mmol).Well-beaten reaction mixture is at room temperature continued to spend the night.Add entry and methylene dichloride, separation of phases.With methylene dichloride with dried over mgso and stripping.During stripping, add a small amount of heptane to help to remove remaining methenyl bromide.The column chromatography purifying obtains 1.02 gram 2-(6-(phenyl dimetylsilyl)-hexyl)-1,1,2-three bromo cyclopropane, colourless liquid.
D.1-(6-(phenyl dimetylsilyl)-hexyl)-cyclopropylene
With 0.95 gram (1.9mmol) 2-(6-(phenyl dimetylsilyl)-hexyl)-1,1, the diethyl ether solution of 2-three bromo cyclopropane is cooled to-78 ℃.(1.4M, 5.7mmol), placed reaction mixture 30 minutes then water cancellation by 4.1 milliliters in ice bath to add excessive lithium methide.Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, 200 milligrams of 1-(6-(phenyl dimetylsilyl)-hexyl)-cyclopropylene obtained, colourless liquid.
The preparation of embodiment 5:1-(alpha, alpha-dimethylbenzyl)-cyclopropylene (compound 5)
A. Alpha, alpha-dimethylbenzyl cyanogen
In with 1000 milliliter of 3 neck flask of mechanical stirring, outside water-bath, internal thermometer, condenser and feed hopper, add 250 gram methyl-sulphoxides, 59 gram (504mmol) α-tolunitriles, and 160 gram (1127mmol) methyl iodide.Internal temperature is risen to+45 ℃, then the speed with 0.7 per second adds the 8350%NaOH aqueous solution.Reinforced finishing after two hours.With dense slurry cooling, with 1000 ml waters and 500 milliliters of ether and 500 milliliters of hexane dilutions.Tell organic layer and concentrated.It comprises single and dimethylated compound.Further add 250 gram methyl-sulphoxides in this enriched material, 60 gram methyl iodide, and the 37 gram 50%NaOH aqueous solution add two hours as described above.After the cooling, use 1000 ml waters, 500 milliliters of ether, and the dilution of 500 milliliters of hexanes obtain organic layer, and it is washed with 500 ml waters, use anhydrous magnesium sulfate drying, and evaporate to dryness in a vacuum, obtain 69 and restrain α, alpha-alpha-dimethyl phenyl cyanide.
H. The alpha, alpha-dimethylbenzyl methyl ketone
In 500 milliliters of round-bottomed flasks with magnetic agitation, reflux exchanger and barrier film, under the dry nitrogen atmosphere, add 30 gram (207mmol) alpha, alpha-dimethylbenzyl cyanogen and 200 milliliters of ether.By means of intubate in three minutes, be added in lithium methide in the ether (1.4M, 160 milliliters, 224mmol).Exothermic heat of reaction is warming up to gentle reflux between charge period.Stir after 20 minutes, will react 100 milliliters of water-reducible concentrated hydrochloric acid aqueous solution quenchers of 45 milliliters of usefulness of adding of passing through slowly.Stir after one hour, separate organic layer, use anhydrous magnesium sulfate drying, and evaporate to dryness in a vacuum, obtain 32 and restrain the alpha, alpha-dimethylbenzyl methyl ketone.
C.1-(alpha, alpha-dimethylbenzyl)-1-vinylchlorid
15 gram (98mmol) POCl3 that in 250 milliliters of round-bottomed flasks of magnetic agitation and reflux exchanger are housed, pack into, 30 gram (145mmol) PC15, and 19.9 gram (123mmol) alpha, alpha-dimethylbenzyl methyl ketone.In oil bath, reaction is heated to 110 ℃.-hour after gas overflow and to stop.To react cooling also is poured on ice and the ammonium hydroxide aqueous solution carefully.Process extract with ether, obtain 1-(alpha, alpha-dimethylbenzyl)-1-vinylchlorid and 1-(alpha, alpha-dimethylbenzyl)-1, the mixture of 1-ethylene dichloride.Vacuum distilling obtains the 1-(alpha, alpha-dimethylbenzyl) of purifying-1-vinylchlorid, 110-120 ℃ of boiling point (23 torr).
D.1-(alpha, alpha-dimethylbenzyl) 1-chloro-2,2-dibromo cyclopropane
Magnetic agitation adds 4.5 gram (25mmol) 1-(α in 100 milliliters of round-bottomed flask dresses of magnetic agitation are housed, α-dimethylbenzyl)-1-vinylchlorid, 25 gram (100mmol) methenyl bromides, 27 gram methylene dichloride, 0.37 gram N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, and 12.4 gram (100mmol) 45%KOH aqueous solution.The cyclopropane that rapid stirring spends the night and obtains wanting, transformation efficiency 20%.Wash water layer with water, again process with fresh methenyl bromide, catalyzer and KOH and spend the night, cause further conversion.Provide enough transformation efficiencys after processing for the third time.With the organic layer evaporate to dryness of solution washing, use hexane solution chromatographic separation on silica gel of 2% ether in a vacuum, obtain 4.2 gram 1-(alpha, alpha-dimethylbenzyl)-1-chloro-2,2-dibromo cyclopropane.
E.1-(alpha, alpha-dimethylbenzyl)-cyclopropylene
In 50 ml flasks with stirring rod and barrier film, under the dry nitrogen atmosphere, add 1.73 gram (4.9mmol) 1-(alpha, alpha-dimethylbenzyl)-1-chloro-2,2-dibromo cyclopropane and 12 milliliters of ether.Cooling added the ether solution of 9.0 milliliters of (12.6mmol) 1.4M lithium methides after 10 minutes by syringe in ice bath.Form precipitation at once.Stir after 10 minutes, will react with 3 ml water cancellation.Remove water layer, with the organic layer anhydrous magnesium sulfate drying, bathe evaporate to dryness under the temperature at+25 ℃ in a vacuum, obtain 0.94 gram 1-(alpha, alpha-dimethylbenzyl)-cyclopropylene.
The preparation of embodiment 6:3-methyl-3-benzyl ring propylene (compound 6)
A.2,2-two bromo-1-methyl isophthalic acid-benzyl ring propane
In 30.4 milliliters of (0.348 mole) methenyl bromide solution of 12.5 milliliters of (0.0963 mole) alpha-methyl styrenes and 1.34 gram (0.00416 mole) Tetrabutyl amonium bromides, add at leisure 20.9 milliliters of (0.400 mole) 50% aqueous sodium hydroxide solutions by means of feed hopper.Be heated to 55 ℃ after one hour, add 20.9 milliliters of (0.400 mole) 50% aqueous sodium hydroxide solutions.After heating in addition 2 hours, cooling is reacted to room temperature when adding hexane and water.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Solvent is removed from filtrate in a vacuum.The vacuum distilling separated product obtains 24.1 grams, 2,2-, two bromo-1-methyl isophthalic acid-benzyl ring propane, is oil.
B.2-bromo-1-methyl isophthalic acid-benzyl ring propane
To 6.40 gram (0.0221 moles) 2, add 2.16 gram (0.0360 mole) Glacial acetic acid and 2.11 gram (0.0323 mole) zinc powders in the 22 gram methanol solutions of 2-two bromo-1-methyl isophthalic acid-benzyl ring propane.After at room temperature stirring 4 hours, in a vacuum desolventizing.In the resistates that produces, add hexane and water.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Vacuum is removed the solvent in the filtrate, obtains 3.24 gram 2-bromo-1-methyl isophthalic acid-benzyl ring propane, is oil, and it can use without further purifying.
C.3-methyl-3-benzyl ring propylene
In 5 milliliters of dimethyl sulfoxide solutions of 1.56 gram (0.00739 mole) 2-bromo-1-methyl isophthalic acid-benzyl ring propane, add 1.429 gram (0.0127 mole) potassium tert.-butoxides.Reaction is heated to 72 ℃ after 4 hours, adds ether and water.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Vacuum is removed the solvent in the filtrate, obtains the pure 3-methyl of 0.88g 70%-3-benzyl ring propylene, is oil.Main By product (roughly 20%) is 1-methyl isophthalic acid-benzyl ring propane.
The preparation of embodiment 7:3-methyl-3-phenoxymethyl ring third-2-alkene (compound 7)
Can be by being similar to the mode that alpha-methyl styrene is converted into 3-methyl-3-benzyl ring propylene (embodiment 6), the methylallyl phenyl ether is converted into the 3-methyl of purity 90%-3-phenoxymethyl ring third-2-alkene.
The preparation of embodiment 8:1-methyl-2-benzyl rings propylene (compound 8)
In 50 ml flasks of stirring rod and barrier film are housed, under the dry nitrogen atmosphere, add 1 milligram 1,10-phenanthroline, 1.34 gram (11.5mmol) N, N, N ', N '-Tetramethyl Ethylene Diamine and 25 milliliters of tetrahydrofuran (THF)s.Mixture is cooled to-30 ℃, adds 1.5 milliliters of (22mmol) 1-methylcyclopropenes by syringe.(by 3-chloro-2-methyl-propylene preparation; See Hopf, H.; Wachholz, G.; Walsh, R.Chem.Ber.1985,118,3579, and Koster, the people such as R, Liebigs Annalen Chem.1973,1219-1235).The hexane liquid that need to add 1.0 milliliters of 1.6M butyllithiums for preparing a kind of dark ferrugineous solution.Add further 6.0 milliliters of 1.6M butyl lithium solutions (9.6mmol) ,-30 ℃ of lower stirrings 15 minutes, obtain the 1-methylcyclopropene solution of lithiumation.Add 1.64 gram cylites, being warmed to slowly in 20 minutes+5 ℃, the color that obtains shoaling.To react with 0.5 ml methanol cancellation, promptly bathe the lower evaporates to dryness of temperature in+25 ℃ in a vacuum, between ether and diluted hydrochloric acid aqueous solution, distribute, use anhydrous magnesium sulfate drying, and evaporate to dryness more in a vacuum, obtain 1.3 and restrain 1-methyl-2-benzyl rings propylene.
Embodiment 9:1-(2-(4-chloro-phenyl-sulphur) ethyl) cyclopropylene (compound 9)
A.2-bromo-4-(1-ethoxy ethoxy)-but-1-ene
With in ice-water bath, the cooling off of 20 milliliters of diethyl ether solutions of 10.38 gram (0.0687 mole) 3-bromo-3-butene-1-ols and 50 milligrams of (0.000263 mole) tosic acid monohydrates, drip to add at leisure 19 milliliters of (0.199 mole) ethyl vinyl ethers, keep internal temperature＜10 ℃.At 0 ℃ after lower 1 hour, add several triethylamines.Reaction mixture is poured on waterborne.Change the mixture that obtains over to separating funnel, separation of phases.With the organic layer of telling salt water washing, then and filtration dry with salt of wormwood.Remove in a vacuum the solvent in the filtrate, obtain 14.04 gram 2-bromo-4-(1-ethoxy ethoxy)-but-1-enes, be oil.
B.1,1,2-, three bromo-2-[2-(1-ethoxy ethoxy)-ethyl]-cyclopropane
In 108 milliliters of dichloromethane solutions and 0.5-0.9 milliliter 45% potassium hydroxide aqueous solution of 14.02 gram (0.0628 mole) 2-bromo-4-(1-ethoxy ethoxy)-but-1-enes, add 16.4 milliliters of (0.118 mole) methenyl bromides and 2.88 gram (0.00628 mole) N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and 28 milliliters of (0.314 mole) 45% potassium hydroxide aqueous solutions.After 3 days reaction mixture is poured on waterborne.Change the mixture that obtains over to separating funnel, separation of phases.In the organic layer that separates, add 2.88 gram (0.00628mol) N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and 28 milliliters of (0.314mol) 45% potassium hydroxide aqueous solutions.After 24 hours, add hexane and water.With mixture by the gravity filtration of qualitative corrugation filter paper.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Remove in a vacuum the solvent in the filtrate, obtain 17.0 gram 1,1,2-, three bromo-2-[2-(1-ethoxy ethoxy)-ethyls]-cyclopropane, be oil.
C.1,1,2-, three bromo-2-(2-hydroxyethyl) cyclopropane
To 16.5 gram (0.0418 moles) 1,1,2-three bromo-2-[2-(1-ethoxy ethoxy)-ethyl]-slurry of cyclopropane in 145 ml methanol and 40 ml waters in, add 0.306 gram (0.00161 mole) tosic acid monohydrate and 145 milliliters of 6M hydrochloric acid.After at room temperature stirring 1 hour, in a vacuum solvent is removed from reaction mixture.In resistates, add ethyl acetate and water.Change the mixture that obtains over to separating funnel, separation of phases.With the organic layer of telling salt water washing, then use MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained 11.9 gram 1,1,2-, three bromo-2-(2-hydroxyethyl) cyclopropane, be oil.
D.1,1,2-, three bromo-2-(2-phenylsulfonyloxy ethyl) cyclopropane
With 3.00 gram (0.00929 moles) 1,1, the dichloromethane solution of 2-three bromo-2-(2-hydroxyethyl) cyclopropane and 0.901 milliliter (0.0111 mole) drip 1.18 milliliters of (0.00929 mole) benzene sulfonyl chlorides of adding by valinche when pyridine solution is cooled to 0 ℃.Be warming up to room temperature.After 3 days, add entry.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, it is pure 1,1 to obtain 3.10 grams 80%, and 2-three bromo-2-(2-phenylsulfonyloxy ethyl) cyclopropane is oil.
E.2-(2-(4-chloro-phenyl-sulphur) ethyl)-1,1,2-three bromo cyclopropane
The methanol solution that adds 0.371 milliliter of (0.00162 mole) 25% sodium methylate in the 3 ml methanol solution of 0.234 gram (0.162 mole) 4-chlorine phenylmercaptan.At room temperature stir about is after 1 hour, in a vacuum desolventizing.In resistates, add 0.750 gram (0.00151 mole) 1,1, the anhydrous DMF solution of 2-three bromo-2-(2-phenylsulfonyloxy ethyl)-cyclopropane.At room temperature stir for after 24 hours, reaction mixture is poured on waterborne, then use ethyl acetate extraction.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained 0.750 gram oil, it then with 0.5% to 1% ether/hexane column chromatography purifying, is obtained 0.500 gram 2-(2-(4-chloro-phenyl--sulphur) ethyl)-1,1,2-three bromo cyclopropane are oil.
F.1-(2-(4-chloro-phenyl-sulphur) ethyl) cyclopropylene
By means of using refractory pebbles valve 0.500 gram (0.0011mol) 2-(2-(4-chloro-phenyl-sulphur) ethyl)-1,1 that under nitrogen atmosphere, packs into, 6 milliliters of diethyl ether solutions of 2-three bromo cyclopropane.When in ice-water bath, cooling off, add at leisure the ether solution of 2.38 milliliters of (0.00334mol) 1.4M lithium methides by syringe.After 15 minutes, add 2 ml waters by means of syringe.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.In bathing desolventizing from filtrate under warm 20 ℃, obtain 0.100 gram 1-(2-(4-chloro-phenyl-sulphur) ethyl) cyclopropylene in a vacuum, be oil.
Embodiment 10:2-(2-phenylsulfonyloxy ethyl)-cyclopropylene (compound 10)
By means of using refractory pebbles valve 0.745 gram (0.00150mol) 1,1 that under nitrogen atmosphere, pack into, 4 milliliters of diethyl ether solutions of 2-three bromo-2-(2-phenylsulfonyloxy ethyl)-cyclopropane.In dry ice/acetone batch, be cooled in-78 ℃, add at leisure the ether solution of 23.45m1 (0.00450mol) 1.4M lithium methide by syringe.In ice-water bath, be warming to 0 ℃ after 15 minutes, then be cooled to-78 ℃ about 30 minutes, then add 2 ml waters by syringe.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Bathe under the temperature at 20 ℃ and in a vacuum solvent to be removed from filtrate, obtain＞0.155 gram has been infected with 70% pure 2-(2-phenylsulfonyloxy ethyl) of 30%1-(2-hydroxyethyl) cyclopropylene-cyclopropylene, has been oil.
The preparation of embodiment 11:2-(1-(4-bromine pyrazoles))-1-ethyl cyclopropylene (compound 11)
A.2-hydroxyl-1-ethyl cyclopropylene
With 1.15 gram (3.6mmol) 1,1,40 milliliters of diethyl ether solutions of 2-three bromo-2-(2-hydroxyethyl) cyclopropane (as mentioned above preparation) are cooled to-78 ℃.The adding lithium methide (1.4M, 10.3 milliliters, 14.4mmol).Reaction mixture is warmed to 5 ℃, and kept 1/2nd hours.To react the water cancellation, separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, thick product is used for next step reaction at once.
B.2-methyl sulphonyl-1-ethyl cyclopropylene
The thick product of above-mentioned reaction is dissolved in 5 milliliters of ether, and in ice bath, cools off.Add triethylamine (1 milliliter), then add 0.49 gram methylsulfonyl chloride (4.3mmol).Reaction mixture was stirred 1 hour.Add entry and other ether and separation of phases.Wash mutually ether with water twice, use the salt water washing, use dried over mgso, and stripping, obtain the light yellow liquid of 380 milligrams of 2-methyl sulphonyls-1-ethyl cyclopropylene.
C.2-(1-(4-bromine pyrazoles))-1-ethyl cyclopropylene
In the suspension of 5 milliliters of DMF, add 0.51 gram 4-bromine pyrazoles (3.5mmol) to 60% sodium hydride (0.13g, 3.3mmol).To react and at room temperature stir 15 minutes, then in ice bath, cool off.Adding 2-methyl sulphonyl-1-ethyl cyclopropylene (280 milligrams, 1.7mmol).Remove ice bath, will react and at room temperature stir 2 hours.In reaction mixture, add ether and water, and separation of phases.With water with other ether extraction.The ether that merges is washed with water three times mutually, use the salt water washing, use dried over mgso, and stripping.The chromatographic separation product obtains 30 milligram of 72% pure 2-(1-(4-bromine pyrazoles))-1-ethyl cyclopropylene.
The preparation of embodiment 12:7-(1-imidazoles)-1-heptyl cyclopropylene (compound 12)
A.1-(1-ethoxy ethoxy)-6-bromohexane
In 40 milliliters of diethyl ether solutions of 80 milligrams of toluenesulphonic acidss that cool off, inject simultaneously 20 gram (110mmol) 6-bromine hexanol and 40 milliliters of ethyl vinyl ethers by the funnel that adds that separates.During 1 hour that injects, the temperature of maintenance reaction mixture is at 7 ℃ or be lower than 7 ℃ temperature.The reaction mixture stirring was longer than 20 minutes, is then added roughly 1 milliliter of triethylamine.With reaction mixture water and salt water washing, dry with salt of wormwood, filter and stripping, obtain the light yellow liquid of 25.7 grams, it can be used without purifying further.
B.9-(1-ethoxy ethoxy)-2-bromine ninth of the ten Heavenly Stems-1-alkene
Process the slurry of 5.6 gram magnesium smear metals (230mmol) in 100 milliliters of THF with a small amount of glycol dibromide.(38.5 grams, 152mmol), holding temperature is at 40-50 ℃ to inject at leisure 1-(1-ethoxy ethoxy)-6-bromohexane in the reaction mixture.After adding end, reaction mixture was deposited 20 minutes, then under 0 ℃, transferred to 33.4 gram (167mmol) 2 by intubate, in 25 milliliters of THF solution of 3-propylene bromide.Reaction mixture 0 ℃ of lower stirring 15 minutes, was then at room temperature stirred then water cancellation 15 minutes.Reaction mixture is transferred in the separating funnel.Add a small amount of 1NHCl, separation of phases with ether phase water and salt water washing, is then used dried over mgso, filters and stripping, obtains the yellow liquid of 33.63 grams, it can be used without purifying further.
C.1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane
With 9-(1-ethoxy ethoxy)-2-bromine ninth of the ten Heavenly Stems-1-alkene (33.63g, 115mmol), 4.1 gram N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, 42 gram 45% potassium hydroxide (337mmol), the mixture of 93 gram methenyl bromides (368mmol) and 280 gram methylene dichloride at room temperature promptly stirred two days.When reaction stopped, reaction mixture changed separating funnel over to, washed with water.Methylene dichloride is changed in the flask mutually, as above process with phase-transfer catalyst and 45% potassium hydroxide of equal amts, then restir 3 days at room temperature.Reaction mixture is washed with water, with dried over mgso methylene dichloride phase, then stripping.Product was at room temperature processed 1 hour with 320 ml methanol and 40 milliliters of 1NHCl.Stripped methanol adds ethyl acetate.With organic phase water and salt water washing, then use 200 milliliters of silica gel treatment.Filter, then stripping obtains 38 gram black products.With its chromatographic separation on silica gel, obtain 19.0 gram 1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane, light yellow liquid.
D.1-(7-hydroxyl heptyl)-cyclopropylene
At-78 ℃ of lower 25 milliliters of diethyl ether solutions processing 1.0 gram 1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane (2.5mmol) with 7.2 milliliters of lithium methides (1.4M, 10mmol).After 5 minutes, reaction mixture is warmed to 0 ℃, and deposits in this temperature.To react and use the saturated ammonium chloride cancellation.With reaction mixture water and salt water washing, use dried over mgso, filter and stripping, obtain 240 milligrams of 1-(7-hydroxyl heptyl)-cyclopropylene.
E.1-(7-mesyloxy heptyl)-cyclopropylene
50 milliliters of diethyl ether solutions of 3.8mmol1-(7-hydroxyl heptyl)-cyclopropylene are cooled off in ice bath.(4.2mmol stirs reaction mixture 2.5 hours under 0 ℃ to add triethylamine (1 milliliter) and 0.48 gram methylsulfonyl chloride.With reaction mixture water and salt water washing, use dried over mgso, filter and stripping, obtain 1-(7-mesyloxy heptyl)-cyclopropylene, it can use without further purifying.
F.7-(1-imidazoles)-1-heptyl cyclopropylene
In ice bath, in the suspension of 5 milliliters of DMF, add 0.14 gram imidazoles (2mmol) to 60% sodium hydride (0.08g, 2mmol).To react and stir 15 minutes, then add 3 milliliters of DMF liquid of 0.3 gram (1.3mmol) 1-(7-mesyloxy heptyl)-cyclopropylene.Reaction mixture was stirred 10 minutes, then remove ice bath, at room temperature stirring reaction is 1 hour.In reaction mixture, add ether and water, and separation of phases.With water with other ether extraction.The ether that merges is washed with water three times mutually, use the salt water washing, use dried over mgso, and stripping.The chromatographic separation product obtains 80 milligrams of 7-(1-imidazoles)-1-heptyl cyclopropylene.
The preparation of embodiment 13:7-(diphenyl amino)-1-heptyl cyclopropylene (compound 13)
Pentanoic (0.42g, 2.5mmol) is cooled to-78 ℃ in 10 milliliters of THF, processes with 1.6 milliliters of (1.4m, 2.2mmol) lithium methides.Add 1-(7-mesyloxy heptyl)-cyclopropylene, remove cryostat, and reaction mixture is warming up to room temperature.To react and place then water cancellation 5.5 hours.In reaction mixture, add ether and water, and separation of phases.Wash mutually ether with water twice, use the salt water washing, use dried over mgso, and stripping.The chromatographic separation product obtains 80 milligrams of 7-(diphenyl amino)-1-heptyl cyclopropylene, is colourless liquid.
The preparation of embodiment 14:1-cyclohexyl ring propylene (compound 14)
By cyclohexane carboxylic acid methyl esters and vinyl trimethyl silyl such as Mizojiri, R.; Urabe, H.; Sato, F.J.Org Chem.2000, preparation 1-cyclohexyl-2-(trimethyl silyl) ring propyl alcohol described in 65,6217.Change this material into cyclopropylene with the similar method described in same reference.
The preparation of embodiment 15:1-((2-carboxy-N-morpholinyl) ethyl)-cyclopropylene
A.2-(2-bromo-allyl group)-diethyl malonate
By with the hexane washing, remove in 21.70 gram (0.542 mole) 60% sodium hydride oil solutions, be oil.To being suspended in 200 milliliters of resistatess in the tetrahydrofuran (THF), add at leisure 84.38 milliliters of (0.556 mole) diethyl malonates by feed hopper.When reaction being cooled to-35 to-10 ℃, add at leisure 100 gram (0.400 moles) 2,3-propylene bromide by feed hopper.Be heated to and refluxed rear 1 hour, will react cool to room temperature, and vacuum concentration.In resistates, add hexane and water, change the mixture that obtains over to separating funnel, and separation of phases.With the organic layer of telling 1N salt acid elution, then with dried over mgso and filtration.In a vacuum solvent is removed from filtrate, obtained 154 gram 2-(2-bromo-allyl group)-diethyl malonates, be oil.
B.2-(2-bromo-allyl group)-propanedioic acid
The mixture of 10.5 gram (0.0376 mole) 2-(2-bromo-allyl group)-diethyl malonates and 37.6 milliliters of (0.470 mole) 50% aqueous sodium hydroxide solutions was at room temperature stirred 4 days.With the reaction mixture ether extraction.The water layer that separates by adding the concentrated hydrochloric acid acidifying, and add ether.Change the mixture that obtains over to separating funnel, separation of phases.The organic layer of telling is also filtered with dried over mgso.In a vacuum solvent is removed from filtrate, obtained the solid of 5.3 gram 2-(2-bromo-allyl group)-propanedioic acid, can continue without purification.
C.4-bromo-penta-obtusilic acid
5.3g (0.0238 mole) is clean, and unpurified 2-(2-bromo-allyl group)-propanedioic acid is heated to 125-130 ℃, keeps 8 hours, obtains 3.73 gram 4-bromo-, penta-obtusilic acid, can continue without purification.
D.4-bromo-penta-obtusilic acid ethyl ester
To 3.73 gram (0.0208 mole) unpurified 4-bromo-penta-obtusilic acids with adding 1.18 milliliters of (0.0162 mole) thionyl chloride in 3 milliliters of chloroformic solutions of 1 DMF.After this mixture heating up to 60 ℃ kept 30 minutes, it is joined in the solution of 2.46 milliliters of (0.0436 mole) ethanol and 1.97 milliliters of (0.024 mole) pyridines and 13 milliliters of methylene dichloride.Stir after 30 minutes, with the reaction mixture vacuum concentration.In resistates, add ether and water.Change the mixture that obtains over to separating funnel, separation of phases.The organic layer of telling is also filtered with dried over mgso.In a vacuum solvent is removed from filtrate, is obtained 3.5 gram 4-bromo-, penta-obtusilic acid ethyl ester, be oil, with it by the vacuum distilling purifying.
E.1,1,2-, three bromo-2-((3-carbonyl oxyethyl group) ethyl)-cyclopropane
To be similar to the mode of the corresponding intermediate of preparation described in the embodiment 9, preparation 1,1,2-three bromo-2-((3-carbonyl oxyethyl group) ethyl-cyclopropyl alkane.
The resistates that obtains is passed through the column chromatography purifying with ether/hexane.
F.1,1,2-, three bromo-2-((2-carboxyl) ethyl)-cyclopropane
With 10.2 gram (0.0269 moles) 1,1,2-, three bromo-2-((the 3-carbonyl oxyethyl group) ethyl) solution of cyclopropane in 40 milliliters of (0.736 mole) 48% Hydrogen bromides and 40 ml waters is heated to backflow, keeps 8 hours, with its cool to room temperature, then pass through Shark
Figure GSA00000039172900291
The filter paper vacuum filtration.Before adding ether, wash isolated solid with water.Solution is changed in the separating funnel, with the saturated sodium bicarbonate aqueous solution washing, be isolated, and by adding the 1N hcl acidifying.Again change the aqueous solution over to separating funnel, and use ether extraction.The organic layer of telling is also filtered with dried over mgso.In a vacuum solvent is removed from filtrate, obtained the solid of 5.9 gram 1,1,2-, three bromo-2-((2-carboxyl))-ethyl cyclopropane, it can directly use.
G.1,1,2-, three bromo-2-((2-carboxy-N-morpholinyl) ethyl)-cyclopropane
To 0.97 gram (0.00276 mole) 1,1,2-three bromo-2-((2-carboxyl))-ethyl-cyclopropyl alkane adds 1 DMF and 0.434 milliliter of (0.00596 mole) thionyl chloride in the slurry of 2 milliliters of chloroforms.After the reflux 15 minutes, with the reaction mixture vacuum concentration.2 milliliters of dichloromethane solutions of resistates are joined in 1 milliliter of dichloromethane solution of 0.486 milliliter of (0.00552 mole) morpholine, it is cooled to-20 ℃.After 30 minutes, with the reaction mixture vacuum concentration.Extract from the 1N hydrochloric acid of minimum with ethyl acetate and to obtain resistates.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained 1.08 gram 1,1,2-, three bromo-2-((2-carboxyl N-morpholinyl) ethyl)-cyclopropane, be oil.
H.1-((2-carboxy-N-morpholinyl) ethyl)-cyclopropylene
Prepare 0.460 gram, 60% pure 1-((2-carboxy-N-morpholinyl) ethyl)-cyclopropylene in the mode that is similar to compound 1.
3-hydroxyl carbonyl methyl isophthalic acid, 2,3-triphenyl cyclopropylene (compound 40) is commercially availabie.
The preparation of embodiment 16:1-(7-(N-piperidyl imino-heptyl))-cyclopropylene (compound 36)
A.1-(7-(enanthaldehyde))-cyclopropylene
1-(7-hydroxyl heptyl)-cyclopropylene (by implementing 12 preparations) is passed through Arrowood, T.L. with the Swem oxygenizement; Kass, S.R.Telrahedrom, the method for describing among 1999,55, the 6739-48 is oxidized to 1-(7-(enanthaldehyde))-cyclopropylene.
B.1-(7-N-piperidyl imino--heptyl))-cyclopropylene
In the ethanolic soln of 100 milligrams of 1-(7-(enanthaldehyde))-cyclopropylene (0.66mmol), add 70 milligrams of (0.70mmol) N-amino piperidines.Reaction mixture was stirred 2 hours, then add ether, water and several acetic acid.Isolate water, with ether phase water and salt water washing, then use dried over mgso, and filter.The stripping solvent obtains 70 milligrams of 1-(7-N-piperidyl imino--heptyl))-cyclopropylene.
The preparation of embodiment 17:1-(3-4-trifluoromethylphenopendant methyl)-2-ethyl cyclopropylene (compound 37)
A.1,1,2-, three bromo-2-ethyl cyclopropane
By preparing 1,1,2-, three bromo-2-ethyl cyclopropane with the used identical method of embodiment 4c by 2-bromo-1-butylene.
B.1-(methylol)-2-ethyl cyclopropylene
With 3.0 gram (10mmol) 1,1,50 milliliters of diethyl ether solutions of 2-three bromo-2-ethyl cyclopropane are cooled to-78 ℃.The adding lithium methide (1.4M, 21.4 milliliters, 30mmol).Reaction mixture is warmed to 5 ℃.(1.20 grams 40mmol), 5 ℃ of lower stirrings 1 hour, then allow to be warming up to room temperature, restir one hour with reaction mixture to add solid polyformaldehyde.To react the water cancellation, separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, obtain 900 milligrams of 1-(methylol)-2-ethyl cyclopropylene, be yellow oil.
C.1-(mesyloxy methyl)-2-ethyl cyclopropylene
In ice bath to 0.70g (7.13mmol) 1-(methylol)-2-ethyl cyclopropylene (compound 3) and 2 milliliters of triethylamines in the solution of 15 milliliters of ether, add 0.86 gram (7.5mmol) methylsulfonyl chloride.Reaction mixture was placed 1.5 hours then water cancellation.Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, obtain 840 milligrams of 1-(mesyloxy methyl)-2-ethyl cyclopropylene, be yellow oil.
D.1-(3-4-trifluoromethylphenopendant methyl)-2-ethyl cyclopropylene
At room temperature (0.41 gram 2.5mmol) joins 0.07g sodium hydride (1.8mmol) in the suspension of 3 milliliters of DMF with the 3-trifloro methyl phenol.After 15 minutes, add 2 milliliters of DMF solution of 0.3 gram (1.7mmol) 1-(mesyloxy methyl)-2-ethyl cyclopropylene, then reaction mixture was stirred 2 hours.Add ethyl acetate and water.Separation of phases is used 1N aqueous sodium hydroxide solution and salt water washing mutually with ethyl acetate, then uses dried over mgso, filters and stripping, obtains 160 milligrams of 1-(3-4-trifluoromethylphenopendant methyl)-2-ethyl cyclopropylene, is tawny liquid.
Embodiment 18:2-octyl group-1-(preparation of 2-(2-boron-1,3-dioxetane))-cyclopropylene (compound 38)
A.2-octyl group-1-(boric acid)-cyclopropylene
Will with and embodiment 1 described in 1.30 gram (3.3mmol) 2-octyl groups-1,1 of same method preparation, the ethereal solution of 2-three bromo cyclopropane is cooled to-78 ℃.The adding lithium methide (1.4M, 5.9 milliliters, 8.3mmol), reaction mixture was stirred 10 minutes, then put into ice bath, placed 30 minutes, and then be cooled to-78 ℃.Adding triisopropyl boric acid ester (0.9 milliliter, 3.9mmol), reaction mixture was stirred 15 minutes, then be warming to 0 ℃.Add entry, ether and the 1NHCl aqueous solution (abundance makes solution be acid).Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, product is dissolved in the ether again, extract three times with the 1N aqueous sodium hydroxide solution.Extract with the acidifying of 6N aqueous hydrochloric acid, is used ether extraction three times.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, obtain the 2-octyl group-1-(boric acid) of 400 milligrams of light yellow solids-cyclopropylene.
B.2-octyl group-1-(2-(2-boron-1,3-dioxy butane (dioxetane)))-cyclopropylene
At room temperature use 0.3 milliliter 1, the 3-dihydroxypropane is processed the mixture of 10 milliliters of pentanes of 270 milligrams of 2-octyl group-1-(boric acid)-cyclopropylene (1.4mmol).1.5 after hour, change reaction mixture over to separating funnel.With pentane solution water and salt water washing, use dried over mgso, filter and stripping, obtain 90 milligram of 50% pure 2-octyl group-1-(2-(2-boron-1,3dioxetane))-cyclopropylene.
NMR prediction: 0.88 (t, 3H), 0.98 (s, 2H), 1.1-1.3 (m, 10H), 1.55 (m, 2H), 1.9 (m, 2H), 2.5 (m, 2H), 4.1-4.4 (m, 4H)
The preparation of embodiment 19:1-methyl-2-(hydroxyl-(3-p-methoxy-phenyl) methyl) cyclopropylene (compound 39)
Under nitrogen keep to bathe temperature under-40 ℃ to about 2 milligram 1, in the mixture of 10-phenanthroline in 50 milliliters of diethyl ether, add successively (2.5 milliliters of Diisopropylamines by syringe, 17.9mmol), diethyl ether (3 milliliters), 1-methylcyclopropene (1.1 grams, 20.4mmol; By 3-chloro-2-methyl-propylene preparation, see Hopf, the people such as H. Chem.Ber.1985,118,3579 and Koster, the people such as R. Liebigs Annalen Chem.1973,1219-1235.).Then add 1.0 milliliters of N-butyllithiums (1.6M hexane solution), until solution remains brown.After this then add the same butyllithium (10.0 milliliters, 16 mmol) of another part.After 15 minutes, reaction is cooled to-70 ℃-40 ℃ of lower stirrings, and adding 3-methoxybenzaldehyde (1.9 milliliters, 15.6mmol).After 3 minutes, will react quencher by adding 3 ml waters.After being warming up to room temperature, separate each layer.Organic phase is also dry in a vacuum with dried over mgso.Resistates is dissolved in diethyl ether, with 1M hydrochloric acid, salt water washing, washs with saturated sodium bicarbonate aqueous solution at last.Separate each layer.Organic phase with dried over mgso and dry in a vacuum, is obtained 1.0 gram 1-methyl-2-(hydroxyl (3-p-methoxy-phenyl) methyl) cyclopropylene.
Embodiment 20:1-phenyl-2.3,3-trichlorine cyclopropylene (compound 41)
By Eicher, theophil; Huch, Volker; Schneider, Volker; Veith, Michael.Synthesis, the method for describing among 1989,5, the 367-72 prepares 1-phenyl-2,3,3-trichlorine cyclopropylene.
Embodiment 21:1-(4-aminomethyl phenyl ketonic oxygen Ji Dingji)-cyclopropylene (compound 44)
A.5,6-two bromo-oneself-1-alcohol
In about 20 milliliters of dichloromethane solutions of the 5-hexen-1-ol (11.23g, 112.3mmol) of ice bath cooling, (5.80 milliliters add 12, about 20 milliliters of dichloromethane solutions 112.3+mmol) to add bromine.Reinforced complete after, mixture is dry in a vacuum, obtain 29.1 grams, 5,6-, two bromo-oneself-1-alcohol.
B.5-bromo-oneself-5-alkene-1-alcohol
To 5 of ice bath cooling, 6-two bromo-oneself-(29.1 grams add tetrahydrofuran (THF) (62.4g, the 112mmol) liquid of 20% potassium tert.-butoxide to 1-alcohol in about 59 milliliters of tetrahydrofuran solutions 112mmol).After reinforced complete, reaction mixture is warmed up to room temperature, stir about 30 minutes.Add then separation of phases of ether and water.With the organic layer dried over mgso of telling, then dry in a vacuum.Resistates is used 5 orifice plate post vacuum distilling purifying, obtain 23.16 grams, 87% pure 5-bromo-oneself-5-alkene-1-alcohol.
C.4-methyl-phenylformic acid 5-bromo-oneself-the 5-alkenyl esters
To the 5-bromo-oneself-5-alkene-1-alcohol (4.39 grams, add in 10.6 gram dichloromethane solutions 24.5mmol) 4-toluene acyl chlorides (3.95 grams, 25.6mmol) and triethylamine (3.3 restrain, 33mmol).At room temperature stir about diluted mixture after 2 hours with diethyl ether, then then used the salt water washing with 1N hydrochloric acid.Separation of phases, the organic layer dried over mgso is then dry in a vacuum, obtain 7.3 gram 4-methyl-phenylformic acid 5-bromo-oneself-the 5-alkenyl esters.
D.4-methyl-phenylformic acid 4-(1,2,2-, three bromo-cyclopropyl)-butyl ester
In round-bottomed flask, drop into 4-methyl-phenylformic acid 5-bromo-oneself-the 5-alkenyl esters (7.3 grams, 24.6mmol), N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (0.30 gram, 0.66mmol), methylene dichloride (25 gram), (25 grams are 98.9mmol) with 45% potassium hydroxide aqueous solution (11.5 grams for methenyl bromide, 92mmol), at room temperature stir 4 days.After adding entry, separate each layer.In the organic layer of telling, add N, N '-dibenzyl-N, N, N ', (0.30 gram, 0.66mmol), (27 grams, 107mmol) (12 restrain methenyl bromide N '-Tetramethyl Ethylene Diamine dibromide, 96mmol) with 45% potassium hydroxide aqueous solution.At room temperature restir added hexane and water after one day.With mixture gravity filtration, and separate each layer by qualitative filter paper.With the organic layer dried over mgso of telling, then dry in a vacuum.Use ethyl acetate/hexane by the column chromatography purifying resistates that obtains, obtain the pure 4-methyl of 4.9 grams 61%-phenylformic acid 4-(1,2,2-, three bromo-cyclopropyl)-butyl ester.
E.4-(1,2,2-, three bromo-cyclopropyl)-Ding-1-is pure
(45.5 grams, (30 grams are 107mmol) with 30 gram water to add 50% wet chemical in 250 gram methanol solutions 97mmol) to 4-methyl-phenylformic acid 4-(1,2,2-, three bromo-cyclopropyl)-butyl ester.With reaction be heated to 60 ℃ about 2 hours, cool to room temperature then.After about 15 hours, (30 grams 107mmol) with 30 gram water, are heated to 60 ℃ with reaction and kept about 2 hours, then cool to room temperature to add 50% aqueous solution salt of wormwood.With the reaction mixture vacuum concentration, the resistates that then obtains with ether extraction.Organic layer is washed with alkalization water (pH10).Separation of phases, organic phase is for using dried over mgso, then dry in a vacuum.Use ether/hexane to pass through the column chromatography purifying resistates, obtain 14.5 grams, 74% pure 4-(1,2,2-, three bromo-cyclopropyl)-Ding-1-alcohol.
F.1-(4-hydroxybutyl)-cyclopropylene
Under nitrogen atmosphere, add 4-(1,2,2-, three bromo-cyclopropyl)-Ding-1-alcohol (5.11 grams, 4 milliliters of diethyl ether solutions 14.5mmol), and be cooled to 0 ℃.Use syringe, add the 1.4M lithium methide diethyl ether (41.6 milliliters, 58.2mmol).After 15 minutes, will react quencher by adding about 2 ml waters.Separation of phases.With the organic layer dried over mgso of telling, and dry in a vacuum, obtain 2.51 gram 1-(4-hydroxybutyl)-cyclopropylene, be oil.
G.1-(4-aminomethyl phenyl ketonic oxygen Ji Dingji)-cyclopropylene
(810 milligrams, 5-10 milliliter dichloromethane solution 7.23mmol) is cooled to 0 ℃ with 1-(4-hydroxybutyl)-cyclopropylene.To wherein add triethylamine (0.895 milliliter, 7.88mmol), then add 4-toluene acyl chlorides (0.794 milliliter, 7.30mmol).About 10 ℃ lower stir 1 hour after, reaction is cooled to 0 ℃, and add triethylamine (0.895 milliliter, 7.88mmol), then add 4-toluene acyl chlorides (0.794 milliliter, 7.30mmol).At room temperature stir about-hour after, with the reaction mixture vacuum concentration.In resistates, add diethyl ether and water.Separation of phases.With the organic layer of telling 1N salt acid elution, then use dried over mgso, and dry in a vacuum, obtain 2.05 oil.Use ethyl acetate/hexane at silica gel upper prop chromatogram purification it, obtain 470 milligram of 50% pure 1-(4-aminomethyl phenyl ketonic oxygen Ji Dingji)-cyclopropylene, with the p-toluic acid of remnants.
Embodiment 22:1-benzyl-2-bromine cyclopropylene (compound 45)
A.1-benzyl-1,2,2-three bromo cyclopropane
Prepare 1-benzyl-1,2 by method shown in the embodiment 1b by 1-(2-bromo-allyl group)-benzene, 2-three bromo cyclopropane.
B.1-benzyl-2-bromine cyclopropylene
With 1-benzyl-1,2,2-three bromo cyclopropane (1.21 the gram, 3.27mmol) and diethyl phosphite (1.69 milliliters, 13.1mmol) and triethylamine (0.455 milliliter 3.26mmol) is at room temperature mixed 24 hours.In reaction mixture, add hexane, it is used 1N salt acid elution.Separation of phases.Water layer is extracted with diethyl ether, and separation of phases.Use diethyl ether/hexane at silica gel upper prop chromatogram purification the organic layer that merges, obtain 300 milligrams of 1-benzyls-2-bromine cyclopropylene, be oil.
Embodiment 23:1-benzyl-2-chlorine cyclopropylene (compound 46)
A.1-(2-bromo-allyl group)-benzene
Prepare 1-(2-bromo-allyl group)-benzene by method shown in the embodiment 1a by 2,3-propylene bromide and phenyl-magnesium-bromide.
B.1-benzyl-1-bromo-2,2-two Cyclopropanoyl Chlorides
To 1-(2-bromo-allyl group)-benzene (6.80 grams, 34.5mmol) (39.4 milliliters of chloroforms, 493mmol) add 45% potassium hydroxide aqueous solution (16.2ml in the solution, 189mmol) and N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (790 milligrams, 1.72mmol).After at room temperature stirring 3 days, add chloroform (2 milliliters) and 45% potassium hydroxide aqueous solution (16.2ml, 189mmol) and N, N ' dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (790 milligrams, 1.72mmol).At room temperature restir added hexane and water after one day.Separation of phases.With the organic layer dried over mgso of telling, and dry in a vacuum, obtaining 6.7 gram 1-benzyl-1-bromo-2,2-two Cyclopropanoyl Chlorides are oil.
C.1-benzyl-2-chlorine cyclopropylene
With 1-benzyl-1-bromo-2, (1.45 grams, about 4 milliliters of diethyl ether solutions 5.18mmol) are cooled to 0 ℃ to 2-two Cyclopropanoyl Chlorides, and are placed under the nitrogen atmosphere.To the ether that wherein adds the 1.4M lithium methide (3.70 milliliters, 5.18mmol) liquid.After 15 minutes, will react quencher by adding 2 ml waters.Separation of phases.With the organic layer dried over mgso of telling, and dry in a vacuum, obtain 720 milligrams of 1-benzyls-2-chlorine cyclopropylene, be oil.
Embodiment 24:1-(the preparation of 2-(furans-2-base ketonic oxygen base ethyl)-cyclopropylene (compound 47)
A.2-bromo-4-(1-ethoxy ethoxy)-but-1-ene
When 20 milliliters of diethyl ether solutions of 10.38 gram (0.0687 mole) commercially available 3-bromo-3-butene-1-ols and 50 milligrams of (0.000263 mole) tosic acid-hydrates are cooled off in ice-water bath, drip to add at leisure 19 milliliters of (0.199 mole) ethyl vinyl ethers, keep internal temperature＜10 ℃.At 0 ℃ after lower 1 hour, add several triethylamines.Reaction mixture is poured on waterborne.Change the mixture that obtains over to separating funnel, separation of phases.With the organic layer of telling salt water washing, then and filtration dry with salt of wormwood.Remove in a vacuum the solvent in the filtrate, obtain 14.04 gram 2-bromo-4-(1-ethoxy ethoxy)-but-1-enes, be oil.
B.1,1,2-tribromo 2-[2-(1-ethoxy ethoxy)-ethyl]-cyclopropane
In 108 milliliters of dichloromethane solutions and 0.5-0.9 milliliter 45% potassium hydroxide aqueous solution of 14.02 gram (0.0628 mole) 2-bromo-4-(1-ethoxy ethoxy)-but-1-enes, add 16.4 milliliters of (0.118 mole) methenyl bromides and 2.88 gram (0.00628 mole) N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and 28 milliliters of (0.314 mole) 45% potassium hydroxide aqueous solutions.After 3 days reaction mixture is poured on waterborne.Change the mixture that obtains over to separating funnel, separation of phases.In the organic layer that separates, add 2.88 gram (0.00628mol) N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and 28 milliliters of (0.314mol) 45% potassium hydroxide aqueous solutions.After 24 hours, to wherein adding hexane and water.With mixture by the gravity filtration of qualitative corrugation filter paper.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Remove in a vacuum the solvent in the filtrate, obtain 17.0 gram 1,1,2-, three bromo-2-[2-(1-ethoxy ethoxy)-ethyls]-cyclopropane, be oil.
C.2-(2-hydroxyethyl)-1,1,2-three bromo cyclopropane
To 16.5 gram (0.0418 moles) 1,1,2-three bromo-2-[2-(1-ethoxy ethoxy)-ethyl]-slurry of cyclopropane in 145 ml methanol and 40 ml waters in, add 0.306 gram (0.00161 mole) tosic acid monohydrate and 145 milliliters of 6M hydrochloric acid.After at room temperature stirring 1 hour, in a vacuum solvent is removed from reaction mixture.In resistates, add ethyl acetate and water.Change the mixture that obtains over to separating funnel, separation of phases.With the organic layer of telling salt water washing, then use MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained 11.9 gram 2-(2-hydroxyethyl)-1,1,2-three bromo cyclopropane are oil.
D.1-(2-hydroxyethyl)-cyclopropylene
With 1.15 gram (3.6mmol) 2-(2-hydroxyethyl)-1,1,40 milliliters of diethyl ether solutions of 2-three bromo cyclopropane (as mentioned above preparation) are cooled to-78 ℃.The adding lithium methide (1.4M, 10.3 milliliters, 14.4mmol).Reaction mixture is warmed to 5 ℃, and kept 1/2nd hours.To react the water cancellation, separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, thick product is used for next step reaction at once.
E) 1-(2-(furans-2-base ketonic oxygen base ethyl)-cyclopropylene
To 0 ℃ 1-(2-hydroxyethyl)-cyclopropylene (300 milligrams, add in about 10 milliliters of dichloromethane solutions 3.56mmol) triethylamine (0.540 milliliter, 3.88mmol) and furans-2-carbonyl chloride (0.356 milliliter, 3.60mmol).At room temperature stir about is after 2 hours, with the reaction mixture vacuum concentration.In resistates, add diethyl ether and water.Separation of phases.With organic layer 1N salt acid elution.Behind the separation of phases, with the organic layer dried over mgso, and dry in a vacuum, obtain 430 milligrams of oil.Use diethyl ether/hexane at silica gel upper prop chromatogram purification it, (2-(furans-2-base ketonic oxygen base ethyl)-cyclopropylene is oil to obtain 20 milligrams of 1-.
The preparation of embodiment 25:1-(7-(4-mesyloxy phenyl)-ketonic oxygen base heptyl)-cyclopropylene (compound 53)
A.1-(1-ethoxy ethoxy)-6-bromohexane
In 40 milliliters of diethyl ether solutions of 80 milligrams of toluenesulphonic acidss that cool off, inject simultaneously 20 gram (110mmol) 6-bromine hexanol and 40 milliliters of ethyl vinyl ethers by the funnel that adds that separates.During 1 hour that injects, the temperature of maintenance reaction mixture is at 7 ℃ or be lower than 7 ℃ temperature.The reaction mixture stirring was longer than 20 minutes, is then added roughly 1 milliliter of triethylamine.With reaction mixture water and salt water washing, dry with salt of wormwood, filter and stripping, obtain the light yellow liquid of 25.7 grams, it can be used without purifying further.
B.9-(1-ethoxy ethoxy)-2-bromine ninth of the ten Heavenly Stems-1-alkene
Process the slurry of 5.6 gram magnesium smear metals (230mmol) in 100 milliliters of THF with a small amount of glycol dibromide.(38.5 grams, 152mmol), holding temperature is at 40-50 ℃ to inject at leisure 1-(1-ethoxy ethoxy)-6-bromohexane in the reaction mixture.After adding end, reaction mixture was deposited 20 minutes, then under 0 ℃, transferred to 33.4 gram (167mmol) 2 by intubate, in 25 milliliters of THF solution of 3-propylene bromide.Reaction mixture 0 ℃ of lower stirring 15 minutes, was then at room temperature stirred then water cancellation 15 minutes.Reaction mixture is transferred in the separating funnel.Add a small amount of 1NHCl, separation of phases with ether phase water and salt water washing, is then used dried over mgso, filters and stripping, obtains the yellow liquid of 33.63 grams, it can be used without purifying further.
C.1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane
With 9-(1-ethoxy ethoxy)-2-bromine ninth of the ten Heavenly Stems-1-alkene (33.63g, 115mmol), 4.1 gram N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, 42 gram 45% potassium hydroxide (337mmol), the mixture of 93 gram methenyl bromides (368mmol) and 280 gram methylene dichloride at room temperature promptly stirred two days.When reaction stopped, reaction mixture changed separating funnel over to, washed with water.Methylene dichloride is changed in the flask mutually, process as previously mentioned with phase-transfer catalyst and 45% potassium hydroxide of equal amts, then restir 3 days at room temperature.Reaction mixture is washed with water, with dried over mgso methylene dichloride phase, then stripping.Product was at room temperature processed 1 hour with 320 ml methanol and 40 milliliters of 1NHCl.Stripped methanol adds ethyl acetate.With organic phase water and salt water washing, then use 200 milliliters of silica gel treatment.Filter, then stripping obtains 38 gram black products.With its chromatographic separation on silica gel, obtain 19.0 gram 1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane, light yellow liquid.
D.1-(7-hydroxyl heptyl)-cyclopropylene
At-78 ℃ of lower 25 milliliters of diethyl ether solutions processing 1.0 gram 1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane (2.5mmol) with 7.2 milliliters of lithium methides (1.4M, 10mmol).After 5 minutes, reaction mixture is warmed to 0 ℃, and deposits in this temperature.To react and use the saturated ammonium chloride cancellation.With reaction mixture water and salt water washing, use dried over mgso, filter and stripping, obtain 240 milligrams of 1-(7-hydroxyl heptyl)-cyclopropylene.
E.1-(7-(4-mesyloxy phenyl) ketonic oxygen base heptyl)-cyclopropylene
To (537 milligrams of 15 ℃ 1-(7-hydroxyl heptyl)-cyclopropylene; 3.47mmol), (764 milligrams of 4-sulfonyloxy methyl yl benzoic acids; 3.82mmol), N; (42.1 milligrams of N-dimethyl aminopyridines; 0.347mmol) and (33.0 milligrams of tosic acid monohydrates; 0.173mmol) about 30 milliliters of dichloromethane solutions in add N, N '-dicyclohexylcarbodiimide (85.8 milligrams, about 10 milliliters of dichloromethane solutions 4.16mmol).At room temperature stir about is after 90 minutes, by extremely hygroscopic filter paper with the reaction mixture vacuum filtration.In filtrate, add entry, and with mixture stir about 30 minutes.Behind the separation of phases, with the organic layer dried over mgso, and dry in a vacuum, obtain the pure 1-(7-(4-mesyloxy phenyl) ketonic oxygen base heptyl) of 1.5 grams 70%-cyclopropylene.
Embodiment 26:1-(2-pyridyl sulfur phenenyl)-cyclopropylene (compound 55)
A.4-bromine penta-obtusilic acid ethyl ester
By Mori, M.; At Journal of Organic Chemistry, the method for describing among 1983,48, the 4058-4067 prepares 4-bromine penta-obtusilic acid ethyl ester Deng the people.
B.3-(1,2,2-, three bromo-cyclopropyl)-ethyl propionate
To 4-bromine penta-obtusilic acid ethyl ester (24.24 grams, 11.7mmol) 148 milliliters of dichloromethane solutions in add (35.3 milliliters of methenyl bromides, 35.1mmol), N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (4.40 the gram, 1.17mmol) and 45% potassium hydroxide aqueous solution (54.2 milliliters, 58.5mmol).After at room temperature stirring 3 days, add entry, separate each layer.In the organic layer of telling, add methenyl bromide (35.3 milliliters, 35.1 mmol), N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (4.40 grams, 1.17mmol), and 45% potassium hydroxide aqueous solution (54.2 milliliters, 58.5mmol).At room temperature restir added hexane and water after 3 days.With mixture gravity filtration, and separate each layer by qualitative filter paper.With the organic layer dried over mgso of telling, then dry in a vacuum.Use ether/hexane at silica gel upper prop chromatogram purification resistates, obtain 20.5 gram 3-(1,2,2-, three bromo-cyclopropyl)-ethyl propionates, be oil.
C.3-(1,2,2-, three bromo-cyclopropyl)-propionic acid
(20.5 grams, 54.0mmol) solution in about 80 ml waters and 80 milliliters of Hydrogen bromides is heated to backflow with 3-(1,2,2-, three bromo-cyclopropyl)-ethyl propionate.After about 4 hours, cooling is reacted to room temperature, and adds ether.Separation of phases.The organic layer of telling is washed with dilute sodium hydroxide aqueous solution, make it pass through the pH test paper and measure enough alkalescence of demonstration.Separation of phases, and by adding dilute hydrochloric acid acidifying water layer.Add ether to water layer.Separation of phases.With the organic layer told with dried over mgso and vacuum concentration.Resistates is made the hexane development, then with the ether development, obtain 3.23 gram 3-(1,2,2-, three bromo-cyclopropyl)-propionic acid solids.
D.1-(3-hydroxypropyl)-1,2,2-three bromo cyclopropane
(850 milligrams, about 1 milliliter of tetrahydrofuran solution 2.42mmol) is cooled to-10 ℃ with 3-(1,2,2-, three bromo-cyclopropyl)-propionic acid.To the tetrahydrofuran (THF) liquid that wherein drip to add at leisure the 1M borane (1.97 milliliters, 1.96mmol).After at room temperature stirring is spent the night, add the mixture of 1 milliliter of one to one Glacial acetic acid and water.With the mixture vacuum concentration.The resistates that obtains is poured in 10 milliliters of saturated sodium bicarbonate aqueous solutions on ice.Add ethyl acetate and separation of phases, this step is repeated.With the organic layer dried over mgso of telling, then vacuum concentration.Resistates is dissolved in ether, uses the saturated sodium bicarbonate aqueous solution washed twice.Separation of phases, and with the organic layer dried over mgso of telling, then vacuum concentration obtains 540 milligrams of 1-(3-hydroxypropyl)-1,2,2-three bromo cyclopropane are oil.
E.1-(3-phenyl sulfonyloxy propyl group)-1,2,2-three bromo-cyclopropane
To 0 ℃ 1-(3-hydroxypropyl)-1, (540 milligrams add (0.155 milliliter of pyridine to 2,2-, three bromo cyclopropane in the cooling solution of about 3 milliliters of methylene dichloride 1.60mmol), 1.92mmol) and the benzene sulfonyl chloride compound (0.203 milliliter, 1.60mmol).After at room temperature stirring 3 days, add entry and separation of phases.With the organic layer told with dried over mgso and vacuum concentration.Resistates is dissolved in ether, with 1N salt acid elution.Separation of phases, with the organic layer dried over mgso of telling, and vacuum concentration, obtaining 500 milligrams of 1-(3-phenyl sulfonyloxy propyl group)-1,2,2-three bromo-cyclopropane are oil.
F.1-(2-pyridyl thiopropyl)-1,2,2-three bromo-cyclopropane
To the 2-mercaptopyridine (0.117 gram, add in about 3 ml methanol solution 1.04mmol) 25% sodium methylate methanol solution (0.239 milliliter, 1.04mmol).After at room temperature stirring one hour, with the reaction mixture vacuum concentration.In the resistates that is dissolved in 3 milliliters of DMFs, add 1-(3-phenyl sulfonyloxy propyl group)-1,2, and 2-three bromo-cyclopropane (500 milligrams, 3 milliliters of DMF solution 1.04mmol).After at room temperature stirring 16 hours, add entry and ether and separation of phases.With the organic layer told with dried over mgso and vacuum concentration.Use ethyl acetate/hexane at silica gel upper prop chromatogram purification resistates, obtain 200 milligrams of 1-(2-pyridyl thiopropyl)-1,2,2-three bromo-cyclopropane are oil.
G.1-(2-pyridyl thiopropyl)-cyclopropylene
With 1-(2-pyridyl thiopropyl)-1,2, (200 milligrams, 2 milliliters of diethyl ether solutions 0.465mmol) are cooled to 0 ℃ to 2-three bromo-cyclopropane, and place under the nitrogen atmosphere.Add in this solution the 1.4M lithium methide (1.00 milliliters, 1.39mmol).After 15 minutes, will react quencher by adding 1 ml water.Separation of phases, with the organic layer dried over mgso of telling, then vacuum concentration obtains 50 milligrams of 1-(2-pyridyl thiopropyl)-cyclopropylene, is oil.
Embodiment 27:1-(8-phenylsulfonyloxy octyl group)-cyclopropylene (compound 56)
A.9,10-two bromo-last of the ten Heavenly stems-1-alcohol
To ice/brine bath cooling the last of the ten Heavenly stems-add about 20 milliliters of dichloromethane solutions of bromine (13.3 milliliters, 0.258 mole) in about 70 milliliters of dichloromethane solutions of 9-alkene-1-alcohol (40.34 grams, 0.258 mole).At room temperature stir about is after 15 minutes, with the reactant vacuum concentration, obtains the oil of 9,10-, two bromo-last of the ten Heavenly stems-1-alcohol, can use without further purifying.
B.9-bromo-last of the ten Heavenly stems-9-alkene-1-alcohol
To 9 of ice bath cooling, in about 140 milliliters of tetrahydrofuran solutions of 10-two bromo-last of the ten Heavenly stems-1-alcohol (81.7 grams, 0.258 mole), add tetrahydrofuran (THF) (24.8 grams, the 0.258 mole) solution of 20% potassium tert.-butoxide.At about 5 ℃ of lower stir abouts 10 minutes and stir about after 15 minutes, with the reaction mixture vacuum concentration at room temperature.In resistates, add entry and ether.Separation of phases.The magnesium that the organic layer of telling is used is dry, and then vacuum concentration obtains 66.1 gram oil.It by the vacuum distilling purifying, is obtained 35.3 grams about 66% pure 9-bromo-last of the ten Heavenly stems-9-alkene-1-alcohol, be oil.
C.2-bromo-10-(1-ethoxy ethoxy)-last of the ten Heavenly stems-1-alkene
(11.75 grams add about 37 milligrams of tosic acid monohydrates in about 15 milliliters of diethyl ether solutions 50.0mmol) to 9-bromo-last of the ten Heavenly stems-9-alkene-1-alcohol.After solution is cooled to approximately-10 ℃, add at leisure ethyl vinyl ether (13.8 milliliters, 144 moles) with the speed that keeps internal temperature to be lower than 10 ℃.After adding several triethylamines, solution with water is then used the salt water washing.The organic layer told is dry with salt of wormwood, vacuum concentration then, obtain the pure 2-bromo-10-(1-ethoxy ethoxy) of 16.2 grams about 72%-last of the ten Heavenly stems-1-alkene, be oil.
D.1,1,2-, three bromo-2-[8-(1-ethoxy ethoxy)-octyl group]-cyclopropane
To 2-bromo-10-(1-ethoxy ethoxy)-last of the ten Heavenly stems-1-alkene (16.2 the gram, 52.7mmol) 90.9 milliliters of dichloromethane solutions in add (13.2 milliliters of methenyl bromides, 158mmol), N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (2.41 the gram, 5.27mmol) and 45% potassium hydroxide aqueous solution (22.6 milliliters, 263mmol).After at room temperature stirring 2 days, add entry, separate each layer.In the organic layer of telling, add N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (2.41 the gram, 5.27mmol) and 45% potassium hydroxide aqueous solution (22.6 milliliters, 263mmol).At room temperature restir added hexane and water after 2 days.With mixture gravity filtration, and separate each layer by qualitative filter paper.With the organic layer dried over mgso of telling, then dry in a vacuum, obtain 24.7 gram 1,1,2-, three bromo-2-[8-(1-ethoxy ethoxy)-octyl groups]-oil of cyclopropane, can use without further purifying.
E.1-(8-hydroxyethyl)-1,2,2-three bromo-cyclopropane
To 1,1,2-, three bromo-2-[8-(1-ethoxy ethoxy)-octyl group]-(24.7 grams add about 44 ml waters, about 337 milligrams of tosic acid monohydrates and about 160 milliliters of 6M hydrochloric acid to cyclopropane in about 160 ml methanol solution 51.5mmol).At room temperature stir about is after 1 hour, with the reaction mixture vacuum concentration.With resistates vacuum distilling purifying, obtain 15.6 and restrain 65% pure 1-(8-hydroxyethyl)-1,2, the oil of 2-three bromo-cyclopropane can directly use.
F.1-(8-phenylsulfonyloxy octyl group)-1,2,2-three bromo-cyclopropane
To 1-(8-hydroxyethyl)-1,2,2-three bromo-cyclopropane (15.6 grams, and about 50 milliliters of dichloromethane solutions adding pyridine 38.3mmol) (3.72 milliliters, 45.9mmol).In acetone/the dry ice bath, solution is cooled to-20 ℃, add simultaneously benzene sulfonyl chloride (4.89 milliliters, 38.3mmol).After at room temperature stirring 16 hours, add pyridine (3.72 milliliters, 45.9mmol) and benzene sulfonyl chloride (4.89 milliliters, 38.3mmol).After at room temperature stirring 5 hours, add pyridine (3.72 milliliters, 45.9mmol) and benzene sulfonyl chloride (4.89 milliliters, 38.3mmol).After at room temperature stirring 16 hours, add then separation of phases of entry.With the organic layer told with dried over mgso and vacuum concentration.Resistates is dissolved in ether, then washs with saturated sodium bicarbonate aqueous solution.Separation of phases, with the organic layer dried over mgso of telling, and vacuum concentration, obtaining 14.5 gram 1-(8-phenylsulfonyloxy octyl group)-1,2,2-three bromo-cyclopropane are oil.
G.1-(phenylsulfonyloxy octyl group)-cyclopropylene
With 1-(phenylsulfonyloxy octyl group)-1,2, about 8 milliliters of diethyl ether solutions of 2-three bromo-cyclopropane (2.7 gram, 4.94 moles) are cooled to 0 ℃ and place under the nitrogen atmosphere.Add in this solution the 1.4M lithium methide ether solution (10.6 milliliters, 14.8mmol).After 15 minutes, will react quencher by adding about 4 ml waters.Separation of phases, with the organic layer dried over mgso of telling, and vacuum concentration, obtain 1.2 gram 1-(phenylsulfonyloxy octyl group)-cyclopropylene, be oil.
Embodiment 28:1-(4-aminomethyl phenyl sulphur octyl group)-cyclopropylene (compound 57)
A.1-(phenylsulfonyloxy octyl group)-cyclopropylene
By 1-(phenylsulfonyloxy octyl group)-1,2,2-three bromo-cyclopropane prepare 1-(phenylsulfonyloxy octyl group)-cyclopropylene by method shown in the embodiment 27.
B.1-(4-aminomethyl phenyl sulphur octyl group)-cyclopropylene
To sodium hydride (60% oil solution, 73.2 milligrams, add in DMF 1.83mmol) (2 milliliters) suspension p-thiocresol (189 milligrams, DMF 1.52mmol) (2 milliliters) solution.At room temperature stir after 15 minutes when bubbling stops, in DMF (2 milliliters), adding 1-(phenylsulfonyloxy octyl group)-cyclopropylene (470 milligrams, 1.52mmol).Behind the stir about 2 hours, add entry and ethyl acetate, then separation of phases.Wash the organic layer of telling with water twice, use dried over mgso, and vacuum concentration, obtain 200 milligrams of 1-(4-aminomethyl phenyl sulphur octyl group)-cyclopropylene, be oil.
Embodiment 29:1-(1H-1,2.4-triazole-2-base sulphur octyl group)-cyclopropylene (compound 58)
A.1-(phenylsulfonyloxy octyl group)-cyclopropylene
By 1-(phenylsulfonyloxy octyl group)-1,2,2-three bromo-cyclopropane prepare 1-(phenylsulfonyloxy octyl group)-cyclopropylene by method shown in the embodiment 27.
B.1-(1H-1,2,4-triazole-2-base sulphur octyl group)-cyclopropylene
To (480 milligrams of 1-(phenylsulfonyloxy octyl group)-cyclopropylene, 1.55mmol) about 2 milliliters of N, (19.8% at tetrahydrofuran (THF) to add potassium tert.-butoxide in the dinethylformamide solution, 734 milligrams, 1.55mmol) and 1H-1,2,4-triazole-3-mercaptan (172 rags, 1.71mmol).At room temperature stir about is after 2 hours, add sodium iodide (87.7 milligrams, 775mmol).Reaction is heated to about 50 ℃ after about 2 hours, adds entry and ethyl acetate, then separation of phases.Wash the organic layer of telling with water twice, use dried over mgso, and vacuum concentration.With resistates with hexane/ethyl acetate at silica gel upper prop chromatogram purification, obtain 30 grams, 70% pure 1-(1H-1,2,4-triazole-2-base sulphur octyl group)-cyclopropylene, be oil.
Embodiment 30:1-(1-methyl-2-pyrrolylcarbonyl oxygen base propyl group)-cyclopropylene (compound 59)
A.1-(3-hydroxypropyl)-1,2,2-three bromo cyclopropane
Prepare 1 (3-hydroxypropyl)-1,2,2-three bromo cyclopropane by the described method of embodiment 26d by 3-(1,2,2-, three bromo-cyclopropyl)-propionic acid.
B.1-(3-hydroxypropyl)-cyclopropylene
With 1-(3-hydroxypropyl)-1,2, (750 milligrams, about 4 milliliters of diethyl ether solutions 2.22mmol) are cooled to 0 ℃ to 2-three bromo cyclopropane, and place under the nitrogen atmosphere.By syringe add the 1.4M lithium methide (6.36 milliliters, 8.90mmol).After 15 minutes, add then separation of phases of about 2 ml waters.With the organic layer dried over mgso of telling, then vacuum concentration obtains 1-(3-hydroxypropyl)-cyclopropylene, can directly use.
C.1-(1-methyl-2-pyrrolylcarbonyl oxygen base propyl group)-cyclopropylene
To (221 milligrams of 1-(3-hydroxypropyl)-cyclopropylene, 2.22mmol) about 15 milliliters of dichloromethane solutions in, add sour (306 milligrams of 1-methyl-2-pyrroles's carboxylic acid, 2.42mmol), (27.0 milligrams of 4-dimethylaminopyridines, 0.222mmol) and the tosic acid monohydrate (21.2 milligrams, 0.111mmol).After mixture is cooled to about 15 ℃, add in batches at leisure N, and N '-dicyclohexylcarbodiimide (550 milligrams, about 10 milliliters of dichloromethane solutions 2.66mmol).At room temperature stir about is after 2 hours, by extremely hygroscopic filter paper with the reaction mixture vacuum filtration.Add then separation of phases of entry.With the organic layer dried over mgso of telling, then vacuum concentration.Use hexane/ethyl acetate at silica gel upper prop chromatogram purification resistates, obtain 15 milligrams of 1-(1-methyl-2-pyrrolylcarbonyl oxygen base propyl group)-cyclopropylene, be oil.
Embodiment 31:1-ethyl-2-(3-(4-chloro-phenyl-)-rattle away-6-ketone-1-yl)-cyclopropylene (compound 60)
A.3-(4-chloro-phenyl-)-rattle away-6-ketone
Can prepare such as the method for the DE 2435244 (1976) described in the embodiment 3 3-(4-chloro-phenyl-)-rattle away-6-ketone.
B.1-(mesyloxy methyl)-2-ethyl cyclopropylene
Prepare 1-(mesyloxy methyl) 2-ethyl cyclopropylene by method shown in the embodiment 17c.
C.1-ethyl-2-(3-(4-chloro-phenyl-)-rattle away-6-ketone-1-yl)-cyclopropylene
Add in DMF (4 milliliters) suspension of the sodium hydride (60% oil solution, 0.08g, 2mmol) in the ice bath 3-(4-chloro-phenyl--rattle away-6-ketone (and 0.41 gram, 2mmol).Stir after 15 minutes, (0.35 restrains, 2mmol) to add 1-(mesyloxy methyl)-2-ethyl cyclopropylene.After at room temperature stirring 45 minutes, add entry and ethyl acetate.Separation of phases.With successively water and the salt water washing of organic layer of telling, then use dried over mgso, dry in a vacuum at last.Use hexane/ethyl acetate at silica gel upper prop chromatogram purification resistates, obtain 340 milligrams of 1-ethyl-2-(3-(4-chloro-phenyl-)-rattle away-6-ketone-1-yl)-cyclopropylene, the off-white color solid.
The preparation of embodiment 32:1-triethylsilyl methylcyclopropene (compound 63)
A.3-Trichloromonosilane base-2-bromopropylene
Such as Hollingworth, G.J.; Lee, T.V.Sweeney, J.B.Synthetic Commun.1996, this compound of preparation described in 26,1117.Product is mixed with hexane and filter.With the filtrate stripping, and need not further purify and use (need not distill).
B.3-triethylsilyl-2-bromopropylene
Add 7 milliliters of (3.0m, 21mmol) ethylmagnesium bromide in 20 milliliters of THF solution of 1.3 gram 3-Trichloromonosilane base-2-bromopropylenes (5mmol) in the ice bath.Reaction is warmed to room temperature, and stirs and spend the night then water cancellation.Add ether, and reaction mixture is transferred in the separating funnel.Add a small amount of 1NHCl, separation of phases with ether phase water and salt water washing, is then used dried over mgso, filters and stripping.Chromatographic separation obtains 300 milligrams of 3-triethylsilyl-2-bromopropylenes.
C.N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide (phase-transfer catalyst)
To 16.5 gram (142mmol) N that stir, N, N ' adds 50.1 gram (292mmol) cylites in the 60 gram acetonitrile solutions of N '-Tetramethyl Ethylene Diamine.Mixture self heats up, and stirs 2.5 hours, and observing has a large amount of precipitations on it.Slurry is diluted with ether, filter, with ether washing and dry, obtain the N that 61.8g wants, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, white solid, fusing point 230-232 ℃.
With similar method, use N, N, N ', N '-tetraethyl-ethylene diamine obtains N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, white solid, decomposes by fusing point 190-193 ℃.
D) 2-triethylsilyl methyl isophthalic acid, 1,2-, three bromo cyclopropane
With 300 milligrams of (1.27mmol) 3-triethylsilyl-2-bromopropylenes, 0.47 restrain 45% potassium hydroxide aqueous solution (3.8mmol), 75 milligrams of N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, and the mixture of 3 milliliters of methylene dichloride is processed with 0.33 milliliter of methenyl bromide (3.8mmol).Well-beaten reaction mixture was at room temperature deposited 5.5 hours.Add entry and methylene dichloride, separation of phases.Methylene dichloride is placed reaction flask mutually, and restrain 45% potassium hydroxide aqueous solution (3.8mmol) and 75 milligrams of N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide processing with other 0.47.The reaction mixture stirring is spent the night, then add entry and other methylene dichloride, and separation of phases.With methylene dichloride with dried over mgso and stripping.During stripping, add a small amount of heptane to help to remove remaining methenyl bromide.The column chromatography purifying obtains 390 milligrams of 2-triethylsilyl methyl isophthalic acids, 1,2-, three bromo cyclopropane, colourless liquid.
E) 1-triethylsilyl methylcyclopropene
With 0.36 gram (0.9mmol) 2-triethylsilyl methyl isophthalic acid, 5 milliliters of diethyl ether solutions of 1,2-, three bromo cyclopropane are cooled to-78 ℃.(1.4M, 2.8mmol), placed reaction mixture 5 minutes, then sampling by 2.0 milliliters in ice bath to add excessive lithium methide.Between sampling date, make the reaction mixture cooling get back to-78 ℃.React with a small amount of methyl alcohol cancellation, and be warming to room temperature.Add other ether and water.Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, 100 milligrams of 1-triethylsilyl methylcyclopropenes obtained, colourless liquid.
The preparation of embodiment 33:1-trimethyl silyl methylcyclopropene (compound 64)
Change commercially available 3-trimethyl silyl-2-bromopropylene into 1-trimethyl silyl methylcyclopropene to be similar to embodiment 1 described mode.
The preparation of embodiment 34:6-(trimethyl silyl)-hexyl ring third-2-alkene (compound 65)
A.2-bromo-8-(trimethyl silyl)-Xin-1-alkene
(50 milliliters, the THF solution of 0.5M 25mmol) cools off in ice bath with commercially availabie pentamethylene two (magnesium bromide).10 milliliters of THF solution that add 2.72 gram (25mmol) trimethylchlorosilanes.Reaction mixture 5 ℃ of lower stirrings 30 minutes, was then at room temperature stirred 1 hour, then be cooled to again 5 ℃.Will be in 6 milliliters of THF 2, (5.0 grams 25mmol) join in the reaction mixture 3-propylene bromide, it is warmed up to room temperature and stirred two hours.With the cancellation of reaction mixture water.Add ether and a small amount of 1NHCl.Separation of phases is with organic phase water and salt water washing, with magnesium chloride drying, then stripping.The column chromatography purifying obtains 1.62 gram 2-bromo-8-(trimethyl silyl)-Xin-1-alkene, water white oil.
B.2-(6-(trimethyl silyl)-hexyl)-1,1,2-three bromo cyclopropane
With 1.52 gram (5.8mmol) 2-bromo-8-(trimethyl silyl)-Xin-1-alkene, 4.3 restrain 45% potassium hydroxide aqueous solution (34mmol), 0.2 gram N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, and the mixture of 10 milliliters of methylene dichloride is processed with 1.5 milliliters of methenyl bromides (17.4mmol).Well-beaten reaction mixture is at room temperature continued to spend the night.Add other 4 grams, 45% potassium hydroxide aqueous solution, and will react and at room temperature stir again one hour.Add entry and methylene dichloride, separation of phases.With methylene dichloride with dried over mgso and stripping.During stripping, add a small amount of heptane to help to remove remaining methenyl bromide.The column chromatography purifying obtains 1.13 gram 2-(6-(trimethyl silyl)-hexyl)-1,1,2-three bromo cyclopropane, water white oil.
C.6-(trimethyl silyl)-hexyl ring third-2-alkene
With 0.96 gram (2.2mmol) 2-(6-(trimethyl silyl)-hexyl)-1,1,10 milliliters of diethyl ether solutions of 2-three bromo cyclopropane are cooled to-78 ℃.(1.4M, 7.1mmol), placed reaction mixture 30 minutes then water cancellation by 5.1 milliliters in ice bath to add excessive lithium methide.Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, 370 milligrams of 6-(trimethyl silyl)-hexyl ring third-2-alkene obtained, colourless liquid.
The preparation of embodiment 35.2-(trimethyl silyl)-ethyl ring third-2-alkene (compound 66)
A.2-bromo-4-(trimethyl silyl)-but-1-ene
5.0 gram (50mmol) 2 to the ice bath cooling add 30 milliliters of commercially available trimethyl silyl methylmagnesium-chlorides (1M, 30mmol) in 20 milliliters of diethyl ether solutions of 3-propylene bromide.Reaction mixture 0 ℃ of lower stirring 30 minutes, then is warmed up to room temperature.Add THF (10 milliliters), and the reaction mixture stirring is spent the night.The water cancellation.Reaction mixture is transferred in the separating funnel.Add a small amount of 1NHCl, separation of phases with ether phase water and salt water washing, is then used dried over mgso, filters and stripping, obtains 4.5 gram 2-bromo-4-(trimethyl silyl)-but-1-enes, can use without further purifying.
B.2-(trimethyl silyl)-ethyl ring third-2-alkene
The mode that is converted into 6-(trimethyl silyl)-hexyl ring third-2-alkene (embodiment 3) to be similar to 2-bromo-8-(trimethyl silyl)-Xin-1-alkene is converted into 2-(trimethyl silyl)-ethyl ring third-2-alkene with 2-bromo-4-(trimethyl silyl)-but-1-ene.
The preparation of embodiment 36:2-octyl group-1-trimethyl silyl cyclopropylene (compound 67)
A.2-bromine last of the ten Heavenly stems-1-alkene
In being housed, 500 milliliter of 3 neck flask of magnetic agitation, feed hopper and reflux exchanger add 17 gram (700mmol) magnesium smear metals.Cover with 20 milliliters of ether with dried nitrogen exchange atmospheric atmosphere and with the magnesium smear metal.Add 2 gram glycol dibromides, have thereon reaction by bubbling and muddy proof.After 5 minutes, add 200 milliliters of ether, and cause mixture to reflux.Slowly add 100 milliliters of ether solutions of 90 gram (503mmol) 1-heptyl bromides with the speed of enough keeping backflow, spend 50 minutes.To react further and reflux 30 minutes, obtain heptyl magnesium bromide solution.
In being housed, 1000 milliliter of 3 neck flask of magnetic agitation, barrier film and reflux exchanger under nitrogen atmosphere, add 75 gram (375mmol) 2,200 milliliters of ether solutions of 3-propylene bromide.In reaction, shift heptyl magnesium bromide solution with the speed that control refluxes by intubate.After refluxing again 60 minutes, reaction is at room temperature stirred spend the night.To react and use the aqueous hydrochloric acid cancellation, use the salt water washing, anhydrous magnesium sulfate drying, rotary evaporation, and distill under 12 torrs by 5 column plate porous sheet-piles and to obtain 52 gram 2-bromines last of the ten Heavenly stems-1-alkene, 105-115 ℃ of boiling point (12 torr).
B.2-octyl group-1,1,2-three bromo cyclopropane
In with 125 milliliters of single neck flasks of magnetic agitation, add 20 gram (91mmol) 2-bromines last of the ten Heavenly stems-1-alkene, 75 gram (297mmol) methenyl bromides, 200 gram methylene dichloride, 2.2 gram N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, and 20 gram (161mmol) 45% potassium hydroxide aqueous solutions.Mixture was stirred 3 days, add thereon 100 ml waters, separate organic layer, with 30 gram methenyl bromides, 2.0 gram N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, and 25 grams, 45% potassium hydroxide aqueous solution is processed again.Restir washes reaction with water two days later, drying, and rotary evaporation also separates with the hexane elution chromatography at silica gel.Obtain 41 gram 2-octyl groups-1,1,2-three bromo cyclopropane.
C.2-octyl group-1-trimethyl silyl cyclopropylene
With 0.98 gram (2.5mmol) 2-octyl group-1,1,10 milliliters of diethyl ether solutions of 2-three bromo cyclopropane are cooled to-78 ℃.The adding lithium methide (1.4M, 5.35 milliliters, 7.5mmol), reaction mixture was stirred 30 minutes, then place ice bath, placed 30 minutes.Add trimethylammonium silicon chlorides (0.81g, 7.5mmol), and reaction mixture is placed then water cancellation in 45 minutes.Add other ether and separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, 370 milligrams of 2-octyl groups-1-trimethyl silyl cyclopropylene obtained, yellow liquid.
The preparation of embodiment 37:1 (2-mesyloxy ethyl)-cyclopropylene (compound 68)
A.2-bromo-4-(1-ethoxy ethoxy)-but-1-ene
When 20 milliliters of diethyl ether solutions of 10.38 gram (0.0687 mole) commercially available 3-bromo-3-butene-1-ols and 50 milligrams of (0.000263 mole) tosic acid monohydrates are cooled off in ice-water bath, drip to add at leisure 19 milliliters of (0.199 mole) ethyl vinyl ethers, keep internal temperature＜10 ℃.At 0 ℃ after lower 1 hour, add several triethylamines.Reaction mixture is poured on waterborne.Change the mixture that obtains over to separating funnel, separation of phases.With the organic layer of telling salt water washing, then and filtration dry with salt of wormwood.In a vacuum solvent is removed from filtrate, obtained 14.04 gram 2-bromo-4-(1-ethoxy ethoxy)-but-1-enes, be oil.
B.1,1,2-tribromo 2-[2-(1-ethoxy ethoxy)-ethyl]-cyclopropane
In 108 milliliters of dichloromethane solutions and 0.5-0.9 milliliter 45% potassium hydroxide aqueous solution of 14.02 gram (0.0628 mole) 2-bromo-4-(1-ethoxy ethoxy)-but-1-enes, add 16.4 milliliters of (0.118 mole) methenyl bromides and 2.88 gram (0.00628 mole) N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and 28 milliliters of (0.314 mole) 45% potassium hydroxide aqueous solutions.After 3 days reaction mixture is poured on waterborne.Change the mixture that obtains over to separating funnel, separation of phases.In the organic layer that separates, add 2.88 gram (0.00628mol) N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide and 28 milliliters of (0.314mol) 45% potassium hydroxide aqueous solutions.After 24 hours, to wherein adding hexane and water.With mixture by the gravity filtration of qualitative corrugation filter paper.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, is obtained 17.0 gram 1,1,2-, three bromo-2-[2-(1-ethoxy ethoxy)-ethyls]-cyclopropane, be oil.
C.2-(2-hydroxyethyl)-1,1,2-three bromo cyclopropane
To 16.5 gram (0.0418 moles) 1,1,2-three bromo-2-[2-(1-ethoxy ethoxy)-ethyl]-slurry of cyclopropane in 145 ml methanol and 40 ml waters in, add 0.306 gram (0.00161 mole) tosic acid monohydrate and 145 milliliters of 6M hydrochloric acid.After at room temperature stirring 1 hour, in a vacuum solvent is removed from reaction mixture.In resistates, add ethyl acetate and water.Change the mixture that obtains over to separating funnel, separation of phases.With the organic layer of telling salt water washing, then use MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained 11.9 gram 2-(2-hydroxyethyl)-1,1,2-three bromo cyclopropane are oil.
C.1-(2-hydroxyethyl)-cyclopropylene
With 1.15 gram (3.6mmol) 2-(2-hydroxyethyl)-1,1,40 milliliters of diethyl ether solutions of 2-three bromo cyclopropane (as mentioned above preparation) are cooled to-78 ℃.The adding lithium methide (1.4M, 10.3 milliliters, 14.4mmol).Reaction mixture is warmed to 5 ℃, and kept 1/2nd hours.To react the water cancellation, separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping.Thick product is used for next step reaction at once.
E) 1-(2-mesyloxy ethyl)-cyclopropylene
The thick product of above-mentioned reaction is dissolved in 5 milliliters of ether, and in ice bath, cools off.Add triethylamine (1 milliliter), then add 0.49 gram methylsulfonyl chloride (4.3mmol).Reaction mixture was stirred 1 hour.Add entry and other ether and separation of phases.Wash mutually ether with water twice, use the salt water washing, use dried over mgso, and stripping, obtain the light yellow liquid of 380 milligrams of 1-(2-mesyloxy ethyl)-cyclopropylene.
The preparation of embodiment 38:1-(7-mesyloxy heptyl)-cyclopropylene (compound 69)
A.1-(1-ethoxy ethoxy)-6-bromohexane
In 40 milliliters of diethyl ether solutions of 80 milligrams of toluenesulphonic acidss that cool off, inject simultaneously 20 gram (110mmol) 6-bromine hexanol and 40 milliliters of ethyl vinyl ethers by the funnel that adds that separates.During 1 hour that injects, the temperature of maintenance reaction mixture is at 7 ℃ or be lower than 7 ℃ temperature.The reaction mixture stirring was longer than 20 minutes, is then added roughly 1 milliliter of triethylamine.With reaction mixture water and salt water washing, dry with salt of wormwood, filter and stripping, obtain the light yellow liquid of 25.7 grams, it can be used without purifying further.
B.9-(1-ethoxy ethoxy)-2-bromine ninth of the ten Heavenly Stems-1-alkene
Process the slurry of 5.6 gram magnesium smear metals (230mmol) in 100 milliliters of THF with a small amount of glycol dibromide.(38.5 grams, 152mmol), holding temperature is at 40-50 ℃ to inject at leisure 1-(1-ethoxy ethoxy)-6-bromohexane in the reaction mixture.After adding end, reaction mixture was deposited 20 minutes, then under 0 ℃, transferred to 33.4 gram (167mmol) 2 by intubate, in 25 milliliters of THF solution of 3-propylene bromide.Reaction mixture 0 ℃ of lower stirring 15 minutes, was then at room temperature stirred then water cancellation 15 minutes.Reaction mixture is transferred in the separating funnel.Add a small amount of 1NHCl, separation of phases with ether phase water and salt water washing, is then used dried over mgso, filters and stripping, obtains the yellow liquid of 33.63 grams, it can be used without purifying further.
C.1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane
With 9-(1-ethoxy ethoxy)-2-bromine ninth of the ten Heavenly Stems-1-alkene (33.63g, 115mmol), 4.1 gram N, N '-dibenzyl-N, N, N ', N '-tetraethyl-ethylene ammonium dibromide, 42 gram 45% potassium hydroxide (337mmol), the mixture of 93 gram methenyl bromides (368mmol) and 280 gram methylene dichloride at room temperature promptly stirred two days.When reaction stopped, reaction mixture changed separating funnel over to, washed with water.Methylene dichloride is changed in the flask mutually, process as previously mentioned with phase-transfer catalyst and 45% potassium hydroxide of equal amts, then restir 3 days at room temperature.Reaction mixture is washed with water, with dried over mgso methylene dichloride phase, then stripping.Product was at room temperature processed 1 hour with 320 ml methanol and 40 milliliters of 1NHCl.Stripped methanol adds ethyl acetate.With organic phase water and salt water washing, then use 200 milliliters of silica gel treatment.Filter, then stripping obtains 38 gram black products.With its chromatographic separation on silica gel, obtain 19.0 gram 1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane, light yellow liquid.
D.1-(7-hydroxyl heptyl)-cyclopropylene
At-78 ℃ of lower 25 milliliters of diethyl ether solutions processing 1.0 gram 1,1,2-, three bromo-2-(7-hydroxyl heptyl) cyclopropane (2.5mmol) with 7.2 milliliters of lithium methides (1.4M, 10mmol).After 5 minutes, reaction mixture is warmed to 0 ℃, and deposits in this temperature.To react and use the saturated ammonium chloride cancellation.With reaction mixture water and salt water washing, use dried over mgso, filter and stripping, obtain 240 milligrams of 1-(7-hydroxyl heptyl)-cyclopropylene.
E.1-(7-mesyloxy heptyl)-cyclopropylene
50 milliliters of diethyl ether solutions of 4.3mmol1-(7-hydroxyl heptyl)-cyclopropylene are cooled off in ice bath.Add triethylamine (1 milliliter) and 0.54 gram methylsulfonyl chloride (4.7mmol), reaction mixture was stirred 2.5 hours under 0 ℃.With reaction mixture water and salt water washing, use dried over mgso, filter and stripping, obtain 0.83 milligram of 1-(7-mesyloxy heptyl)-cyclopropylene.
The preparation of embodiment 39:1-(7-second sulphur heptyl)-cyclopropylene (compound 70)
0.35 gram (1.5mmol) 1-(7-mesyloxy heptyl)-cyclopropylene and 0.36 mixture that restrains the DMF liquid of 80% sulfur alcohol sodium (4.5mmol) were at room temperature stirred one hour.Add ether and water and separation of phases.Organic phase with 1N sodium hydroxide solution, water (secondary) and salt water washing, is used dried over mgso, filter and stripping.Chromatographic separation obtains the colourless liquid of 140 milligrams of 1-(7-second sulphur heptyl)-cyclopropylene.
The preparation of embodiment 40:1-bromo-2-octyl group-cyclopropylene (compound 71)
A.2-bromine last of the ten Heavenly stems-1-alkene
In being housed, 500 milliliter of 3 neck flask of magnetic agitation, feed hopper and reflux exchanger add 17 gram (700mmol) magnesium smear metals.Cover with 20 milliliters of ether with dried nitrogen exchange atmospheric atmosphere and with the magnesium smear metal.Add 2 gram glycol dibromides, have thereon reaction by bubbling and muddy proof.After 5 minutes, add 200 milliliters of ether, and cause mixture to reflux.Slowly add 100 milliliters of ether solutions of 90 gram (503mmol) 1-heptyl bromides with the speed of enough keeping backflow, spend 50 minutes.To react further and reflux 30 minutes, obtain heptyl magnesium bromide solution.
In being housed, 1000 milliliter of 3 neck flask of magnetic agitation, barrier film and reflux exchanger under nitrogen atmosphere, add 75 gram (375mmol) 2,200 milliliters of ether solutions of 3-propylene bromide.In reaction, shift heptyl magnesium bromide solution with the speed that control refluxes by intubate.After refluxing again 60 minutes, reaction is at room temperature stirred spend the night.To react and use the aqueous hydrochloric acid cancellation, use the salt water washing, anhydrous magnesium sulfate drying, rotary evaporation, and distill under 12 torrs by 5 column plate porous sheet-piles and to obtain 52 gram 2-bromines last of the ten Heavenly stems-1-alkene, 105-115 ℃ of boiling point (12 torr).
B.N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (phase-transfer catalyst)
To 16.5 gram (142mmol) N that stir, N, N ' adds 50.1 gram (292mmol) cylites in the 60 gram acetonitrile solutions of N '-Tetramethyl Ethylene Diamine.Mixture self heats up, and stirs 2.5 hours, and observing has a large amount of precipitations on it.Slurry is diluted with ether, filter, with ether washing and dry, obtain the N that 61.8g wants, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, white solid, fusing point 230-232 ℃.
C.2-octyl group-1,1,2-three bromo cyclopropane
In with 125 milliliters of single neck flasks of magnetic agitation, add 20 gram (91mmol) 2-bromines last of the ten Heavenly stems-1-alkene, 75 gram (297mmol) methenyl bromides, 200 gram methylene dichloride, 2.2 gram N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, and 20 gram (161mmol) 45% potassium hydroxide aqueous solutions.Mixture was stirred 3 days, add thereon 100 ml waters, separate organic layer, with 30 gram methenyl bromides, 2.0 gram N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide, and 25 grams, 45% potassium hydroxide aqueous solution is processed again.Restir washes reaction with water two days later, drying, and rotary evaporation also separates with the hexane elution chromatography at silica gel.Obtain 41 gram 2-octyl groups-1,1,2-three bromo cyclopropane.
D.1-bromo-2-octyl group-cyclopropylene
By means of make by the refractory pebbles valve under nitrogen atmosphere, pack into 3.18 the gram (0.00813mol) 1,1,2-three bromo-2-octyl groups--6 milliliters of diethyl ether solutions of cyclopropane.When in ice-water bath, cooling off, add at leisure the ether solution of 5.81 milliliters of (0.00813mol) 1.4M lithium methides by syringe.After 15 minutes, add 2 ml waters by means of syringe.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.In bathing desolventizing from filtrate under warm 20 ℃, obtain 1.43 gram 1-bromo-2-octyl group-cyclopropylene in a vacuum, be oil.
The preparation of embodiment 41:3-methyl-3-amyl group-cyclopropylene (compound 72)
A.1,1-two bromo-2-methyl-2-amyl group-cyclopropane
In 14.4 milliliters of (0.162 mole) methenyl bromide solution of 7.01 milliliters of (0.0446 mole) 2-methyl-heptan-1-alkene, add 0.635 gram (0.00193 mole) Tetrabutyl amonium bromide and 15.1 milliliters (0.185 mole), 50% aqueous sodium hydroxide solution.After being heated to 55 ℃ 1 hour, will react cool to room temperature, and add hexane and water.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Solvent is removed from filtrate in a vacuum.Vacuum distilling purifying resistates obtains 10.9 grams, 1,1-, two bromo-2-methyl-2-amyl group-cyclopropane, is oil.
B.2-bromo-1-methyl-1-pentene base-cyclopropane
To 6.59 gram (0.0232 moles) 1, add 1.47 milliliters of (0.0255 mole) Glacial acetic acid and 1.49 gram (0.0227 mole) zinc powders in about 20 ml methanol solution of 1-two bromo-2-methyl-2-amyl group-cyclopropane.Stir after 1 hour, in reaction mixture, add 1.47 milliliters of (0.0255 mole) Glacial acetic acid and 1.49 gram (0.0227 mole) zinc powders.Behind the stir about 2 hours, with the reaction mixture vacuum concentration.After adding hexane and water, change the mixture that obtains over to separating funnel, and separation of phases.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, it is pure to obtain 2.2 gram 2-bromo-1-methyl-1-pentene base-cyclopropane 95%, is oil.
C.3-methyl-3-amyl group-cyclopropylene
In 5 milliliters of dimethyl sulfoxide solutions of 1.03 gram (0.502 mole) 2-bromo-1-amyl group-cyclopropane, add 0.563 gram (0.502 mole) potassium tert.-butoxide.Be heated to 85 ℃ after 2 hours, add 0.075 other gram (0.00516 mole) potassium tert.-butoxide.Reaction is heated to 85 ℃ after 1 hour, adds ether and water.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.Solvent is removed from filtrate in a vacuum.Resistates is absorbed in 4 milliliters of methyl-sulphoxides, to wherein adding 0.6 gram (0.536 mole) potassium tert.-butoxide.To react 90 ℃ of heating after 7 hours, add entry and ethyl acetate, then change the mixture that obtains in separating funnel separation of phases.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained the mixture of 180 milligrams of 50%3-methyl-3-amyl group-cyclopropylene and the trimethyl carbinol.
The preparation of embodiment 42:3-methyl-3-nonyl-cyclopropylene (compound 73)
Can prepare this compound by the mode that is similar to compound 2.Obtain 40%3-methyl-3 nonyls-cyclopropylene, the mixture of 30%1-methyl isophthalic acid nonyl-cyclopropane and 20%1-methyl isophthalic acid-nonyl-2-bromine cyclopropane.
The preparation of embodiment 43:1-heptyl-2-methyl-cyclopropylene (compound 74)
10-phenanthroline, the solution of 1.74 milliliters of Tetramethyl Ethylene Diamines and 20 milliliters of tetrahydrofuran (THF)s under nitrogen atmosphere, pack 1 milligram 1 into by means of using the refractory pebbles valve.Be cooled in-30 ℃, adding 1.5 milliliters of 1-methylcyclopropenes by plastic injector.(by 3-chloro-2-methyl-propylene preparation; See Hopf, H.; Wachholz, G.; Walsh, R.Chem.Ber.1985,118,3579, and Koster, the people such as R, Liebigs Annalen Chem.1973,1219-1235).When in-40 ℃ of baths, cooling off, add at leisure the hexane liquid of 8 milliliters of (11.5mmol) 1.6M n-Butyl Lithiums by syringe.-30 ℃ lower 15 minutes, drip to add 1.90 milliliters of (11.5mmol) 1-indoles heptane by syringe.In natural warming to 5 ℃, stir after 30 minutes, with reaction mixture vacuum-drying under 20 ℃ bath temperature.After adding ether and 1N hydrochloric acid, change the mixture that obtains over to separating funnel, and separation of phases.With organic layer MgSO 4Dry also filtration.Under 20 ℃ of bath temperature, in a vacuum solvent is removed from filtrate.Resistates with hexane column chromatography purifying, is obtained 0.700 gram 1-heptyl-2-methyl-cyclopropylene, be oil.
The embodiment 44:1-bromo-2-(preparation of 2-(carbonyl (acetoxy-methyl)) ethyl-cyclopropyl alkene (compound 75)
A.2-(2-bromo-allyl group)-diethyl malonate
By with the hexane washing, remove in 21.70 gram (0.542 mole) 60% sodium hydride oil solutions, be oil.To being suspended in 200 milliliters of resistatess in the tetrahydrofuran (THF), add at leisure 84.38 milliliters of (0.556 mole) diethyl malonates by feed hopper.When reaction being cooled to-35 to-10 ℃, add at leisure 100 gram (0.400 moles) 2,3-propylene bromide by feed hopper.Be heated to and refluxed rear 1 hour, will react cool to room temperature, and vacuum concentration.In resistates, add hexane and water, change the mixture that obtains over to separating funnel, and separation of phases.With the organic layer of telling 1N salt acid elution, then with dried over mgso and filtration.In a vacuum solvent is removed from filtrate, obtained 154 gram 2-(2-bromo-allyl group)-diethyl malonates, be oil.
B.2-(2-bromo-allyl group)-propanedioic acid
The mixture of 10.5 gram (0.0376 mole) 2-(2-bromo-allyl group)-diethyl malonates and 37.6 milliliters of (0.470 mole) 50% aqueous sodium hydroxide solutions was at room temperature stirred 4 days.With the reaction mixture ether extraction.The water layer that separates by adding the concentrated hydrochloric acid acidifying, and add ether.Change the mixture that obtains over to separating funnel, separation of phases.The organic layer of telling is also filtered with dried over mgso.In a vacuum solvent is removed from filtrate, obtained the solid of 5.3 gram 2-(2-bromo-allyl group)-propanedioic acid, can continue without purification.
C.4-bromo-penta-obtusilic acid
5.3g (0.0238 mole) is clean, and unpurified 2-(2-bromo-allyl group)-propanedioic acid is heated to 125-130 ℃, keeps 8 hours, obtains 3.73 gram 4-bromo-, penta-obtusilic acid, can continue without purification.
D.4-bromo-penta-obtusilic acid ethyl ester
To 3.73 gram (0.0208 mole) unpurified 4-bromo-penta-obtusilic acids with adding 1.18 milliliters of (0.0162 mole) thionyl chloride in 3 milliliters of chloroformic solutions of 1 DMF.After this mixture heating up to 60 ℃ kept 30 minutes, it is joined in the solution of 2.46 milliliters of (0.0436 mole) ethanol and 1.97 milliliters of (0.024 mole) pyridines and 13 milliliters of methylene dichloride.Stir after 30 minutes, with the reaction mixture vacuum concentration.In resistates, add ether and water.Change the mixture that obtains over to separating funnel, separation of phases.The organic layer of telling is also filtered with dried over mgso.In a vacuum solvent is removed from filtrate, is obtained the oil of 3.5 gram 4-bromo-, penta-obtusilic acid ethyl ester, with it by the vacuum distilling purifying.
E.1,1,2-, three bromo-2-(2-(carbonyl oxyethyl group)) ethyl-cyclopropyl alkene
To be similar to preparation 2-octyl group-1,1, the mode of 2-three bromo cyclopropane (embodiment 1) prepares 1,1,2-, three bromo-2-(2-(carbonyl oxyethyl group)) ethyl-cyclopropyl alkene.
F.1,1,2-, three bromo-2-(2-(carboxyl)) ethyl-cyclopropyl alkene
With 10.2 gram (0.0269 moles) 1, ((3-carbonyl oxyethyl group) ethyl-cyclopropyl alkene is heated to backflow to 1,2-, three bromo-2-in the solution of 40 milliliters of (0.736 mole) 48% Hydrogen bromides and 40 ml waters, kept 8 hours, with its cool to room temperature, then pass through Shark The filter paper vacuum filtration.Before adding ether, wash isolated solid with water.Solution is changed in the separating funnel, with the saturated sodium bicarbonate aqueous solution washing, be isolated, and by adding the 1N hcl acidifying.Again change the aqueous solution over to separating funnel, and use ether extraction.The organic layer of telling is also filtered with dried over mgso.In a vacuum solvent is removed from filtrate, obtained the solid of 5.9 gram 1,1,2-, three bromo-2-((2-carboxyl)) ethyl-cyclopropyl alkene, can directly use without further purifying.
G.1,1,2-, three bromo-2-(2-(carbonyl (acetoxy-methyl)) ethyl-cyclopropyl alkene
To 0.800 gram (0.00228 mole) 3-1,1, about 2 milliliters of anhydrous N of 2-three bromo-2-(2-(carboxyl)) ethyl-cyclopropyl alkene, add 0.224 milliliter of (0.00228 mole) bromomethyl acetate in the dinethylformamide solution, then add 0.396 milliliter of (0.00228 mole) diisopropylethylamine.Reaction is heated to 60 ℃ after 2 hours, adds entry and ether.Change the mixture that obtains over to separating funnel, separation of phases.With the water layer ethyl acetate extraction.With successively water and the salt water washing of organic phase that merges.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate, obtained 0.900 gram, 1,1,2-, three bromo-2-(2-(carbonyl (acetoxy-methyl)) ethyl-cyclopropyl alkene.
H.1-bromo-2-(2-(carbonyl (acetoxy-methyl))-ethyl-cyclopropyl alkene
To 0.800 gram (0.00202 mole) 1,1,2-, three bromo-2-(add 0.281 milliliter of (0.00202 mole) triethylamine in 1.04 milliliters of (0.00808 mole) diethyl phosphite solution of 2-(carbonyl (acetoxy-methyl)) ethyl-cyclopropyl alkene.At room temperature stir about was absorbed in reaction mixture in the hexane after 16 hours, with 1N salt acid elution.Then with the water layer ether extraction.The organic phase that merges is washed with the 3N aqueous sodium carbonate.With organic layer MgSO 4Dry also filtration.Under 20 ℃ of bath temperature, in a vacuum solvent is removed from filtrate.Resistates is placed under the above reaction conditions again, and subsequently with the same manner aftertreatment.Use ether/hexane to pass through the column chromatography purifying resistates, (2-(carbonyl (acetoxy-methyl))-ethyl-cyclopropyl alkene is oil to obtain 180 milligrams of 1-bromo-2-.
The embodiment 45:1-bromo-2-(preparation of 2-(carbonyl oxyethyl group)-ethyl-cyclopropyl alkene (compound 76)
To be similar to by 1,1,2-three bromo-2-(2-(carbonyl (acetoxy-methyl))-ethyl-cyclopropyl alkene (embodiment 5) the preparation 1-bromo-2-(mode of 2-(carbonyl (acetoxy-methyl))-ethyl-cyclopropyl alkene, by 1, (2-(carbonyl oxyethyl group)-ethyl-cyclopropyl alkene prepares 1-bromo-2-(2-(carbonyl oxyethyl group)-ethyl-cyclopropyl alkene to 1,2-, three bromo-2-.
The embodiment 46:1-bromo-2-(preparation of 2-(carboxyl)-ethyl-cyclopropyl alkene (compound 77)
(add 0.0768 gram (1.37mmol) potassium hydroxide in 2 milliliters of absolute ethanol solution of 2-(carbonyl oxyethyl group)-ethyl-cyclopropyl alkene to 200 milligrams of (0.913mmol) 1-bromo-2-.Stir after 1 hour, add ether and water.Change the mixture that obtains over to separating funnel, separation of phases.Behind the water layer that adds 1N concentrated hydrochloric acid acidifying separation, add ether.Change the mixture that obtains over to separating funnel, separation of phases.With organic layer MgSO 4Dry also filtration.In a vacuum solvent is removed from filtrate under 20 ℃ of bath temperature, (2-(carboxyl)-ethyl-cyclopropyl alkene,＞70% is pure, is oil to obtain 160 milligrams of 1-bromo-2-.
The preparation of embodiment 47:1-octyl group-3-carboxyl-cyclopropylene (compound 78)
A.1-octyl group-3-(carbonyl oxygen base oxethyl)-cyclopropylene
Pass through Mueller, P. by 1-decine and ethyl diazoacetate; Pautex, N.; The method of Helv.Chirn Acta 1990,73,1233 prepares 1-octyl group-3-(carbonyl oxygen base oxethyl)-cyclopropylene.
B.1-octyl group-3-carboxyl-cyclopropylene
1-octyl group-3-(carbonyl oxygen base oxethyl)-cyclopropylene (1.12g, 5mmol) and 100 milliliters of 0.2N potassium hydroxide are at room temperature stirred a week.Add ether and separation of phases.With aqueous phase as acidified and use dichloromethane extraction.Organic phase with dried over mgso and stripping, is obtained 0.8 gram 1-octyl group-3-carboxyl-cyclopropylene.
Embodiment 48:1-trimethyl silyl-2,3, the preparation of 3-trimethylammonium cyclopropylene (compound 79)
By preparing compound 5 employed identical methods by 2-bromine last of the ten Heavenly stems-1-alkene, prepare compound 79 by 2-bromo-3-methyl-2-butene, be 36% diethyl ether solution.
The preparation of embodiment 49:1-(butyl dimetylsilyl)-2-methylcyclopropene (compound 80)
By preparing compound 5 employed identical methods, prepare compound 80 by the 2-bromopropylene by 2-bromine last of the ten Heavenly stems-1-alkene.
The preparation of embodiment 50:1-triethylsilyl-2-methylcyclopropene (compound 81)
By preparing compound 5 employed identical methods, prepare compound 81 by the 2-bromopropylene by 2-bromine last of the ten Heavenly stems-1-alkene.
The preparation of embodiment 51:1-(7-t-butyldimethylsilyl oxygen base heptyl)-cyclopropylene (compound 82)
A.1-(7-hydroxyl heptyl)-cyclopropylene
Prepare 1-(7-hydroxyl heptyl)-cyclopropylene with the identical method described in the embodiment 7.
B.1-(7-tertiary butyl methyl-silicane base oxygen base heptyl)-cyclopropylene
To 1-(7-hydroxyl heptyl)-cyclopropylene (1.07g, 3.47mmol) 19.4 milliliters of dichloromethane solutions in, add tert-butyldimethylsilyl chloride compound (.562 gram, 3.75mmol) and N, N-dimethyl aminopyridine (.213g, 1.74mmol) and triethylamine (.368ml, 2.64mmol.).After reaction mixture at room temperature stirred 2 hours, add N, N-dimethyl aminopyridine (.213g, 1.74mmol) and triethylamine (.368ml, 2.64mmol).After in addition 45 minutes, will react quencher by adding about 3 milliliters of saturated aqueous ammonium chlorides.Separation of phases.The organic layer of telling is used salt solution, saturated sodium bicarbonate aqueous solution and water washing successively.To again tell organic layer, use dried over mgso, and vacuum concentration, 1.2 grams obtained.Resistates with 5% ethyl acetate/hexane column chromatography purifying, is obtained 440 milligrams of (theoretical 47%) 1-(7-t-butyldimethylsilyl oxygen base heptyl)-cyclopropylene, be oil. The preparation of embodiment 52:1-(mesyloxy methyl)-2-ethyl cyclopropylene (compound 83)
A.1,1,2-, three bromo-2-ethyl cyclopropane
By preparing 1,1,2-, three bromo-2-ethyl cyclopropane with embodiment 5 used identical methods by 2-bromo-1-butylene.
B.1-(methylol)-2-ethyl cyclopropylene
With 3.0 gram (10mmol) 1,1,50 milliliters of diethyl ether solutions of 2-three bromo-2-ethyl cyclopropane are cooled to-78 ℃.The adding lithium methide (1.4M, 21.4 milliliters, 30mmol).Reaction mixture is warmed to 5 ℃.(1.20 grams 40mmol), 5 ℃ of lower stirrings 1 hour, then allow to be warming up to room temperature, restir one hour with reaction mixture to add solid polyformaldehyde.To react the water cancellation, separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, obtain the yellow oil of 900 milligrams of 1-(methylol)-2-ethyl cyclopropylene.
A.1-(mesyloxy methyl)-2-ethyl cyclopropylene
In ice bath to 0.70g (7.13mmol) 1-(methylol)-2-ethyl cyclopropylene (compound 3) and 2 milliliters of triethylamines in the solution of 15 milliliters of ether, add 0.86 gram (7.5mmol) methylsulfonyl chloride.Reaction mixture was placed 1.5 hours then water cancellation.Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, obtain the yellow oil of 840 milligrams of 1-(mesyloxy methyl)-2-ethyl cyclopropylene.
The preparation of embodiment 53:1-(diethoxy-sulfenyl phosphoryl sulfenyl methyl)-2-ethyl cyclopropylene (compound 84)
A.1-(mesyloxy methyl)-2-ethyl cyclopropylene
By preparing 1-(mesyloxy methyl) 2-ethyl cyclopropylene with embodiment 13 employed identical methods by 1-(methylol)-2-ethyl cyclopropylene.
B.1-(diethoxy-sulfenyl phosphoryl sulfenyl methyl)-2-ethyl cyclopropylene
With 1-(mesyloxy methyl)-2-ethyl cyclopropylene (.66 gram, 3.75mmol) and disulfide group phosphoric acid 0,0 '-diethyl ester, sylvite (.84g, 3.75mmol) mixes with 4.4 milliliters of dimethyl formamides.The reaction mixture stirring after 4 hours, is then added entry and ether.Separation of phases.Ether is washed with water more than twice mutually, with then using dried over mgso, and stripping, obtain 510 milligrams of (theoretical 51%) 1-(diethoxy-sulfenyl phosphoryl sulfenyl methyl)-2-ethyl cyclopropylene, be oil.
The preparation of embodiment 54:1-(4-mesyloxy butyl)-cyclopropylene (compound 85)
A.5,6-two bromo-oneself-1-alcohol
In about 20 milliliters of dichloromethane solutions of the 5-hexen-1-ol (11.23g, 112.3mmol) of ice bath cooling, (5.80 milliliters add 12, about 20 milliliters of dichloromethane solutions 112.3+mmol) to add bromine.Reinforced complete after, with mixture vacuum-drying, obtain 29.1 grams, 5,6-, two bromo-oneself-1-alcohol.
B.5-bromo-oneself-5-alkene-1-alcohol
To 5 of ice bath cooling, 6-two bromo-oneself-(29.1 grams add tetrahydrofuran (THF) (62.4g, the 112mmol) liquid of 20% potassium tert.-butoxide to 1-alcohol in about 59 milliliters of tetrahydrofuran solutions 112mmol).After reinforced complete, reaction mixture is warmed up to room temperature, stir about 30 minutes.Add then separation of phases of ether and water.With the organic layer dried over mgso of telling, then dry in a vacuum.Resistates is used 5 orifice plate post vacuum distilling purifying, obtain 23.16 grams, 87% pure 5-bromo-oneself-5-alkene-1-alcohol.
C.4-methyl-phenylformic acid 5-bromo-oneself-the 5-alkenyl esters
To the 5-bromo-oneself-5-alkene-1-alcohol (4.39 grams, add in 10.6 gram dichloromethane solutions 24.5mmol) 4-toluene acyl chlorides (3.95 grams, 25.6mmol) and triethylamine (3.3 restrain, 33mmol).At room temperature stir about diluted mixture after 2 hours with diethyl ether, then then used the salt water washing with 1N hydrochloric acid.Separation of phases, the organic layer dried over mgso is then dry in a vacuum, obtain 7.3 gram 4-methyl-phenylformic acid 5-bromo-oneself-the 5-alkenyl esters.
D.4-methyl-phenylformic acid 4-(1,2,2-, three bromo-cyclopropyl)-butyl ester
In round-bottomed flask, drop into 4-methyl-phenylformic acid 5-bromo-oneself-the 5-alkenyl esters (7.3 grams, 24.6mmol), N, N '-dibenzyl-N, N, N ', N '-Tetramethyl Ethylene Diamine dibromide (0.30 gram, 0.66mmol), methylene dichloride (25 gram), (25 grams are 98.9mmol) with 45% aqueous solution potassium hydroxide (11.5 grams for methenyl bromide, 92mmol), at room temperature stir 4 days.After adding entry, separate each layer.In the organic layer of telling, add N, N '-dibenzyl-N, N, N ', (0.30 gram, 0.66mmol), (27 grams, 107mmol) (12 restrain methenyl bromide N '-Tetramethyl Ethylene Diamine dibromide, 96mmol) with 45% aqueous solution potassium hydroxide.At room temperature restir added hexane and water after one day.With mixture gravity filtration, and separate each layer by qualitative filter paper.With the organic layer dried over mgso of telling, then dry in a vacuum.Use ethyl acetate/hexane by the column chromatography purifying resistates that obtains, obtain the pure 4-methyl of 4.9 grams 61%-phenylformic acid 4-(1,2,2-, three bromo-cyclopropyl)-butyl ester.
E.4-(1,2,2-, three bromo-cyclopropyl)-Ding-1-is pure
(45.5 grams, (30 grams are 107mmol) with 30 gram water to add 50% wet chemical in 250 gram methanol solutions 97mmol) to 4-methyl-phenylformic acid 4-(1,2,2-, three bromo-cyclopropyl)-butyl ester.With reaction be heated to 60 ℃ about 2 hours, cool to room temperature then.After about 15 hours, (30 grams 107mmol) with 30 gram water, are heated to 60 ℃ with reaction and kept about 2 hours, then cool to room temperature to add 50% aqueous solution salt of wormwood.With the reaction mixture vacuum concentration, the resistates that then obtains with ether extraction.Organic layer is washed with alkalization water (pH10).Separation of phases, organic phase is for using dried over mgso, then dry in a vacuum.Use ether/hexane to pass through the column chromatography purifying resistates, obtain 14.5 grams, 74% pure 4-(1,2,2-, three bromo-cyclopropyl)-Ding-1-alcohol.
F.1-(4-hydroxybutyl)-cyclopropylene
Under nitrogen atmosphere, add 4-(1,2,2-, three bromo-cyclopropyl)-Ding-1-alcohol (5.11 grams, 4 milliliters of diethyl ether solutions 14.5mmol), and be cooled to 0 ℃.Use syringe, add the 1.4M lithium methide diethyl ether (41.6 milliliters, 58.2mmol).After 15 minutes, will react quencher by adding about 2 ml waters.Separation of phases.With the organic layer dried over mgso of telling, and vacuum-drying, obtain 2.51 gram 1-(4-hydroxybutyl)-cyclopropylene, be oil.
G.1-(4-mesyloxy butyl)-cyclopropylene
(2.43 grams, about 10 milliliters of dichloromethane solutions 21.6mmol) cool off in-20 ℃ of baths with 1-(4-hydroxybutyl)-cyclopropylene.Add in the mixture triethylamine (3.32 milliliters, 23.7mmol) and methylsulfonyl chloride (1.67 milliliters, 21.6mmol).After about one hour, in reaction, add then separation of phases of entry.With the organic layer dried over mgso of telling, and vacuum-drying.Add about 8 milliliters of methylene dichloride in the resistates, triethylamine (1.39 milliliters, 10mmol) and methylsulfonyl chloride (0.701 milliliter, 9.1mmol).After about one hour, in reaction, add then separation of phases of entry.With the organic layer dried over mgso of telling, and vacuum-drying, obtain the pure 1-of 2.9g70% (4-mesyloxy butyl)-cyclopropylene, be oil.
The preparation of embodiment 55:2-octyl group-1-(boric acid)-cyclopropylene (compound 86)
With 1.30 gram (3.3mmol) 2-octyl groups-1,1,20 milliliters of diethyl ether solutions of 2-three bromo cyclopropane (embodiment 5) are cooled to-78 ℃.The adding lithium methide (1.4M, 5.9 milliliters, 8.3mmol), reaction mixture was stirred 10 minutes, then put into ice bath, placed 30 minutes, and then be cooled to-78 ℃.Adding triisopropyl boric acid ester (0.9 milliliter, 3.9mmol), reaction mixture was stirred 15 minutes, then be warming to 0 ℃.Add entry, ether and the 1NHCl aqueous solution (enough making the aobvious acidity of solution).Separation of phases.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, product is dissolved in the ether again, extract three times with the 1N aqueous sodium hydroxide solution.Extract with the acidifying of 6N aqueous hydrochloric acid, is used ether extraction three times.Ether is washed with water mutually, use the salt water washing, use dried over mgso, and stripping, obtain the 2-octyl group-1-(boric acid) of 400 milligrams of light yellow solids-cyclopropylene.
The preparation of embodiment 56:2-methyl isophthalic acid-(boric acid, single isopropyl esters)-cyclopropylene (compound 87)
With about 2 milligram 1, about 50 milliliters of diethyl ether solutions of 10-phenanthroline are cooled to-40 ℃, and place under the nitrogen atmosphere.To wherein by syringe add diisopropylamine (3.33 milliliters, 23.8mmol) and the 1-methylcyclopropene (1.90 milliliters, 27.8mmol; By 3-chloro-2-methyl-propylene preparation; See Hopf, H.; Wachholz, C.; Walsh, R.Chem.Ber.1985,118,3579, and Koster, people Liebigs Annalen Chem.1973, the 1219-1235 such as R.).Then add 1.7 milliliters of N-butyllithiums (1.6M hexane solution), until solution remains brown.After this then add the same butyllithium of another part (14.9 milliliters, 23.8mmol).After stirring 15 minutes under-40 ℃, and adding triisopropyl boric acid ester (4.60 milliliters, 19.8mmol).After about 10 minutes, add 12 milliliters of 6N hydrochloric acid.After stirring 15 minutes under-10 ℃, separation of phases.With the organic layer dried over mgso of telling, then vacuum concentration obtains 3.5 gram 2-methyl isophthalic acid-(boric acid, single isopropyl esters)-cyclopropylene, is oil.
Can prepare in a similar manner following compound:
Table 1: other compound
Figure GSA00000039172900631
Compound number R 1 R 2 R 3 R 4 Purity % Note
16 H H 4-methoxyl group-phenoxy group-methyl CH 3 30 30%1-(4-methoxyphenoxy methyl)-1-methyl cyclopropane
17 Benzyl H H H
18 Styroyl H H H
19 H H Styroyl CH 3 55 36%1-styroyl-1-methyl cyclopropane
20 H H Benzyl CH 3 50 24%1-benzyl-1-methyl cyclopropane
21 2-cyclohexyl-ethyl H H H
[0511]
22 Suberyl-methyl H H H
23 Cyclohexyl-methyl H H H
24 The 4-methyl-benzyl H H H
25 The 3-phenyl propyl H H H
26 2-methoxyl group-benzyl H H H
27 The 4-phenyl butyl H H H
28 2-(4-oxygen phenyl) ethyl H H H 72
29 The 3-methyl-benzyl H H H
30 2,4,6-trimethylammonium-benzyl H H H 40 49%3-(2,4,6-trimethylphenyl)-2-bromopropylene
31 Cyclopentyl-methyl H H H
32 7-(1-pyrroles)-heptyl H H H
33 3-(2-(DOX))-propyl group H H H 75 The precursor of 10% tribromo cyclopropane
34 7-(1-(1,2,4-triazole))-heptyl H H H
35 2-(2 pyridyl sulfenyl)-ethyl H H H
42 2-(4,6-dimethyl pyrimidine-2-yl)-ethyl H H H
43 2-(4-pyridine thio)-ethyl H H H 50 50% ethyl acetate
48 2-(3-furyl acyloxy)-ethyl H H H
49 2-(cumarone-2-base carbonyl oxygen base) ethyl H H H
50 2-(5,6-dichloropyridine-3-base carbonyl oxygen base)-ethyl H H H
51 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base carbonyl oxygen base)-ethyl H H H
52 2-(the basic ketonic oxygen base of N-t-BOC-isothiazolidine-4)-ethyl H H H
54 7-(2-tetrachloro furyl carbonyl oxygen base)-heptyl H H H
61 3-(pyrazine-2-base ketonic oxygen base)-propyl group H H H 50％ 50% solvent
62 2-(4-(1H-pyrroles-1-base phenyl) ketonic oxygen base)-ethyl H H H
Use various light splitting technologies qualitative to compound.The NMR data of compound 1-35 provide in table 2.For the compound that comprises impurity, do not report the chemical shift of impurity, adjust integration in order to only consider the contribution of target compound.
Table 2:NMR data
Compound # NMR
1 (CDCl3)：1.0(d，2H)，3.8(s，2H)，6.6(m，1H)，7.2(d，2H)，7.25(d，2H)
2 (CDCl3)：1.0(d，2H)，4.0(s，2H)，6.6(m，1H)，6.95(d，1H)，7.0(m，1H)，7.2(d，1H)
3 (CDCl3)：0.88(d，2H)，1.3(d，2H)，1.5-1.8(m，2H)，2.0-2.2(m，2H)，2.5(m，2H)，3.7- 3.9(m，2H)，4.1-4.2(m，2H)，4.55(m，1H)，6.5(m，1H)
4 (CDCl3)：0.25(s，6H)，0.7-0.8(m，2H)，0.87(d，2H)，1.2-1.4(m，6H)，1，5-1.7(m， 2H)，2.45(t，2H)，6.45(bs，1H)，7.3-7.45(m，3H)，7.45-7.6(m，2H)
5 (CDCl3)：1.05(s，2H)，1.53(s，6H)，6.5(s，1H)，7.1-7.5(m，5H).
6 (d6 Acetone)：1.6(s，3H)，7.1-7.3(m，5H)，7.45(s，2H)
7 (CDCl3)：1.3(s，3H)，3.9(s，2H)，6.8-7.0(m，3H)，7.25(m，2H)，7.35(s，2H)
8 (CDCl3)：0.89(2H，s)，2.03(3H，s)，3.75(2H，s)，7.1-7.4(5H，m)
9 (CDCl3)：0.94(d，2H)，2.8(t，2H)，3.1(t，2H)，6.6(m，1H)，7.3(m，4H)
10 (CDCl3)：0.85(d，2H)，2.8(t，2H)，4.3(t，2H)，6.6(m，1H)，7.6(m，2H)，7.7(m，1H)， 7.9(m，2H)
11 (CDCl3)：0.92(d，2H)，1.58(s，4H)，3.05(t，2H)，4.55(t，2H)，6.6(bs，1H)，7.39(s， 1H)，7.47(s，1H)
12 (CDCl3)：0.87(d，2H)，1.2-1.4(m，6H)，1.57(m，2H)，1.79(m，2H)，2.47(td，2H)， 3.92(t，2H)，6.44(m，1H)，6.90(bs，1H)，7.06(bs，1H)，7.46(bs，1H)
13 (CDCl3)：0.87(d，2H)，1.2-1.4(m，6H)，1.5-1.8(m，4H)，2.47(t，2H)，3.67(t，2H)， 6.42(bs，1H)，6.9-7.1(m，6H)，7.2-7.4(m，4H)
14 (CDCl3)：0.88(d，2H)，1.2-1.5(m，5H)，1.55-2.0(m，5H)，2.4-2.6(m，2H)，6.40 (t，1H)
15 (CDCl3)：0.90(d，2H)，2.6-2.9(m，4H)，3.6-3.8(m，8H)，6.5(m，1H)
16 (CDCl3)：1.2(s，3H)，3.8(s，3H)，3.9(s，2H)，6.8(m，4H)，7.35(s，2H)
17 (CDCl3)：1.1(d，2H)，3.8(s，2H)，6.5(m，1H)，7.2-7.35(m，5H)
18 (CDCl3)：0.92(d，2H)，2.8(t，2H)，2.9(t，2H)，6.45(m，1H)，7.15-7.3(m，5H)
19 (CDCl3)：1.18(s，3H)，1.78(m，2H)，2.42(m，2H)，7.1-7.2(m，3H)，7.2-7.3(m，2H)， 7.3(s，2H)
20 (CDCl3)：1.17(s，3H)，2.76(s，2H)，7.1(m，2H)，7.15-7.3(m，3H)，7.35(s，2H)
21 (CDCl3)：0.89(d，2H)，0.88-1.0，(m，1H)，1.1-1.35(m.4H)，1.47(q，2H)，1.6- 1.85(m，4H)，2.48(td，2H)，6.42(t，1H)
22 (CDCl3)：0.87(d，2H)，1.15-1.3，(m，2H)，1.35-1.9(m，11H)，2.40(dd，2H)，6.43 (t，1H)
23 (CDCl3)：0.87(d，2H)，0.9-1.05，(m，2H)，1.1-1.35(m，3H)，1.4-1.8(m，6H)，2.37 (dd，2H)，6.40(t，1H)
24 (CDCl3)：1.0(d，2H)，2.3(s，3H)，3.8(s，2H)，6.56(m，1H)，7.1(m，4H)
25 (CDCl3)：0.9(d，2H)，1.9(m，2H)，2.45(t，2H)，2.6(t，2H)，6.5(m，1H)，7.1-7.3(m，5H)
26 (CDCl3)：1.0(d，2H)，3.8(s，3H)，6.55(m，1H)，6.9(m，2H)，7.2(m，2H)
[0515]
27 (CDCl3)：0.88(d，2H)，1.6-1.75(m，4H)，2.55(t，2H)，2.65(t，2H)，6.4(m，1H)， 7.15(m，3H)，7.25(m，2H)
28 (CDCl3)：0.9(d，2H)，2.7-2.8(m，2H)，2.8-2，9(m，2H)，6.5(m，1H)，7.15(d，2H)， 7.3(d，2H)
29 (CDCl3)：1.0(d，2H)，2.3(s，3H)，3.8(s，2H)，6.58(m，1H)，7.1(m，3H)，7.2(m，1H)
30 (CDCl3)：0.9(d，2H)，2.25(m，9H)，3.75(s，2H)，6.45(m，1H)，6.85(s，1H)
31 (CDCl3)：0.89(d，2H)，1.1-1.3(m，2H)，1.45-1.65(m，4H)，1.65-1.85(m，2H)， 2.15(m，1H)，2.45(d，2H)，6.44(m，1H)
32 (CDCl3)：0.87(d，2H)，1.2-1.4(m，6H)，1.56(pentet，2H)，1.87(pentet，2H)，2.46 (td，2H)，4.12(t，2H)，6.23(t，1H)，6.42(t，1H)，7.36(d，1H)，7.50(d，1H)
33 (CDCl3)：0.89(d，2H)，1.7(m，4H)，2.5(m，2H)，3.8-4.0(m，4H)，4.9(m，1H)， 6.47(m，1H)
34 (CDCl3)：0.87(d，2H)，1.2-1.4(m，6H)，1.57(m，2H)，1.88(m，2H)，2.47(t，2H)， 4.17(t，2H)，6.43(bs，1H)，7.94(s，1H)，8.04(s，1H)
35 (CDCl3)：0.97(d，2H)，2.9(t，2H)，3.4(t，2H)，6.6(m，1H)，6.98(m，1)，7.16(m，1H)， 7.49m，1H)，8.4(m，1H)
36 (CDCl3)：0.9(d，2H)，1.2-1.9(m，H)，2.25(m，2H)，2.45(m，2H)，2.9(t，4H)，6.45 (m，1H)，6.95(m，1H)
37 (CDCl3)：0.8-1.2(m，5H)，2.3(q，2H)，5.1(s，3H)，7.0-7.5(m，4H)
38 (CDCl3)：0.9(m，5H)，1.2-1.8(m，14H)，2.6(t，2H)，4.0-4.2(m，4H)
39 (CDCl3)：1.04(d，2H)，2.10(s，3H)，2.2(d，1H)，3.8(s，3H)，5.65(bs，1H)，6.85(d， 1H)，6.9(m，2H)，7.3(d，1H)
41 (CDCl3)：7.5(m，3H)，7.7(m，2H)
42 (CDCl3)：0.97(d，2H)，2.4(s，6H)，2.95(t，2H)，3.4(t，2H)，6.55(m，1H)，6.7(s， 1H)
43 (CDCl3)：0.9(d，2H)，2.9(t，2H)，3.3(t，2H)，6.65(m，1H)，7.15(m，2H)，8.45(m， 2H)
44 (CDCl3)：0.9(d，2H)，1.55-1.9(m，6H)，2.4(s，3H)，4.3(t，2H)，6.5(m，1H)，7.2 (d，2H)，7.9(d，2H)
45 (CDCl3)：1.6(s，2H)，3.81(s，2H)，7.2-7.4(m，5H)
46 (CDCl3)：1.6(s，2H)，3.8(s，2H)，7.2-7..(m，5H)
47 (CDCl3)：0.9(d，2H)，2.95(t，2H)，4.7(d，2H)，6.5(m，1H)，6.6(m，1H)，7.2(m， 1H)，7.6(M，1H)
48 (CDCl3)：0.95(d，2H)，2.9(t，2H)，4.5(t，2H)，6.6(m，1H)，6.7(d，1H)，7.4(d， 1H)，8.0(s，1H)
49 (CDCl3)：0.99(d，2H)，3.05(t，2H)，4.65(t，2H)，6.7(m，1H)，7.3-7.8(m，5H)
50 (CDCl3)：0.9(d，2H)，2.98(t，2H)，4.61(t，2H)，6.7(m，1H)，8.35(s，1H)，8.9(s， 1H)
51 (CDCl3)：0.9(d，2H)，3.0(m，5H)，4.6(t，2H)，6.7(m，1H)
52 (CDCl3)：0.9(d，2H)，1.4(d，9H)，2.8(t，2H)，3.2-3.5(m，2H)，4.7-4.9(m，5H)，6.6 (m，1H)
53 (CDCl3)：0.88(d，2H)，1.2-1.9(m，10H)，2.48(t，2H)，3.08(s，3H)，4.36(t，2H)， 6.45(m，1H)，8.03(d，2H)，8.23(d，2H)
54 (CDCl3)：0.95(d，2H)，1.2-1.4(m，6H)，1.5-1.7(m，4H)，1.8-2.1(m，4H)，2.5(t， 2H)，3.9-4.2(m，4H)，4.5(m，1H)，6.45(m，1H)
55 (CDCl3)：0.9(d，2H)，2.05(m，2H)，2.7(m，2H)，3.2(m，2H)，6.5(m，1H)，7.0(t， 1H)，7.2(d，1H)，7.5(t，1H)，8.4(d，1H)
[0516]
56 (CDCl3)：0.9(d，2H)，1.3-1.75(m，8H)，2.4-2.55(m，4H)，3.6(m，2H)，4.1(t， 2H)，6.45(m，1H)，7.5-7.7(m，3H)，7.9(m，2H)
57 (CDCl3)：0.9(d，2H)，1.3-1.7(m，14H)，2.0(s，3H)，3.65(t，2H)，6.45(m，1H)，7.1 (d，2H)，7.25(d，2H)
58 (CDCl3)：0.9(d，2H)，1.3-1.8(m，12H)，2.4(m，2H)，3.2(t，2H)，6.45(m，1H)， 7.25(s，1H)，8.15(s，1H)
59 (CDCl3)：0.9(d，2H)，1.3(m，2H)，2.6(t，2H)，3.95(s，3H)，4.3(t，2H)，6.1(m， 1H)，6.5(m，1H)，6.8(m，1H)，6.95(m，1H)
60 (CDCl3)：0.97(t，3H)，1.1(s，2H)，2.4(m，2H)，5.2(s，2H)，7.05(d，1H)，7.45(d， 2H)，7.7(d，1H)，7.74(d，2H)
61 (CDCl3)：0.95(d，2H)，2.1(m，2H)，2.7(t，2H)，4.5(t，2H)，6.55(m，1H)，8.7(d， 2H)，9.32(s，1H)
62 (CDCl3)：0.9(d，2H)，2.9(t，2H)，4.55(t，2H)，6.35(m，2H)，6.65(m，1H)，7.15 (m，2H)，7.45(d，2H)，8.1(d，2H)
63 (CDCl3)：0.55(q，6H)，0.88(d，2H)，0.94(t，9H)，1.99(s，2H)，6.25(bs，1H).
64 (CDCl3)：0(s，9H)，0.82(d，2H)，1.91(s，2H)，6.22(bs，1H).
65 (CDCl3)：0(s，9H)，0.45-0.65(m，2H)，0.91(d，2H)，1.25-1.5(m，6H)，1.60 (pentet.2H)，2.50(t d，2H)，6.45(t，1H).
66 (CDCl3)：0(s，9H)，0.79(m，2H)，0.90(d，2H)，2.48(td，2H)，6.37(t，1H).
67 (CDCl3)：0.09(s，9H)，0.65(s，2H)，0.82(t，3H)，1.2-1.4(m，10H)，1.55(pentet， 2H)，2.47(t，2H).
68 (CDCl3)：0.98(d，2H)，2.96(tdq，2H)，3.04(s，3H)，4.47(t，2H)，6.75(bs，1H).
69 (CDCl3)：0.88(d，2H)，1.2-1.45(m，6H)，1.6(pentet，2H)，1.75(pentet，2H)，2.45 (td，2H)，3.00(s，3H)，4.23(t，2H)，6.4(t，1H).
70 (CDCl3)：0.88(d，2H)，1.25(t，3H)，1.25-1.45(m，6H)，1.5-1.75(m，4H)，2.4- 2.65(m，6H)，6.43(t，1H).
71 (CDCl3)：0.88(t，3H)，1.2-1.4(m，10H)，1.5(s，2H)，1.6(m，2H)，2.4(t，2H)
72 (CDCl3)：0.9(t，3H)，1.15(s，3H)，1.15-1.5(m，6H)，1.7(m，2H)，7.35(s，2H)
73 (CDCl3)：0.9(t，3H)，1.1(s，3H)，1.15-1.5(m，16H)，7.34(s，2H)
74 (CDCl3)：0.77(s，2H)，0.9(t，3H)，1.15-1.4(m，8H)，1.55(m，2H)，2(t，3H)， 2.35(m，2H)
75 (CDCl3)：1.55(s，2H)，2.1(s，3H)，2.75(m，2H)，2.8(m，2H)，5.77(s，2H)
76 (CDCl3)：1.3(t，3H)，1.55(s，2H)，2.6(t，2H)，2.8(t，2H)，4.1(q，2H)
77 (CDCl3)：1.56(s，2H)，2.65(t，2H)，2.8(t，2H)
78 (CDCl3)：0.88(t，3H)，1.1-1.5(m，10H)，1.6(pentet，2H)，2.13(d，2H)，2.51(t， 2H)，6.33(bs，1H).
79 (CDCl3)：0(s，9H)，0.95(s，6H)，1.96(s，3H).
80 (CDCl3)：0.16(8，6H)，0.67(t，2H)，0.75(s，2H)，0.91(t，3H)，1.25-1.45 (m，2H)，2.25(s，3H).
81 (CDCl3)：0.64(q，6H)，0.74(s，2H)，0.95(t，9H)，2.24(s，3H).
82 (CDCl3)：0(s，6H)，0.84(m，11H)，1.2-1.6(m.10H)，2.45(t，2H)，3.55(t， 2H)，6.45(m，1H)
83 (CDCl3)：1.12(s，2H)，1.20(t，3H)，2.53(q，2H)，3.05(s，3H)，5.18(s， 2H).
84 (CDCl3)：0.9(s，2H)，1.3(t，3H)，1.4(t，6H)，2.5(m，2H)，3.9(d，2H)，4.1- 4.4(m，4H)
85 (CDCl3)：0.9(d，2H)，1.7-1.9(m，4H)，2.6(t，2H)，3.0(s，3H)，4.3(t.2H)，
[0517]
6.5(m，1H)
86 (CDCl3)：0.88(s，2H，and t，3H)，1.2-1.4(m，8H)，1.5-1.7(m，4H)，2.61 (t，2H)，4.53(br，s，2H).
87 (d6DMSO)：0.7(d，2H)，1.1(d，6H)，2.2(d，3H)，3.8(m，1H)，8.05(br.s， 1H)
Biological activity:
The check of tomato epinasty
Purpose: this test method is used for measuring when experimental compound is used with the composition of volatile gases or spray solution, the ability of the Epinasty reaction that ethene is induced in the experimental compound blocking-up tomato.
Processing tank has the size suitable to test plant, and is air-locked.Each processing tank is equipped with reusable barrier film to be used for the injection of ethene.Test plant is Patio kind tomato seedling, and per three inches square plastic basins are planted two strains.
Volatile gases is processed need to be contained in 4.8L capacity polystyrene processing tank with two basin Patio var. tomatoes, has 50X9mm to comprise the plastics Petri dish of Gelman filter bed half (top or lower part) in the case.The experimental compound that will be dissolved in 1.0 milliliters of proper amies in the acetone is pipetted on the filter bed, and processing tank is sealed at once.The ethylene gas that after four hours final concn is equaled 10ppm v/v is injected in the encapsulation process case.After 16 hours processing tank is opened in extraction hood; allow blowing air, plant is engraved the visible vestige, to represent and to compare with undressed control group through the ethene processing; come protective plant in case the degree of the epinasty that ethene is induced represented with 0 to 10 minute by giving with experimental compound.Fully protection of expression in 10 minutes.Expression in 0 minute is to not protection of ethylene action.Gas processing concentration is volume/volume.
Processing is used in sprinkling need to use the DeVilbiss atomizer, with whole leaves and the stem with two basin Patio var. tomatoes, with being dissolved in 10% acetone/90% water and covering fully with the experimental compound of the appropriate amount of 0.05%SilwettL-77 tensio-active agent.With plant at the drying hood Air dry four hours, then change in the airtight 4.8L polystyrene processing tank.
The ethylene gas that final concn is equaled 10ppm v/v is injected in the encapsulation process case.After 16 hours processing tank is opened in extraction hood; allow blowing air; plant is engraved the visible vestige; to represent and to compare with undressed control group through the ethene processing; come protective plant with the degree of the epinasty that hinders ethene and induce, with expression in 0 to 10 minute by giving with experimental compound.Fully protection of expression in 10 minutes.Expression in 0 minute is to not protection of ethylene action.
When using with gas or sprays, the activity of compound of the present invention in the test of tomato epinasty provides in table 3.
Table 3: the activity of compound of the present invention in the test of tomato epinasty
Compound # Gas@1000ppm Gas@10ppm Sprays@10ppm
1 NT 10 10
2 NT 10 7
3 NT 8 0
4 NT 4 10
5 NT 5 2
6 7 2.5 1
7 10 4 2
8 10 0 0
9 NT 10 10
10 NT 10 10
11 8 a 2 0
12 10 b 5.5 3.5
13 NT 0 10
14 NT NT NT
15 NT 10 0
16 10 c 3.75 4.5
17 NT 9 2
18 NT 10 6
19 7.5 2 2
20 7 0 0
21 NT 10 10
22 NT 9 10
23 NT 10 10
24 NT 10 10
25 NT 10 10
26 NT 10 5
27 NT 10 10
28 NT 9.5 8
29 NT 10 10
30 8 3 0
31 NT 9 7.5
32 10 3 10
33 NT 8 0
34 10 4.5 9
35 NT 10 9
36 10 c 5 3
37 2 0 0
38 10(@850ppm) 3 0
[0528]
39 10 2 0
40 NT 7 0
41 2 0 0
42 3(@343.4ppm) NT 2
43 NT 10 0
44 7 0 0
45 10 5 0
46 10 5 0
47 10(@551ppm) 0 0
48 NT 10 NT
49 9(@343.4ppm) 0 0
50 9 0 0
51 3 0 0(8@1000ppm)
52 3 0 2(10@1000ppm)
53 10 0 0
54 2 0 0
55 10(@800ppm) NT 3
56 NT 5 10
57 10 0 2
58 NT 3 0
59 NT 3 4
60 0 4 0
61 10(@438ppm) 0 0
62 10(@509ppm) 0 0
63 NT 10 10
64 NT 10 9
65 NT 10 6
66 NT 10 10
67 NT 6 3
68 10 3 5
69 8 0 0
70 NT 2 10
aUnder 600ppm, measure
bUnder 850ppm, measure
cUnder 500ppm, measure
NT represents not have mensuration.
Compound # Gas @1000 ppm Gas @500 ppm Gas @10 ppm Sprays @10 ppm
71 10 NT 1 3
[0534]
72 9 NT 0 2
73 8 NT 0 0
74 10 NT 0 0
75 NT NT 10 0
76 NT NT 10 0
77 NT NT 8 2
78 5 10 0 0
NT represents not have mensuration.
Compound # Gas@1000ppm Gas@10ppm Sprays@10ppm
79 NT 10 NT
80 7 0 0
81 10 0 0
82 10 3 0
83 10 4 2
84 10 0 0
85 10 0 0
86 NT 10 0
NT represents not have mensuration.

Claims (4)

1. the compound of a following formula:
Figure FDA00002443226800011
Wherein:
A) R 2, R 3And R 4H, R 1Be:
-(CH 2)n-G
Wherein:
I) n is 0 to 8 integer;
Ii) G is selected from and replaces or unsubstituted phenyl, and its substituting group is independently selected from 1-3 methyl, methoxyl group or halogen; Cyclopentyl; Cyclohexyl; Suberyl; Pyrryl; Triazolyl; 1,3-dioxolane base; Imidazoles-1-base and thiophene-2-base.
2. cyclopropene derivatives, it is selected from: 1-chloro-4-ring third-1-thiazolinyl methyl-benzene, 1-(2-thienyl) methyl-cyclopropylene, 1-(6-(phenyl dimetylsilyl)-hexyl)-cyclopropylene, 1-(α, α-dimethylbenzyl)-cyclopropylene, 1-(2-(4-chloro-phenyl-sulphur) ethyl) cyclopropylene, 2-(2-phenylsulfonyloxy ethyl)-cyclopropylene, 7-(1-imidazoles)-1-heptyl cyclopropylene, 7-(diphenyl amino)-1-heptyl cyclopropylene, 1-((2-carboxy-N-morpholinyl) ethyl)-cyclopropylene, 1-((2-carboxy-N-morpholinyl) ethyl)-cyclopropylene, 1-(2-(furans-2-base ketonic oxygen base ethyl))-cyclopropylene, 1-(7-(4-mesyloxy phenyl)-ketonic oxygen base heptyl)-cyclopropylene, 1-(2-pyridyl thiopropyl)-cyclopropylene, 1-(8-phenylsulfonyloxy octyl group)-cyclopropylene, 1-(4-aminomethyl phenyl sulphur octyl group)-cyclopropylene, 1-(1H-1,2,4-triazole-2-base sulphur octyl group)-cyclopropylene, 1-(1-methyl-2-pyrrolylcarbonyl oxygen base propyl group)-cyclopropylene, 1-triethylsilyl methylcyclopropene, 1-trimethyl silyl methylcyclopropene, 6-(trimethyl silyl)-hexyl ring third-2-alkene, 2-(trimethyl silyl)-ethyl ring third-2-alkene, 1-(2-mesyloxy ethyl)-cyclopropylene, 1-(7-mesyloxy heptyl)-cyclopropylene, 1-(7-second sulphur heptyl)-cyclopropylene, 1-(7-t-butyldimethylsilyl oxygen base heptyl)-cyclopropylene, 1-(4-mesyloxy butyl)-cyclopropylene, 1-(7-(N-piperidyl imino-heptyl))-cyclopropylene and compound
Figure FDA00002443226800021
R wherein 1, R 2, R 3And R 4As follows:
Figure FDA00002443226800022
3. method that suppresses the ethene effect in the plant comprises with the cyclopropene derivatives of the following formula of ethene suppressing effect significant quantity or the step of its composition and plant contact:
Figure FDA00002443226800031
Wherein:
A) R 2, R 3And R 4H, R 1Be:
-(CH 2)n-G
Wherein:
I) n is 0 to 8 integer;
Ii) G is selected from and replaces or unsubstituted phenyl, and its substituting group is independently selected from 1-3 methyl, methoxyl group or halogen; Cyclopentyl; Cyclohexyl; Suberyl; Pyrryl; Triazolyl; 1,3-dioxolane base; Imidazoles-1-base and thiophene-2-base.
4. a method that suppresses the ethene effect in the plant comprises with the compound as claimed in claim 2 of ethene suppressing effect significant quantity and the step of plant contact.
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