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HK1170478A - Spiro epoxides as intermediates - Google Patents

Spiro epoxides as intermediates Download PDF

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Publication number
HK1170478A
HK1170478A HK12111140.2A HK12111140A HK1170478A HK 1170478 A HK1170478 A HK 1170478A HK 12111140 A HK12111140 A HK 12111140A HK 1170478 A HK1170478 A HK 1170478A
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Hong Kong
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radical
alkyl
group
substituted
haloalkyl
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HK12111140.2A
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Chinese (zh)
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J‧N‧斯卡特
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辛根塔有限公司
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Spirocyclic epoxides as intermediates
The present invention relates to novel compounds, a process for their preparation and their use for the preparation of intermediates of herbicidally active substituted 4-phenyl-3, 5-pyrandiones, 4-phenyl-3, 5-thiopyrandiones and 6-phenylcyclohexane-1, 3, 5-triones.
Herbicidal 4-phenyl-3, 5-pyrandiones, 4-phenyl-3, 5-thiopyrandiones and 6-phenylcyclohexane-1, 3, 5-triones and methods for these compounds are described, for example, in WO 08/071405.
We have found that certain substituted epoxy ketones are useful as key intermediates in processes for preparing such herbicidally active diketo and trione compounds. These epoxy ketones can be obtained in high yields and, moreover, have considerable advantages compared with the known processes.
The present invention relates to compounds of formula (I),
in the formula
R1Is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4An alkylsulfonyl group;
R2is hydrogen, halogen, methylsulfonyloxy, C1-C4A haloalkylsulfonyloxy group, a p-toluenesulfonyloxy group, an optionally substituted aryl group or an optionally substituted heteroaryl group;
r is 0, 1, 2 or 3;
if R is 1, then R3Is C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl, cyano, or nitro; or if R is 2 or 3, the substituent R3Independently of one another are C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl, cyano, or nitro;
y is O, S, SO2Or CO;
R4、R5、R6and R7Independently of one another are hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical C1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl radical C1-C4Alkyl radical, C1-C4Alkylsulfonyl radical C1-C4Alkyl, cyclopropyl or by C1-or C2Alkyl radical, C1-or C2Haloalkyl or halo-substituted cyclopropyl; cyclobutyl or quilt C1-or C2An alkyl-substituted cyclobutyl group; oxetanyl or oxetanyl radicals or substituted by C1-or C2Alkyl-substituted oxetanyl; c5-C7Cycloalkyl radicals or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl wherein the methylene group of the cycloalkyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; c4-C7Cycloalkenyl radicals or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C4-C7Cycloalkenyl, wherein the methylene group of the cycloalkenyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; cyclopropyl group C1-C5Alkyl or by C1-or C2Alkyl radical, C1-or C2Haloalkyl or halogen substituted cyclopropyl C1-C5An alkyl group; cyclobutyl group C1-C5Alkyl or by C1-or C2Alkyl-substituted cyclobutyl C1-C5An alkyl group; oxetanyl radical C1-C5Alkyl or by C1-or C2Alkyl-substituted oxetanyl radicals C1-C5An alkyl group; c5-C7Cycloalkyl radical C1-C5Alkyl or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl radical C1-C5Alkyl, wherein the methylene group of the cycloalkyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; c4-C7Cycloalkenyl radical C1-C5Alkyl or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C4-C7Cycloalkenyl radical C1-C5Alkyl, wherein the methylene group of the cycloalkenyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; phenyl or quilt C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkyl carbonyl substituted phenyl; benzyl or C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkylcarbonyl-substituted benzyl; heteroaryl or by C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4An alkylcarbonyl-substituted heteroaryl; or
R4And R5Or R is6And R7Joined together to form a 5-to 7-membered saturated or unsaturated ring in which the methylene group is optionally replaced by an oxygen or sulfur atom, or is formed by C1-or C2An alkyl-substituted 5-7 membered saturated or unsaturated ring wherein the methylene group of said ring is optionally replaced by an oxygen or sulfur atom; or
R4And R7Joined together to form a 5-7 membered saturated or unsaturated ring which is unsubstituted or substituted with: c1-or C2Alkyl radical, C1-or C2Alkoxy radical, C1-or C2Alkoxy radical C1-or C2Alkyl, hydroxy, halogen, phenyl or by C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkyl halidesRadical, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkyl carbonyl substituted phenyl; heteroaryl or by C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4An alkylcarbonyl-substituted heteroaryl;
the invention also relates to a novel process for the preparation of compounds of formula I.
The invention further relates to a process for the preparation of 4-phenyl-3, 5-pyrandiones, 4-phenyl-3, 5-thiopyrandiones and 6-phenylcyclohexane-1, 3, 5-triones of the formula (A) below using the compounds of the formula I as intermediates.
In the substituent definitions of the compounds of the formula I, alkyl substituents having 1 to 6 carbon atoms and the (halo) alkyl moieties of alkoxy, alkylthio, etc. are preferably methyl, ethyl, propyl, butyl, pentyl and hexyl, in the form of their straight-chain and branched isomers. Suitable cycloalkyl groups contain 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferably, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are contained. Suitable cycloalkenyl groups contain 4 to 7 carbon atoms and no more than 3 double bonds. Preferred halogens are fluorine, chlorine and bromine. Preferred examples of aryl groups are phenyl and naphthyl. Preferred examples of heteroaryl groups are thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, oxadiazolyl, thiadiazolyl and pyridazinyl, and if appropriate, N-oxides and salts of these heteroaryl groups are also preferably employed. These aryl and heteroaryl groups can be substituted by one or more substituents, wherein the preferred substituents are halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl, nitro or cyano. In a preferred group of said compounds of the formula I, R1Is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl or C1-C4-haloalkoxy.
In another preferred group of said compounds of formula I, R2Is halogen, aryl or heteroaryl; or aryl or heteroaryl, each substituted with: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, phenoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl radical, C3-C6Cycloalkyl radical, C1-C4Alkylsulfonyloxy, C1-C4Halogenoalkylsulfonyloxy, C1-C4Alkoxy radical C1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl radical C1-C4Alkyl radical, C1-C4Alkylsulfonyl radical C1-C4Alkyl, nitro, cyano, thiocyanato, hydroxy, amino, C1-C6Alkylamino radical, C1-C6Dialkylamino radical, C3-C6Cycloalkylamino, morpholino, thiomorpholino, C1-C6Alkylcarbonylamino, C1-C6Alkoxycarbonylamino group, C3-C6Alkenyloxycarbonylamino, C3-C6Alkynyloxycarbonylamino group, C1-C6Alkylamino carbonylamino, di (C)1-6Alkyl) aminocarbonylamino, formyl, C1-C6Alkylcarbonyl group, C2-C6Alkenylcarbonyl radical, C2-C6Alkynyl carbonyl, carboxyl, C1-C6Alkoxycarbonyl radical, C3-C6Alkenyloxycarbonyl radical, C3-C6Alkynyloxycarbonyl, carboxamide (carboxamido), C1-C6Alkylaminocarbonyl, di (C)1-C6Alkyl) aminocarbonyl, C1-C6Alkyl carbonyloxy, C1-C6Alkylamino carbonyloxy, di (C)1-C6Alkyl) aminocarbonyloxy or C1-C6An alkylthio carbonylamino group.
Preferably, R in the compound of formula I2Is halogen, aryl or heteroaryl; or an aryl or heteroaryl group substituted with: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenoxy, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl, nitro or cyano.
More preferably, R2Is phenyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl, oxadiazolyl and thiadiazolyl radicals, and the N-oxides and salts of these radicals, in which the rings are unsubstituted or substituted by halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl, nitro or cyano.
In even more preferred compounds of formula I, R2Is phenyl or pyridyl or phenyl or pyridyl substituted with: halogen, nitro, cyano, C1-C2Alkyl radical, C1-C2Haloalkyl, C1-C2Alkoxy or C1-C2A haloalkoxy group.
In a particularly preferred group of compounds, R2Is phenyl substituted in the para position by halogen, especially chlorine, and optionally further substituted by halogen, nitro, C1-C2Alkyl radical, C1-C2Haloalkyl, C1-C2Alkoxy or C1-C2Haloalkoxy substitution.
R3Preferably hydrogen (r is 0) or C1-C6Alkyl, particularly preferably hydrogen.
If R is 1, R3Is preferably C1-C3An alkyl group.
Preferred compounds of formula I are those wherein R4、R5、R6And R7Independently of one another are hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radicalC1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl radical C1-C4Alkyl radical, C1-C4Alkylsulfonyl radical C1-C4An alkyl group; c5-C7Cycloalkyl radicals or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl, and wherein methylene is optionally replaced by oxygen or a sulfur atom or a sulfinyl or sulfonyl group; c5-C7Cycloalkyl radical C1-C5Alkyl or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl radical C1-C5Alkyl, and wherein methylene is optionally replaced by oxygen or a sulphur atom or a sulphinyl or sulphonyl group.
More preferably R4、R5、R6And R7Independently of one another are hydrogen, C1-C2Alkyl radical, C1-C2Haloalkyl or C1-C2Alkoxy radical C1-C2An alkyl group.
In a preferred group of compounds of the formula (I), R1Is ethyl, methyl or cyclopropyl, R2Is phenyl or substituted by halogen or C1-C2Alkyl-substituted phenyl, R3Is hydrogen, R4、R5、R6And R7Independently of one another are C1-C2An alkyl group.
In another preferred group of compounds of the formula (I), R1Is methyl, ethyl, cyclopropyl, n-propyl, halogen, trifluoromethoxy, difluoromethoxy and trifluoromethyl, R4、R5、R6And R7Independently of one another are hydrogen, methyl and ethyl, R2Is halogen or substituted halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Haloalkoxy or C1-C4Alkoxy-substituted phenyl radicals, R3Is a hydrogen atom, and is,
y is oxygen, wherein
More preferably, R1Is ethyl or cyclopropyl, R4、R5、R6And R7Is methyl, R2Is phenyl substituted once or twice by fluorine, chlorine, methoxy or methyl, R3Is hydrogen, Y is oxygen, wherein
Most preferably, R1Is ethyl, R4、R5、R6And R7Is methyl, R2Is 4-chlorophenyl, 2, 4-dichlorophenyl and 2-fluoro-4-chlorophenyl, R3Is hydrogen and Y is oxygen.
In another preferred group of compounds of the formula (I), R1Is ethyl, trifluoromethyl, cyclopropyl, difluoromethoxy, trifluoromethoxy, fluoro, bromo or iodo, R4、R5、R6And R7Independently of one another is hydrogen or methyl, R2Is bromo, 4-chlorophenyl, 2-fluoro-4-chlorophenyl, 2, 4-dichlorophenyl, R3Is H, Y is O, wherein
More preferably, R1Is ethyl, cyclopropyl, R4、R5、R6And R7Is methyl, R2Is bromo, 4-chlorophenyl, 2-fluoro-4-chlorophenyl or 2, 4-dichlorophenyl, R3Is H and Y is O.
In another aspect of the present invention we have found, quite surprisingly, that compounds of formula I are readily converted to 4-phenyl-3, 5-pyrandiones, 4-phenyl-3, 5-thiopyrandiones and 6-phenylcyclohexane-1, 3, 5-triones of formula (A) in the presence of an acid.
Reaction scheme 1
Formula (III) Y, R1、R2、R3、r、R4、R5、R6And R7As defined above.
Suitable acids includeAcids, such as mineral and organic acids, for example sulfuric acid, hydrochloric acid, hydrogen chloride, p-toluenesulfonic acid, acetic acid and formic acid, and Lewis acids, such as metal halides, for example boron trifluoride, aluminum chloride, iron chloride, tin (IV) chloride, zinc bromide, lithium perchlorate, and trifluoromethanesulfonates, such as scandium trifluoromethanesulfonate and ytterbium trifluoromethanesulfonate. Mixtures of these acids may also be used. Conversion of a compound of formula (I) to a compound of formula (A) may be considered as an example of a semipinacol rearrangement (see, e.g., M.Paulson, M.Daliya and C.Asokan, Synth.Commun. (2007), 37(5), 661- "665; S.Sankaraman and J.Nesakumar, J.Chem.Soc, Perkin Trans.1, (1999), (21), 3173-" 3175; K.hsRee and R.Bienfat, Archiv der Phazie, (1984), 317(5), 385-93; H.Kamath, A.Sahasramudhe, B.Bapat and S.Kulkarni, Indian J.Chem., Section B (1981), 20B (12), 1094-6; G.Schynan D.Jhan, Buhai, J.196and S.Kulkarn, Indian J.Chem., Section B (1981), 20B (12), 1094-6; G.Jchan.J.19610, Buhal, J.19610, Oraku., 10, Rock.400, and S.400. Chebular.400, S.400, S.7, S.. The reaction conditions employed in the process of the invention are similar to those described in the above-mentioned documents or can be deduced by the person skilled in the art. Suitable solvents are selected to be compatible with the acid used and include chlorinated hydrocarbons, alcohols, ethers, aromatic hydrocarbons and organic acids such as dichloromethane, dichloroethane, diethyl ether, acetic acid, formic acid, toluene, benzene, methanol, ethanol, isopropanol and tetrahydrofuran. Mixtures of solvents may also be used. The reaction is preferably carried out in dichloroethane using concentrated sulfuric acid. The preferred reaction temperature is from-50 ℃ to 83 ℃, more preferably from-50 ℃ to 40 ℃. Other preferred reaction conditions are the reaction at temperatures of from 0 ℃ to 60 ℃ using lithium perchlorate solutions in ether and ytterbium triflate in an amount of from 0.1 to 100 mol% as acid.
The difference between the present process and the process described in the above document is:
(a) easy access to starting material
(b) The reaction process is short
(c) Avoids using more toxic reagent
(d) The reactant volume concentration was high (up to 20% shown, example P1 step 4).
(e) Broadly-and in particular 2-and 5-substituted phenyl derivatives as initial compounds
(f) The product yield is generally higher, an
(g) The process of the present invention is economically and ecologically advantageous as a step in a continuous reaction sequence for the preparation of known herbicidally active 4-phenyl-3, 5-pyrandiones, 4-phenyl-3, 5-thiopyrandiones and 6-phenylcyclohexane-1, 3, 5-triones of formula (A). The preparation process according to the invention is therefore particularly suitable for the economical, large-scale preparation of diketones and triones of the formula (A).
In another aspect of the invention, the compounds of formula (I) are obtainable by epoxidation of compounds of formula (B) as shown in the following reaction scheme:
formula (III) Y, R1、R2、R3、r、R4、R5、R6And R7As defined above. The compounds of formula (B) are novel compounds specifically designed for use as intermediates in the synthesis of compounds of formula (I), and are also another aspect of the present invention.
Epoxidation the epoxidation may be carried out by reacting a compound of formula (B) with a suitable oxidizing agent, such as an organic peroxide or a metal hypochlorite, for example dimethyldioxirane, sodium hypochlorite, hydrogen peroxide, tert-butyl peroxide or trifluoroperacetic acid. Epoxidation may optionally be carried out using a suitable base (such as an alkali metal hydroxide or carbonate, an alkaline earth metal hydroxide or carbonate, or an amine base, such as 1, 8-diazabicyclo [5.4.0] undec-7-ene), optionally in a suitable solvent (such as an alcohol, a halogenated hydrocarbon, or an aromatic compound, such as methanol, ethanol, dichloromethane, or toluene) and at a suitable temperature. The epoxidation reaction can also be carried out under biphasic conditions, wherein a phase transfer agent is also employed, typically in an amount of 0.001-50 mol%. The phase transfer reagent is preferably quaternary ammonium salt, crown ether, polyethylene glycol or phosphorus salt, and the phase transfer is carried out at a proper temperature. Similar reactions are described in The literature (see, e.g., I.K. Korobitsyn, O.P. Studzinskii, The Russian Journal of Organic Chemistry (1969), 5(8), 1493-5; A.Halasz, Z.Jambor, A.Levai, C.Nemes, T.Patonay and G.Toth, J.chem.Soc, PerkinTrans.1, (1996), (4), 395-400; N.Yousif, F.Gad, A.Fahmy, M.Amine and H.Sayed, Phosorus, Sulfur and Silicon Elements (1996), 117, 11-19; T.Ooi, D.Ooa, M.Tamura K.oka, J.Am.chem and Related (1996), 117, 11-19; T.Ooi, D.Oua, M.Tamura K.K.J.Am.103; Chart.103, 22-35, 22-78, 22-35, Abkura, Abies, Abies.A.9, Tokyna, Tokyo, Sjohnson, Sk.7, Sjohnson, Sk.7, Sk. Mixtures of oxidizing agents, bases, solvents may also be used. The epoxidation is preferably carried out with hydrogen peroxide and a metal hydroxide, in particular lithium hydroxide or sodium hydroxide, in methanol at temperatures of-10 ℃ to 60 ℃.
The compound of formula (B) may be prepared by condensing a compound of formula (C) with a benzaldehyde of formula (D) in a suitable base and optionally in a suitable solvent (see, for example, A. Lagrange, S. Forestier, G.Lang and B.Luppi, EP368717A 1; D.C. Rowlands, US 2776239; E.tamate, Journal of the Chemical Society of Japan, (1957), 78, 1293-7).
Preferred bases are metal hydroxides, such as sodium hydroxide or potassium hydroxide, or metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium tert-butoxide. The solvent is preferably dimethoxyethane, dioxane, tetrahydrofuran, diethyl ether or an aliphatic alcohol such as methanol, ethanol or isopropanol. Mixtures of bases and, especially, solvents can also be used.
Compounds of formula (C) wherein Y is O are known compounds (see, e.g., M.Newman and W.Reichle, org.Synth.Coll.Vol.V. (1973), 1024; Y.Zal' kid, E.Venus-Danilova and V.Ryabtsova, Russian Journal of General Chemistry, (1950), 20, 2222-9; M.Bertrand, J.Dulcere, G.Gil, J.Grinaldi and P.Sylvestre-Pantier, Tetrahedron Letters (1976), (18), 1507-8) or can be prepared using known methods using known compounds. Compounds of the formula (C) in which Y is C.O are known (see, for example, N.J.Turro, D.R.Morton, E.Hedaya, M.E.Kent, P.D' Angelo, P.Schissel, tetrahedron letters (1971), (27), 2535-8; P.A.Krapcho, D.R.Rao, M.P.Silton, B.Abegaz, Journal of Organic Chemistry (1971), 36(25), 3885-90; S.N.Crane, T.J.Jenkins, D.J.Burnell, Journal of Organic Chemistry (1997), 62(25), 8722-8729; S.N.Crane, D.J.Burnell, Journal of Organic Chemistry (1997), 1998), 11 (25), 8722-5729; S.N.Crane, D.J.Burnek.Burnek, Journal of Organic Chemistry (1998), Journal of chemical Chemistry (5763, Journal of Organic Chemistry (1998), and obtainable by the methods of C.J.R.J.R.S.R.T.R.R.D.S.S.J.S.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.. Y is S, SO or SO2The compound of formula (C) is a known compound (see, for example, E.R. Buchman, H.Cohen, Journal of the American Chemical Society (1944), 66, 847-8; A.W.D.Avison, F.Bergel, J.W.Haworth, US 2408519: K.G.Mason, M.A.Smith, E.S.Stern, EJ.A.Elvidle, Journal of the Chemical Society [ Section ]]C：Organic(1967)，(21)，2171-6；T.A.Magee，Thomas A.DE 2033454；I.Tabushi，Y.Tamaru，Z.Yoshida，T.Sugimoto, Journal of the American Chemical Society (1975), 97(10), 2886-91; aldrich, g.h.berezin, b.i.dittmar, i.bruce, DE 2516554; tabushi, Y.Tamaru, Z.Yoshida, Bulletin of the chemical society of Japan (1978), 51(4), 1178-82; reinhoudt, j.geevers, w.p.Trompenaars, s.harkema, g.j.van Hummel, Journal of Organic Chemistry (1981), 46(2), 424-34; duus, Synthesis (1985), (6-7), 672-4; schatz, Science of Synthesis (2002), 9, 287-422), or can be prepared using known methods using known compounds.
The compounds of the formula (D) are either known compounds or can be prepared by formylation of compounds of the formula (E) in which Hal is chlorine, bromine or iodine, preferably bromine or iodine.
In the formula R1、R2、R3And r and Hal are as defined above. Preferred compounds of formula (D) are compounds of formula (D1),
in the formula R1、R3And R is as defined above, R20And R30Independently of one another, are hydrogen, methyl, methoxy, fluorine, chlorine or bromine. The compounds of formula (D) are novel compounds, the novel compounds of formula (D1) being specifically designed for use as intermediates in the synthesis of compounds of formula (I), and they are also another aspect of the present invention.
Suitable conditions for effecting the formylation of aryl halides are known and include, for example, reacting an aryl halide with a suitable organometallic reagent such as isopropyl magnesium chloride, n-butyl lithium, sec-butyl lithium or tert-butyl lithium, or reacting an aryl halide with a suitable alkali metal or alkaline earth metal such as lithium or magnesium in a suitable solvent such as diethyl ether, dimethoxyethane or tetrahydrofuran. The resulting aryl metal reagent is then reacted with a suitable formylating agent, such as N, N-dimethylformamide or N-formylmorpholine. Alternatively, compounds of formula (D) may be prepared by reacting a compound of formula (E) (where Hal may also be a pseudohalide, such as a triflate) with a carbonylation reagent (such as carbon monoxide) in the presence of a suitable catalyst, base and reducing agent (see, for example, l.ashfield and c.barnard, org.process res.dev., 11(1), 39-43, 2007). The compounds of formula (E) are either known compounds (see, for example, WO 2008/071405) or can be synthesised using known compounds using standard chemical transformations.
Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (F) (wherein halo is chloro, bromo or iodo, preferably chloro or bromo) with a compound of formula (D), as shown in the reaction scheme below.
(F) The reaction of (a) and (D) may be carried out using a suitable base, optionally in a suitable solvent and at a suitable temperature. The base preferably employs an alkali metal or alkaline earth metal hydroxide (e.g., sodium hydroxide, lithium hydroxide or potassium hydroxide), an alkali metal or alkaline earth metal alkoxide (e.g., sodium methoxide, sodium ethoxide or potassium tert-butoxide), an alkali metal or alkaline earth metal carbonate (e.g., potassium carbonate or sodium carbonate, or sodium hydrogencarbonate), a metal amide (e.g., lithium diisopropylamide, lithium hexamethyldisilazide or lithium 2, 2, 6, 6-tetramethylpiperidine), an organic metal (e.g., butyllithium or ethylmagnesium bromide), or a metal hydride (e.g., sodium hydride or potassium hydride). Suitable solvents include chlorinated hydrocarbons, ethers, alcohols, aromatic hydrocarbons and polar aprotic solvents in each case, such as 1, 2-dimethoxyethane, tetrahydrofuran, 1, 4-dioxane, diethyl ether, dibutyl ether, dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide, benzene, toluene, methanol, ethanol, isopropanol or tert-butanol, and the solvent chosen should be compatible with the base under the reaction conditions. The epoxidation reaction can also be carried out under biphasic conditions, wherein a phase transfer agent is also employed, typically in an amount of 0.001-50 mol%. The phase transfer agent is preferably quaternary ammonium salt, crown ether, polyethylene glycol or phosphorus salt. The reaction is most preferably carried out using lithium diisopropylamide in tetrahydrofuran at a temperature of-100 ℃ to 60 ℃. The conversion of a compound of formula (F) into a compound of formula (I) can be regarded as an example of glycidyl ester condensation (Dazens condensation) (see, for example, W.N. Wassef, M.M.El-Barky, Journal of Chemical Research, Synopses (1990), (12), 402-3; J.Li, X.Liu, X.Li, Yo uji Huaxue (2007), 27(11), 1428-garland; Y.Tong, Y.Cheng, X.Guo, S.Wu, Hecheng Huaxue (2007), 15 (15), 102-104; C.Parmenon, J.Guillard, AuD.Caignnard, N.Heheuyer, B.Staels, V.ot dinuchez, J.Jutin, C.Daczat, A.Ktorzar, M.V.upright, N.Hechenyuyer, J.J.J.J.Cheng, Mascheng-Sancheng, J.J.J.J.J.J.Cheng, Shicheng, J.11, J.J.J.J.Cheng, Shicheng, Shicheng. Cheng. Shicheng. Shichen, Shicheng. Shichen, Shiniu, Shicheng. Shiniu, Shicheng. Shiniu, Shicheng. Shig. Shiniu.
Compounds of formula (F) wherein Y is O or known compounds (see, for example, H.Richet, R.Dulou, R., G.Dupont, Bulletin de la society Chimique de France (1947), 693-9; H.Richet, Ann.Chim. [12 ]](1948)，3317-54；I.K.Korobitsyna，Yu.K.Yur′ev，Yu.A.Cheburkov，E.M.Lukina，Russian Journalof General Chemistry(1955)，25，734-8；I.K.Korobitsyna，Yu.K.Yur′ev，Yu.A.Cheburkov，E.M.Lukina，Russian Journal of General Chemistry(1955)，25，690-702；F.Leonard，A.Wajngurt，H.Horn，Journal of Organic Chemistry(1956)，21，1400-4；I.K.Korobitsyna，I.G.Zhukova，V.A.Kuvshinova，N.N.Gaidamovich，Yu.K.Yur′ev，Doklady Akademii NaukSSSR(1957)，114，327-30；I.K.Korobitsyna，I.G.Zhukova，I.G，Yu.K.Yur′ev，RussianJournal of General Chemistry(1959)，29，2190-6；I.K.Korobitsyna，L.L.Rodina，L.M.Stashkova，Chemistry of Heterocyclic Compounds(1966)，(6)，843-7；GHoehne, f.marschner, k.praefcke, p.weyerstahl, chem.be. (1975), 108(2), 673-82; saimoto, T.Hiyama, H.Nozaki, Bull.Chem.Soc.Jpn., (1983), 56(10), 3078-87; A.M.Zvonok, N.M.Kuz' menok, I.G.Tishchenko, L.S.Staniswevskii, Russian Journal of General Chemistry (1985), 21(6), 1330-4) or may be prepared under known conditions using a compound of formula (C). Y is S, SO and SO2The compound of formula (F) of (A) may be a known compound (see, for example, M.Polievka, L.Uhlar, V.Patek, Petrochemia (1973), 13(5-6), 156-60; N.N.Novitskaya, B.V.Flekhter, G.M.Prokhorov, A.S.Lukmanova, G.A.Tolstikov, G.V.Leplyanin, S.A.Lange, M.V.Strashcrov, SU 468920A 1; P.H.Mcbe, W.Router, Tetrahedron Letters (1976), (1), 85-6; T.S.Chou, C.Y.Tsai, Tetrahedron Letters (1992), 33-4), or a compound of formula (C42029) may be prepared under known conditions. Compounds of formula (F) where Y is C ═ O can be prepared using compounds of formula (C) under analogous halogenation conditions.
The following examples further illustrate the invention, but are not intended to limit the invention.
Preparation examples:
example P1: preparation of 4- (5-bromo-2-ethylphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 5-bromo-2-ethyl-benzaldehyde
Isopropyl magnesium chloride (55ml, 110mmol, 2M solution in tetrahydrofuran) was added dropwise at-20 ℃ in a solution of 4-bromo-1-ethyl-2-iodobenzene (31.8g, 103mmol) in anhydrous tetrahydrofuran (250ml) (as described in WO 2008/071405) over a period of 10 minutes. Once the addition was complete, the reaction mixture was stirred at-20 ℃ for 3 hours, then anhydrous N, N-dimethylformamide (16.0ml, 200mmol) was added dropwise. The reaction mixture was further stirred at room temperature for 2.5 hours, and then, left to stand overnight. 2M hydrochloric acid (90ml) was added and the crude product was extracted into dichloromethane. The organic layers were combined and dried over magnesium sulfate, then filtered and the filtrate was evaporated under reduced pressure to give 5-bromo-2-ethyl-benzaldehyde (21.20g) as an orange liquid.
Step 2: preparation of 4- (5-bromo-2-ethylbenzylidene) -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cold solution of dihydro-2, 2, 5, 5-tetramethyl-3 (2H) -furanone (13.4g, 94.34mmol) in dry 1, 2-dimethoxyethane (32ml) was added sodium methoxide (5.6g, 103.8mmol) in one portion and the reaction mixture was stirred at this temperature for 5 min. Then, a solution of 5-bromo-2-ethyl-benzaldehyde (20g, 94.34mmol) in 1, 2-dimethoxyethane (32ml) was added dropwise over a period of 10 minutes to the resulting slurry. Then, the solution was stirred at 0 ℃ for 1 hour, then, diluted with diethyl ether and washed with 2M hydrochloric acid (2 times). The organic components were combined and dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to give 4- (5-bromo-2-ethylbenzylidene) -2, 2, 5, 5-tetramethyldihydrofuran-3-one (30.2g) as a yellow liquid.
And step 3: preparation of 2- (5-bromo-2-ethylphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 35 ℃ solution of 4- (5-bromo-2-ethylbenzylidene) -2, 2, 5, 5-tetramethyldihydrofuran-3-one (32.07g, 95.15mmol) in methanol (1570ml) was added 50% aqueous hydrogen peroxide (8.10ml, 142.73mmol) followed immediately by 2M aqueous lithium hydroxide (9.51ml, 19.03 mmol). The reaction mixture was stirred at 35 ℃ for exactly 1 hour and then quenched with saturated sodium metabisulfite (340ml) and distilled water (340 ml). Stir at room temperature for 15 minutes, then concentrate the solvent in vacuo (to about 500ml) at which point the product precipitates as a yellow solid. To this suspension was added distilled water (500ml) and the product was isolated by filtration. Washed separately with distilled water and the solid was dried under vacuum overnight to give 2- (5-bromo-2-ethylphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one as a yellow solid. The product was used directly in the next step without further purification.
1H NMR(CDCl3)：δ7.47-7.40(m，2H)，7.10(d，1H)，4.43(s，1H)，2.62-2.60(m，2H)，1.40(s，3H)，1.37(s，3H)，1.30-1.20(m，6H)，0.78(s，3H)。
And 4, step 4: preparation of 4- (5-bromo-2-ethylphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To an ice-cold concentrated sulfuric acid solution (2ml) was added a solution of the second solution 2- (5-bromo-2-ethylphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (0.995g, 2.82mmol) in 1, 2-dichloroethane (2ml) dropwise over a period of 5 minutes. This biphasic mixture was stirred vigorously at 0 ℃ for 1h and then poured into ice-cold water (15 ml). The aqueous mixture was then concentrated in vacuo to remove all organic volatiles to give a free-flowing solid. The solid was filtered, dried under vacuum and washed with hexane to give 4- (5-bromo-2-ethylphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (0.81g) as a cream-colored solid.
1H NMR(CDCl3)：δ7.48(1H，dd)，7.23-7.21(2H，m)，5.60(1H，s)，2.45-2.33(2H，m)，1.60(6H，d)，1.48(6H，d)，1.10(3H，t)。
Example P2: preparation of 4- (5-bromo-2-ethylphenyl) -2, 2, 6-trimethylpyran-3, 5-dione
Step 1: preparation of 4-bromo-2, 2, 5-trimethyldihydrofuran-3-one
To an anhydrous chloroform solution (75ml) of 4-bromo-2, 2, 5-trimethyl-2, 5-dihydrofuran-3-yl acetate (19.14g, 0.11mol) (as described in T.Hiyama et al. Bull. chem. Soc. Jpn., 56, 3078-3087 (1983)) at-20 ℃ was added dropwise a solution (200ml) of bromine in anhydrous chloroform (18.00g, 0.11mol) over 45 minutes. Stirred at this temperature for 30 minutes, then the reaction mixture was heated to room temperature and then further stirred for 1 hour. After dilution with chloroform (250ml), the organic phase was washed with dilute aqueous sodium bicarbonate solution and then with brine, whereby the phases were separated. The organic solvent was removed under reduced pressure to give 4-bromo-2, 2, 5-trimethyldihydrofuran-3-one (23.50g) as a dark yellow oil. This material was used in the next step without purification.
Step 2: preparation of 2- (5-bromo-2-ethylphenyl) -4, 6, 6-trimethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a solution of lithium diisopropylamide (0.12mol) in anhydrous tetrahydrofuran (150ml) at-70 ℃ was added a second solution of 4-bromo-2, 2, 5-trimethyl-4, 5-dihydro-3 (2H) -furanone (23.5g, 0.11mol) in anhydrous tetrahydrofuran (40ml) at a rate to maintain the internal temperature of the solution below-65 ℃. Once the addition was complete, the reaction mixture was further stirred at-70 ℃ for 20 minutes, and then a solution of 2-ethyl-5-bromobenzaldehyde (23.9g, 0.11mol) in anhydrous tetrahydrofuran (40ml) was added dropwise over a period of 20 minutes. After stirring at-70 ℃ for a further 20 minutes, the reaction mixture was warmed to room temperature and then stirred for 30 minutes. The reaction mixture was then poured into ice/water (500ml) (acidified to pH 3 with 2M hydrochloric acid) and extracted with ethyl acetate (3 × 100 ml). The organic components were combined, washed with water and brine, and then dried over magnesium sulfate. The suspension was filtered and the filtrate was concentrated in vacuo to give a mixture of 2- (5-bromo-2-ethylphenyl) -4, 6, 6-trimethyl-1, 5-dioxaspiro [2.4] heptan-7-one and 2-ethyl-5-bromobenzaldehyde (40.50g) in a ratio of about 3: 1. This material was used in the next step without purification.
1H NMR(CDCl3)：δ7.47(m，1H)，7.41(m，1H)，7.10(d，1H)，4.47(q，1H)，4.39(s，1H)，2.60(q，2H)，1.38(s，3H)，1.35(s，3H)，1.23(t，3H)，0.70(d，3H)。
And step 3: preparation of 4- (5-bromo-2-ethylphenyl) -2, 2, 6-trimethylpyran-3, 5-dione
To an ice-cold concentrated sulfuric acid solution (50ml) was added a solution of crude 2- (5-bromo-2-ethylphenyl) -4, 6, 6-trimethyl-1, 5-dioxaspiro [2.4] heptan-7-one (40g) in 1, 2-dichloroethane (50ml) over a period of 20 minutes. After stirring at 0 ℃ for a further 1h, the reaction mixture was poured carefully onto ice (500g) and the two phases were separated. The aqueous phase was further extracted with dichloromethane (2 × 100ml) and all organic components were then combined, washed with water and concentrated under reduced pressure. The crude product was redissolved in ethyl acetate (500ml) and extracted into 0.5M aqueous potassium carbonate and washed with additional ethyl acetate (2 times). The aqueous phase was then carefully acidified with concentrated hydrochloric acid and the product extracted with ethyl acetate (3 × 150 ml). The organic components were combined, washed with brine, then dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product was further purified by flash column chromatography to give 4- (5-bromo-2-ethylphenyl) -2, 2, 6-trimethylpyran-3, 5-dione (14.10g) as a yellow foam.
1H NMR(CDCl3): δ 1.08(m, 3H), 1.38-1.62(m, 9H), 2.25(m, 2H), 4.38 and 4.71(m, 1H), 5.72 and 5.83(2x br s, 1H), 7.20(m, 2H), 7.48(m, 1H).
Example P3: 4- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 4' -chloro-4-trifluoromethyl-biphenyl-3-carboxaldehyde
To a mixture of 3-chloro-6-trifluoromethylbenzaldehyde (1.0g, 4.79mmol), 4-chlorobenzeneboronic acid (1.12g, 7.19mmol), potassium phosphate (2.03g, 9.59mmol), dicyclohexyl- (2 ', 6' -dimethoxy-biphenyl-2-yl) -phosphane (0.079g, 0.19mmol) and palladium acetate (0.022g, 0.096mmol), degassed benzene (9ml) was added, and then, the mixture was further purged with nitrogen. The suspension is subsequently sealed and then stirred at room temperature for 5 minutes and heated at 160 ℃ for 1 hour by microwave radiation. After cooling, the reaction mixture was partitioned between 2M hydrochloric acid and dichloromethane and the aqueous phase was further extracted with dichloromethane (2 times). The organic components were combined and then evaporated under reduced pressure to give the crude product which was then purified by flash column chromatography (eluting with 100% hexane to 10% ethyl acetate in hexane) to give 4' -chloro-4-trifluoromethyl-biphenyl-3-carboxaldehyde (1.78g) as an orange gum. This material was used directly in the next step.
Step 2: preparation of 4- [1- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cooled solution (10ml) of 2, 2, 5, 5-tetramethyldihydrofuran-3-one (0.887g, 6.25mmol) in 1, 2-dimethoxyethane was added sodium methoxide (0.405g, 7.50mmol) in one portion. The reaction mixture was stirred at 0 ℃ for 30 minutes, then a solution of 4' -chloro-4-trifluoromethyl-biphenyl-3-carboxaldehyde (1.779g, 6.25mmol) in 1, 2-dimethoxyethane (10ml) was added dropwise. The reaction mixture was stirred at 0 ℃ for 30 minutes, then at room temperature for a further 1 hour, then partitioned between 1M hydrochloric acid and dichloromethane. The aqueous phase was re-extracted with dichloromethane and then all organic phases were combined and evaporated to give 4- [1- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (2.50g) as a yellow gum. This material was used directly in the next step.
And step 3: preparation of 2- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a solution of 4- [1- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (2.50g, 6.12mmol) in methanol (75ml) at 35 ℃ was added 50% aqueous hydrogen peroxide (0.70ml, 12.2mmol) and then immediately 2M aqueous lithium hydroxide (0.76ml, 1.52 mmol). The mixture was stirred at 35 ℃ for 45 minutes, then cooled to room temperature and quenched with saturated sodium metabisulfite solution. The resulting crude product was extracted with diethyl ether (2 times), then all organic phases were combined and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to give 2- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (2.59g) as a yellow gum. This material was used directly in the next step.
And 4, step 4: preparation of 4- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To an ice-cooled solution of crude 2- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (2.59g, 6.12mmol) in dichloroethane (25ml) was added concentrated sulfuric acid (5ml), followed by stirring at this temperature for 2 hours. The reaction mixture was poured into ice, extracted with dichloromethane (2 times) and the resulting organic phase was evaporated under reduced pressure to give a brown gum. Purification by flash column chromatography (isohexane to 30% ethyl acetate in isohexane as eluent) followed by reverse phase preparative HPLC gave 4- (4' -chloro-4-trifluoromethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (0.370g) as a white solid.
1H NMR(CDCl3)：δ7.85(d，1H)，7.69(d，1H)，7.53(d，2H)，7.44(d，2H)，7.39(s，1H)，1.60(app.d，6H)，1.48(s，6H)。
Example P4: preparation of 4- (5-bromo-2-iodophenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 5-bromo-2-iodobenzaldehyde
To a solution of-80 deg.C 5-bromo-2-iodobenzonitrile (5.00g, 16.00mmol) in anhydrous tetrahydrofuran (80ml) was added dropwise diisobutylaluminum hydride (16.0ml, 16.0mmol, 1M in toluene) over a period of 10 minutes. The reaction mixture was stirred at-80 ℃ for 1 hour, then warmed to room temperature and stirred overnight. Then, diisobutylaluminum hydride (16.0ml, 16.0mmol, 1M toluene solution) was added dropwise at room temperature, and the reaction mixture was further stirred for 1 hour. After careful quenching with 2M hydrochloric acid (cooling in an ice bath), the resulting crude product was extracted with ethyl acetate (2 times), then all organic phases were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and then purified by flash column chromatography (isohexane to 10% ethyl acetate isohexane eluent) to give 5-bromo-2-iodobenzaldehyde (0.85 g).
Step 2: preparation of 4- [1- (5-bromo-2-iodophenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cooled solution of 2, 2, 5, 5-tetramethyldihydrofuran-3-one (0.388g, 2.73mmol) in anhydrous 1, 2-dimethoxyethane (5ml) was added sodium methoxide (0.177g, 3.27mmol) in one portion. The reaction mixture was stirred at this temperature for 5 minutes, then a solution of 5-bromo-2-iodobenzaldehyde (0.850g, 2.73mmol) in 1, 2-dimethoxyethane (5ml) was added dropwise. The reaction mixture was further stirred at 0 ℃ for 30 minutes, and then at room temperature for 1 hour. After partitioning between 1M hydrochloric acid and dichloromethane, the organic phase was separated and the aqueous phase was extracted again with additional dichloromethane. All organic phases were combined and then concentrated in vacuo to give 4- [1- (5-bromo-2-iodophenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (1.18g) as a yellow gum.
And step 3: preparation of 2- (5-bromo-2-iodophenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 35 ℃ solution of 4- [ 1-5-bromo-2-iodophenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (1.18g, 2.73mmol) in methanol (50ml) was added 50% aqueous hydrogen peroxide (0.31ml, 5.46mmol) and then immediately 2M aqueous lithium hydroxide (0.34ml, 0.68 mmol). The mixture was stirred at 35 ℃ for 3 hours, then quenched with saturated aqueous sodium metabisulfite and extracted with dichloromethane. The organic phase was separated and the aqueous phase was re-extracted with dichloromethane. All organic phases were combined and then evaporated under reduced pressure to give 2- (5-bromo-2-iodophenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one as an oil which was used directly in the next step.
And 4, step 4: preparation of 4- (5-bromo-2-iodophenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To 2- (5-bromo-2-iodophenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (the product obtained in step 3) was added ice-cold concentrated sulfuric acid, and the reaction mixture was stirred at room temperature for 30 minutes. After dilution with distilled water, the product is extracted with dichloromethane (2 times), and the organic phases are then pooled and evaporated under reduced pressure. Purification by flash column chromatography (20% ethyl acetate in isohexane to ethyl acetate as eluent) gave 4- (5-bromo-2-iodophenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (0.225g) as a beige solid.
1H NMR(CDCl3)：δ7.80(d，1H)，7.33(m，1H)，7.25(m，1H)，1.66(s，3H)，1.60(s，3H)，1.55(s，3H)，1.48(s，3H)。
Example P5: preparation of 4- (5-bromo-2-trifluoromethoxyphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 4- [1- (5-bromo-2-trifluoromethoxyphenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cooled solution of 2, 2, 5, 5-tetramethyldihydrofuran-3-one (2.84g, 20.00mmol) in anhydrous 1, 2-dimethoxyethane (6ml) was added sodium methoxide (1.19g, 22.04mmol) in one portion. After stirring at this temperature for 5 minutes, 5-bromo-2-trifluoromethoxybenzaldehyde (4.84g, 18.00mmol) in 1, 2-dimethoxyethane (6ml) was added dropwise over 10 minutes, followed by further stirring at 0 ℃ for 1 hour. The reaction mixture was warmed to room temperature, diluted with ether and washed with 2M hydrochloric acid (2 times). The organic components were combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to give 4- [ [1- (5-bromo-2-trifluoromethoxyphenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (7.06g) as a yellow liquid.
Step 2: preparation of 2- (5-bromo-2-trifluoromethoxyphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a solution of 4- [1- (5-bromo-2-trifluoromethoxyphenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (7.06g, 18.00mmol) in methanol (300ml) at 35 ℃ was added 50% aqueous hydrogen peroxide (1.80ml, 27.00mmol) and then immediately 2M aqueous lithium hydroxide (1.80ml, 3.60 mmol). After stirring for 1 hour at this temperature, the reaction mixture was cooled and then quenched with 10% sodium metabisulfite solution (negative KI-starch indicator test). The reaction mixture was extracted with diethyl ether (3 times), and then the organic phase was further washed with saturated aqueous sodium bicarbonate solution (2 times), then with brine. All organic components were combined and dried over magnesium sulfate, filtered, and the filtrate was evaporated in vacuo to give 2- (5-bromo-2-trifluoromethoxyphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (6.34g, 86%) as a yellow oil.
1H NMR(CDCl3): δ 7.84(s, 0.4H, isomer a), 7.56(s, 0.6H, isomer B), 7.52(d, 0.6H, isomer B), 7.48(d, 0.4H, isomer a), 7.15(d, 0.6H, isomer B), 7.07(d, 0.4H, isomer a), 4.46(m, 1H, isomers a and B), 1.47(s, 1.2H, isomer a), 1.39-1.28(m, 7.8H, isomers a and B), 1.12(s, 1.2H, isomer a), 0.83(s, 1.8H, isomer B).
And step 3: preparation of 4- (5-bromo-2-trifluoromethoxyphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To an ice-cold concentrated sulfuric acid solution (10ml) was added dropwise a solution of the second solution 2- (5-bromo-2-trifluoromethoxyphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (6.34g, 15.00mmol) in 1, 2-dichloroethane (10ml) over a period of 5 minutes. The biphasic mixture was stirred vigorously at 0 ℃ for 2 hours, then poured into ice water and washed with a small amount of 1, 2-dichloroethane/water. The mixture was then concentrated in vacuo to remove all organic solvent and obtain a self-flowing solid. The solid was filtered, then washed with isohexane, and then dried under vacuum overnight. The solid was then redissolved in ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give 4- (5-bromo-2-trifluoromethoxyphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (4.17g, 68%).
1H NMR(CDCl3)：δ7.57(dd，1H)，7.24(d，2H)，1.52(br.s，12H)。
Example P6: preparation of 4- (4-bromo-4' -chlorobiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 4-bromo-4' -chlorobiphenyl-3-carboxaldehyde
To-75 ℃ 4-bromo-4' -chloro-3-iodobiphenyl (4.80g, 0.012mol) (described in WO 2008/071405) in anhydrous diethyl ether/tetrahydrofuran (120ml, 1: 1) was added isopropyl magnesium bromide (18.96ml, 15% tetrahydrofuran solution) dropwise, with the internal temperature kept below-70 ℃. Once the addition was complete, the reaction mixture was stirred at-75 ℃ for 2 hours and then heated to-45 ℃. Next, anhydrous N, N-dimethylformamide (1.71g, 0.0184mol) was added dropwise, the temperature was kept below-40 ℃ and then warmed to room temperature and quenched with 2M hydrochloric acid (60 ml). The reaction mixture was further diluted with diethyl ether, the two phases were separated and the aqueous phase was additionally extracted with diethyl ether. The organic extracts were combined, washed with brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The crude product was purified by flash column chromatography (2% ethyl acetate in hexane as eluent) to give 4-bromo-4' -chlorobiphenyl-3-carboxaldehyde (2.7g, 75%) as a white solid.
Step 2: preparation of 4- [1- (4-bromo-4' -chlorobiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cooled solution of dihydro-2, 2, 5, 5-tetramethylfuran-3-one (1.37g, 9.68mmol) in anhydrous 1, 2-dimethoxyethane (10ml) was added sodium methoxide (0.575g, 10.60mmol) in one portion, and stirred at this temperature for 10 minutes. To this slurry was added dropwise a second solution of 4-bromo-4' -chlorobiphenyl-3-carboxaldehyde (2.60g, 8.80mmol) in 1, 2-dimethoxyethane (10 ml). When the addition was complete, the reaction mixture was stirred at 0 ℃ for 1 hour and then quenched with 2M hydrochloric acid (50 ml). After stirring again for 1 hour, the solution was diluted with diethyl ether, the two phases separated and the aqueous phase was further extracted with diethyl ether (2 times). The combined organic phases were further washed with brine, then dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 4- [1- (4-bromo-4' -chlorobiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (3.40g, 92%) as a yellow gum.
And step 3: preparation of 2- (4-bromo-4' -chlorobiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a solution of 4- [1- (4-bromo-4' -chlorobiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (3.40g, 9.03mmol) in methanol (140ml) at 35 ℃ was added 50% aqueous hydrogen peroxide (1.04ml, 15.60mmol) and then immediately 2M aqueous lithium hydroxide (1.15ml, 2.30 mmol). The reaction mixture was stirred at 35 ℃ for an additional 45 minutes, then cooled to room temperature and quenched with saturated sodium metabisulfite. After extraction of the product into diethyl ether (3 times), the organic phase was separated and washed with water and then dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to give 2- (4-bromo-4' -chlorobiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (3.0g) as a yellow solid. The material is pure enough to be used directly in the next step.
And 4, step 4: preparation of 4- (4-bromo-4' -chlorobiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Concentrated sulfuric acid (6.5ml) was added to an ice-cold solution of 2- (4-bromo-4' -chlorobiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (3.00g, 6.90mmol) in dichloromethane (3.5ml) at a rate that maintained the internal temperature below 5 ℃. After the addition was complete, the reaction mixture was stirred for 20 minutes, and then distilled water (25ml) was added dropwise at 0 ℃. The reaction mixture was kept at 5-10 ℃ for 5 minutes and then concentrated in vacuo to remove the organic solvent. The aqueous phase was filtered and the resulting solid triturated with hexanes to give 4- (4-bromo-4' -chlorobiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (2.56g, 85%).
NMR(CDCl3)：δ7.75(d，1H)，7.49(d，2H)，7.45(dd，1H)，7.40(s，2H)，7.36(s，1H)，5.56(br.s，1H)，1.65(s，3H)，1.58(s，3H)，1.53(s，3H)，1.47(s，3H)。
Example P7: preparation of 4- (5-bromo-2-fluorophenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 4- [1- (5-bromo-2-fluorophenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cold solution of dihydro-2, 2, 5, 5-tetramethylfuran-3-one (4.56g, 32.10mmol) in anhydrous 1, 2-dimethoxyethane (25ml) was added sodium methoxide (1.91g, 35.10mol) in one portion. After stirring at this temperature for 10 minutes, a solution of a second solution of 5-bromo-2-fluorobenzaldehyde (5.93g, 29.10mmol) in 1, 2-dimethoxyethane (45ml) was added dropwise, followed by further stirring at 0 ℃ for 45 minutes. The reaction mixture was cooled with 2M hydrochloric acid (50ml) and then diluted with diethyl ether and the two phases separated. The aqueous phase was further extracted with diethyl ether (2 times), then all organic phases were combined, washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to give 4- [1- (5-bromo-2-fluorophenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (9.30g, 96%) as a yellow gum.
Step 2: preparation of 2- (5-bromo-2-fluorophenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 35 ℃ solution of 4- [1- (5-bromo-2-fluorophenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (9.30g, 29.00mmol) in methanol (280ml) was added 50% aqueous hydrogen peroxide (3.36ml, 50.40mmol) and immediately thereafter 2M aqueous lithium hydroxide (3.68ml, 7.36 mmol). Stirring was continued for 1 hour at this temperature, then the reaction mixture was cooled to room temperature, then quenched with saturated sodium metabisulphite (100ml) and extracted with ether (3 times). All organic components were combined and dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 2- (5-bromo-2-fluorophenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (6.60g, 68%) as a yellow gum.
And step 3: preparation of 4- (5-bromo-2-fluorophenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To a solution of 2- (5-bromo-2-fluorophenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (6.60g, 19.30mmol) in methylene chloride (8ml) was added dropwise an ice-cold solution of concentrated sulfuric acid (13.8ml) to the second solution, the temperature being kept below 5 ℃. The reaction mixture was further stirred for 30 minutes, then extracted with distilled water (50ml) to cool. After stirring for a further 10 minutes, the organic material is removed in vacuo and the resulting precipitate is filtered and then triturated with water. After washing with hexane, the solid was dried to give 4- (5-bromo-2-fluorophenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (4.30g, 65%).
1H NMR(CDCl3)：δ7.5(m，1H)，7.34(m，1H)，7.06(m，1H)，5.69(br.s，1H)，1.56(d，6H)，1.52(d，6H)。
Example P8: preparation of 4- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) -2266-tetramethylpyran-35-dione
Step 1: preparation of 4 '-chloro-2' -fluoro-4-hydroxybiphenyl-3-carboxaldehyde
To a mixture of 5-bromosalicylaldehyde (30.0g, 0.15mol), 2-fluoro-4-chlorobenzeneboronic acid (30.0g, 0.17mol) and sodium carbonate (24.0g, 0.23mol) were added 1, 2-dimethoxyethane (225ml) and distilled water (75ml), and the suspension was stirred under a nitrogen atmosphere. Then, to this mixture was added [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (4.5g, 7.5mmol), followed by heating and refluxing for one night. After cooling to room temperature, it was diluted with distilled water (500ml) and dichloromethane (500ml), the two phases were separated and the aqueous phase was extracted again with dichloromethane (2 × 500 ml). The organic phases were combined, washed with brine (800ml) and then dried over magnesium sulphate. The suspension was filtered and the filtrate was concentrated in vacuo. The crude material was then purified by flash column chromatography (5-10% ethyl acetate in isohexane as eluent) to give 4 '-chloro-2' -fluoro-4-hydroxybiphenyl-3-carboxaldehyde (33.61g, 89%) as a pale yellow solid.
Step 2: preparation of 4 '-chloro-2' -fluoro-3-formylbiphenyl-4-yl trifluoromethanesulfonate
To an ice-cold solution of a mixture of 4 '-chloro-2' -fluoro-4-hydroxybiphenyl-3-carboxaldehyde (33.60g, 0.13mol) and pyridine (31.0ml, 0.36mol) in anhydrous dichloromethane (700ml) was added dropwise trifluoromethanesulfonic anhydride (27.0ml, 0.16mmol) over a period of 30 minutes while the temperature was kept below 10 ℃. The reaction mixture was then warmed to room temperature and stirred overnight. After dilution with distilled water (500ml) and dichloromethane (500ml), the two layers were separated and the aqueous phase was extracted again with dichloromethane (2 × 500 ml). The organic phases were combined, washed with brine (800ml), then dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography (10% ethyl acetate in hexanes eluant) to provide 4 '-chloro-2' -fluoro-3-formylbiphenyl-4-yl trifluoromethanesulfonate as a yellow oil.
And step 3: preparation of 4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-carboxaldehyde
To a mixture of 4 '-chloro-2' -fluoro-3-formylbiphenyl-4-yl trifluoromethanesulfonate (30.0g, 0.078mol), cyclopropylboronic acid (8.80g, 0.10mol), potassium phosphate (58.40g, 0.28mol) and sodium bromide (8.0g, 0.078mol) was added toluene (300ml) under a nitrogen atmosphere, followed by addition of distilled water (30 ml). Then, tetrakis (triphenylphosphine) palladium (9.60g, 8.40mmol) was added to this mixture in one portion, and then the mixture was kept at 100 ℃ for one night. After cooling to room temperature, the mixture was diluted with distilled water (500ml) and ethyl acetate (500ml), the two layers were separated and the aqueous phase was extracted again with ethyl acetate (2 × 500 ml). The organic fractions were combined, washed with distilled water (1L) then brine (1L) and dried over magnesium sulfate. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel followed by flash column chromatography on basic alumina (10% ethyl acetate in hexane as eluent) to give 4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-carboxaldehyde (7.6g, 36%).
And 4, step 4: preparation of 4- [1- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cold solution of dihydro-2, 2, 5, 5-tetramethylfuran-3-one (8.40g, 0.059mol) in anhydrous 1, 2-dimethoxyethane (75ml) was added sodium methoxide (3.60g, 0.066mol) in one portion, and the mixture was stirred at this temperature for 30 minutes. Then, a solution of 4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-carboxaldehyde (14.80g, 0.054mmol) was added dropwise over a period of 20 minutes at a temperature below 10 ℃. The reaction mixture was stirred at this temperature for 1 hour, then warmed to room temperature and diluted with diethyl ether and distilled water. The two phases were separated and the aqueous phase was extracted again with diethyl ether (2 times). The organic phases were combined, washed with brine and then dried over magnesium sulphate. The suspension was filtered and the filtrate was concentrated in vacuo to give 4- [1- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (19.80g) which was pure enough to be used directly in the next step.
And 5: preparation of 2- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 35 ℃ solution of 4- [1- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (19.80g, 0.050mol) in methanol (830ml) was added 50% aqueous hydrogen peroxide (5.00ml, 0.075mmol) and then immediately 2M aqueous lithium hydroxide (5.00ml, 0.01 mol). The mixture was stirred at this temperature for a further 2 hours and then allowed to cool to room temperature. The reaction mixture was then quenched with 10% sodium metabisulfite (negative KI-starch indicator test) and then diluted with diethyl ether. Most of the methanol was removed under vacuum and the crude mixture was partitioned between distilled water and diethyl ether. The aqueous phase was further extracted with diethyl ether (2 times), then all organic phases were combined, washed with saturated sodium bicarbonate (2 times), then brine. After dehydration over magnesium sulfate, the suspension was filtered and the filtrate was concentrated in vacuo to give 2- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one as a yellow foam. The material is pure enough to be used directly in the next step without purification.
1H NMR(CDCl3)：δ7.48(s，1H)，7.39(d，1H)，7.32(t，1H)，7.24-7.12(m，2H)，7.00(d，1H)，4.76(s，1H)，1.84-1.76(m，1H)，1.42-1.26(m，9H)，1.11-0.96(m，2H)，0.88-0.79(m，4H)，0.78-0.71(m，1H)。
Step 6: preparation of 4- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To a mixture of 2- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (18.20g, 0.044mol) and ytterbium triflate (2.40g, 4.40mmol) was added a 5M lithium perchlorate solution (prepared from 46ml diethyl ether and 24.40g lithium perchlorate). The resulting suspension was stirred at room temperature for 3 days, then diluted with diethyl ether (85ml), and ytterbium triflate (7.80g, 0.014mol) was additionally added. Stirring was continued for a further 3 days at room temperature, additional ytterbium triflate (13.63g, 0.025mol) was added and the reaction mixture was stirred for 11 days. Finally, excess lithium perchlorate (24.40g, 0.23mol) was added in one portion and the mixture was kept at 27 ℃ (internal temperature) for 1 day. The reaction mixture was partitioned between diethyl ether and distilled water, the two phases were separated and the aqueous phase was extracted with diethyl ether (2 times). The organic phases were combined, washed with brine and then dried over magnesium sulphate. The suspension was filtered and the filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography (10% ethyl acetate in hexane as eluent) to give an oil which was triturated with hexane to give 4- (4 '-chloro-4-cyclopropyl-2' -fluorobiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (4.78g) as a white solid.
1H NMR(CDCl3)：δ7.47(d，1H)，7.38(t，1H)，7.23(s，1H)，7.21-7.12(m，3H)，5.68(s，1H)，1.75(m，1H)，1.62(s，6H)，1.49(s，6H)，0.92-0.82(m，2H)，0.81-0.75(m，1H)，0.61-0.53(m，1H)。
Example P9: preparation of 4- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 2 ', 4' -dichloro-4-hydroxybiphenyl-3-carboxaldehyde
To a mixture of 5-bromosalicylaldehyde (30.0g, 0.15mol), 2, 4-dichlorophenylboronic acid (32.0g, 0.17mol) and sodium carbonate (24.0g, 0.23mol) were added 1, 2-dimethoxyethane (225ml) and distilled water (75ml), and the suspension was stirred under a nitrogen atmosphere. Then, to this mixture was added [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (4.5g, 7.5mmol), followed by heating and refluxing for one night. After cooling to room temperature, it was diluted with distilled water (500ml) and dichloromethane (500ml), the two phases were separated and the aqueous phase was extracted again with dichloromethane (2 × 500 ml). The organic phases were combined, washed with brine (800ml) and then dried over magnesium sulphate. The suspension was filtered and the filtrate was concentrated in vacuo. Finally, the crude material was purified by flash column chromatography (10% ethyl acetate in isohexane as eluent) to give 2 ', 4' -dichloro-4-hydroxybiphenyl-3-carboxaldehyde (32.73g, 82%) as a pale yellow solid.
Step 2: preparation of 2 ', 4' -dichloro-3-formylbiphenyl-4-yl trifluoromethanesulfonate
To an ice-cold mixture of 2 ', 4' -dichloro-4-hydroxybiphenyl-3-carboxaldehyde (31.70g, 0.12mol) and pyridine (25.0ml, 0.29mol) in dry dichloromethane (650ml) was added dropwise trifluoromethanesulfonic anhydride (22.0ml, 0.13mmol) over 30 minutes at a temperature of 0-10 ℃. The reaction mixture was then warmed to room temperature and stirred overnight. After dilution with distilled water (500ml) and dichloromethane (300ml), the two layers were separated and the organic phase was further washed with saturated aqueous copper sulphate solution (3X500ml), water (500ml) and then brine (500 ml). After dehydration over magnesium sulfate, the solvent was removed in vacuo and the crude product was purified by flash column chromatography (10% ethyl acetate in hexane as eluent) to afford the 2 ', 4' -dichloro-3-formylbiphenyl-4-yl trifluoromethanesulfonate as a yellow oil.
And step 3: preparation of 2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-carboxaldehyde
To a mixture of trifluoromethanesulfonic acid 2 ', 4' -dichloro-3-formylbiphenyl-4-yl ester (30.0g, 0.075mol), cyclopropylboronic acid (8.50g, 0.097mol), potassium phosphate (56.30g, 0.27mol) and sodium bromide (7.7g, 0.075mol) was added toluene (300ml) under a nitrogen atmosphere, followed by addition of distilled water (30 ml). Then, tetrakis (triphenylphosphine) palladium (9.30g, 0.0081mol) was added to this mixture in one portion, and then the mixture was kept at 100 ℃ for one night. After cooling to room temperature, the mixture was diluted with distilled water (500ml) and ethyl acetate (500ml), and the two phases were separated. The aqueous phase was extracted again with ethyl acetate (2 × 500ml) and then the organic phases were combined, washed with distilled water (1L) and then brine (1L). After drying over magnesium sulfate, the suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (2-10% ethyl acetate in hexane as eluent) followed by flash column chromatography on basic alumina (10% ethyl acetate in hexane as eluent) to give 2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-carboxaldehyde (11.7g, 54%).
And 4, step 4: preparation of 4- [1- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cold solution of dihydro-2, 2, 5, 5-tetramethylfuran-3-one (15.70g, 0.11mol) in anhydrous 1, 2-dimethoxyethane (285ml) was added sodium methoxide (6.50g, 0.12mol) in one portion, and the mixture was stirred at this temperature for 30 minutes. Then, a solution of 2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-carboxaldehyde (13.70g, 0.047mmol) was added dropwise over a period of 20 minutes at a temperature below 10 ℃. The reaction mixture was stirred at this temperature for 2 hours, then warmed to room temperature and diluted with diethyl ether and distilled water. The two phases were separated and the aqueous phase was extracted again with diethyl ether (2 times). The organic phases were combined, washed with brine and then dried over magnesium sulphate. The suspension was filtered and the filtrate was concentrated in vacuo. The aqueous phase was further acidified with 2M hydrochloric acid and then extracted with diethyl ether (2 times), dried over magnesium sulfate and concentrated in vacuo. All organic phases were combined, diluted with toluene and azeotroped (4 times) to give 4- [1- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (20.0g) which was pure enough to be used directly in the next step.
And 5: preparation of 2- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 35 ℃ solution of 4- [1- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (20.0g, 0.048mol) in methanol (800ml) was added 50% aqueous hydrogen peroxide (4.80ml, 0.072mmol) followed immediately by 2M aqueous lithium hydroxide (4.80ml, 9.60 mmol). The mixture was stirred at this temperature for a further 2 hours and then allowed to cool to room temperature. The reaction mixture was then quenched with 10% sodium metabisulfite (negative KI-starch indicator test) and then diluted with diethyl ether. Most of the methanol was removed under vacuum and the crude mixture was partitioned between distilled water and diethyl ether. The aqueous phase was further extracted with diethyl ether (2 times), then all organic phases were combined, washed with saturated sodium bicarbonate (2 times), then brine. After dehydration over magnesium sulfate, the suspension was filtered and the filtrate was concentrated in vacuo to give 2- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (17.80g) as a yellow foam. The material is pure enough to be used directly in the next step without purification.
1H NMR(CDCl3)：δ7.49(s，1H)，7.37(s，1H)，7.37-7.25(m，2H)，7.20(d，1H)，6.99(d，1H)，4.75(s，1H)，1.80(m，1H)，1.40-1.28(m，9H)，1.10-0.98(m，2H)，0.90-0.80(m，4H)，0.75-0.80(m，1H)。
Step 6: preparation of 4- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To a mixture of 2- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (17.80g, 0.041mol) and ytterbium triflate (2.20g, 4.41mmol) was added 5M lithium perchlorate solution (prepared from 42ml diethyl ether and 22.30g lithium perchlorate). The resulting suspension was stirred at room temperature for 17 days, at which stage diethyl ether (42ml), lithium perchlorate (22.3g, 0.21mol) and ytterbium triflate (19.8g, 0.035mol) were further added. Then, the reaction mixture was kept at 27 ℃ (internal temperature) for 1 day, and then partitioned between diethyl ether and distilled water. The two phases were separated, the aqueous phase was extracted with diethyl ether (2 times), then all organic phases were combined, washed with brine and then dried over magnesium sulfate. The suspension was filtered and the filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography (ethyl acetate/hexane as eluent) to give an oil which was triturated with hexane to give 4- (2 ', 4' -dichloro-4-cyclopropylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (2.80g) as a white solid.
1H NMR(CDCl3)：δ7.48(s，1H)，7.38(dd，1H)，7.29(s，2H)，7.16-7.11(m，2H)，5.69(s，1H)，1.76(m，1H)，1.61(d，6H)，1.49(d，6H)，0.92-0.86(m，2H)，0.82-0.76(m，1H)，0.62-0.54(m，1H)。
Example P10: preparation of 4- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 2 ', 4' -dichloro-4-ethylbiphenyl-3-carboxaldehyde
A suspension of 5-bromo-2-ethylbenzaldehyde (1.0g, 4.7mmol), 2, 4-dichlorophenylboronic acid (1.34g, 7.0mmol) and sodium carbonate (0.99g, 7.98mmol) in a mixed solvent of 1, 2-dimethoxyethane (12ml) and distilled water (4ml) was stirred under a nitrogen atmosphere and then purged with nitrogen (2 times). Then [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (1.15g, 1.41mmol) was added in one portion and the suspension was purged again with nitrogen and then heated under reflux overnight. After cooling to room temperature, the reaction mixture was diluted with distilled water (10ml) and extracted with dichloromethane (10 ml). The aqueous phase was extracted again with dichloromethane (2 times), the organic phases were combined and finally washed with brine and then dried over magnesium sulfate. The crude product was purified by flash column chromatography (isohexane to 75: 25 isohexane/ethyl acetate eluent) to give 2 ', 4' -dichloro-4-ethylbiphenyl-3-carboxaldehyde as a yellow oil.
Step 2: preparation of 4- [1- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
Sodium methoxide (0.481g, 0.0089mol) was added in one portion to an ice-cold solution of 2, 2, 5, 5-tetramethyldihydrofuran-3-one (1.15g, 0.0081mol) in 1, 2-dimethoxyethane (2 ml). The reaction mixture was then stirred at this temperature for 5 minutes, then a second solution of 2 ', 4' -dichloro-4-ethylbiphenyl-3-carboxaldehyde (2.02g, 0.0072mol) in 1, 2-dimethoxymethane (2.7ml) was added. After stirring at 0 ℃ for a further 2 hours, the reaction mixture was left at room temperature overnight. The crude solution was poured into 2M hydrochloric acid and extracted with ether (3 times). The organic phases were combined, washed with brine, then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to give 4- [1- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one as a yellow gum.
Step 3A: preparation of 2- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 55 ℃ solution of 4- [ [1- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (2.04g, 0.0051mol) in methanol (24ml) was added a hydrogen peroxide solution (0.43ml, 0.0076mmol, 50% wt solution) and immediately thereafter an aqueous lithium hydroxide solution (0.25ml, 0.0005 mol). The reaction mixture was heated at this temperature for 30 minutes, then rapidly cooled to room temperature and quenched with saturated sodium thiosulfate. The resulting crude product was extracted with diethyl ether (3 times), then all organic phases were combined and dried over magnesium sulfate. The residue was purified by flash column chromatography (isohexane with 5% ethyl acetate to isohexane with 25% ethyl acetate) to give 2- [ (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) methylene ] -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one as a yellow gum.
And step 3B: preparation of 2- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a toluene solution (3.7ml) of 4- [1- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (0.500g, 1.24mmol) were added an aqueous sodium hypochlorite solution (3.30g, 6.20mmol, 14% active chlorine) and tetrabutylammonium hydrogensulfate (0.013g, 0.04mmol), and then, the biphasic mixture was stirred at 50 ℃ for 4 hours. The reaction mixture was then diluted with toluene, the phases were separated and the organic phase was washed with distilled water (2 times). The organic phase was dried over sodium sulfate and then concentrated in vacuo to give 2- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one as a white solid.
Step 4A: preparation of 4- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To an ice-cold concentrated sulfuric acid solution (6ml) was added dropwise a solution of a second solution of 2- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (1.90g, 0.0045mol) in 1, 2-dichloroethane (6ml) over a period of 5 minutes. This biphasic mixture was stirred vigorously at 0 ℃ for 2 hours, then poured into ice and extracted with diethyl ether. All organic phases were combined, washed with brine, then dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to give 4- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione as a yellow gum.
1H NMR(CDCl3)：δ7.48(d，1H)，7.43(m，2H)，7.30(m，2H)，7.13(d，1H)，5.71(br.s，1H)，2.55-2.44(m，2H)，1.62(s，6H)，1.49(app.d，6H)，1.17(t，3H)。
And step 4B: preparation of 4- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To a solution of 2- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (0.0418g, 0.10mmol) in toluene (0.3ml) was added p-toluenesulfonic acid monohydrate (0.019g, 0.10 mmol). Then, the mixture was kept at 150 ℃ for 1 hour, and then cooled to room temperature. The reaction mixture was poured into distilled water, dried over sodium sulfate, and then concentrated in vacuo to give 4- (2 ', 4' -dichloro-4-ethylbiphenyl-3-yl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione.
Example P11: preparation of 4- (5-bromo-2-difluoromethoxyphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
Step 1: preparation of 5-bromo-2-difluoromethoxybenzaldehyde
To a suspension of 5-bromosalicylaldehyde (7.60g, 0.038mol) and cesium carbonate (17.30g, 0.053mol) in anhydrous N, N-dimethylformamide (55ml) was added sodium difluorochloroacetate (13.30g, 0.087mol), followed by distilled water (10 ml). The reaction mixture was heated at 100 ℃ for 6 hours (large solid pieces were scooped up with a spatula), then cooled to room temperature and quenched with concentrated hydrochloric acid (15 ml). After further stirring for 2 hours, the reaction mixture was diluted with distilled water and extracted with ethyl acetate (2 times). The organic phases were combined, washed with 2M aqueous sodium hydroxide, brine and then dried over magnesium sulfate. The suspension was filtered and the filtrate was concentrated in vacuo to give 5-bromo-2-trifluoromethoxybenzaldehyde (5.66g) which was pure enough to be used directly in the next step.
Step 2: preparation of 4- [1- (5-bromo-2-difluoromethoxyphenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one
To an ice-cold solution of 2, 2, 5, 5-tetramethyldihydrofuran-3-one (3.60g, 0.025mol) in anhydrous 1, 2-dimethoxyethane (8ml) was added sodium methoxide (1.51g, 0.028mol) in one portion. After stirring at this temperature for 5 minutes, a solution of 5-bromo-2-difluoromethoxybenzaldehyde (5.66g, 0.023mol) in 1, 2-dimethoxyethane (8ml) was added dropwise over a period of 10 minutes, followed by further stirring at 0 ℃ for 1 hour. The reaction mixture was warmed to room temperature, diluted with ether and washed with 2M hydrochloric acid (2 times). The organic fractions were combined, dried over magnesium sulfate and evaporated in vacuo to give 4- [1- (5-bromo-2-difluoromethoxyphenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (8.89g) as a yellow oil.
And step 3: preparation of 2- (5-bromo-2-difluoromethoxyphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one
To a 35 ℃ solution of 4- [1- (5-bromo-2-difluoromethoxyphenyl) methylene ] -2, 2, 5, 5-tetramethyldihydrofuran-3-one (8.89g, 0.023mol) in methanol (380ml) was added 50% aqueous hydrogen peroxide (2.30ml, 0.034mol) followed immediately by 2M aqueous lithium hydroxide (2.30ml, 0.0046 mmol). After stirring for 1 hour at this temperature, the reaction mixture was cooled and then quenched with 10% sodium metabisulfite solution (negative KI-starch indicator test). The reaction mixture was extracted with diethyl ether (3 times), and then the organic phase was further washed with saturated aqueous sodium bicarbonate solution (2 times), then with brine. All organic components were combined and dried over magnesium sulfate, filtered, and the filtrate was evaporated in vacuo to give 2- (5-bromo-2-difluoromethoxyphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (7.22g) as a yellow gum.
And 4, step 4: preparation of 4- (5-bromo-2-difluoromethoxyphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione
To an ice-cold concentrated sulfuric acid solution (12ml) was added a solution of the second solution 2- (5-bromo-2-difluoromethoxyphenyl) -4, 4, 6, 6-tetramethyl-1, 5-dioxaspiro [2.4] heptan-7-one (7.22g, 18.00mmol) in 1, 2-dichloroethane (12ml) dropwise over a period of 5 minutes. The biphasic mixture was stirred vigorously at 0 ℃ for 2 hours and then allowed to stand at room temperature overnight. The reaction mixture was poured into ice water and washed with a small amount of 1, 2-dichloroethane/water and then concentrated under vacuum to remove all organic solvents. Next, the crude product was extracted into ethyl acetate (3 times), then all organic phases were combined, washed with brine and dried over magnesium sulfate. The suspension was filtered, the filtrate concentrated in vacuo, then purified by flash column chromatography (10-25% ethyl acetate in hexane as eluent) to give an oil, which was triturated with hexane to give 4- (5-bromo-2-difluoromethoxyphenyl) -2, 2, 6, 6-tetramethylpyran-3, 5-dione (2.08g) as a white solid.
1H NMR(CDCl3): δ 7.54(dd, 0.75H, isomer a), 7.51(dd, 0.25H, isomer B), 7.37(d, 0.75H, isomer a), 7.32(d, 0.25H, isomer B), 7.15(d, 0.75H, isomer a), 7.06(d, 0.25H, isomer), 6.32(t, 0.75H, isomer a), 6.29(t, 0.25H, isomer B)1H), 5.86(s, 0.75H, isomer a), 5.28(s, 0.25H, isomer a), 1.58-1.44(m, 12H, isomers a and B).

Claims (16)

1. A compound of formula I
In the formula
R1Is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4An alkylsulfonyl group;
R2is hydrogen, halogen, methylsulfonyloxy, C1-C4A haloalkylsulfonyloxy group, a p-toluenesulfonyloxy group, an optionally substituted aryl group or an optionally substituted heteroaryl group;
is 0, 1, 2 or 3;
if R is 1, then R3Is C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl, cyano, or nitro; or if R is 2 or 3, the substituent R3Independently of one another are C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl, cyano, or nitro;
y is O, S, SO2Or CO;
R4、R5、R6and R7Independently of one another are hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical C1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl radical C1-C4Alkyl radical, C1-C4Alkylsulfonyl radical C1-C4Alkyl, cyclopropyl or by C1-or C2Alkyl radical, C1-or C2Haloalkyl or halo-substituted cyclopropyl; cyclobutyl or quilt C1-or C2An alkyl-substituted cyclobutyl group; oxetanyl or oxetanyl radicals or substituted by C1-or C2Alkyl-substituted oxetanyl; c5-C7Cycloalkyl radicals or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl wherein the methylene group of the cycloalkyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; c4-C7Cycloalkenyl radicals or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C4-C7Cycloalkenyl, wherein the methylene group of the cycloalkenyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; cyclopropyl group C1-C5Alkyl or by C1-or C2Alkyl radical, C1-or C2Haloalkyl or halogen substituted cyclopropyl C1-C5An alkyl group; cyclobutyl group C1-C5Alkyl or by C1-or C2Alkyl-substituted cyclobutyl C1-C5An alkyl group; oxetanyl radical C1-C5Alkyl or by C1-or C2Alkyl-substituted oxetanyl radicals C1-C5An alkyl group; c5-C7Cycloalkyl radical C1-C5Alkyl or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl radical C1-C5Alkyl, wherein the methylene group of the cycloalkyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; c4-C7Cycloalkenyl radical C1-C5Alkyl or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C4-C7Cycloalkenyl radical C1-C5Alkyl, wherein the methylene group of the cycloalkenyl moiety is optionally replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group; phenyl or quilt C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkyl carbonyl substituted phenyl; benzyl or C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkylcarbonyl-substituted benzyl; heteroaryl or by C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4An alkylcarbonyl-substituted heteroaryl; or
R4And R5Or R is6And R7Joined together to form a 5-to 7-membered saturated or unsaturated ring in which the methylene group is optionally replaced by an oxygen or sulfur atom, or is formed by C1-or C2An alkyl-substituted 5-7 membered saturated or unsaturated ring wherein the methylene group of said ring is optionally replaced by an oxygen or sulfur atom; or
R4And R7Joined together to form a 5-7 membered saturated or unsaturated ring which is unsubstituted or substituted with: c1-or C2Alkyl radical, C1-or C2Alkoxy radical, C1-or C2Alkoxy radical C1-or C2Alkyl, hydroxy, halogen, phenyl or by C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkyl carbonyl substituted phenyl; heteroaryl or by C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl, halogen, nitro, cyano, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl or C1-C4Alkyl carbonyl substituted heteroAn aryl group;
2. the compound of claim 1, wherein R1Is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl or C1-C4-haloalkoxy.
3. The compound of claim 1, wherein R2Is halogen, aryl or heteroaryl; or aryl or heteroaryl, each substituted with: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, phenoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl radical, C3-C6Cycloalkyl radical, C1-C4Alkylsulfonyloxy, C1-C4Halogenoalkylsulfonyloxy, C1-C4Alkoxy radical C1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl radical C1-C4Alkyl radical, C1-C4Alkylsulfonyl radical C1-C4Alkyl, nitro, cyano, thiocyanato, hydroxy, amino, C1-C6Alkylamino radical, C1-C6Dialkylamino radical, C3-C6Cycloalkylamino, morpholino, thiomorpholino, C1-C6Alkylcarbonylamino, C1-C6Alkoxycarbonylamino group, C3-C6Alkenyloxycarbonylamino, C3-C6Alkynyloxycarbonylamino group, C1-C6Alkylamino carbonylamino, di (C)1-6Alkyl) aminocarbonylamino, formyl, C1-C6Alkylcarbonyl group, C2-C6Alkenylcarbonyl radical, C2-C6Alkynyl carbonyl, carboxyl, C1-C6Alkoxycarbonyl radical, C3-C6Alkenyloxycarbonyl radical, C3-C6Alkynyloxycarbonyl, carboxamide (carboxamido), C1-C6Alkylaminocarbonyl, di (C)1-C6Alkyl) aminocarbonyl, C1-C6Alkyl carbonyloxy, C1-C6Alkylamino carbonyloxy, di (C)1-C6Alkyl) aminocarbonyloxy or C1-C6An alkylthio carbonylamino group.
4. A compound according to claim 3, wherein R in the compound of formula I2Is halogen, aryl or heteroaryl; or an aryl or heteroaryl group substituted with: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenoxy, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl, nitro or cyano.
5. The compound of claim 4, wherein R2Is phenyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl, oxadiazolyl and thiadiazolyl, and the N-oxides and salts of these radicals, where the rings are unsubstituted or substituted byGroup-substituted halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Halogenoalkylthio, C1-C4Halogenoalkylsulfinyl, C1-C4Haloalkylsulfonyl, nitro or cyano.
6. The compound of claim 5, wherein R2Is phenyl or pyridyl or phenyl or pyridyl substituted with: halogen, nitro, cyano, C1-C2Alkyl radical, C1-C2Haloalkyl, C1-C2Alkoxy or C1-C2A haloalkoxy group.
7. The compound of claim 6, wherein R2Is phenyl substituted by halogen at para-position, and can be further substituted by halogen, nitryl and C1-C2Alkyl radical, C1-C2Haloalkyl, C1-C2Alkoxy or C1-C2Haloalkoxy substitution.
8. The compound of claim 1, wherein R3Is hydrogen or C1-C6An alkyl group.
9. The compound of claim 1, wherein R is 1 if R is3Is C1-C3An alkyl group.
10. A compound according to claim 1, wherein R4、R5、R6And R7Independently of one another are hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical C1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl radical C1-C4Alkyl radical, C1-C4Alkylsulfonyl radical C1-C4An alkyl group; c5-C7Cycloalkyl radicals or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl, and wherein methylene is optionally replaced by oxygen or a sulfur atom or a sulfinyl or sulfonyl group; c5-C7Cycloalkyl radical C1-C5Alkyl or by C1-or C2Alkyl or C1-or C2Haloalkyl-substituted C5-C7Cycloalkyl radical C1-C5Alkyl, and wherein methylene is optionally replaced by oxygen or a sulphur atom or a sulphinyl or sulphonyl group.
11. The compound of claim 10, wherein R4、R5、R6And R7Independently of one another are hydrogen, C1-C2Alkyl radical, C1-C2Haloalkyl or C1-C2Alkoxy radical C1-C2An alkyl group.
12. The compound of claim 1, wherein Y is O.
13. The compound of claim 1, wherein R1Is ethyl, methyl or cyclopropyl, R2Is phenyl or substituted by halogen or C1-C2Alkyl-substituted phenyl, R3Is hydrogen, R4、R5、R6And R7Independently of one another are C1-C2Alkyl and Y is O. .
14. A process for the preparation of a compound of formula I,
wherein R is1-R7And n is as defined in claim 1, said method comprising reacting a compound of formula (F)
With a compound of formula (D).
15. A process for the preparation of a compound of formula I,
wherein R is1-R7And n is as defined in claim 1, said method comprising reacting a compound of formula (C)
With a compound of the formula (D),
to obtain the compound of the formula (B),
and then further reacted with an oxidizing agent.
16. A process for the preparation of a compound of formula (A),
the method comprises reacting a compound of formula (I)
With an acid.
HK12111140.2A 2009-05-29 2010-05-25 Spiro epoxides as intermediates HK1170478A (en)

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