WO2006088963A1 - Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans - Google Patents

Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans Download PDF

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Publication number
WO2006088963A1
WO2006088963A1 PCT/US2006/005345 US2006005345W WO2006088963A1 WO 2006088963 A1 WO2006088963 A1 WO 2006088963A1 US 2006005345 W US2006005345 W US 2006005345W WO 2006088963 A1 WO2006088963 A1 WO 2006088963A1
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Prior art keywords
formula
compound
alkyl
reacting
halogen
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French (fr)
Inventor
Guozhi Wang
Charles E. Hatch, Iii
Jaidev S. Goudar
Russell Patera
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Bayer CropScience AG
FMC Corp
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Bayer CropScience AG
FMC Corp
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Priority to EP06735147A priority Critical patent/EP1853614A4/en
Priority to JP2007556263A priority patent/JP2008530221A/en
Priority to BRPI0607720-0A priority patent/BRPI0607720A2/en
Priority to US11/816,486 priority patent/US20080319209A1/en
Publication of WO2006088963A1 publication Critical patent/WO2006088963A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • This invention is in the field of chemical processes; more specifically, an improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from halogen or alkyl and x is 2, 3, 4, 5 or 6; are useful insecticides and have been described in United States Patent number 6,987,194, the disclosure of which is incorporated herein by reference. Disadvantages of processes to produce these compounds include less than optimal yields, less than optimal cycle times and high catalyst loadings.
  • R 3 , R 4 , R 5 , R 6 and x are as defined above; are key intermediates in the process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans.
  • the present invention improves the process for preparing compounds of formula I.
  • overall yield, cycle times and catalyst loading are improved for the production of (disubstirutedpropenyl) phenylalkyl substituted dihydrobenzofurans.
  • R ,3" and R 4 are selected from halogen
  • R 5 and R 6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
  • R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R and R taken together with an alkyl or aryl, forming a cyclic ester;
  • R 3 and R 4 are as defined above;
  • R 7 and R 8 are as defined above;
  • R 5 and R 6 are as defined above;
  • R 9 and R 10 are independently selected from halogen, hydroxyl or
  • R 11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
  • R 5 , R 6 R 10 and x are as defined above;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and x are as defined above;
  • the "about” range shall be not more than 10% of the absolute value of an end point or 10% of the range recited, whichever is less.
  • alkyl As used in this specification and unless otherwise indicated the substituent terms "alkyl”, “alkoxy”, and “haloalkyl”, used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms.
  • Halogen “halide” or “halo” refers to fluorine, bromine, iodine, or chlorine.
  • ambient temperature refers to a temperature in the range of about 20° C to about 30° C. Certain solvents, catalysts, and the like are known by their acronyms.
  • DMAC N,N-dimethylacetamide
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • glymes refers to a class of solvents comprised of monoglyme, diglyme, triglyme, tetraglyme, and polyglyme.
  • GC refers to gas chromatography or gas chromatographic methods of analyses.
  • the present invention relates to a process for preparing a compound of formula I:
  • R 3 and R 4 are selected from halogen
  • R 5 and R 6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
  • R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R 7 and R 8 taken together with an alkyl or aryl, forming a cyclic ester;
  • R 3 and R 4 are as defined above; and R 7 and R 8 are as defined above;
  • R 5 and R 6 are as defined above;
  • R 9 and R 10 are independently selected from halogen, hydroxyl or -OSO 2 R 11 wherein R 11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
  • R 5 , R 6 R 10 and x are as defined above;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and x are as defined above;
  • the reaction of step b) can be conducted in the presence of a catalyst; at elevated temperature.
  • the catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine,/>-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
  • the catalyst can be present in a concentration of from about 0.1% by weight to about 15% by weight.
  • the elevated temperature can be in the range of 30°C to 120°C.
  • the reaction of step c) can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature.
  • the solvent can be tetrahydrofuran, toluene, xylene, acetone, acetonitrile, 1 ,2-dichloroethane, triethylamine,/>-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof.
  • the catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine ⁇ -toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
  • the catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight.
  • the elevated temperature can be in the range of 30°C to 110°C.
  • the reaction of step d) can be conducted with a base; as a hydrolysis in the presence of an acid; in the presence of a solvent; in the presence of a catalyst.
  • the solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, triethylamine,/?- dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof.
  • the catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine,/?-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
  • the catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight.
  • R and R are selected from halogen;
  • R 5 and R 6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
  • R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R and R taken together with alkyl or aryl, forming a cyclic ester;
  • R 9 and R 10 are independently selected from halogen, hydroxyl
  • R 3 , R 4 , R 7 , R 8 , R 10 and x are as defined above;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and x are as defined above;
  • the reaction of step a) can be conducted in the presence of a catalyst; at elevated temperature.
  • the catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamme,/7-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
  • the catalyst can be present in a concentration of from about 0.1 % by weight to about 15% by weight.
  • the elevated temperature can be in the range of 30 0 C tO lOO 0 C.
  • the reaction of step b) can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature.
  • the solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, triethylamine,/>-dioxane, N,N- dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof.
  • the catalyst can be polyethylene glycol, dimethylaminopyridine, triethylarnine,/>-toruenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
  • the catalyst can be present in a concentration of from about 0.1 % by weight to about 20% by weight.
  • the elevated temperature can be in the range of 30°C to 110 0 C.
  • the reaction of step c) can be conducted with a base; as a hydrolysis in the presence of an acid; in the presence of a solvent; in the presence of a catalyst.
  • the solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof.
  • the catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine,/?-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
  • the catalyst can be present in a concentration of from about 0.1 % by weight to about 20% by weight.
  • R 3 and R 4 are selected from halogen
  • R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R 7 and R 8 taken together with an alkyl or aryl, forming a cyclic ester.
  • R > 5 and j ⁇ R> 6 are independently selected from halogen or alkyl;
  • R 10 is selected from halogen, hydroxyl or -OSO 2 R 11 wherein R 11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
  • Another embodiment of the present invention is a compound of formula IV:
  • R 3 and R 4 are selected from halogen;
  • R 5 and R 6 are independently selected from halogen or alkyl;
  • R and R are independently selected from hydrogen, alkyl, aryl or R and R 8 taken together with an alkyl or aryl, forming a cyclic ester; and
  • x is 2, 3, 4, 5 or 6.
  • R 3 and R 4 are selected from halogen
  • R and R are independently selected from hydrogen, alkyl, aryl or R and R taken together with an alkyl or aryl, forming a cyclic ester;
  • R 10 is selected from halogen, hydroxyl or -OSO2R 11 wherein R 11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
  • R 3 and R 4 are halogen
  • R 5 and R 6 are alkyl wherein R 9 and R 10 are halogen m
  • R 3 and R 4 are halogen wherein R 10 is halogen and R 5 and R 6 are alkyl
  • dialkyl 4-hydroxybenzenephosphate (A) for example diethyl 4-hydroxybenzenephosphate
  • a halogenating agent for example sulfurylchloride
  • step (b) of Example 1 2,2-dialkyl-2,3-dihydrobenzo[b]furan-7-ol (B) was reacted with a 1,4-dihaloalkane (C), for example 1,4-dihalobutane, in the presence of a base and a catalyst at elevated temperature to form a l-(2,2-dialkyl(2,3- dihydrobenzo[2,3-b]furan-7-yloxy))-4-haloalkane, a compound of formula III, for example l-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))-4-halobutane.
  • C 1,4-dihaloalkane
  • C 1,4-dihalobutane
  • step (c) of Example 1 dialkyl 3,5-dihalo-4-hydroxybenzenephosphate, a compound of formula II, for example diethyl 3,5-dihalo-4- hydroxybenzenephosphate, was reacted with a l-(2,2-dialkyl(2,3-dihydrobenzo[2,3- b]furan-7-yloxy))-4-haloalkane, a compound of formula III, for example l-(2,2- dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))-4-halobutane, in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(2,2- dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))alkoxy]-3,5- dihalobenzenephosphate, a compound of formula IV, for example diethyl 4-[4-(2,2- dialky
  • a compound of formula IV
  • R 3 and R 4 are halogen from halogen, hydroxyl or -OSO 2 R 11 , where R 1 ' is alkyl or aryl '
  • dialkyl 3,5-dihalo-4- hydroxybenzenephosphate a compound of formula II, for example diethyl 3,5- dihalo-4-hydroxybenzenephosphate
  • a compound of formula II for example diethyl 3,5- dihalo-4-hydroxybenzenephosphate
  • C 1 ,4-disubstitutedalkane
  • 1,4-disubstitutedbutane 1,4-disubstitutedbutane
  • a dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula V, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate can be reacted with 2,2-dialkyl-2,3- dihydrobenzo[b]furan-7-ol (B) in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3- b]furan-7-yloxy))alkoxy]-3,5-dihalobenzenephosphate, a compound of formula IV, for example diethyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7- yloxy))butoxy]-3 ,5-dihalobenzenephosphate.
  • B 2,2-dialkyl-2,

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Abstract

An improved process is described for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans. TMs improved process is focused on steps to produce key intermediates, namely compounds of formula I, where R3, R4, R5, R6 and x are defined herein.

Description

Improved Process for Preparing (Disubstitutedpropenyl) Phenyϊalkyl Substituted Dihydrobenzofurans
This application claims the benefit of U.S. Provisional Application No. 60/653,736, filed February 17, 2005.
Field of the Invention:
This invention is in the field of chemical processes; more specifically, an improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans.
Background:
(Disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans, such as:
Figure imgf000002_0001
wherein R1, R2, R3, R4, R5 and R6 are independently selected from halogen or alkyl and x is 2, 3, 4, 5 or 6; are useful insecticides and have been described in United States Patent number 6,987,194, the disclosure of which is incorporated herein by reference. Disadvantages of processes to produce these compounds include less than optimal yields, less than optimal cycle times and high catalyst loadings. Compounds represented by formula I:
Figure imgf000002_0002
wherein R3, R4, R5, R6 and x are as defined above; are key intermediates in the process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans.
Summary of the Invention
The present invention improves the process for preparing compounds of formula I. As a result of the present invention, overall yield, cycle times and catalyst loading are improved for the production of (disubstirutedpropenyl) phenylalkyl substituted dihydrobenzofurans. Specifically, it has now been found that a compound of formula I:
Figure imgf000003_0001
I wherein
R ,3" and R4 are selected from halogen;
R5 and R6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
can be prepared in excellent yield and purity by a process comprising:
a) reacting a compound of formula (A) :
Figure imgf000003_0002
Formula (A) wherein R7 and R8 are independently selected from hydrogen, alkyl, aryl or R and R taken together with an alkyl or aryl, forming a cyclic ester;
with a halogenating agent in the presence of a base to form a compound of formula II:
Figure imgf000004_0001
Formula II wherein
R3 and R4 are as defined above; and
R7 and R8 are as defined above;
eacting a compound of formula (B):
Figure imgf000004_0002
Formula (B)
wherein R5 and R6 are as defined above;
with a compound of formula (CJ:
R9^(CH2)χ \ iv
Formula (C) wherein R9 and R10 are independently selected from halogen, hydroxyl or
-OSO2R 11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula III:
Figure imgf000005_0001
Formula III
wherein R5, R6 R10 and x are as defined above;
c) reacting a compound of formula II with a compound of formula III in the presence of a base to form a compound of formula IV:
Figure imgf000005_0002
Formula IV
wherein R3, R4, R5, R6, R7, R8 and x are as defined above; and
d) reacting a compound of formula IV to form a compound of formula I. Definitions
The modifier "about" is used herein to indicate that certain preferred operating ranges, such as ranges for molar ratios for reactants, material amounts, and temperature, are not fixedly determined. The meaning will often be apparent to one of ordinary skill. For example, a recitation of a temperature range of about 120° C to about 135° C in reference to, for example, an organic chemical reaction would be interpreted to include other like temperatures that can be expected to favor a useful reaction rate for the reaction, such as 105° C or 150° C. Where guidance from the experience of those of ordinary skill is lacking, guidance from the context is lacking, and where a more specific rule is not recited below, the "about" range shall be not more than 10% of the absolute value of an end point or 10% of the range recited, whichever is less.
As used in this specification and unless otherwise indicated the substituent terms "alkyl", "alkoxy", and "haloalkyl", used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms. "Halogen", "halide" or "halo" refers to fluorine, bromine, iodine, or chlorine. The term "ambient temperature" refers to a temperature in the range of about 20° C to about 30° C. Certain solvents, catalysts, and the like are known by their acronyms. These include the acronyms "DMAC" meaning N,N-dimethylacetamide, "DMF" meaning N,N-dimethylformamide, "THF" meaning tetrahydrofuran. The term "glymes" refers to a class of solvents comprised of monoglyme, diglyme, triglyme, tetraglyme, and polyglyme. The term "GC" refers to gas chromatography or gas chromatographic methods of analyses.
Detailed Description of the Invention
The present invention relates to a process for preparing a compound of formula I:
Figure imgf000007_0001
wherein
R3 and R4 are selected from halogen;
R5 and R6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
said process comprising:
a) reacting a compound of formula (A) :
Figure imgf000007_0002
Formula (A)
wherein R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester;
with a halogenating agent in the presence of a base to form a compound of formula II:
Figure imgf000008_0001
Formula II wherein
R3 and R4 are as defined above; and R7 and R8 are as defined above;
b) reacting a compound of formula (B):
Figure imgf000008_0002
Formula (B)
wherein R5 and R6 are as defined above;
with a compound of formula (C):
R9^(CH2)χ \
Formula (C) wherein
R9 and R10 are independently selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula III: -
Figure imgf000009_0001
Formula III
wherein R5, R6 R10 and x are as defined above;
c) reacting a compound of formula II with a compound of formula III in the presence of a base to form a compound of formula IV:
Figure imgf000009_0002
Formula IV
wherein
R3, R4, R5, R6, R7, R8 and x are as defined above; and
d) reacting a compound of formula IV to form a compound of formula I.
The reaction of step b) can be conducted in the presence of a catalyst; at elevated temperature. The catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine,/>-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1% by weight to about 15% by weight. The elevated temperature can be in the range of 30°C to 120°C. The reaction of step c) can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature. The solvent can be tetrahydrofuran, toluene, xylene, acetone, acetonitrile, 1 ,2-dichloroethane, triethylamine,/>-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof. The catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine^-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight. The elevated temperature can be in the range of 30°C to 110°C.
The reaction of step d) can be conducted with a base; as a hydrolysis in the presence of an acid; in the presence of a solvent; in the presence of a catalyst. The solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, triethylamine,/?- dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof. The catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine,/?-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight.
Another embodiment of the present invention is a process for preparing a compound of formula I:
Figure imgf000010_0001
wherein
R and R are selected from halogen; R5 and R6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
said process comprising:
a) reacting a compound of formula II:
Figure imgf000011_0001
Formula II wherein R3 and R4 are as defined above; and
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R and R taken together with alkyl or aryl, forming a cyclic ester;
with a compound of formula (C):
R9^(CH2)x \
K.
Formula (C) wherein R9 and R10 are independently selected from halogen, hydroxyl
Or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula V:
Figure imgf000012_0001
Formula V
wherein
R3, R4, R7, R8, R10 and x are as defined above;
reacting a compound of formula V with a compound of formula (B):
Figure imgf000012_0002
Formula (B)
wherein R > 5 a „„nd j τ R> 6 are as defined above;
in the presence of a base to form a compound of formula IV:
Figure imgf000012_0003
Formula IV
wherein R3, R4, R5, R6, R7, R8 and x are as defined above; and
c) reacting a compound of formula IV to form a compound of formula I.
The reaction of step a) can be conducted in the presence of a catalyst; at elevated temperature. The catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamme,/7-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1 % by weight to about 15% by weight. The elevated temperature can be in the range of 300C tO lOO0C.
The reaction of step b) can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature. The solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, triethylamine,/>-dioxane, N,N- dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof. The catalyst can be polyethylene glycol, dimethylaminopyridine, triethylarnine,/>-toruenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1 % by weight to about 20% by weight. The elevated temperature can be in the range of 30°C to 1100C.
The reaction of step c) can be conducted with a base; as a hydrolysis in the presence of an acid; in the presence of a solvent; in the presence of a catalyst. The solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane,
Figure imgf000013_0001
dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof. The catalyst can be polyethylene glycol, dimethylaminopyridine, triethylamine,/?-toluenesulfonic acid, phosphorous pentoxide, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1 % by weight to about 20% by weight.
Another embodiment of the present invention -is a compound of formula II:
Figure imgf000014_0001
Formula II wherein
R3 and R4 are selected from halogen; and
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester.
Another embodiment of the present invention is a compound of formula III:
Figure imgf000014_0002
Formula III wherein
R > 5 and j τ R> 6 are independently selected from halogen or alkyl; R10 is selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6. Another embodiment of the present invention is a compound of formula IV:
Figure imgf000014_0003
Formula IV
wherein R3 and R4 are selected from halogen; R5 and R6 are independently selected from halogen or alkyl; R and R are independently selected from hydrogen, alkyl, aryl or R and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6.
Yet another embodiment of the present invention is a compound of formula V:
Figure imgf000015_0001
Formula V
wherein
R3 and R4 are selected from halogen;
1 Si V S
R and R are independently selected from hydrogen, alkyl, aryl or R and R taken together with an alkyl or aryl, forming a cyclic ester; R10 is selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
The following examples illustrate processes for preparing compounds of formulae I, II, III, IV and V.
Figure imgf000016_0001
(A) II
R3 and R4 are halogen
Figure imgf000016_0002
wherein R5 and R6 are alkyl wherein R9 and R10 are halogen m
Figure imgf000016_0003
R3 and R4 are halogen wherein R10 is halogen and R5 and R6 are alkyl
Figure imgf000016_0004
Figure imgf000017_0001
a) Halogenating Agent/Base/-20°C to 20°C/2-4 hours b)Base/Catalyst/30°C to 120°C/4-8 hours c) Base/Catalyst/Solveniy30oC to 70°C/22~26 hours d) Base/Solvent/Ambient Temperature/2- 16 hours
In the first step (a) of Example 1, dialkyl 4-hydroxybenzenephosphate (A), for example diethyl 4-hydroxybenzenephosphate, was reacted with a halogenating agent, for example sulfurylchloride, in the presence of a base at reduced temperature to form dialkyl 3,5-dihalo-4-hydroxybenzenephosphate, a compound of formula II, for example diethyl 3,5-dihalo-4-hydroxybenzenephosphate.
In step (b) of Example 1, 2,2-dialkyl-2,3-dihydrobenzo[b]furan-7-ol (B) was reacted with a 1,4-dihaloalkane (C), for example 1,4-dihalobutane, in the presence of a base and a catalyst at elevated temperature to form a l-(2,2-dialkyl(2,3- dihydrobenzo[2,3-b]furan-7-yloxy))-4-haloalkane, a compound of formula III, for example l-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))-4-halobutane.
In step (c) of Example 1, dialkyl 3,5-dihalo-4-hydroxybenzenephosphate, a compound of formula II, for example diethyl 3,5-dihalo-4- hydroxybenzenephosphate, was reacted with a l-(2,2-dialkyl(2,3-dihydrobenzo[2,3- b]furan-7-yloxy))-4-haloalkane, a compound of formula III, for example l-(2,2- dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))-4-halobutane, in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(2,2- dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))alkoxy]-3,5- dihalobenzenephosphate, a compound of formula IV, for example diethyl 4-[4-(2,2- dialkyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5- dihalobenzenephosphate.
In step (d) of Example 1, a dialkyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3- b]furan-7-yloxy))alkpxy]τ3,5-dihalobenzenephosphate, a compound of formula IV, for example diethyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7- yloxy))butoxy]-3,5-dihalobenzenephosphate, was reacted with abase at ambient temperature to form a 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7- yloxy))alkoxy]-3,5-dihaloρhenol (I), for example 4-[4-(2,2-dialkyl(2,3- dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dihaloρhen.ol.
Example 2
Figure imgf000018_0001
π wherein R9 and R10 are independently selected
R3 and R4 are halogen from halogen, hydroxyl or -OSO2R11, where R1 ' is alkyl or aryl '
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000019_0001
a) Base/Catalyst/30°C to 100°C /4-48 hours b)Base/Catalyst/Solvent/30°C to 110"C/4-26 hours c) Base/Solvent/ Ambient Temperature/2- 16 hours _____
In the first step (a) of Example 2, dialkyl 3,5-dihalo-4- hydroxybenzenephosphate, a compound of formula II, for example diethyl 3,5- dihalo-4-hydroxybenzenephosphate, can be reacted with a 1 ,4-disubstitutedalkane (C), for example 1,4-disubstitutedbutane, in the presence of a base and a catalyst at elevated temperature to form dialkyl 4-(4-substitutedalkoxy)-3 ,5- dihalobenzenephosphate, a compound of formula V, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate.
In step (b) of Example 2, a dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula V, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate, can be reacted with 2,2-dialkyl-2,3- dihydrobenzo[b]furan-7-ol (B) in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3- b]furan-7-yloxy))alkoxy]-3,5-dihalobenzenephosphate, a compound of formula IV, for example diethyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7- yloxy))butoxy]-3 ,5-dihalobenzenephosphate.
In step (c) of Example 2, a dialkyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3- b]furan-7-yloxy))alkoxy]-3,5-dihalobenzenephosphate, a compound of formula IV, for example diethyl 4-[4-(2,2-dialkyl(2,3-dihydrobenzo[2,3-b]furan-7- yloxy))butoxy]-3,5-dihalobenzenephosphate, can be reacted as in Example 1 to produce the expected product (T).
While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly this invention includes all modifications encompassed within the spirit and scope as defined by the following claims.

Claims

What is claimed is:
1. A process for preparing a compound of formula I:
Figure imgf000021_0001
wherein
R , 3j and R4 are selected from halogen;
R5 and R6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
said process comprising:
a) reacting a compound of formula (A) :
Figure imgf000021_0002
Formula (A)
wherein R7 and R8 are independently selected from hydrogen, alkyl, aryl or R and R taken together with an alkyl or aryl, forming a cyclic ester;
with a halogenating agent in the presence of a base to form a compound of formula II:
Figure imgf000022_0001
Formula II wherein
R3 and R4 are as defined above; and R7 and R8 are as defined above;
eacting a compound of formula (B):
Figure imgf000022_0002
Formula (B)
wherein R5 and R6 are as defined above;
with a compound of formula (C):
R9^(CH2)χ \ K
Formula (Q wherein
R9 and R10 are independently selected from halogen, hydroxyl or -OSO2R11 wherein R is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula III:
Figure imgf000023_0001
Formula III
wherein R5, R6 R10 and x are as defined above;
c) reacting a compound of formula II with a compound of formula III in the presence of a base to form a compound of formula IV:
Figure imgf000023_0002
Formula IV
wherein R3, R4, R5, R6, R7, R8 and x are as defined above; and
d) reacting a compound of formula IV to form a compound of formula I.
2. The process of claim 1 wherein the reacting of step b) is conducted in the presence of a catalyst.
3. The process of claim 1 wherein the reacting of step b) is conducted at elevated temperature.
4. The process of claim 1 wherein the reacting of step c) is conducted in.the- presence of a solvent.
5. The process of claim 1 wherein the reacting of step c) is conducted in the presence of a catalyst.
6. The process of claim 1 wherein the reacting of step c) is conducted at elevated temperature.
7. The process of claim 1 wherein the reacting of step d) is with a base.
8. The process of claim 1 wherein the reacting of step d) is a hydrolysis in the presence of an acid.
9. The process of claim 1 wherein the reacting of step d) is conducted in the presence of a solvent.
10. The process of claim 1 wherein the reacting of step d) is conducted in the presence of a catalyst.
11. A process for preparing a compound of formula I:
Figure imgf000024_0001
wherein
R3 and R4 are selected from halogen;
R5 and R6 are independently selected from halogen or alkyl; and x is 2, 3, 4, 5 or 6;
said process comprising: reacting a compound of formula II:
Figure imgf000025_0001
Formula II wherein
R3 and R4 are as defined above; and
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester;
with a compound of formula (0:
R9^(CH2)X \
K.
Formula (C) wherein
R9 and R10 are independently selected from halogen, hydroxyl
Figure imgf000025_0002
wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula V:
Figure imgf000025_0003
Formula V wherein
R3, R4, R7, R8, R10 and x are as defined above;
b) reacting a compound of formula V with a compound of formula (B):
Figure imgf000026_0001
Formula (B)
wherein R > 5 and ] r R>6 are as defined above;
in the presence of a base to form a compound of formula IV:
Figure imgf000026_0002
Formula IV
wherein τ>4 τ»5
Figure imgf000026_0003
R4, R , - Rr>63, T R>7', R and x are as defined above; and
c) reacting a compound of formula IV to form a compound of formula I.
12. The process of claim 11 wherein the reacting of step a) is conducted in the presence of a catalyst.
13. The process of claim 11 wherein the reacting of step a) is conducted at elevated temperature.
14. The process of claim 11 wherein the reacting of step b) is conducted in the presence of a solvent.
15. The process of claim 11 wherein the reacting of step b) is conducted in the presence of a catalyst.
16. The process of claim 11 wherein the reacting of step b) is conducted at elevated temperature.
17. The process of claim 11 wherein the reacting of step c) is with a base.
18. The process of claim 11 wherein the reacting of step c) is a hydrolysis in the presence of an acid.
19. The process of claim 11 wherein the reacting of step c) is conducted in the presence of a solvent.
20. The process of claim 11 wherein the reacting of step c) is conducted in the presence of a catalyst.
21. A compound of formula II:
Figure imgf000027_0001
Formula II wherein
R3 and R4 are selected from halogen; and R7 and Rs are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester.
22. A compound of formula III:
Figure imgf000028_0001
Formula III wherein
R5 and R6 are independently selected from halogen or alkyl; R10 is selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
23. A compound of formula IV :
Figure imgf000028_0002
Formula IV wherein
R and R are selected from halogen;
R5 and R6 are independently selected from halogen or alkyl;
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6.
24. A compound of formula V:
Figure imgf000029_0001
Formula V
wherein
R3 and R4 are selected from halogen;
R and R are independently selected from hydrogen, alkyl, aryl or R and R taken together with an alkyl or aryl, forming a cyclic ester; R10 is selected from halogen, hydroxyl Or-OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
PCT/US2006/005345 2005-02-17 2006-02-16 Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans Ceased WO2006088963A1 (en)

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