CA2207572C - Process for the production of 2-(substituted benzoyl)-1,3 cyclohexanediones - Google Patents
Process for the production of 2-(substituted benzoyl)-1,3 cyclohexanediones Download PDFInfo
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- CA2207572C CA2207572C CA002207572A CA2207572A CA2207572C CA 2207572 C CA2207572 C CA 2207572C CA 002207572 A CA002207572 A CA 002207572A CA 2207572 A CA2207572 A CA 2207572A CA 2207572 C CA2207572 C CA 2207572C
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- alkyl
- hydrogen
- haloalkyl
- independently
- alkoxy
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- -1 2-(substituted benzoyl)-1,3 cyclohexanediones Chemical class 0.000 title claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical group 0.000 claims abstract description 19
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 18
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 11
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 10
- 230000008707 rearrangement Effects 0.000 claims abstract description 7
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 239000012429 reaction media Substances 0.000 claims abstract description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 108010011222 cyclo(Arg-Pro) Proteins 0.000 description 17
- 239000002585 base Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 5
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical group COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing a compound of formula (I), where R1, R2, R3, R4, R5 and R6 are independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, NO2, C1-4 alkyl, C1- 4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl; R8, R9 and R10 independently are hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, phenoxy or substituted phenoxy; RbS(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(O)- in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy; SO2NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl; or any two of R8, R9 and R10 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from O N or S and which may be optionally substituted by C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =NOC1-4 alkyl, or halogen; which process comprises the rearrangement of a compound of formula (II), where R1, R2. R3, R4. R5, R6, R7, R8, R9 and R10 are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.
Description
Process for the production of 2-(substituted benzoyl)-1,3 cyclohexanediones The present invention relates to the production of 2-(substituted benzoyl)-1,3-cyclohexanedione compounds.
2-(substituted benzoyl)-1,3-cyclohexanediones are known as herbicides from for example US Patent No. 4,780,127, US Patent No. 4,806,146, US Patent No. 4,946,981, US Patent No. 5,006,158, WO 9408988 and 4J0 9404524. One method of producing these compounds is by re-arrangement of an enol ester. This method is described in US Patent No. 4,780,127 and US
Patent No. 4,695,673. In these rearrangement reactions the presence of hydrogen cyanide or cyanide anion is described as essential (generally in an amount of 1-10 mol percent with respect to the enol ester). In an industrial scale process it is desirable to avoid the use of such materials. Surprisingly it has now been found that in certain solvents it is possible to perform the rearrangement in the absence of hydrogen cyanide or cyanide anion.
According to the present invention there is provided a process for preparing a compound of formula (I) where R1, R2, R3, R4, R5 and R6 are independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, N02, C -4 alkyl, C -4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl;
R~, R9 and R1~ independently are hydrogen, halogen, C alk 1_4 yl~ C1_4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, N02, phenoxy or substituted phenoxy; RbS(0)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(0)-in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
S02NRgRh in which Rg and Rh independently are hydrogen or C alkyl; or any two of R8, R9 and R10 together with the carbon atoms tolwhich they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from 0, N or S and which may be optionally substituted by C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =NOC1-4 alkyl or halogen; which process comprises the rearrangement of a compound of formula (II) where R1, ' R2l R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent ! . characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.
As used herein the term "alkyl", refers to straight or branched chains. The term "haloalkyl" refers to an alkyl group substituted by at least one halogen. Similarly the term "haloalkoxy" refers to an alkoxy group substituted by at least one halogen. As used herein the term , "halogen" refers to fluorine, chlorine, bromine and iodine.
Suitable optional substituents for phenoxy groups R8, Rg and RIO
include halogen such as fluorine and chlorine and CI-4 haloalkyl.
A preferred group of compounds of formula (I) are those where RI, R2, R3, R4, R5 and R6 are independently hydrogen or CI-6 alkyl; R~ is halogen, cyano, N02, C -4 alkyl, C -4 haloalkyl, CI-4 alkoxy or RaS in which Ra is CI-4 alkyl; R~, R9 and RI~ independently are hydrogen, halogen, CI-4 alkyl, CI-4 alkoxy, CI-4 haloalkyi, CI-4 haloalkoxy, CN, N02, phenoxy or substituted phenoxy; RbS(0)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is CI-4 alkyl, CI-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is CI-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or CI-4 alkyl;
RfC(0)- in which Rf is hydrogen, CI-4 alkyl, CI-4 haloalkyl or CI-4 alkoxy;
or S02NRgRh in which Rg and Rh independently are hydrogen or CI-4 alkyl.
Preferably RI, R2, R3, R4, R5 and R6 are independently hydrogen or CI-4 alkyl. More preferably RI, R2, R5 and R6 are hydrogen and R3 and R4 are independently hydrogen or methyl.
R~ is preferably halogen or NO2. A preferred value for R8 is hydrogen.
R9 is preferably hydrogen or CI-4 alkoxy, especially ethoxy. Most preferably R9 is hydrogen.
Preferably RIO is a group RbS(0)nOm where Rb, n and m are as defined above. More preferably m is zero, n is 2 and Rb is CH3 or CZH~. Most preferably RIO is a group CH3S02 attached to the benzoyl group at the 4-position.
Suitable bases include both organic bases such as trialkylamines and inorganic bases such as alkali metal carbonates and phosphates. The trialkylamines are preferably tri(lower alkyl) amines having from 1 to 6, preferably 1 to 4 carbon atoms per alkyl group. A particularly preferable amine is triethylamine. Suitable inorganic bases include sodium carbonate, potassium carbonate and trisodium phosphate. Even a bicarbonate such as potassium bicarbonate will function effectively in this reaction when used ' PCTlGB96/00081 in combination with a Bipolar aprotic solvent such as dimethylformamide.
Preferred bases are sodium carbonate and potassium carbonate.
T
The base is used in an amount of from about 1 to about 4 moles per mole of enol ester, preferably about 2 moles per mole.
As used herein the expressions "substantially free of hydrogen cyanide or cyanide anion" means that neither of these moieties is deliberately added to the reaction medium.
Preferred solvents for the process are acetonitrile, dimethylformamide, tetrahydrofuran and mixtures of these solvents with non-polar solvents such as toluene and xylene.
In general, depending on the nature of the reactants, the base and the solvent the rearrangements may be conducted at temperatures from 0°C, up to about 100°C. Preferably the temperature is at a maximum of about 80°C.
Most preferably the temperature is from about 20°C, to about 70°C. In some cases, for instance when there is a possible problem of excessive by-product formation (for instance, when using an orthonitro benzoyl halide) the temperature should be kept at about 40°C maximum.
The process may be carried out using the enol ester as the starting material, or with generation of the enol ester in situ, for instance by reaction of a compound of formula (III) where R1, R2, R3, R4, R5 and R6 are as defined in relation to formula (I) with a compound of formula (IV) where R~, R8, R9 and R10 are as defined in relation to formula (I) and Z is a halo, preferably chloro.
4Jhen the enol ester is utilised as a starting material it may be prepared by any of a number of known means, including acylation of a compound of formula (III) with, a compound of formula (IV).
ThA nrnr~~~..+,.. ..r _ ...,. r",4u,.,,",r~ "~ compounds of formula (I) according to this invention, may be advantageously carried out starting with compounds of formula (III) and formula (IV) may be carried out with or without isolation of the intermediate enol ester. When carried out in two steps, the compound of formula (III) and the compound of formula (IV) are reacted in the presence of a moderate base such as sodium carbonate or triethylamine.
The enol ester isolated from the resulting product mix by known techniques, for instance washing the resultant solution with acid and base, and with saturated sodium chloride solution, and drying. Such a technique is advantageous when a different solvent is preferred for the second step -_4_ the rearrangement of the enol ester to the compound of formula (I). The dried enol ester may be mixed with an appropriate solvent such. as acetonitrile, or tetrahydrofuran and contacted with the appropriate amounts ' of moderate base and heated to an temperature, to produce the final product.
Alternatively, the enol ester may be retained in the reaction product and the second stage may be carried out (using the same solvent) by adding additional base if necessary to produce the compound of formula (I).
Comparable yields can be obtained either with or without isolation of the enol ester.
The compound of formula (I) is obtained from this reaction in the form of its salt. The desired acylated compound of formula (I) may be obtained with acidification and extraction with an appropriate solvent.
The process of the invention is illustrated by the following example.
Acetonitrile (25g) was charged to a 4 necked 250m1 flamed dried round bottom flask previously purged with N2 and sealed to a Drierite guard tube and oil bubbler. 1,3 cyclohexanedione (5.0g) and sodium carbonate powder (12.0g) were charged to give a red slurry. This mass was heated to 55-57°C
and held for 20 minutes. 2-chloro-4-(methylsulphonyi) benzoyl chloride (ll.Og) was added to acetonitrile (25g) and warmed gently to obtain a complete solution. This solution was added to the mass dropwise over 20 minutes at 55-57°C to give a pale yellow slurry. The mass was held at 55-57°C for 17 hours. The required compound of formula (I) as the sodium salt was produced in 82% yield.
In a second example the acetronitriie in Example 1 was replaced by dimethylformamide and the sodium carbonate was replaced with an equimolar amount of potassium carbonate. Following the same procedures, the reaction was complete 20 minutes after the acid chloride additions was ended and the yield of the required compound of formula (I) as the potassium salt was 54%.
The procedure of Example 1 was repeated using triethylamine in place of sodium carbonate and DMF in place of acetonitrile. The reaction was complete after 4 hours with a yield of 45%.
CHEMICAL FORMULAE
(IN DESCRIPT10N) R~ R~ ~ Rio R; O Rv (I) R= ~ Ra Rv O R' Z
R~R
O
R
io / R
Ra v Rs R O-r ' (i1) e ~ ~ R
O
R~ Rz O
R
(III) ' R
Rs ' R O
Rio R°
Z-(I~
R'
Patent No. 4,695,673. In these rearrangement reactions the presence of hydrogen cyanide or cyanide anion is described as essential (generally in an amount of 1-10 mol percent with respect to the enol ester). In an industrial scale process it is desirable to avoid the use of such materials. Surprisingly it has now been found that in certain solvents it is possible to perform the rearrangement in the absence of hydrogen cyanide or cyanide anion.
According to the present invention there is provided a process for preparing a compound of formula (I) where R1, R2, R3, R4, R5 and R6 are independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, N02, C -4 alkyl, C -4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl;
R~, R9 and R1~ independently are hydrogen, halogen, C alk 1_4 yl~ C1_4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, N02, phenoxy or substituted phenoxy; RbS(0)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(0)-in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
S02NRgRh in which Rg and Rh independently are hydrogen or C alkyl; or any two of R8, R9 and R10 together with the carbon atoms tolwhich they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from 0, N or S and which may be optionally substituted by C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =NOC1-4 alkyl or halogen; which process comprises the rearrangement of a compound of formula (II) where R1, ' R2l R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent ! . characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.
As used herein the term "alkyl", refers to straight or branched chains. The term "haloalkyl" refers to an alkyl group substituted by at least one halogen. Similarly the term "haloalkoxy" refers to an alkoxy group substituted by at least one halogen. As used herein the term , "halogen" refers to fluorine, chlorine, bromine and iodine.
Suitable optional substituents for phenoxy groups R8, Rg and RIO
include halogen such as fluorine and chlorine and CI-4 haloalkyl.
A preferred group of compounds of formula (I) are those where RI, R2, R3, R4, R5 and R6 are independently hydrogen or CI-6 alkyl; R~ is halogen, cyano, N02, C -4 alkyl, C -4 haloalkyl, CI-4 alkoxy or RaS in which Ra is CI-4 alkyl; R~, R9 and RI~ independently are hydrogen, halogen, CI-4 alkyl, CI-4 alkoxy, CI-4 haloalkyi, CI-4 haloalkoxy, CN, N02, phenoxy or substituted phenoxy; RbS(0)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is CI-4 alkyl, CI-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is CI-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or CI-4 alkyl;
RfC(0)- in which Rf is hydrogen, CI-4 alkyl, CI-4 haloalkyl or CI-4 alkoxy;
or S02NRgRh in which Rg and Rh independently are hydrogen or CI-4 alkyl.
Preferably RI, R2, R3, R4, R5 and R6 are independently hydrogen or CI-4 alkyl. More preferably RI, R2, R5 and R6 are hydrogen and R3 and R4 are independently hydrogen or methyl.
R~ is preferably halogen or NO2. A preferred value for R8 is hydrogen.
R9 is preferably hydrogen or CI-4 alkoxy, especially ethoxy. Most preferably R9 is hydrogen.
Preferably RIO is a group RbS(0)nOm where Rb, n and m are as defined above. More preferably m is zero, n is 2 and Rb is CH3 or CZH~. Most preferably RIO is a group CH3S02 attached to the benzoyl group at the 4-position.
Suitable bases include both organic bases such as trialkylamines and inorganic bases such as alkali metal carbonates and phosphates. The trialkylamines are preferably tri(lower alkyl) amines having from 1 to 6, preferably 1 to 4 carbon atoms per alkyl group. A particularly preferable amine is triethylamine. Suitable inorganic bases include sodium carbonate, potassium carbonate and trisodium phosphate. Even a bicarbonate such as potassium bicarbonate will function effectively in this reaction when used ' PCTlGB96/00081 in combination with a Bipolar aprotic solvent such as dimethylformamide.
Preferred bases are sodium carbonate and potassium carbonate.
T
The base is used in an amount of from about 1 to about 4 moles per mole of enol ester, preferably about 2 moles per mole.
As used herein the expressions "substantially free of hydrogen cyanide or cyanide anion" means that neither of these moieties is deliberately added to the reaction medium.
Preferred solvents for the process are acetonitrile, dimethylformamide, tetrahydrofuran and mixtures of these solvents with non-polar solvents such as toluene and xylene.
In general, depending on the nature of the reactants, the base and the solvent the rearrangements may be conducted at temperatures from 0°C, up to about 100°C. Preferably the temperature is at a maximum of about 80°C.
Most preferably the temperature is from about 20°C, to about 70°C. In some cases, for instance when there is a possible problem of excessive by-product formation (for instance, when using an orthonitro benzoyl halide) the temperature should be kept at about 40°C maximum.
The process may be carried out using the enol ester as the starting material, or with generation of the enol ester in situ, for instance by reaction of a compound of formula (III) where R1, R2, R3, R4, R5 and R6 are as defined in relation to formula (I) with a compound of formula (IV) where R~, R8, R9 and R10 are as defined in relation to formula (I) and Z is a halo, preferably chloro.
4Jhen the enol ester is utilised as a starting material it may be prepared by any of a number of known means, including acylation of a compound of formula (III) with, a compound of formula (IV).
ThA nrnr~~~..+,.. ..r _ ...,. r",4u,.,,",r~ "~ compounds of formula (I) according to this invention, may be advantageously carried out starting with compounds of formula (III) and formula (IV) may be carried out with or without isolation of the intermediate enol ester. When carried out in two steps, the compound of formula (III) and the compound of formula (IV) are reacted in the presence of a moderate base such as sodium carbonate or triethylamine.
The enol ester isolated from the resulting product mix by known techniques, for instance washing the resultant solution with acid and base, and with saturated sodium chloride solution, and drying. Such a technique is advantageous when a different solvent is preferred for the second step -_4_ the rearrangement of the enol ester to the compound of formula (I). The dried enol ester may be mixed with an appropriate solvent such. as acetonitrile, or tetrahydrofuran and contacted with the appropriate amounts ' of moderate base and heated to an temperature, to produce the final product.
Alternatively, the enol ester may be retained in the reaction product and the second stage may be carried out (using the same solvent) by adding additional base if necessary to produce the compound of formula (I).
Comparable yields can be obtained either with or without isolation of the enol ester.
The compound of formula (I) is obtained from this reaction in the form of its salt. The desired acylated compound of formula (I) may be obtained with acidification and extraction with an appropriate solvent.
The process of the invention is illustrated by the following example.
Acetonitrile (25g) was charged to a 4 necked 250m1 flamed dried round bottom flask previously purged with N2 and sealed to a Drierite guard tube and oil bubbler. 1,3 cyclohexanedione (5.0g) and sodium carbonate powder (12.0g) were charged to give a red slurry. This mass was heated to 55-57°C
and held for 20 minutes. 2-chloro-4-(methylsulphonyi) benzoyl chloride (ll.Og) was added to acetonitrile (25g) and warmed gently to obtain a complete solution. This solution was added to the mass dropwise over 20 minutes at 55-57°C to give a pale yellow slurry. The mass was held at 55-57°C for 17 hours. The required compound of formula (I) as the sodium salt was produced in 82% yield.
In a second example the acetronitriie in Example 1 was replaced by dimethylformamide and the sodium carbonate was replaced with an equimolar amount of potassium carbonate. Following the same procedures, the reaction was complete 20 minutes after the acid chloride additions was ended and the yield of the required compound of formula (I) as the potassium salt was 54%.
The procedure of Example 1 was repeated using triethylamine in place of sodium carbonate and DMF in place of acetonitrile. The reaction was complete after 4 hours with a yield of 45%.
CHEMICAL FORMULAE
(IN DESCRIPT10N) R~ R~ ~ Rio R; O Rv (I) R= ~ Ra Rv O R' Z
R~R
O
R
io / R
Ra v Rs R O-r ' (i1) e ~ ~ R
O
R~ Rz O
R
(III) ' R
Rs ' R O
Rio R°
Z-(I~
R'
Claims (9)
1. A process for preparing a compound of formula (I):
where R1, R2, R3, R4, R5 and R6 are independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, NO2, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl; R8, R9 and R10 independently are hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, phenoxy or substituted phenoxy; RbS(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(O)-in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
SO2NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl;
or any two of R8, R9 and R10 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from O, N or S and which may be optionally substituted by C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =NOC1-4 alkyl, or halogen; which process comprises the rearrangement of a compound of formula (II):
where R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.
where R1, R2, R3, R4, R5 and R6 are independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, NO2, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl; R8, R9 and R10 independently are hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, phenoxy or substituted phenoxy; RbS(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(O)-in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
SO2NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl;
or any two of R8, R9 and R10 together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from O, N or S and which may be optionally substituted by C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =NOC1-4 alkyl, or halogen; which process comprises the rearrangement of a compound of formula (II):
where R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.
2. A process according to claim 1 where R1, R2, R3, R4. R5 and R6 are independently hydrogen or C1-6 alkyl; R7 is halogen, cyano, N0 2, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or RaS in which Ra is C1-4 alkyl;
R8, R9 and R10 independently are hydrogen, halogen, Cl-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, N0 2, phenoxy or substituted phenoxy; R b S(0)n 0m in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-~ alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(0)- in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy; or S02NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl.
R8, R9 and R10 independently are hydrogen, halogen, Cl-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, N0 2, phenoxy or substituted phenoxy; R b S(0)n 0m in which m is 0 or 1, n is 0, 1 or 2 and Rb is C1-~ alkyl, C1-4 haloalkyl, phenyl or benzyl, NHCORc in which Rc is C1-4 alkyl, NRdRe in which Rd and Re independently are hydrogen or C1-4 alkyl; RfC(0)- in which Rf is hydrogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy; or S02NRgRh in which Rg and Rh independently are hydrogen or C1-4 alkyl.
3. A process -according to claim 1 or claim 2 where R1, R2, R5 and R6 are hydrogen and R3 and R4 are independently hydrogen or methyl.
4. A process according to any one of the preceding claims where R7 is halogen or N02.
5. A process according to any one of the preceding claims where R8 is hydrogen.
6. A process according to any one of the preceding claims where R9 is hydrogen or C1-4 alkoxy.
7. A process according to any one of the preceding claims where R10 is a group CH3S02 attached to the benzoyl group at the 4- position.
8. A process according to any one of the preceding claims where the solvent is acetonitrile, dimethylformamide, tetrahydrofuran or mixtures of these solvents with toluene or xylene.
9. A process according to any one of the preceding claims where the base is triethylamine, sodium carbonate or potassium carbonate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9501433.8 | 1995-01-25 | ||
| GBGB9501433.8A GB9501433D0 (en) | 1995-01-25 | 1995-01-25 | Chemical process |
| PCT/GB1996/000081 WO1996022957A1 (en) | 1995-01-25 | 1996-01-16 | Process for the production of 2-(substituted benzoyl)-1,3 cyclohexanediones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2207572A1 CA2207572A1 (en) | 1996-08-01 |
| CA2207572C true CA2207572C (en) | 2006-12-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002207572A Expired - Fee Related CA2207572C (en) | 1995-01-25 | 1996-01-16 | Process for the production of 2-(substituted benzoyl)-1,3 cyclohexanediones |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2207572C (en) |
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1996
- 1996-01-16 CA CA002207572A patent/CA2207572C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CA2207572A1 (en) | 1996-08-01 |
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