WO2003035636A2 - Process for the preparation of 3 - isochromanone - Google Patents

Process for the preparation of 3 - isochromanone Download PDF

Info

Publication number
WO2003035636A2
WO2003035636A2 PCT/GB2002/004451 GB0204451W WO03035636A2 WO 2003035636 A2 WO2003035636 A2 WO 2003035636A2 GB 0204451 W GB0204451 W GB 0204451W WO 03035636 A2 WO03035636 A2 WO 03035636A2
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
compound
isochromanone
base
followed
Prior art date
Application number
PCT/GB2002/004451
Other languages
French (fr)
Other versions
WO2003035636A3 (en
Inventor
Alan John Whitton
Raymond Vincent Heavon Jones
Alastair Mackie Hay
Original Assignee
Syngenta Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Syngenta Limited filed Critical Syngenta Limited
Priority to AU2002329441A priority Critical patent/AU2002329441A1/en
Publication of WO2003035636A2 publication Critical patent/WO2003035636A2/en
Publication of WO2003035636A3 publication Critical patent/WO2003035636A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/62—Preparation of carboxylic acid halides by reactions not involving the carboxylic acid halide group

Definitions

  • This invention relates to a chemical process and more particularly to a process for preparing 3-isochromanone.
  • 3-Isochromanone is useful in the manufacture of certain agricultural products, especially agricultural fungicides of the strobilurin type.
  • 3-Isochromanone is a well known compound and a number of methods for its preparation are described in the chemical literature. For example, it can be prepared: (i) by the Baeyer-Villiger oxidation of 2-indanone using hydrogen peroxide in sulphuric acid and acetic anhydride (Syn.Commun. 2 [1972], 139; Synthesis [1973], 107) or using 3-chloro- peroxybenzoic acid combined with trifluoroacetic acid (Syn.Commun.
  • the present invention is directed towards an alternative process for manufacturing 3- isochromanone.
  • R and X are halo, with an aqueous base to a pH of 7 to 14 followed by acidification; or (b) adding the compound of the general formula (II), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or (c) treating the compound of the general formula (II), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8.
  • the halo values of R and X include fluoro, chloro, bromo and iodo. Typically they are chloro or bromo and usually chloro. R and X may be the same or different, but will often be the same, for example, both chloro or both bromo.
  • any aqueous base preferably a strong aqueous base
  • an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide.
  • organic bases preferably non-nucleophilic ones, such as sterically hindered tertiary amines like N.N-diisopropylethylamine may be used.
  • TJ the compound in liquid form or a solution of it in a suitable inert solvent is treated with the aqueous base to a pH of 7 or more, preferably to a pH of between 11 and 14.
  • Basification may be carried out at a temperature of from 10°C to 100°C, for example, from 20°C to 90°C, but for practical reasons is preferably carried out at an elevated temperature, suitably from 50°C to 80°C, for example, from 55°C to 70°C and typically from 60°C to 65°C.
  • Any suitable solvent may be used.
  • solvents include aromatic hydrocarbons such as benzene and toluene, halogenated aromatic hydrocarbons such as fluorobenzene or chlorobenzene and ethers such as tert-butyl methyl ether and tert-amyl methyl ether.
  • the pH is adjusted to about 1 using a strong acid, for example, a mineral acid such as hydrochloric acid.
  • a strong acid for example, a mineral acid such as hydrochloric acid.
  • This acidification step may be carried out at a temperature of from 10°C to 100°C, for example, from 20°C to 90°C, but for practical reasons it is preferably carried out at an elevated temperature, suitably from 50°C to 80°C, for example, from 55°C to 70°C and typically from 60°C to 65°C.
  • the resulting 3-isochromanone may be isolated by filtration or, if a solvent is employed, recovered from the organic phase by normal techniques such as distillation, crystallisation or precipitation or used directly in further processing.
  • a catalyst may also be used to assist ring closure.
  • a catalytic amount of an iodide such as an alkali metal iodide, typically potassium iodide
  • compound (II) or a solution of it in a suitable solvent is added to water and the pH maintained between 5 and 8, for example between 5.5 and 7, typically between 6 and 6.5, by the simultaneous addition of a base.
  • Any suitable base may be used, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium or potassium hydroxide.
  • a mild base such as an alkali metal bicarbonate, for example, potassium bicarbonate.
  • organic bases preferably non-nucleophilic ones, such as sterically hindered tertiary amines like N,N-di sopropyl- ethylamine may be used.
  • the base may be added continuously or gradually portion-wise.
  • the resulting 3- isochromanone may be isolated by filtration or, if a solvent is used, recovered from the organic phase by normal techniques such as distillation, crystallisation or precipitation or used directly in further processing.
  • a catalyst such as an iodide to assist ring closure.
  • the compound of the general formula (IT) or a solution of it in a suitable solvent is treated with water or aqueous acid. Whether water or acid is used, the pH of the reaction mixture will fall to about 1 due to hydrolysis of the acid chloride. Treatment with a base to adjust the pH to between 5 and 8 yields 3-isochromanone, which may be isolated by filtration or, if a solvent is used, recovered from the organic phase by normal techniques such as distillation, crystallisation or precipitation or used directly in further processing.
  • Any suitable base may be used for pH adjustment, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium or potassium hydroxide, an alkali metal carbonate, a phosphate or a mild base such as an alkali metal bicarbonate, for example, potassium bicarbonate.
  • organic bases preferably non-nucleophilic ones, such as sterically hindered tertiary amines like N,N-diwopropylethylamine may be used.
  • the compound of general formula (II) may be prepared by reacting a compound of general formula (HI):
  • halogenating agent any halogenating agent capable of replacing a hydrogen atom in the methyl side-chain of compound (III) with the appropriate halogen atom, i.e. the halogen atom which is X.
  • X is chloro or bromo
  • chlorinating or brominating agents that may be used for the side chain chlorination or bromination of toluene or a toluene derivative are suitable.
  • Such agents include sulphuryl chloride, chlorine, bromine and N-bromosuccinimide, and will normally be used in conjunction with a free radical initiator, for example heat or light or a chemical compound of a type used to initiate free radical reaction, such as a peroxide, a peracid or an azo compound.
  • a free radical initiator for example heat or light or a chemical compound of a type used to initiate free radical reaction, such as a peroxide, a peracid or an azo compound.
  • the halogenation is conveniently carried out by adding the halogenating agent to the compound of formula (HI) optionally in an inert solvent.
  • a suitable solvent is, for example, an aromatic hydrocarbon such as benzene or a halogenated aromatic hydrocarbon such as fluorobenzene or chlorobenzene.
  • the halogenation is preferably carried out at an elevated temperature, suitably from 50°C to 90°C, for example, from 60°C to 80°C. Any amount of halogenating agent may be used.
  • the free radical initiator may be a suitable source of heat or light or a chemical compound of a type used to initiate free radical reactions, such as a peroxide, a peracid or an azo compound.
  • a peroxide a peracid or an azo compound.
  • Particularly suitable are 2,2 -azobisz.s ⁇ butyronitrile (ALB ⁇ ) and 2,2 -azobis(2- methylbutyronitrile) (AMB ⁇ ).
  • AMB ⁇ 2,2 -azobisz.s ⁇ butyronitrile
  • AMB ⁇ 2,2 -azobis(2- methylbutyronitrile)
  • the quantity of catalyst used is typically from 0.01 to 0.1 moles per mole of compound (IH), for example from 0.01 to 0.05 moles per mole.
  • the compound of general formula (UJ) may be prepared from o-tolylacetic acid by reaction with any suitable halogenating agent known for the preparation of acyl halides.
  • suitable halogenating agent known for the preparation of acyl halides.
  • Such agents include phosphorus halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, hydrogen halides such as hydrogen bromide, iodide and hydrogen fluoride, and oxalyl halides such as oxalyl chloride and oxalyl bromide, phosgene, thionyl bromide and thionyl chloride.
  • Thionyl chloride is a particularly convenient chlorinating agent for the chlorination of o-tolylacetic acid, which is reported, for example, in J. Am. Chem. Soc. 79, 5721-4 (1957).
  • the reaction may be carried out by adding the solid o-tolylacetic acid to thionyl chloride with or without the presence of a standard catalyst such as N,N-dimethylformamide.
  • a standard catalyst such as N,N-dimethylformamide.
  • Excess thionyl chloride may be removed for recycle or used as the chlorination solvent in a subsequent preparation.
  • an inert solvent may be used for the reaction.
  • the thionyl chloride may be added to the o-tolylacetic acid in the solvent.
  • R and X have the meanings given above, with an aqueous base to a pH of 7 to 14 followed by acidification; or
  • the compound of the general formula (HI) is chlorinated using sulphuryl chloride, with a free radical initiator present, to form a compound of general formula (H) wherein X is chloro and R has the meaning given above.
  • R is chloro.
  • the amount of sulphuryl chloride used is suitably in the range of from 1 to 7 moles per mole of the starting o-tolylacetic acid.
  • the free radical initiator is preferably 2,2 - azobiswobutyronitrile or 2,2 -azobis(2-methylbutyronitrile).
  • R and X have the meanings given above, with an aqueous base to a pH of 7 to 14 followed by acidification; or
  • o-tolylacetic acid is added in portions to thionyl chloride at 20 to 25°C.
  • the mixture of o-tolylacetyl chloride and thionyl chloride so formed is heated to 75 to 80°C and a radical initiator added or applied in the case of UN light.
  • Sulphuryl chloride is added to the mixture over an extended period.
  • the thionyl chloride is removed by vacuum distillation, the residue cooled and taken up in toluene and the mixture heated to and held at 60-65°C.
  • aqueous solution of a base is added slowly to the toluene solution, optionally with an iodide catalyst, and the pH of the aqueous phase adjusted to pH 12 by aliquot addition of further base. After stirring at 60 to 65°C, concentrated hydrochloric acid is added and the pH adjusted to 1. After a further period of stirring at 60 to 65°C, the organic and aqueous layers are separated, and the product recovered from the organic layer.
  • This 'one pot' process lends itself to telescoping, for example, by carrying out the two chlorination steps in one operation by using a mixture of thionyl chloride and sulphuryl chloride.
  • 3-Isochromanone is useful, inter alia, as an intermediate in the manufacture of agricultural products, especially fungicides of the strobilurin type, for example, those described in EP-A-278595.
  • the invention is illustrated by the following Examples in which:
  • the thionyl chloride was removed by vacuum distillation (50° at 20mmHg), the residue cooled to 20-25° and toluene added (20 ml).
  • potassium iodide (0.04g; 0.24mmol.) was added followed by aqueous potassium hydroxide solution (21% w/w;) and the pH of the aqueous phase adjusted to ca. pH 12 by aliquot addition of the base; (total of 42.7g; 0.160mol. added.)
  • the two-phase mixture was stirred at 60-65°C for 1.5 hours and then cooled to 20-25°C.
  • Concentrated hydrochloric acid (12.3g; 0.121mol.) was added and the pH adjusted to ca. pH 1.
  • the mixture was stirred at 60-65°C, for 1 hour. After separation at 60°C analysis of the organic layer showed 3-isochromanone which by quantitative GC this represented 18.9% yield from o-tolylacetic acid.
  • the reaction was endothermic with the evolution of gas.
  • the reaction mixture was held at 75-80°C for 1 hour.
  • the reaction mixture was cooled to 20-25°C and added to 30%w/w aqueous potassium bicarbonate solution (66g; 0.20mol) containing potassium iodide (O.lg; .0006mmol) at 45-50°C over 0.75 hour.
  • the biphasic mixture was stirred at 45 to 50°C for 0.5 hour, then settled and separated.
  • the lower aqueous phase was extracted with chlorobenzene (40 ml).
  • the organic phases were then combined and washed with saturated brine solution (40 ml).
  • the organic phase and the original aqueous phase were re-combined and acidified to pH 1 by the addition of concentrated hydrochloric acid (20g: 0.197mol).
  • the mixture was stirred at 60 to 65°C for 1.5 hour. After separation at 60°C, analysis of the organic layer showed 3-isochromanone which by quantitative GC analysis this represented 14.6% yield from o-tolylacetic acid.
  • a portion of the organic phase (63.8g from a total of 114.6g) was stirred with 20% w/w aqueous potassium hydroxide solution (39. lg; 0.14mol) at 60-65°C for 1.5 hours.
  • the pH of the aqueous phase was 12.
  • the two phases were separated at 60-65°C.
  • toluene (25.0g) was added followed by acidification to pH 1 by the addition of concentrated hydrochloric acid (18.2g; 0.180mol).
  • the biphasic mixture was stirred at 60 to 65°C for 1.5 hours. After separation at 60-65°C, analysis of the organic layer showed 3- isochromanone which by quantitative GC analysis this represented 50.2% yield from o- tolylacetic acid.
  • the thionyl chloride was removed by vacuum distillation (ca. 60°C at lOmbar) the residue cooled to 20-25°C and toluene added (20ml).
  • the toluene solution was added to 30%w/w aqueous potassium bicarbonate solution (33g; 0.10 mol) containing potassium iodide (0.05g; 0. 3 mmol) at 45-50°C over 0.33 hour.
  • the pH of the aqueous phase at the end of the addition was 7.
  • the biphasic mixture was stirred at 60°C for 1 hour, the pH readjusted to 7 to 8 by the addition of solid potassium bicarbonate (7g; 0.07 mol), stirred at 60°C for 0.5 hour then cooled to 30°C.
  • the reaction was endothermic with the evolution of acidic gas.
  • the reaction was held at 75-80°C for 90 minutes before analysis by GC, after treatment with methanol, indicated 53.6% (by area) of the desired product and unreacted o- tolylacetyl chloride (29.8% by area).
  • the thionyl chloride was removed by vacuum distillation (60°C at 30 mbar) the residue cooled to 20-25°C and toluene added (20 ml).
  • Water (5ml) containing potassium iodide (0.05g; 0.3mmol) was added to the reaction mixture, which was then heated to 40- 45°C.
  • Aqueous potassium bicarbonate (20%w/w solution; 49g; O.lOmol) was then added over 20 minutes.
  • the pH of aqueous phase at the end of the addition was 7.
  • the biphasic mixture was stirred at 60°C for 1 hour.
  • the reaction mixture was left stirring overnight at 20- 25°C.
  • the pH of the aqueous phase dropped to 1.
  • the reaction was endothermic with the evolution of acidic gas and the reaction was held at 75-80°C for 40 minutes.
  • the phosphorus oxychloride was removed by vacuum distillation (60°C at 10 mbar) the residue cooled to 20-25° and toluene added (25g.).
  • Solid potassium iodide (0.05g, 0.3mmol) was added to the toluene solution followed by 20%w/w potassium hydroxide solution (70.4g, 0.025mol) allowing the exotherm to take the reaction temperature to 60 to 65°C.
  • the pH of the aqueous phase at the end of the addition was 12.
  • the biphasic mixture was stirred at 60-65°C for 0.5 hour and the pH readjusted to 11-12 by the addition of 20%w/w potassium hydroxide solution (22g; 0.08 mol). The mixture was stirred at 60 to 65 °C for 1 hour then separated. Fresh toluene (25g) was added to the aqueous layer, followed by concentrated hydrochloric acid added over 0.5 hour (17.0g; 0.17mol). The acidic biphasic mixture (pH 1) was warmed to 60-65°C and stirred for 1 hour. After separation at 60-65°C, analysis of the organic layer showed the presence of 3-isochromanone whichby quantitative GC analysis this represented 26.5% yield from o-tolylacetic acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

A process is described for the preparation of 3-isochromanone having the general formula (I): the process comprising reacting ο-tolylacetic acid with a suitable halogenating agent to form a compound of general formula (III): wherein R is halo, reacting the compound of general formula (III) with a suitable halogenating agent to form a compound of the general formula (II): wherein X is halo; and (a) treating a compound of the general formula (II): with an aqueous base to a pH of 7 to 14 followed by acidification; or (b) adding the compound of the general formula (II) to water with the simultaneous addition of base to maintain the pH between 5 and 8; or (c) treating the compound of the general formula (II)with water or aqueous acid followed by pH adjustment to a pH between 5 and 8. Typically both R and X are chloro. 3-Isochromanone is useful, inter alia, as an intermediate in the manufacture of agricultural products, especially fungicides of the strobilurin type.

Description

CHEMICAL PROCESS
This invention relates to a chemical process and more particularly to a process for preparing 3-isochromanone. 3-Isochromanone is useful in the manufacture of certain agricultural products, especially agricultural fungicides of the strobilurin type.
3-Isochromanone is a well known compound and a number of methods for its preparation are described in the chemical literature. For example, it can be prepared: (i) by the Baeyer-Villiger oxidation of 2-indanone using hydrogen peroxide in sulphuric acid and acetic anhydride (Syn.Commun. 2 [1972], 139; Synthesis [1973], 107) or using 3-chloro- peroxybenzoic acid combined with trifluoroacetic acid (Syn.Commun. 9 [1989], 829); (ii) from 2-methoxycarbonylmethylbenzoic acid by (a) treatment with ethylchloroformate in triethylamine and (b) sodium borohydride (Chem.Pharm.Bull.) 16 [1968], 492, 496); (iii) from isochroman-3-ol and chromium trioxide (Tet.lett. [1973], 2359); (iv) by the ring closure of 2-bromo- or 2-chloromethylphenylacetic acid under basic conditions (Zh.Org.Khim. [1973] 9 (10), 2145-9; WO 97/48692), the 2-chloromethylphenylacetic acid being obtained by reacting o-tolylacetic acid with sulphuryl chloride in the presence of a free radical initiator and the 2-bromomethylphenylacetic acid being obtained by reacting o-tolylacetic acid with N-bromosuccinimide; or
(v) via the carbonylation of o-xylene-α,α'-dichloride (WO 97/00850; WO 98/56784; WO 99/10335; WO 00/17186; EP-A-0949256).
The present invention is directed towards an alternative process for manufacturing 3- isochromanone.
According to the present invention there is provided a process for the preparation of 3-isochromanone having the general formula (I):
Figure imgf000002_0001
which comprises:
(a) treating a compound of the general formula (II):
Figure imgf000002_0002
wherein R and X are halo, with an aqueous base to a pH of 7 to 14 followed by acidification; or (b) adding the compound of the general formula (II), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or (c) treating the compound of the general formula (II), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8. The halo values of R and X include fluoro, chloro, bromo and iodo. Typically they are chloro or bromo and usually chloro. R and X may be the same or different, but will often be the same, for example, both chloro or both bromo. In alternative (a), any aqueous base, preferably a strong aqueous base, may be used, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium or potassium hydroxide. Also, organic bases, preferably non-nucleophilic ones, such as sterically hindered tertiary amines like N.N-diisopropylethylamine may be used. Either the compound (TJ) in liquid form or a solution of it in a suitable inert solvent is treated with the aqueous base to a pH of 7 or more, preferably to a pH of between 11 and 14. Basification may be carried out at a temperature of from 10°C to 100°C, for example, from 20°C to 90°C, but for practical reasons is preferably carried out at an elevated temperature, suitably from 50°C to 80°C, for example, from 55°C to 70°C and typically from 60°C to 65°C. Any suitable solvent may be used. Typically solvents include aromatic hydrocarbons such as benzene and toluene, halogenated aromatic hydrocarbons such as fluorobenzene or chlorobenzene and ethers such as tert-butyl methyl ether and tert-amyl methyl ether. After treatment with the base, the pH is adjusted to about 1 using a strong acid, for example, a mineral acid such as hydrochloric acid. This acidification step may be carried out at a temperature of from 10°C to 100°C, for example, from 20°C to 90°C, but for practical reasons it is preferably carried out at an elevated temperature, suitably from 50°C to 80°C, for example, from 55°C to 70°C and typically from 60°C to 65°C. The resulting 3-isochromanone may be isolated by filtration or, if a solvent is employed, recovered from the organic phase by normal techniques such as distillation, crystallisation or precipitation or used directly in further processing. To facilitate processing it may be beneficial to use different solvents for the basification and acidification steps and the invention includes this possibility. A catalyst may also be used to assist ring closure. For example, a catalytic amount of an iodide, such as an alkali metal iodide, typically potassium iodide, has been found helpful. In alternative (b), compound (II) or a solution of it in a suitable solvent is added to water and the pH maintained between 5 and 8, for example between 5.5 and 7, typically between 6 and 6.5, by the simultaneous addition of a base. Any suitable base may be used, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium or potassium hydroxide. However, it is preferred, for ease of pH control, to use a mild base such as an alkali metal bicarbonate, for example, potassium bicarbonate. Also, organic bases, preferably non-nucleophilic ones, such as sterically hindered tertiary amines like N,N-di sopropyl- ethylamine may be used.
The base may be added continuously or gradually portion-wise. The resulting 3- isochromanone may be isolated by filtration or, if a solvent is used, recovered from the organic phase by normal techniques such as distillation, crystallisation or precipitation or used directly in further processing. As with alternative (a), it may be helpful to use a catalyst such as an iodide to assist ring closure. To avoid problems with product crystallisation, it is preferable to treat the compound of general formula (II) with the base at a temperature of from 40°C to 80°C, suitable from 50°C to 70°C, and typically at about 60°C.
In alternative (c), the compound of the general formula (IT) or a solution of it in a suitable solvent is treated with water or aqueous acid. Whether water or acid is used, the pH of the reaction mixture will fall to about 1 due to hydrolysis of the acid chloride. Treatment with a base to adjust the pH to between 5 and 8 yields 3-isochromanone, which may be isolated by filtration or, if a solvent is used, recovered from the organic phase by normal techniques such as distillation, crystallisation or precipitation or used directly in further processing. Any suitable base may be used for pH adjustment, for example, an alkali metal or alkaline earth metal hydroxide, such as sodium or potassium hydroxide, an alkali metal carbonate, a phosphate or a mild base such as an alkali metal bicarbonate, for example, potassium bicarbonate. Also, organic bases, preferably non-nucleophilic ones, such as sterically hindered tertiary amines like N,N-diwopropylethylamine may be used.
The compound of general formula (II) may be prepared by reacting a compound of general formula (HI):
Figure imgf000004_0001
wherein R has the meaning given above, with a suitable halogenating agent. By suitable halogenating agent is meant, any halogenating agent capable of replacing a hydrogen atom in the methyl side-chain of compound (III) with the appropriate halogen atom, i.e. the halogen atom which is X. Where X is chloro or bromo, chlorinating or brominating agents that may be used for the side chain chlorination or bromination of toluene or a toluene derivative are suitable. Such agents include sulphuryl chloride, chlorine, bromine and N-bromosuccinimide, and will normally be used in conjunction with a free radical initiator, for example heat or light or a chemical compound of a type used to initiate free radical reaction, such as a peroxide, a peracid or an azo compound.
The halogenation is conveniently carried out by adding the halogenating agent to the compound of formula (HI) optionally in an inert solvent. A suitable solvent is, for example, an aromatic hydrocarbon such as benzene or a halogenated aromatic hydrocarbon such as fluorobenzene or chlorobenzene. The halogenation is preferably carried out at an elevated temperature, suitably from 50°C to 90°C, for example, from 60°C to 80°C. Any amount of halogenating agent may be used. However, for efficiency, and particularly in the case of sulphuryl chloride, it is desirable to use at least one mole of agent for each mole of the compound (IH) and preferably up to 7 moles of halogenating agent per mole of o-tolylacetic acid.
The free radical initiator may be a suitable source of heat or light or a chemical compound of a type used to initiate free radical reactions, such as a peroxide, a peracid or an azo compound. Particularly suitable are 2,2 -azobisz.sσbutyronitrile (ALBΝ) and 2,2 -azobis(2- methylbutyronitrile) (AMBΝ). The quantity of catalyst used is typically from 0.01 to 0.1 moles per mole of compound (IH), for example from 0.01 to 0.05 moles per mole.
The compound of general formula (UJ) may be prepared from o-tolylacetic acid by reaction with any suitable halogenating agent known for the preparation of acyl halides. Such agents include phosphorus halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, hydrogen halides such as hydrogen bromide, iodide and hydrogen fluoride, and oxalyl halides such as oxalyl chloride and oxalyl bromide, phosgene, thionyl bromide and thionyl chloride. Thionyl chloride is a particularly convenient chlorinating agent for the chlorination of o-tolylacetic acid, which is reported, for example, in J. Am. Chem. Soc. 79, 5721-4 (1957). In this case, the reaction may be carried out by adding the solid o-tolylacetic acid to thionyl chloride with or without the presence of a standard catalyst such as N,N-dimethylformamide. Excess thionyl chloride may be removed for recycle or used as the chlorination solvent in a subsequent preparation. Alternatively, an inert solvent may be used for the reaction. In this case the thionyl chloride may be added to the o-tolylacetic acid in the solvent.
According to one aspect of the present invention there is provided a process for the preparation of 3-isochromanone having the general formula (I):
Figure imgf000006_0001
which comprises reacting a compound of general formula (IH):
Figure imgf000006_0002
wherein R has the meaning given above, with a suitable halogenating agent to form a compound of the general formula (II):
Figure imgf000006_0003
wherein R and X have the meanings given above; and (a) treating a compound of the general formula (II):
Figure imgf000006_0004
wherein R and X have the meanings given above, with an aqueous base to a pH of 7 to 14 followed by acidification; or
(b) adding the compound of the general formula (II), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or
(c) treating the compound of the general formula (H), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8.
In this aspect of the present invention, the compound of the general formula (HI) is chlorinated using sulphuryl chloride, with a free radical initiator present, to form a compound of general formula (H) wherein X is chloro and R has the meaning given above. Conveniently R is chloro. The amount of sulphuryl chloride used is suitably in the range of from 1 to 7 moles per mole of the starting o-tolylacetic acid. The free radical initiator is preferably 2,2 - azobiswobutyronitrile or 2,2 -azobis(2-methylbutyronitrile).
In another aspect of the present invention there is provided a process for the preparation of 3-isochromanone having the general formula (I):
Figure imgf000007_0001
which comprises reacting o-tolylacetic acid with a suitable halogenating agent to form a compound of general formula (HI):
wherein R has the meaning given abo Cve, CC0" - reacting the compound of general formula (HI) with a suitable halogenating agent to form a compound of the general formula (H):
Figure imgf000007_0002
wherein R and X have the meanings given above; and (a) treating a compound of the general formula (H):
Figure imgf000007_0003
wherein R and X have the meanings given above, with an aqueous base to a pH of 7 to 14 followed by acidification; or
(b) adding the compound of the general formula (H), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or
(c) treating the compound of the general formula (H), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8. The o-tolylacetic acid starting material is a known compound that is commercially available.
In a typical 'one pot' process for preparing 3-isochromanone, o-tolylacetic acid is added in portions to thionyl chloride at 20 to 25°C. The mixture of o-tolylacetyl chloride and thionyl chloride so formed is heated to 75 to 80°C and a radical initiator added or applied in the case of UN light. Sulphuryl chloride is added to the mixture over an extended period. The thionyl chloride is removed by vacuum distillation, the residue cooled and taken up in toluene and the mixture heated to and held at 60-65°C. An aqueous solution of a base is added slowly to the toluene solution, optionally with an iodide catalyst, and the pH of the aqueous phase adjusted to pH 12 by aliquot addition of further base. After stirring at 60 to 65°C, concentrated hydrochloric acid is added and the pH adjusted to 1. After a further period of stirring at 60 to 65°C, the organic and aqueous layers are separated, and the product recovered from the organic layer.
This 'one pot' process lends itself to telescoping, for example, by carrying out the two chlorination steps in one operation by using a mixture of thionyl chloride and sulphuryl chloride.
3-Isochromanone is useful, inter alia, as an intermediate in the manufacture of agricultural products, especially fungicides of the strobilurin type, for example, those described in EP-A-278595. The invention is illustrated by the following Examples in which:
GC = gas chromatography
MS = mass spectrometry g = grammes ml millilitres mm = millimetres °C degrees centigrade mol = moles mmol = millimoles
AH3Ν = 2,2'-azobiswobutyronitrile ww//ww == weight by weight
AMBN= 2,2'-azobis(2-methylbutyronitrile)
EXAMPLE 1 o-Tolylacetic acid (9.75g; O.065mol) was added in portions to thionyl chloride (56g; 0.466mol) at 20-25°C. The reaction showed an endotherm with the evolution of acidic gases. Qualitative analysis of an analytical sample by GC after treatment with methanol to convert to the methyl ester indicated a ca 99% (by area) conversion to o-tolylacetyl chloride. The o-tolylacetyl chloride in thionyl chloride mixture was heated to 75-80°C and AIBN was added (0.2g; 1.2mmol.) followed by sulphuryl chloride over 0.75 hours (10.9g at 97% strength = 10.5g at 100%; 0.078mol.) The reaction was endothermic with the evolution of acidic gases. A small sample qualitatively analysed by GC after treatment with methanol, indicated the formation of o-chloromethylphenylacetyl chloride (37% by area).
The thionyl chloride was removed by vacuum distillation (50° at 20mmHg), the residue cooled to 20-25° and toluene added (20 ml).
To the toluene solution, potassium iodide (0.04g; 0.24mmol.) was added followed by aqueous potassium hydroxide solution (21% w/w;) and the pH of the aqueous phase adjusted to ca. pH 12 by aliquot addition of the base; (total of 42.7g; 0.160mol. added.) The two-phase mixture was stirred at 60-65°C for 1.5 hours and then cooled to 20-25°C. Concentrated hydrochloric acid (12.3g; 0.121mol.) was added and the pH adjusted to ca. pH 1. The mixture was stirred at 60-65°C, for 1 hour. After separation at 60°C analysis of the organic layer showed 3-isochromanone which by quantitative GC this represented 18.9% yield from o-tolylacetic acid.
EXAMPLE 2 Thionyl chloride (17.6g; 0.146mol) was added to a solution of o-tolylacetic acid (20.0g; 0.133mol) in chlorobenzene (60g) at 45°C, over ca. 0.75 hours. A second aliquot of thionyl chloride (3.4g; 0.028mol) was added over 5 minutes. The extent of formation of the acid chloride was measured by GC analysis after treatment with methanol to convert to the methyl ester.
The o-tolylacetyl chloride/chlorobenzene mixture was heated to 75-80°C and 2,2'- azobw(2-methylbutyronitrile) (AMBN) was added (0.5g; 0.2.6mmol) followed by sulphuryl chloride (22.3g at 97% strength = 21.6g at 100%; 0.160 mol.) over 0.5 hours. The reaction was endothermic with the evolution of gas. The reaction mixture was held at 75-80°C for 1 hour. A sample analysed by GC after treatment with methanol indicated 12% (by area) of unreacted o-tolylacetyl chloride remaining.
The reaction mixture was cooled to 20-25°C and added to 30%w/w aqueous potassium bicarbonate solution (66g; 0.20mol) containing potassium iodide (O.lg; .0006mmol) at 45-50°C over 0.75 hour. The biphasic mixture was stirred at 45 to 50°C for 0.5 hour, then settled and separated. The lower aqueous phase was extracted with chlorobenzene (40 ml). The organic phases were then combined and washed with saturated brine solution (40 ml). The organic phase and the original aqueous phase were re-combined and acidified to pH 1 by the addition of concentrated hydrochloric acid (20g: 0.197mol). The mixture was stirred at 60 to 65°C for 1.5 hour. After separation at 60°C, analysis of the organic layer showed 3-isochromanone which by quantitative GC analysis this represented 14.6% yield from o-tolylacetic acid.
A portion of the organic phase (63.8g from a total of 114.6g) was stirred with 20% w/w aqueous potassium hydroxide solution (39. lg; 0.14mol) at 60-65°C for 1.5 hours. The pH of the aqueous phase was 12. The two phases were separated at 60-65°C. To the lower aqueous phase, toluene (25.0g) was added followed by acidification to pH 1 by the addition of concentrated hydrochloric acid (18.2g; 0.180mol). The biphasic mixture was stirred at 60 to 65°C for 1.5 hours. After separation at 60-65°C, analysis of the organic layer showed 3- isochromanone which by quantitative GC analysis this represented 50.2% yield from o- tolylacetic acid. EXAMPLE 3 o-Tolylacetic acid (lOg; 0.067mol) was added in portions to thionyl chloride (60g; 0.504 mol) at 20-25°C. The reaction showed an endotherm with the evolution of gas.
The o-tolylacetyl chloride in thionyl chloride mixture was heated to 75-80°C and AMBN was added (0.26g; 1.3mmol) followed by sulphuryl chloride over 1 hour (18.6g at 97% strength = 18g at 100%; 0.134mol). The reaction was endothermic with the evolution of gas. A sample, analysed by GC after treatment with methanol, indicated the presence of o- chloromethylphenylacetyl chloride (39% by area) and unreacted o-tolylacetyl chloride (43% by area).
The additions of AMBN and sulphuryl chloride were repeated as above two more times, the sulphuryl chloride being added over 1 hour and 0.5 hour with a hold period at 75- 80°C for 0.5 hour after each addition. A fourth and final aliquot of AMBN was added (0.26g; 1.3mmol) followed by sulphuryl chloride over 0.5 hour (9.3g at 97% strength = 9g at 100%; 0.067mol). A sample, analysed by GC after treatment with methanol, indicated the presence of o-chloromethylphenylacetyl chloride (31% by area) and unreacted o-tolylacetyl chloride (2% by area).
The thionyl chloride was removed by vacuum distillation (ca. 60°C at lOmbar) the residue cooled to 20-25°C and toluene added (20ml). The toluene solution was added to 30%w/w aqueous potassium bicarbonate solution (33g; 0.10 mol) containing potassium iodide (0.05g; 0. 3 mmol) at 45-50°C over 0.33 hour. The pH of the aqueous phase at the end of the addition was 7. The biphasic mixture was stirred at 60°C for 1 hour, the pH readjusted to 7 to 8 by the addition of solid potassium bicarbonate (7g; 0.07 mol), stirred at 60°C for 0.5 hour then cooled to 30°C.
Concentrated hydrochloric acid was added over 0.25 hour (10. lg; O.lmol). The acidic biphasic mixture (pH 1) was warmed to 60°C and stirred for 1.5 hours. After separation at 60°C, analysis of the organic layer showed 3-isochromanone which by quantitative GC analysis this represented 22.8% yield from o-tolylacetic acid. EXAMPLE 4 o-Tolylacetic acid (lOg; 0.067mol) was added in portions to thionyl chloride (60g; 0.50mol) at 20-25°C. The reaction was endothermic with the generation of acidic gas. The o-tolylacetyl chloride in thionyl chloride mixture was heated to 75-80°C and AMBN was added (0.26g; 1.3mmol) followed by sulphuryl chloride (23.2g at 97% strength = 22.5g at 100%; 0.167mol) over 1.75 hours. The reaction was endothermic with the evolution of acidic gas. The reaction was held at 75-80°C for 90 minutes before analysis by GC, after treatment with methanol, indicated 53.6% (by area) of the desired product and unreacted o- tolylacetyl chloride (29.8% by area).
The thionyl chloride was removed by vacuum distillation (60°C at 30 mbar) the residue cooled to 20-25°C and toluene added (20 ml). Water (5ml) containing potassium iodide (0.05g; 0.3mmol) was added to the reaction mixture, which was then heated to 40- 45°C. Aqueous potassium bicarbonate (20%w/w solution; 49g; O.lOmol) was then added over 20 minutes. The pH of aqueous phase at the end of the addition was 7. The biphasic mixture was stirred at 60°C for 1 hour. The reaction mixture was left stirring overnight at 20- 25°C. The pH of the aqueous phase dropped to 1. The acidic biphasic mixture (pH 1) warmed to 60°C and stirred for 1.5 hours. After separation at 60°C analysis of the organic layer showed 3-isochromanone which by quantitative GC this represented 27.6% yield from o-tolylacetic acid. EXAMPLE 5 o-Tolylacetic acid (lOg; 0.067mol) was added in portions to phosphorus oxychloride (60g; 0.387mol) at 20-25°C. The o-tolylacetyl chloride/phosphorus oxychloride mixture was heated to 75-80°C and AMBN was added (0.26g; 0.0013mol) followed by sulphuryl chloride (18.6g at 97% strength = 18g at 100%; 0.134mol) over 0.25 hour. The reaction was endothermic with the evolution of acidic gas and the reaction was held at 75-80°C for 40 minutes. The phosphorus oxychloride was removed by vacuum distillation (60°C at 10 mbar) the residue cooled to 20-25° and toluene added (25g.). Solid potassium iodide (0.05g, 0.3mmol) was added to the toluene solution followed by 20%w/w potassium hydroxide solution (70.4g, 0.025mol) allowing the exotherm to take the reaction temperature to 60 to 65°C. The pH of the aqueous phase at the end of the addition was 12. The biphasic mixture was stirred at 60-65°C for 0.5 hour and the pH readjusted to 11-12 by the addition of 20%w/w potassium hydroxide solution (22g; 0.08 mol). The mixture was stirred at 60 to 65 °C for 1 hour then separated. Fresh toluene (25g) was added to the aqueous layer, followed by concentrated hydrochloric acid added over 0.5 hour (17.0g; 0.17mol). The acidic biphasic mixture (pH 1) was warmed to 60-65°C and stirred for 1 hour. After separation at 60-65°C, analysis of the organic layer showed the presence of 3-isochromanone whichby quantitative GC analysis this represented 26.5% yield from o-tolylacetic acid.

Claims

CLA S
1. A process for the preparation of 3-isochromanone having the general formula (I):
Figure imgf000013_0001
which comprises:
(a) treating a compound of the general formula (H):
wherein R and X are halo O, with aOn aquerous base to - a pH of 7 to 14 followed by acidification; or (b) adding the compound of the general formula (H), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or (c) treating the compound of the general formula (H), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8.
2. A process for the preparation of the compound of general formula (H) as defined in claim 1 which comprises reacting a compound of general formula (HI):
wherein R has the meanin Cg givenC above0,0 w"ith a su -itable halogenating agent.
3. A process for the preparation of 3-isochromanone having the general formula (I):
Figure imgf000013_0002
which comprises reacting a compound of general formula (HI):
Figure imgf000014_0001
wherein R has the meaning given in claim 1, with a suitable halogenating agent, to form a compound of the general formula (H):
Figure imgf000014_0002
wherein R and X have the meanings given in claim 1 ; and (a) treating a compound of the general formula (II):
Figure imgf000014_0003
wherein R and X have the meanings given in claim 1, with an aqueous base to a pH of 7 to 14 followed by acidification; or
(b) adding the compound of the general formula (H), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or
(c) treating the compound of the general formula (H), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8.
A process according to claim 3, wherein the compound of formula (HI) is chlorinated using sulphuryl chloride, with a free radical initiator present, to form a compound of general formula (H) wherein X is chloro.
A process for the preparation of 3-isochromanone having the general formula (I):
Figure imgf000014_0004
which comprises reacting o-tolylacetic acid with a suitable halogenating agent to form a compound of general formula (HI):
Figure imgf000015_0001
wherein R has the meaning given in claim 1, reacting the compound of general formula (III) with a suitable halogenating agent to form a compound of the general formula (II):
Figure imgf000015_0002
wherein R and X have the meanings given in claim 1; and (a) treating a compound of the general formula (ϋ):
Figure imgf000015_0003
wherein R and X have the meanings given in claim 1, with an aqueous base to a pH of 7 to 14 followed by acidification; or
(b) adding the compound of the general formula (H), as defined in (a) above, to water with the simultaneous addition of base to maintain the pH between 5 and 8; or
(c) treating the compound of the general formula (H), as defined in (a) above, with water or aqueous acid followed by pH adjustment to a pH between 5 and 8.
A process according to any one of the previous claims wherein R is chloro.
A process according to any one of claims 1 to 3 and 5 wherein X is chloro.
A process according to any one of claims 1 to 5 wherein R and X are both chloro.
PCT/GB2002/004451 2001-10-24 2002-10-02 Process for the preparation of 3 - isochromanone WO2003035636A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002329441A AU2002329441A1 (en) 2001-10-24 2002-10-02 Process for the preparation of 3 - isochromanone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0125473.9A GB0125473D0 (en) 2001-10-24 2001-10-24 Chemical process
GB0125473.9 2001-10-24

Publications (2)

Publication Number Publication Date
WO2003035636A2 true WO2003035636A2 (en) 2003-05-01
WO2003035636A3 WO2003035636A3 (en) 2003-10-30

Family

ID=9924396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/004451 WO2003035636A2 (en) 2001-10-24 2002-10-02 Process for the preparation of 3 - isochromanone

Country Status (4)

Country Link
AR (1) AR036948A1 (en)
AU (1) AU2002329441A1 (en)
GB (1) GB0125473D0 (en)
WO (1) WO2003035636A2 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8592165B2 (en) 2006-11-10 2013-11-26 Glycotope Gmbh Carbohydrate specific cellular immunity inducing microorganisms and fractions thereof
US9051356B2 (en) 2006-09-10 2015-06-09 Glycotope Gmbh Use of human cells of myeloid leukaemia origin for expression of antibodies
CN105061375A (en) * 2015-08-31 2015-11-18 江苏七洲绿色化工股份有限公司 Method for preparing 3-isochromanone
US9700610B2 (en) 2011-08-22 2017-07-11 Glycotope Gmbh Microorganisms carrying a tumor antigen
CN115772147A (en) * 2022-12-23 2023-03-10 长沙钰腾新材料有限公司 Method for synthesizing 3-isochromone or derivative thereof
US11872289B2 (en) 2018-05-18 2024-01-16 Daiichi Sankyo Co., Ltd. Anti-MUC1 antibody-drug conjugate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048692A1 (en) * 1996-06-17 1997-12-24 Zeneca Limited Process for preparing 3-isochromanone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048692A1 (en) * 1996-06-17 1997-12-24 Zeneca Limited Process for preparing 3-isochromanone

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BLANKLEY C J ET AL: "Synthesis and Structure-Activity Relationships of Potent New Angiotensin Converting Enzyme Inhibitors Containing saturated Bicyclic Amino Acids" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 30, 1987, pages 992-998, XP001061648 ISSN: 0022-2623 *
BLEASDALE ET AL.: "2-Benzopyran-3-one" J. CHEM. SOC., CHEM. COMMUN.,1983, pages 1095-1096, XP009003668 *
HOEFT, EUGEN ET AL: "Preparation of N-substituted 1-oxo- and 3-oxo-1,2,3,4- tetrahydroisoquinolines" J. PRAKT. CHEM. (1966), 32(1-2), 12-19, XP009003667 *
LEMAIRE, C. ET AL: "Synthesis of chalcogeno lactones. II. 3,4-Dihydro-1H-2-benzothiin-3-one 3,4-dihydro-1H-2-benzoselenin-3-one and 3,4-dihydro-1H-2-benzotellurin-3- one" JOURNAL OF HETEROCYCLIC CHEMISTRY (1983), 20(3), 811-12, XP009003652 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9051356B2 (en) 2006-09-10 2015-06-09 Glycotope Gmbh Use of human cells of myeloid leukaemia origin for expression of antibodies
US10280230B2 (en) 2006-09-10 2019-05-07 Glycotope Gmbh Use of human cells of myeloid leukemia origin for expression of antibodies
US8592165B2 (en) 2006-11-10 2013-11-26 Glycotope Gmbh Carbohydrate specific cellular immunity inducing microorganisms and fractions thereof
US9494587B2 (en) 2006-11-10 2016-11-15 Glycotope Gmbh Microorganisms or fractions thereof capable of activating cellular immunity against carbohydrates
US9700610B2 (en) 2011-08-22 2017-07-11 Glycotope Gmbh Microorganisms carrying a tumor antigen
CN105061375A (en) * 2015-08-31 2015-11-18 江苏七洲绿色化工股份有限公司 Method for preparing 3-isochromanone
US11872289B2 (en) 2018-05-18 2024-01-16 Daiichi Sankyo Co., Ltd. Anti-MUC1 antibody-drug conjugate
CN115772147A (en) * 2022-12-23 2023-03-10 长沙钰腾新材料有限公司 Method for synthesizing 3-isochromone or derivative thereof
CN115772147B (en) * 2022-12-23 2024-03-22 长沙钰腾新材料有限公司 Synthesis method of 3-isochromone or derivative thereof

Also Published As

Publication number Publication date
GB0125473D0 (en) 2001-12-12
AU2002329441A1 (en) 2003-05-06
WO2003035636A3 (en) 2003-10-30
AR036948A1 (en) 2004-10-13

Similar Documents

Publication Publication Date Title
WO2003035636A2 (en) Process for the preparation of 3 - isochromanone
JPS6212212B2 (en)
US6008381A (en) Process for preparing 3-isochromanone
JPH08127562A (en) Production of 4'-bromomethyl-2-cyanobiphenyl
US6229040B1 (en) 3-cyano-2,4,5-trifluoro-benzoyl fluoride and intermediate products for the production thereof
EP1853548A1 (en) Process for the preparation of benzoic acid derivatives via a new intermediate of synthesis
EP2264015A1 (en) Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
EA008040B1 (en) Method for the production of benzophenones
US5068458A (en) Chemical process for halogenating 2-methyl-6-methoxynaphthalene
US6580002B2 (en) Process for the preparation of trifluoromethyl-substituted biphenylcarboxylic acids and novel trichloromethyl-and trifluoromethyl-substituted biphenylcarbonitriles
JPS62161740A (en) Production of phenylpropionic acid derivative
US4560794A (en) Process for preparing methoxytrifluoromethylnaphthoic acid from methylnaphthoic acid
JP3874925B2 (en) Method for producing chloromethylphenylacetic acid
JP5047427B2 (en) Process for the production of substituted benzoyl chlorides
JP3531943B2 (en) Improved process for preparing 4-methylsulfonylbenzoic acid derivatives and intermediates and intermediates
KR20010078281A (en) Process for the preparation of 3,5-bis-(trifluoromethyl)-benzoyl chlorides and novel 3,5-bis-(trihalogenomethyl)- and 3,5-dimethylbenzoyl halides
JPH10114736A (en) Production of 2-methyl-1-(4-(alkylthio)phenyl)-2-morpholino-1-propanone
JPH03127753A (en) Production of 4-chloro-4'-hydroxybenzophenones
US20030236431A1 (en) 2-bromomethyl-6-methyl-benzoic acid and a process for the preparation thereof
JP2595109B2 (en) Process for producing novel fluorobenzotrichloride compounds and fluorobenzoic acids
CA2376982C (en) Process for the preparation of tetrafluorohalogenbenzenes
JPH08198805A (en) Production of alkylbenzoylchloride
JPH02240042A (en) Preparation of benzophenone
JPH07165638A (en) New fluorobenzotrichloride compound
JPH0543553A (en) Production of 3, 5-dichloropyrazole-4-carboxylic acid esters

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP