WO2010116121A1

WO2010116121A1 - Processes for making isoxazoline derivatives

Info

Publication number: WO2010116121A1
Application number: PCT/GB2010/000607
Authority: WO
Inventors: Jonathan Wesley Paul Dallimore; Myriem El Qacemi; John Williams; Anthony Marian Kozakiewicz
Original assignee: Syngenta Ltd
Current assignee: Syngenta Ltd
Priority date: 2009-04-09
Filing date: 2010-03-29
Publication date: 2010-10-14
Anticipated expiration: 2011-10-09
Also published as: AR076223A1; WO2010116121A8; GB0906289D0; TW201036953A

Abstract

The present invention relates to a process for making isoxazoline herbicides (or isoxazoline herbicide precursors), to the intermediate used in this process, and to two processes for making the intermediate.

Description

PROCESSES FOR MAKING ISOXAZOLINE DERIVATIVES

The present invention relates to a process for making isoxazoline herbicides (or isoxazoline herbicide precursors), to an intermediate to be used in this process and to several processes for making the intermediate.

Certain isoxazoline herbicides (and isoxazoline herbicide precursors) have been disclosed, for example, in EP 1,203,768 and EP 1,364,946. For example, 4,5-dihydro- 5,5-dimethyl-3-[(phenylmethyl)thio]-isoxazole (CAS RN 326828-96-0) was disclosed as a herbicide and as an intermediate in the synthesis of 4,5-dihydro-5,5-dimethyl-3- [(phenylmethyl)sulfonyl]-isoxazole (CAS RN 326829-12-3) in EP 1,203,768. Therefore, the compounds of formula (I) are referred to as isoxazoline herbicides or as isoxazoline herbicide precursors. Routes to isoxazoline herbicides (or isoxazoline herbicide precursors) have been disclosed, for example, in EP 1,541,561. However, there is a need for further processes to isoxazoline herbicides (or isoxazoline herbicide precursors).

The present invention therefore provides a process for making a compound of formula (I)

where

R¹ and R² are independently hydrogen, Q-Cgalkyl or C₃-C₁₀cycloalkyl or R¹ and R² join to form together with the carbon atom to which they are attached a C₃-Ciocycloalkyl ring;

R³ and R⁴ are independently hydrogen or C)-C₈alkyl or R³ and R⁴ join to form together with the carbon atom to which they are attached a C₃-Ci₀cycloalkyl ring;

R⁵ and R⁶ are independently hydrogen or Ci-C₈alkyl;

Y is aryl or aryl substituted by one to five R⁷, or heteroaryl or heteroaryl substituted by one.to five R⁷; and- each R⁷ is independently cyano, nitro, halogen, Ci-Cgalkyl, Cj-C₈haloalkyl, Ci-C₈alkoxy- or Ci-Cghaloalkoxy-; which comprises reacting a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined for a compound of formula (I); with a Grignard reagent of formula (III) thereof

R⁶V R⁵

X (III)

M'

where R⁵, R⁶ and Y are as defined for a compound of formula (I) and M^Λ is MgBr or

MgCl; in the presence of an anhydrous solvent and under a protective atmosphere.

The compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

Alkyl groups (either alone or as part of a larger group, such as alkoxy-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop- 2-yl, butyl, but-2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. Unless indicated to the contrary, the alkyl groups are preferably Ci-C₆, more preferably Ci-C₄, most preferably Ci-C₃ alkyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.

Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C₃-C₈, more preferably C₃-C₆ cycloalkyl groups.

Aryl groups are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Unless indicated to the contrary, aryl groups are preferably phenyl and naphthyl, with phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Heteroaryl groups are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Unless indicated to the contrary, monocyclic heteroaryl groups are preferred, with pyrazolyl and triazolyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Preferred values of R¹, R², R³, R⁴, R⁵, R⁶, Y and R⁷ for the compounds of formula (I) and (II) are, in any combination, as set out below.

Preferably R¹ is Ci-Cgalkyl or C₃-Ci₀cycloalkyl, more preferably Cj-Cgalkyl, even more preferably methyl or ethyl, most preferably methyl.

Preferably R² is Ci-C₈alkyl or C₃-C]₀cycloalkyl, more preferably Cj-Cgalkyl, even more preferably methyl or ethyl, most preferably methyl.

Preferably R³ is hydrogen or CpCsalkyl, more preferably hydrogen.

Preferably R⁴ is hydrogen or CpCsalkyl, more preferably hydrogen.

Preferably R⁵ is hydrogen.

Preferably R⁶ is hydrogen.

Preferably Y is phenyl or phenyl substituted by one to five R⁷, or heteroaryl or heteroaryl substituted by one to five R⁷ (where heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl), more preferably phenyl or phenyl substituted by one to five R⁷, or heteroaryl or heteroaryl substituted by one to five R⁷ (where heteroaryl is pyrazolyl or triazolyl), even more preferably phenyl or phenyl substituted by one to five R⁷, most preferably phenyl. - A -

Preferably each R⁷ is independently halogen, Cj-Csalkyl, Cj-Cghaloalkyl, C]- C₈alkoxy- or Ci-Cghaloalkoxy-, more preferably chloro, fluoro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy- or trifluoromethoxy-.

Scheme A shows the process for making a compound of formula (I) from a compound of formula (II) (process 1).

Scheme A

(H) (I)

Process 1 :

Compounds of formula (I) can be made by reacting a thiocyanato-isoxazoline of formula (II) where R¹, R², R³ and R⁴ are as defined for a compound of formula (I) with a Grignard reagent of formula (III) where R⁵, R⁶ and Y are as defined for a compound of formula (I) and M^A is MgBr or MgCl, in the presence of an anhydrous solvent and under a protective atmosphere.

Grignard reagents of formula (III) are commercially available or can be made by methods known to the person skilled in the art. It is preferred that M^Λ is MgBr.

The solvent can be any anhydrous solvent which does not react with the Grignard reagent, for example an anhydrous ether, such as anhydrous tetrahydrofuran.

The atmosphere can be any gas which does not react with the Grignard reagent, for example a nitrogen atmosphere or an argon atmosphere. It is preferred that atmosphere is a nitrogen atmosphere.

The reaction is preferably carried out at a temperature of from^" -20⁰C to +70⁰C, more preferably of from -5°C to ambient temperature, most preferably at 0⁰C.

Similar reactions of thiocyanato-substituted heterocycles with benzylic Grignard reagents have been described in the literature, for example, in Chemical & Pharmaceutical Bulletin, 37, 618 (1989). Compounds of formula (II) are novel and as such form a further aspect of the invention. Therefore, the invention provides a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined for a compound of formula (I).

The compounds of formula (II) may exist in different geometric or optical isomers or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

Examples of compounds of formula (II) which illustrate the present invention are given in Table 1.

Table 1 :

Table 1 provides 2 compounds of formula (II) where R¹, R², R³ and R⁴ have the values specified.

The present invention also provides processes for making a compound of formula

(II). Firstly, the present invention provides a process for making a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined for a compound of formula (I); which comprises reacting an isoxazoline derivative of formula (IV) or a salt thereof

where R , R , R and R⁴ are as defined for a compound of formula (I) and LG is a leaving group; with a thiocyanate salt in the presence of an acid and in the presence of a solvent.

Secondly, the present invention provides a process for making a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined for a compound of formula (I); which comprises reacting an isothiouronium-isoxazoline of formula (V) or a salt thereof

where R¹, R², R³ and R⁴ are as defined for a compound of formula (I); with a cyanogen salt in the presence of a base and in the presence a solvent. Scheme B shows the processes for making a compound of formula (II) (process 2, process 3).

Scheme B

(V)

Process 2:

Compounds of formula (II) as defined for process 1 can be made by reacting an isoxazoline derivative of formula (IV) or a salt thereof where R¹, R², R³ and R⁴ are as defined for a compound of formula (I) and LG is a leaving group, with a thiocyanate salt in the presence of an acid and in the presence of a solvent.

The leaving group can be any chemical group which can be readily displaced by a nucleophile. The leaving group can be, for example, a halogen atom, such as a bromo group or a chloro group, or a nitro group, or a sulfonyl, such as methylsulfonyl or phenylsulfonyl. It is preferred that the leaving group is chloro or nitro.

The preparation of certain bromo-isoxazolines is described, for example, in WO 2006/038657.

The preparation of certain chloro-isoxazolines is described, for example, in EP 1,203,768.

The preparation of certain nitro-isoxazolines is described, for example, in WO 2001/046163.

The preparation of certain methylsulfonyl-isoxazolines is described, for example, in EP 1,203,768. The preparation of certain phenylsulfonyl-isoxazolines is described, for example, in WO 2007/071900.

The thiocyanate salt is of the formula M^BSCN where M^B is a metal cation, for example an alkali metal cation, such as a sodium cation or a potassium cation. It is preferred that M^B is a sodium cation. Thiocyanate salts of the formula M^BSCN are commercially available.

The acid can be any acid which facilitates the reaction, for example an organic acid, such as formic acid, acetic acid or trifluoroacetic acid, or an inorganic acid, such as aqueous hydrochloric acid. It is preferred that the acid is formic acid.

The solvent can be any solvent which does not react with the isoxazoline derivative, for example dichloromethane, ethanol, or an excess of the organic acid which is used to facilitate the reaction. It is preferred that the solvent is an excess of formic acid.

The reaction is preferably carried out at a temperature of from 0⁰C to 200°C, more preferably of from 0°C to 100°C, most preferably at ambient temperature.

Similar reactions have been described in the literature with various outcomes. A thiocyanato-substituted heterocycle was obtained, for example, in Bioorganic & Medicinal Chemistry Letters, 17, 225, (2007), a isothiocyanato-substiruted heterocycle was obtained, for example, in Monatshefte fuer Chemie, 135, 45, (2004), and a mixture of thiocyanato-substituted heterocycle and of isothiocyanato-substituted heterocycle was obtained, for example, in Yakugaku Zasshi, 108, 437, (1988).

Process 3 :

Compounds of formula (II) as defined for process 1 can be made by reacting an isothiouronium-isoxazoline of formula (V) or a salt thereof where R¹, R², R³ and R⁴ are as defined for a compound of formula (I), with a cyanogen salt in the presence of a base and in the presence a solvent.

The preparation of isothiouronium-isoxazolines is described, for example, in EP 1,829,868. The isothiouronium-isoxazoline is usually isolated as a salt, for example the hydrochloric acid salt.

The cyanogen salt is of formula X^ΛCN where X^A is a halide, such as chloride or a bromide. It is preferred that X^A is bromide. Cyanogen salts of formula X^ACN are commercially available. The base can be any base which facilitates the reaction, for example a carbonate, such as potassium carbonate, sodium carbonate or potassium hydrogen carbonate, or a hydroxide, such as potassium hydroxide, or an alkoxide, such as sodium alkoxide. It is preferred that the base is potassium carbonate.

The solvent can be any solvent which does not react with the isothiouronium- isoxazoline, polar solvents such as ethanol, acetonitrile, dimethylformamide, water or a mixture of thereof, being particularly preferred. It is preferred that the solvent is acetonitrile or a mixture of acetonitrile and water.

The reaction is preferably carried out at a temperature of from 0°C to 200°C, more preferably of from 0°C to 100⁰C, most preferably at ambient temperature.

Similar reactions have been described in, for example, Chemical and Pharmaceutical Bulletin, 12, 182, (1964), Journal fuer Praktische Chemie (Leipzig), 326, 159 (1984), and Tetrahedron Letters, 32, 2505 (1991).

The following Examples further illustrate, but do not limit, the invention.

Preparation Examples

The following abbreviations were used throughout this section: s = singlet; bs = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, sept = septet; m = multiplet; Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl.

1. Process 1

Example 1.1 : Preparation of 3-benzylsulfanyl-5,5-dimethyl-4,5-dihydro-isoxazole

To a stirred solution of 5,5-dimethyl-3-thiocyanato-4,5-dihydro-isoxazole (Example 2.1 - Example 2.5 and Example 3.1 - Example 3.2) (250 mg, 1.6 mmol) in anhydrous tetrahydrofuran ("THF") (3 ml) was added benzyl magnesium chloride (2M in tetrahydrofuran) (0.9 ml, 1.8 mmol) dropwise over a period of 5 minutes at 0°C under a nitrogen atmosphere. An additional amount of anhydrous tetrahydrofuran (6 ml) was added at 0°C. After 5 minutes the reaction mixture was poured into water and the mixture extracted with diethyl ether. The organic extract was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 1 :4 to 1 :0) to give the title compound as a yellow solid (304 mg, 83% yield). IH-NMR (CDCl₃, 400 MHz): 1.41 (s, 6H), 2.78 (s, 2H), 4.27 (s, 2H), 7.32 (m, 5H) ppm.

2. Process 2

Example 2.1 : Preparation of 5,5-dimethyl-3-thiocvanato-4.5-dihydro-isoxazole

To a solution of 3-chloro-5,5-dimethyl-4,5-dihydro-isoxazole (preparation described, for example, in WO 2007/096576) (2.00 g, 15 mmol) in formic acid (12 ml) was added sodium thiocyanate (1.46 g, 18 mmol) in one portion at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate (saturated), dried over magnesium sulfate and concentrated to give the title compound as an orange oil (2.05 g, 88% yield). IH-NMR (CDCl₃, 400 MHz): 1.50 (s, 6H), 3.1 (s, 2H) ppm.

Example 2.2: Alternative preparation of 5,5-dimethyl-3-thiocyanato-4,5-dihydro- isoxazole

fl-9 Me KSCN N-O _Mβ

"-AX M,e HCO₂H N _^==^ sΛΛ_u Me Potassium thiocyanate (1.75 g, 18 mmol) and 3-chloro-5,5-dimethyl-4,5-dihydro- isoxazole (preparation described, for example, in WO 2007/096576) (2.01g, 15 mmol) were suspended in formic acid (12 ml, 318 mmol) and the reaction mixture stirred at ambient temperature for 7 hours. The reaction mixture was diluted with diethyl ether and the mixture washed successively with water, aqueous sodium hydroxide (4M) and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: diethyl ether / hexane 0:1 to 1 : 19) to give a colorless oil (2.0 g, 89% yield).

Example 2.3: Alternative preparation of 5,5-dimethyl-3-thiocyanato-4,5-dihydro- isoxazole

Potassium thiocyanate (160 mg, 1.65 mmol) was suspended in ethanol (3 ml) and 3-chloro-5,5-dimethyl-4,5-dihydro-isoxazole (preparation described, for example, in WO 2007/096576) (2.01g, 15 mmol) was added with stirring at ambient temperature. Aqueous hydrochloric acid (36% w/v) (0.03 ml) was added and the reaction mixture stirred at ambient temperature for 2 hours. Additional aqueous hydrochloric acid (concentrated) (0.5 ml) was added and the reaction mixture stirred at ambient temperature for 30 minutes and then stored at ambient temperature for 16 hours. IH- NMR (CDCl₃, 400 MHz) analysis of a sample showed that the title compound was formed in 55% yield and that the remainder of the material was starting material.

Example 2.4: Alternative preparation of 5,5-dimethyl-3-thiocvanato-4,5-dihvdro- isoxazole

Potassium thiocyanate (160 mg, 1.65 mmol) and 3-chloro-5,5-dimethyl-4,5- dihydro-isoxazole (preparation described, for example, in WO 2007/096576) (210 mg, 1.57 mmol) were suspended in dichloromethane (3.0 ml). Trifluoroacetic acid ("TFA") (0.11 ml) was added and the reaction mixture stirred at ambient temperature for 9 hours. The reaction mixture was stored at ambient temperature for 15 hours. The reaction mixture was quenched by addition of water and washed with aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase extracted with diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: diethyl ether / hexane 0:1 to 1 :9) to afford the title compound (170 mg, 66% yield).

Example 2.5: Alternative preparation of 5,5-dimethyl-3-thiocyanato-4,5-dihvdro- isoxazole

To a stirred solution of 5,5-dimethyl-3-nitro-4,5-dihydro-isoxazole (Example 4.1) (432 mg, 3.0 mmol) in formic acid (12 ml) was added potassium thiocyanate (388 g, 4.0 mmol) in one portion at ambient temperature. The reaction mixture was heated at 70⁰C for 1 hour. The reaction mixture was allowed to cool to ambient temperature and diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate (saturated), dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 1 :6) to give the title compound as a yellow oil (320 mg, 68% yield). 3. Process 3

Example 3.1: Alternative preparation of 5,5-dimethyl-3-thiocvanato-4,5-dihydro- isoxazole

To a suspension of 2-(5,5-dimethyl-4,5-dihydro-isoxazol-3-yl)-isothiourea hydrochloride (preparation described, for example, in EP 1,829,868) (20.6 g, 0.1 mol) and potassium carbonate (28.0 g, 0.2 mol) in acetonitrile (200 ml) was added cyanogen bromide (17.0 g, 0.16 mol) in one portion at ambient temperature. The reaction mixture was stirred at ambient temperature for 37 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was triturated with a mixture of hexane and diethyl ether (1 :1) (200 ml). The resulting suspension was filtered and the filtrate concentrated. The residue was purified by column chromatography on silica gel (eluent: diethyl ether / hexane 1:1) to give the title compound as an oil (10.5 g, 67% yield).

Example 3.2: Alternative preparation of 5,5-dimethyl-3-thiocyanato-4,S-dihydro- isoxazole

To a suspension of 2-(5,5-dimethyl-4,5-dihydro-isoxazol-3-yl)-isothiourea hydrochloride (preparation described, for example, in EP 1,829,868) (20.6 g, 0.10 mol) and potassium carbonate (27.2 g, 0.20 mol) in acetonitrile (400 ml) was added cyanogen bromide (15.3 g,_ 0J5 mol) in one portion at ambient temperature followed by water (10 ml). The reaction mixture was stirred at ambient temperature for 34 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was partitioned between water (1 1) and diethyl ether (1 1), the phases were separated and the organic extract washed with water (1 1), dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: diethyl ether / hexane 1 : 1) to give the title compound as a pale yellow liquid (11.8 g, 76% yield).

4. Preparation of intermediates

Example 4.1 : Preparation of 5,5-dimethyl-3-nitro-4,5-dihvdro-isoxazole

To a suspension of sodium nitrite (2.07 g, 30 mmol) in dimethylformamide ("DMF") (15 ml) was added 1,3 dibromo-3-methylbutane (commercially available) (2.30 g, 10 mmol) dropwise over a period of 5 minutes at ambient temperature. The reaction mixture was heated at 50°C for 1 hour. The reaction mixture was concentrated, diluted with diethyl ether, filtered through a plug of cellulose (such as Hyflo Super-Cel®) and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 1 :6) to give the title compound as a yellow oil (465 mg, 32% yield). IH-NMR (CDCl₃, 400 MHz): 1.58 (s, 6H), 3.26 (s, 2H) ppm.

Claims

CLAIMS:

1. A process for making a compound of formula (I)

where

R and R are independently hydrogen, Q-Csalkyl or C₃-Ci₀cycloalkyl or R and R join to form together with the carbon atom to which they are attached a C₃-C₁₀cycloalkyl ring;

R³ and R⁴ are independently hydrogen or Ci-Cgalkyl or R³ and R⁴ join to form together with the carbon atom to which they are attached a C₃-C₁₀cycloalkyl ring;

R⁵ and R⁶ are independently hydrogen or Ci-C₈alkyl;

Y is aryl or aryl substituted by one to five R⁷ or heteroaryl or heteroaryl substituted by one to five R⁷; and each R⁷ is independently cyano, nitro, halogen, Q-Cgalkyl, Q-Cghaloalkyl, Q-Csalkoxy- or Q-Cshaloalkoxy-; which comprises reacting a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined for a compound of formula (I); with a Grignard reagent of formula (III)

2. A process according to claim 1 where a process according to claim 4 or claim 5 precedes the process of claim 1.

3. A compound of formula (II)

where R¹, R², R³ and R⁴ are as defined in claim 1.

4. A process for making a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined in claim 1; which comprises reacting an isoxazoline derivative of formula (IV) or a salt thereof

where R¹, R², R³ and R⁴ are as defined in claim 1 and LG is a leaving group; with a thiocyanate salt in the presence of an acid and in the presence of a solvent.

5. A process for making a compound of formula (II)

where R¹, R², R³ and R⁴ are as defined in claim 1; which comprises reacting an isothiouronium-isoxazoline of formula (V) or a salt thereof

where R , R , R and R are as defined in claim 1; with a cyanogen salt in the presence of a base and in the presence a solvent.

6. A process according to any one of claims 1, 2, 4 or 5 or a compound according to claim 3 where R¹ and R² are Ci-Cgalkyl, R³, R⁴, R⁵ and R⁶ are hydrogen and Y is phenyl or phenyl substituted by one to five R⁷, or heteroaryl or heteroaryl substituted by one to five R⁷ (where heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl).

7. A process according to claim 6 or a compound according to claim 6 where R¹ and R² are Ci-C₈alkyl, R³, R⁴, R⁵ and R⁶ are hydrogen and Y is phenyl or phenyl substituted

8. A process according to claim 7 or a compound according to claim 7 where R¹ and R² are methyl, R³, R⁴, R⁵ and R⁶ are hydrogen and Y is phenyl.