Processes to prepare 3-substituted-3-aminonitriles are disclosed in W095/31448; W094/21617 and EPA0135252.

The present invention provides a process for the preparation of a compound of formula (I) :

wherein Ru ils hydrogen, optionally substituted Cl-6 alkyl, optionally substituted 2-6 alkenyl, optionally substituted 2-6 alkynyl, optionally substituted C1 6 alkoxy, optionally substituted Cl-6 alkylthio or optionally substituted 3-7 cycloalkyl ; and R2 is hydrogen, halogen, optionally substituted Ci-6 alkyl, optionally substituted 2-6 alkenyl, optionally substituted 2-6 alkynyl, optionally substituted Cul-6 alkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfinyl, optionally substituted C1-6 alkylsulfonyl, cyano, nitro, formyl, optionally substituted Cl-6 alkylcarbonyl, optionally substituted Cl-6 alkoxycarbonyl or SFs ; or R1 and R2 together with the atoms to which they are attached may be joined to form a five, six or seven-membered saturated or unsaturated ring carbocylic or heterocyclic ring which may contain one or two heteroatoms selected from 0, N or S and which may be optionally substituted by C1-6 alkyl, C1-6 haloalkyl or halogen; the process comprising reacting aqueous ammonia with a compound of formula (II) :

or a metal salt derived therefrom where Ri and R2 are as defined in relation to formula (I).

Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl or

neo-pentyl. When present, the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, HO2C, Cl 1o alkoxy (itself optionally substituted by halogen or Cl-lo alkoxy), aryl (Cl-4) alkoxy, Cl-lo alkylthio, Cl-lo alkylcarbonyl, Cl-lo alkoxycarbonyl, Cl-6 alkylaminocarbonyl, di (Cl 6 alkyl) aminocarbonyl, (Cl 6) alkylcarbonyloxy, optionally substituted phenyl, heteroaryl, aryloxy, arylcarbonyloxy, heteroaryloxy, heterocyclyl, heterocyclyloxy, C3 7 cycloalkyl (itself optionally substituted with (C1-6) alkyl or halogen), C3 7 cycloalkyloxy, CS-7 cycloalkenyl, Cl-6 alkylsulfonyl, C1-6 alkylsulfinyl, tri (Ci-4) alkylsilyl, tri (C1-4) alkylsilyl (C1-6) alkoxy, aryldi (C1-4) alkylsilyl, (Cl-4) alkyldiarylsilyl and triarylsilyl.

Alkenyl and alkynyl moieties can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)-or (Z)-configuration.

Examples are vinyl, allyl and propargyl. When present, the optional substituents on alkenyl or alkynyl include one or more of halogen, aryl and C3-7 cycloalkyl.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl moieties are alkyl moieties which are substituted with one or more of the same or different halogen atoms and are, for example, CF3, CF2C1, CF3CH2 or CHF2CH2.

Aryl includes naphthyl, anthracyl, fluorenyl and indenyl but is preferably phenyl.

The term heteroaryl refers to an aromatic ring containing up to 10 atoms including one or more heteroatoms (preferably one or two heteroatoms) selected from 0, S and N.

Examples of such rings include pyridine, pyrimidine, furan, quinoline, quinazoline, pyrazole, thiophene, thiazole, oxazole and isoxazole.

The terms heterocycle and heterocyclyl refer to a non-aromatic ring containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected from 0, S and N. Examples of such rings include 1,3-dioxolane, tetrahydrofuran and morpholine. It is preferred that heterocyclyl is optionally substituted by C1-6 alkyl.

Cycloalkyl includes cyclopropyl, cyclopentyl and cyclohexyl. The optional substituents for cycloalkyl include halogen, cyano and 1-3 alkyl.

Cycloalkenyl includes cyclopentenyl and cyclohexenyl. The optional substituents for cycloalkenyl include C1-3 alkyl, halogen and cyano.

Carbocyclic rings include aryl, cycloalkyl and cycloalkenyl groups.

For substituted phenyl moieties, heterocyclyl and heteroaryl groups it is preferred that one or more substituents are independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy (C1-6) alkyl, C1-6 alkoxy, CI-6 haloalkoxy, CI-6 alkylthio, C1-6 haloalkylthio, C1-6

alkylsulfinyl, Cl-6 haloalkylsulfinyl, Cul-6 alkylsulfonyl, Cl-6 haloalkylsulfonyl, 2-6 alkenyl, 2-6 haloalkenyl, 2-6 alkynyl, C3-7 cycloalkyl, nitro, cyano, C02H, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, R3R4N or R3R4NC (O) wherein R3 and R4 are, independently, hydrogen or C1-6alkyl.

Haloalkenyl moieties are alkenyl moieties which are substituted with one or more of the same or different halogen atoms.

The compounds of formulae (I) and (IT) 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.

Preferably the process uses a metal salt derived from a compound of formula (U) (for example, a potassium, sodium or lithium salt). More preferably the process uses a potassium or sodium salt derived from a compound of formula (II).

Rl is preferably hydrogen, Ci-6 alkyl, 2-6 alkenyl, Cl-6 haloalkyl, Cl-6 alkoxy (Ci-6) alkyl, Ci-6 haloalkoxy (Cl-6) alkyl, Ci-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, Cl- 6 haloalkylthio or C3-6 cycloalkyl.

Ra is preferably hydrogen, halogen, Cl-6 alkyl, Cl-6 haloalkyl, Cl-6 alkoxy, Cl-6 haloalkoxy, C1-6 alkoxy (Cl-6) alkyl, C1-6 alkylthio or SF5 ; or R1 and R2 together with the atoms to which they are attached form a cyclopentane ring, a cyclohexane ring or a benzene ring, each optionally substituted by C1-6 alkyl, Cl-6 haloalkyl or halogen.

R1 is more preferably C1-6 alkyl, Cl-6 haloalkyl, C1-6 alkoxy (Cl-6) alkyl, C1-6 haloalkoxy (Cl-6) alkyl, C1-6 alkoxy or C1-6 haloalkoxy. Even more preferably R1 is C1-4 alkyl (especially Cl-2 alkyl) and most preferably R1 is ethyl.

R2 is more preferably halogen, C1-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, C1-6 alkoxy (C1-6) alkyl or C1-6 haloalkoxy. Most preferably R2 is hydrogen.

Preferably the molar ratio of ammonia to the compound of formula (II) or metal salt derived therefrom is from 5: 1 to 20: 1.

Preferably the process is performed in the presence of a buffering agent. Preferably the buffering agent is an ammonium salt (for example, ammonium carbonate, ammonium phosphate or ammonium sulfate). More preferably the buffering agent is ammonium carbonate.

Preferably the molar ratio of buffering agent to the compound of formula (t or metal salt derived therefrom is from 1: 1 to 5: 1.

Preferably the process is performed in the temperature range 40-120°C, more preferably 50-100 °C and most preferably 60-70 °C.

Preferably the process is performed for a duration of from 3 to 24hours, more preferably from 4 to 12hours and most preferably from 5 to 6hours.

Preferably the concentration of ammonia is 20-40% by weight, more preferably 25-35% by weight.

In a preferred embodiment, the process is performed in the additional presence of gaseous ammonia.

Compounds of formula (I may be prepared by reacting a suitable ester with an appropriate nitrile compound in the presence of a base or by processes analogous to those disclosed in W095/31448.

The present invention is illustrated by the following Examples. Selected NMR data and melting point data are presented in the Examples. For NMR data, no attempt has been made to list every absorption. The following abbreviations are used throughout the Examples: ppm = parts per million q = quartet s = singlet m = multiplet t = triplet br = broad EXAMPLE 1 This Example illustrates the preparation of 3-amino-2-pentenenitrile.

The potassium salt of 3-ketopentanenitrile (lg ; 7.4mmole), aqueous ammonia (5ml of a 35% by weight solution of ammonia ; ca. lOOmmole ammonia) and ammonium sulphate (1.2g; 9mmole) were charged to a Carius tube and heated in an aluminium block overnight at ca. 80°C. The Carius tube was transferred to an electrically heated oil bath, stirred at 80°C for a further 5 hours and then left to cool overnight. The reaction mixture was filtered to remove a white solid and the filter cake was washed with dichloromethane. The filtrate was extracted with more dichloromethane (twice) and the combined organic solutions were dried over magnesium sulphate prior to evaporating to dryness under water pump pressure with a bath temperature of 50°C to give a dark straw coloured oil. (Yield: 470mg).

'H NMR (CDC13) 8 : 1.15 (2H, m) (a) + (b); 2.2 (lH, q) (c); 2.4 (lH, q) (d); 3.8 (lH, s) (e); 4.05 (lH, s) (f) ; 5.0 (lH, br. s) (g); 4.85 (lH, br. s) (h) ppm.

EXAMPLE 2 This Example illustrates an alternative preparation of 3-amino-2-pentenenitrile.

The potassium salt of 3-ketopentanenitrile (70g; 519mmole), aqueous ammonia (350ml of a 35% by weight solution of ammonia ; ca. 6.3mole ammonia) and ammonium carbonate (63g; ca. 650mmole) were charged to a 600 ml stainless steel hydrogenation vessel which was sealed and heated to 65°C. After 5hours at this temperature the heating and stirring were turned off and the vessel was left standing. The excess pressure in the vessel was then vented via an aqueous scrubber. The vessel contents were extracted with dichloromethane (three times) and the organic solution was evaporated to dryness under water pump pressure with a bath temperature of 45°C to give a dark straw coloured oil. This was azeotroped twice with ethanol to remove any traces of water. (Yield: 40.2g; 81% based on starting potassium salt). An NMR analysis revealed the presence of ethanol. Therefore, the oil was dissolved in dichloromethane, whereupon a glutinous white solid was precipitated. Magnesium sulphate was added, the mixture was filtered and the filtrate was evaporated to dryness under water pump pressure with a bath temperature of 45°C to give the desired product. (Yield: 37.3g; 75% based on starting potassium salt).

EXAMPLE 3 This Example illustrates an alternative preparation of 3-amino-2-pentenenitrile.

3-Ketopentanenitrile (80g; 825mmole) and aqueous ammonia (400ml of a 35% by weight solution of ammonia; ca. 7.8mole ammonia) were charged to a 600 ml stainless steel autoclave which was sealed and purged with nitrogen. The reaction mixture was heated to 60°C at ldegree/minute and stirred for 6 hrs, before the heating and stirring were turned off and the reaction mixture was left to stand overnight. There was no residual pressure in the vessel after it had cooled to room temperature. The reaction mixture was extracted with dichloromethane (three times) and the extracts were dried over magnesium sulphate and

evaporated to dryness under water pump pressure with a bath temperature of 50°C to give the desired product as a yellow oil. (Yield: 53.4g; ca. 66% based on starting keto nitrile).

EXAMPLE 4 This Example illustrates an alternative preparation of 3-amino-2-pentenenitrile.

3-Ketopentanenitrile (412g; 4.24mole) and aqueous ammonia (1.6 litres of a 25% by weight solution of ammonia ; ca. 23mole ammonia) were charged to a 3.71itre stainless steel hydrogenation autoclave which was sealed and purged with nitrogen. Anhydrous gaseous ammonia (ca. 275g; ca. l6mole) was then charged as a liquefied gas to a sample cylinder which was inverted and attached to the autoclave via a needle valve. Water cooling was applied to the coil in the autoclave and the needle valve leading to the ammonia was slightly opened in order to allow a small amount of the liquefied gas to run into the autoclave. The pressure in the reaction vessel rose but there was no indication of any exotherm. The needle valve was opened fully to allow all of the ammonia to run into the vessel; the pressure rose to 50psi (3.44xlO6Nxri 2) initially but dropped back to 15psi (1.03xlO6Nm~2) on stirring for 30minutes.

The sample cylinder was isolated from the autoclave and the reaction mixture was heated to 60°C at ldegree/minute and stirred for 6hours, before the heating and stirring were turned off and the reaction mixture was left to stand overnight. The residual pressure in the autoclave after it had cooled to room temperature was 9psi (6.20x105Nm~2). The reaction mixture was discharged from the autoclave, as a dark green solution, which was divided into twoportions.

Water (250ml) was added to the first portion which was then extracted with dichloromethane (four times) (traces of a interfacial solid precipitated during these extractions; this was left in the aqueous phase). The extracts were filtered through HYFLO and were evaporated to dryness under water pump pressure with a bath temperature of 50°C to give the desired product as a green oil which was azeotroped with ethanol to remove any last traces of water. (Yield: 136g; 66% based on staring keto nitrile). The second portion was extracted with dichloromethane without the addition of water. There was slightly more pressure build up during these extractions. The organic solution was treated as above to give the desired product as a green oil. (Yield: 152g; 74% based on starting keto nitrile).

EXAMPLE 5 This Example illustrates an alternative preparation of 3-amino-2-pentenenitrile.

The potassium salt of 3-ketopentanenitrile (59g; ca. 0. 43mole), aqueous ammonia (300ml of a 35% by weight solution of ammonia ; ca. 5.4mole ammonia) and ammonium

sulphate (71g ; ca. 0. 54mole) were charged to a 600 ml stainless steel hydrogenation autoclave which was sealed, stirred for 15minutes and then heated to 60°C at 1°C/minute. The generated pressure at 60°C was ca. 35psi (2.41xlO6Nm~2). The reaction mixture was stirred for 16hours, before the heating was turned off and the vessel was allowed to cool with stirring. The reaction had reached an internal temperature of 58°C overnight. It was then cooled to 30°C and the residual pressure of 6psi (4.13xlO5Nm~2) was vented via a aqueous scrubber. The reaction mixture was filtered to remove granular solid which was then washed thoroughly with dichloromethane. The filtrate was extracted with more dichloromethane (3 times 100ml) and the combined organic washing and extracts were dried over magnesium sulphate and evaporated to dryness under water pump pressure with a bath temperature of 45°C to give the desired product as an orange oil. (Yield: 15. 3g; 36% based on potassium salt of keto nitrile).