GB2109375A

GB2109375A - Benzylpyrimidine synthesis and intermediates

Info

Publication number: GB2109375A
Application number: GB08231983A
Authority: GB
Inventors: Roy Archibald Swaringen; John Fred Eaddy; Thomas Ranney Henderson
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1981-11-09
Filing date: 1982-11-09
Publication date: 1983-06-02
Also published as: CH664959A5; CH664961A5; DE3241134C2; FR2516081B1; GB8515931D0; GB2161158B; FR2516081A1; GB8515932D0; JPH07606B2; GB2161805A; JPH0549665B2; JPH08188574A; JPH069576A; CH658246A5; JPS5888368A; GB2109375B; DE3241134A1; GB2161805B; CH664960A5; JPH09227530A

Abstract

2,4-Diamino-5-(4-amino- and 4- loweralkylamino-3,5-disubstituted- benzyl)-pyrimidines are prepared by novel methods using 2,6-disubstituted anilines and pyrimidines. Several novel intermediates are involved.

Description

SPECIFICATION Benzylpyrimidine synthesis and intermediates The present invention relates to a process for preparing a group of substituted 2,4-diamino-5benzylpyrimidines.

German Patent Application No. 2 443 682 discloses inter alia compounds of the formula (I):

and salts thereof, wherein R' and R2 are the same or different and each is C, 3 alkyl, C, 3 alkoxy, C2-3 alkenyl or C23 alkenyloxy and Z is amino or alkyl substituted amino. These compounds are described as having antibacterial activity and 2,4-diamino-5-(4-amino-3, 5-dimethoxybenzyl)pyri- midine was subsequently disclosed as possessing good diuretic activity.

German Patent Application No. 2 634 358 discloses inter alia compounds of the formula (II):

and salts thereof, wherein R3 is a halogen atom and Z is amino or alkyl substituted amino. These compounds were also described as having antibacterial activity.

A novel synthesis of the compounds of the formulae (I) and (II) has now been discovered.

Accordingly, the present invention provides a process for the preparation of compound of the formula (III):

or a salt thereof, wherein R4 and R4" are the same or different and each is a hydrogen atom or a Alkyl group, R5 is halogen, C, 4alkyl or C1-4alkoxy and R6 is halogen, C, 4alkyl or C, 4alkoxy, which process comprises the reaction of a compound of the formula (IV):

wherein R4, R5 and R6 are as herein before defined with (i) 2,4-diamino-5-hydroxymethyl pyrimidine, or a C, 4ether thereof, (ii) formaldehyde and a secondary amine R7R8NH to give a compound of the formula (V)::

which is then reacted with a compound of the formula (VI):

to give a compound of the formula (VII):

followed by the reductive removal of the group R9 when R9 is not hydrogen, wherein R4, R5 and R6 are as hereinbefore defined, R7 and R8 are both C1-4 alkyl or R7R8NH represents morpholine or piperidine and R9 is hydrogen, hydroxy, C15 alkythio or mercapto, or (iii) 5-dimethylaminomethyluracil followed by the sequential alkylation of the amino group (where desired), halogenation and animation of the resultant uracil derivative of the formula (VIII)::

and thereafter in any of variants (i), (ii) or (iii), optionaly alkylating one compound of the formula (III) wherein R4" is hydrogen to give a compound of the formula (III) wherein R4" is C, 4alkyl.

This process is particularly suitable for the preparation of those compounds wherein R4 is hydrogen. Suitable R5 and R6 are the same and each is methoxy, chlorine or C, 4alkyl.

Variation (i) of the process is suitably carried out in a solvent capable of dissolving both reactants; polar non-phenolic solvents are particularly suitable, at a non-extreme temperature, for example between 25"C and 1 75 C and preferably between 50"C and 1 50"C. The reaction is preferably carried out in the presence of an acid, for example hydrochloric, acetic, methanesulfonic or p-toluenesulfonic acids. A preferred solvent is acetic acid.

The preparation of the compound of the formula (V) is variant (ii) of the process is carried out under the conditions described for the preparation of Mannich bases by Miocque and Vierfond (Bull. Soc. Chem. France 1970, 1896). The reaction is conveniently carried out in the presence of 0.5 mole of an acid, such as acetic acid, to 1 mole of each of the other ingredients. The compound of the formula (VI) is then reacted with a slight excess of the compound of the formula (V) in the presence of an acid such as p-toluenesulfonic acid. The reaction is normally carried out at an elevated temperature, suitably between 100" and 200"C in a solvent having a suitably high boiling point, for example a glycol such as ethylene glycol.The dethiation is suitably carried out by hydrogenolysis in the presence of a transition metal catalyst. Raney nickel is particularly suitable for this process. This reaction is normally carried out in a polar solvent, for example a C, 4 alkanol such as methanol or ethanol.

In variation (iii) the reaction of a compound of the formula (IV) with 5-dimethylaminomethylu racil is normally carried out in an inert high boiling polar solvent, for example a high boiling C26 alkanol such as ethylene glycol, at between 1 00, and 200"C for example between 130 and 160"C. The reaction is normally carried out under acidic conditions, for example in the presence of hydrochloric acid. The halogenation of the compound of the formula (VIII) and subsequent amination may conveniently be carried out by methods well known to those skilled in the art, for example by using the reaction conditions described in U.K. Patent No. 875 562 or 1 1 32 082 or German Offenlegungschrift 2 258238.

The alkylation of the amino group in variant (iii) of the process is carried out under conditions, well known to those skilled in the art, that will not effect the uracil part of the molecule, for example by the reaction of the amine with formic acid and the appropriate aldehyde. Preferably the reaction will be a methylation in which case the aldehyde will be formaldehyde. The optional alkylation of the amino group NR4H is carried out under conditions that will not affect the amino groups attached on the pyrimidine ring. Again suitable conditions are known to those skilled in the art, for example the reaction with formic acid and the appropriate aldehyde.

The compounds of the formula (VII), (VIII) are novel intermediates and as such form an important part of the present invention. The compound of the formula (IX):

wherein R4, R5 and R6 are as hereinbefore defined is also a novel intermediate forming part of the present invention.

Example 1 Preparation of 2, 6-Diisopropyl-4-piperidinomethylaniline Following the conditions described by Miocque and Vierfond (Bull. Soc. Chim. France 1970, 1896), 2,6-diisopropylaniline (17.73 g, 0.10 mol), 37% aqueous formaldehyde (8.1 mL, 0.10 mol), piperidine (8.52 g, 0.10 mol), acetic acid (3.00 g, 0.05 mol), and ethanol (25 mL) were allowed to boil together until the temperature of the solution reached 92"C. The solution was then refluxed for 24 hours. The product was distilled under vacuum (122-140"C at 0.7-0.8 mm) to give the title compound (17.57 g, 64%). 'H NMR (CDCl3): 81.25 (d, 12, CH3), 1.50 (m, 6, (CH2)2), 2.35 (m, 4, N(CH2)2), 2.95 (m, 2, CH), 3.35 (s, 2, Ar-CH2), 3.70 (broad s, 2, NH2), 7.0 (s, 2, Ar-H).

Example 2 Preparation of 2, 6-Diethyl-4-piperidinomethylaniline A solution of 2,6-diethylaniline (29.85 g, 0.20 mol), 37% aqueous formaldehyde (16.2 mL, 0.20 mol, piperidine (17.03 g 0.20 mol, acetic acid (6.00 g, 0.10 mol), and ethanol (25 mL) was reacted under conditions similar to Example 1 The title compound (28.49 g, 57.8%) was isolated by vacuum distillation (115-125 C at 0.05 mm). 1H NMR (CDCI2): 81.25 (t, 6, CH3), 1.50 (m, 6, (CH2)3), 2.35 (m, 4, N (CH2)2), 2.55 (q, 4, CH2 Me), 3.45 (s, 2, ArCH2)" 3.55 (broad s, 2, NH2), 6.90 (s, 2, ArH).

Example 3 Preparation of 2, 6-Diisopropyl-4-(N, N-dimethylaminomethyl)aniline A solution of 2,6-diisopropylaniline (35.45 g, 0.20 mol), 37% aqueous formaldehyde (16.2 mL, 0.20 mol), N,N-dimethylamine (9.02 g, 0.20 mol), acetic acid (6.00 g, 0.10 mol), and ethanol (25 mL) was reacted under conditions similar to Example 1.

The title compound (12.05 g, 26%) was isolated by vacuum distillation (112-120 C, 0.2 mm). 1H NMR (CDCI3): 81.25 (d, 12, CH3), 2.20 (s, 6, N Me2), 2.95 (m, 2, CH), 3.35 (s, 2, ArCH2), 3.70 (broad s, 2, NH2), 7.0 (s, 2, ArH).

Example 4 Preparation of 2,6,-Diisopropyl-4-morpholinomethylaniline A solution of 2,6-diisopropylaniline (35.45 g, 0.20 mol), 37% aqueous formaldehyde (16.2 mL, 0.20 mol), morpholine (17.42 g, 0.20 mol), acetic acid (6.00 g, 0.10 mol), and ethanol (25 mL) were reacted under conditions similar to Example 1. After concentration on the rotary evaporator, the residue was dissolved in diethyl ether and washed with aqueous sodium bicarbonate and water. After drying the ether solution, a solution of hydrogen chloride (0.20 mol) in ethanol was added. Filtration and drying gave the hydrochloride salt of the title compound (47.58 g, 76%). The salt (20.0 g, 0.6 mol) was dissolved in acetone and treated with solid potassium bicarbonate. Upon filtration and evaporation of solvent, the title compound was obtained (16.27 g, 92.2%). Calculated for C,7H28N2O: C, 73.87; H, 10.21; N, 10.13.

Found: C, 74.04; H, 10.31; N, 10.17.

Example 5 Preparation of 2, 4-Diamino-5-(4-amino-3, 5-diisopropylbenzyl)-6-methylthiopyrimidine To 2,4-diamino-6-methylthiopyrimidine (1.56 g, 10.0 mmol) in ethylene glycol (50 mL) at 1 14'C was added a solution of V (R4= H, R5 = R6 = CHMe2, NR7R8 = morpholino, 3.32 g, 12.0 mmol) in ethylene glycol (25 mL) and p-toluenesulfonic acid monohydrate (0.1 9 g, 1.0 mmol). The temperature was maintained between 125"C and 140"C for 31 hours. The solvent was distilled in vacuo and 3N hydrochloric acid (20 mL) was added to the residue.The crude hydrochloride salt of the title compound (3.44 g, 90.0%) was dissolved in methanol, treated with charcoal, filtered, and evaporated until crystallization began. The slurry was diluted with isopropanol, filtered and dried to give the purified hydrochloride salt of the title compound (2.58 9, 68%).

The title compound was obtained by the addition of concentrated ammonium hydroxide (6 mL) to an aqueous solution of the hydrochloride salt (1.67 g, 4.37 mmol). Filtration and drying gave the title compound (1.38 g, 91.4%). 1H NMR (CDCl3): 61.30 (d, 12, CH3), 2.60 (s, 3, SCH3), 3.0 (m, 2, CH), 3.6 (broad s, 2, ArNH2), 3.35 (s, 2, ArCH2), 4.7 (broad s, 4, NH2), 7.0 (s, 2, ArH).

In a similar manner, VI (R9 = SUCH2, 1.56 g, 10.0 mmol) was reacted with V (R4 = H, R5 = R6 = CHMe2, NR7R8 = piperidino, 3.29 g, 12.0 mmol) to give the title compound (1.41 g, 41%).

Also, under similar conditions, VI (R9 = SUCH2, 1.56 g, 10.0 mmol) was reacted with V (R4=H, R5 =R6=CHMe2, R7=R8=CH3, 2.81 g, 12.0 mmol) to give the title compound (0.97 g, 28.4%).

Example 6 Preparation of 2,4,-Diamino-5-(4-amino-3,5-diisopropylbenzyl)pyrimidine A solution of VII (R4 = H, Re = Re = CHMe2, R9 = SCH3, 0.50 g, 1.45 mmol) in methyl cellusolve (10 mL) and water (0.5 mL) was refluxed for six hours with T-1 Raney nickel (3 g).

The solution was filtered and evaporated, and the residue triturated with hot hexane to give the title compound (0.36 g, 84%), m.p. 177-180"C.

Example 7 Preparation of 2,4,-Diamino-5-(4-amino-3, 5-diisopropylbenzyl)-6-hydroxypyrimidine A solution of VI H2O (R9 = OH, 1.44 g, 10.0 mmol), V (R4 = H, R5 = R6 = CHMe2, NR7R8= morpholino, 3.32 g, 12.0 mmol), and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) in ethylene glycol (75 mL) was heated for 42 hours at 133-138"C. The solvent was distilled under vacuum and 3N hydrochloric acid (20 mL) was added to the residue. The resulting hydrochloric salt was isolated, dissolved in water, and neutralized by the addition of concentrated ammonium hydroxide to give the title compound (2.36 g, 74.9%).The title compound was purified by recrystallization from ethanol (1.44 g, 45.7%). 1H NMR (DMSO-d6): 81.05 (d, 6, CH2), 2.90 (m, 2, CH), 3.30 (s, 2, ArCH2), 4.15 (broad s, 2, ArNH2), 5.45 (broad s, 2, NH2), 4.15 (broad s, 2, NH2), 6.80 (s, 2, ArH), 9.90 (s, 1, OH).

The title compound may be converted to VII (R9 = H) by sequential reaction with methanesulfonyl chloride to give VII (R9 = OSO2Me), followed by catalytic hydrogenation with palladium to give VII (R9 = H), as, for example, in U.K. Patent No. 1 542 804.

Example 8 Preparation of 2,4-Diamino-5-(4-amino-3,5-diisopropylbenzyl)pyrimidine A solution ofVl (R9=H, 1.10 g, 10.0 mmol), V(R4=H, Re=R6=CHMe2, NR7R8 = morpho- lino, 3.32 g, 12.0 mmol), and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) in ethylene glycol (50 mL) was heated for 52 hours at 150-160"C. The solvent was distilled under vacuum and 3N hydrochloric acid (20 mL) added to the residue. The resulting solution was washed with methylene chloride and evaporated to an oil which crystallized upon standing.

The crystals were triturated with isopropanol, filtered, and dried to give the hydrochloride salt of the title compound (1.51 g 45%), which was crystallized from ethanol (1.04 9, 68.9%).

Addition of 3N sodium hydroxide to an aqueous solution of the hydrochloride salt (0.74 g, 2.20 mmol) gave the title compound (0.509, 76%). 1H NMR (DMSO-d6): 61.15 (d, 12, CH3), 2.95 (m, 2, CH), 3.50 (s, 2, ArCH2), 4.50 (broad s, 2, ArNH2), 6.15 (broad s, 2, NH2), 6.80 6.55 (broad s, 2, NH2), (s, 2, ArH), 7.40 (s, 1, pyrimidine 5-H), M.p. 179-182"C.

Example 9 Preparation of 5-Dimethylaminomethyluracil Hydrochloride Uracil (56.05 g, 0.50 mol) was refluxed with dimethylamine hydrochloride (81.55 g, 1.0 mol) and 37% aqueous formaldehyde (61 mL. 1.0 mol) in water (100 mL) for two days. The solvent was evaporated and the product triturated with methanol. After filtration and drying, the title compound was isolated (80.6 g, 78.3%). 1H NMR (DMSO-d6 + D2O): 62.90 (s, 6, NMe2), 4.10 (s, 2, NCH2), 7.95 (s, 1, uracil 6-H).

Example 10 Preparation of 5-(4-amino-3, 5-diisopropylbenzyl)uracil A mixture of 5-dimethylaminomethyluracil hydrochloride (10.28 9, 50.0 mmol) and 2,6diisopropylaniline (10.64 9, 60.0 mmol) in ethylene glycol (75 mL) was heated for 4+ hours at 134-137"C. After cooling, the title compound was filtered, washed with ethanol, and dried (5.55 9, 37%). A second crop was obtained from the mother liquor upon standing (3.24 9, 21.5%). The two crops were combined and recrystallized from methanol to give the purified title compound (5.84 g, 38.8%). Calculated for C'7H23N302: C, 67.75; H, 7.69; N, 13.94. Found C, 67.59; H, 7.75; N,13.88.

The title compound may be converted to VII (R4 = H, R5 = R6 = CHMe2, R9 = H) via sequential halogenation and amination as described, for example, in U.K. Patent No. 875 562 or 1 1 32 082, or German Offenlegungschrift 2 258238.

Example 11 Preparation of 2,4-Diamino-5-(4-amino-3, 5-dimethoxybenzyl)pyrimidine A mixture of 2,4-diamino-5-hydroxymethylpyrimidine (4.30 g, 30.0 mmol), prepared form 2,4diamino-5-cyanopyrimidine as described in U.K. Patent No. 1 413 472, 2,6-dimethoxyaniline (5.05 g, 33.0 mmol), acetic acid (60 mL), and concentrated hydrochloric acid (4.2 mL) was refluxed for 4+ hours, cooled, and filtered to give the hydrochloride salt of the title compound (7.13 g, 76.2%). The salt was dissolved in water and the solution made basic with concentrated ammonium hydroxide. The resulting precipitate was filtered, washed with water, and dried to give the title compound (5.18 9, 62.7%). Calculated for C,3H17N502: C, 56.72; H, 6.22; N, 25.4. Found: C, 56.63; H, 6.29; N, 25.39.

Other compounds of formula Ill prepared by variant (i) of this process are exemplified in Table TABLE I calculated found R4 R5 Re Yield, % C H N C H N H CHMe2 CHMe2 55.1 68.19 8.42 23.39 68.08 8.49 23.17 H Et Et 61.4 66.39 7.80 25.81 66.14 8.03 25.71 H Me Me 70.7 64.17 7.05 28.78 63.94 6.97 28.79 H Me Et 63.3 65.34 7.44 27.21 65.03 7.49 27.11 H Me CHMe2 54.5 66.39 7.80 25.81 66.07 7.77 25.57 H Et CHMeEt 66.2 68.20 8.42 23.39 68.11 8.54 23.37 H Me CMe3 43.0 65.67 8.27 23.64 65.72 8.34 23.60a H CI Cl 28.6 46.50 3.90 24.65 46.15 3.99 24.31 H Br Br 39.4 34.42 3.20 18.24 34.15 3.27 18.12b H Cl Me 60.1 54.65 5.35 26.55 54.45 5.32 26.33 Et Me Me 42.9 66.39 7.80 25.81 66.15 7.86 25.72 a Calculated for C16H23N5 0.25 H2O 0.20 MeOH. NMR confirms the presence and amount of MeOH.Karl Fisher analysis: 1.49% H2O b Calculated for C11H11Br2N5 0.6 H2O Karl Fisher analysis: 2.9% H2O.

5-(4-Amino-3, 5-dimethoxybenzyl)-2, 4-(1 H, 3H)-pyrimidinedione A mixture of 10.049 (49 mmol) of 5-/(dimethylamino)methyl/uracil hydrochloride (B. Roth, J.Z. Strelitz, and B. S. Hauckman, J. Med. Chem. 23, 379 (1980) and 7.48 9 (49 mmol) of 2,6-dimethoxyaniline (mp 73-74.5"; prepared from 2,6-dimethoxybenzoic acid by the procedure in Org. Reactions 3, 330 (1946)) in 50 mL of ethylene glycol under nitrogen was heated at 145 for 5 hours. The mixture was cooled and the precipitated solid was collected, suspended in 300 mL of boiling ethanol and collected to give 3.91 g (29%) of the title compound; mp 243-245" (dec.). Anal. Calculated for C13H15N304.-H2O:C, 55.41; H, 5.54; N, 14.91. Found: C, 55.46; H, 5.54; N, 14.94.A second crop 2.09 (15%) was obtained by concentration of the ethanol extract.

5-(3, 5-Dimethoxy-4-dimethylaminobenzyl)-2, 4-(1 H, 3H)-pyrimidinedione To a solution of 5-(4-amino-3,5-dimethoxybenzyl)-2,4-(1 H, 3H)-pyrimidinedione (5.49, 19.5 mmol) in 88% formic acid (70 mL) was added 37% formaldehyde (1.75 9). After refluxing 18 hrs, the reaction was cooled and 2 mL of conc. HCI were added. The solution was evaporated and the residue was dissolved in 200 mL of water. Neutralization of this solution with 5N sodium hydroxide gave 2.25 g (89%) of the title compound; mp 228-230" (dec.). Anal.

Calculated for C15H19N2O4.0.1H2O: C, 58.66; H, 6.30; N, 13.68. Found: C, 58.55; H, 6.30; N, 13.69.

2, 4-Dichloro-5-(3, 5-dimethoxy-4-dim eth ylamin obenzyl)pyrimidine A mixture of 5.02 9 (16.4 mmol) of 5-(3,5-dimethoxy-4-dimethylaminobenzyl-2,4-(1 H, 31')- pyrimidinedione in 100 ml of phosphoryl chloride was heated at reflux for 90 minutes. The excess POCI3 was removed in vacuo and the residue was dissolved in dichloromethane and washed with aquoues sodium bicarbonate solution of neutrality, then with water. The solution was dried over MgS04, then passed through a silica gel column eluting with dichloromethane: methanol/1 9:1. The fractions containing product were combined and concentrated to an oil; 3.75 9 (67%). The structure was confirmed by NMR.

2, 4-Diamino-5-(3, 5-dimethoxy-4-dimethylaminobenzyl)pyrimidine A solution of 3.47 9 (10.1 mmol) of 2,4-dichlorn-5-(3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine in 200 mL of ethanol saturated with ammonia was heated in an autoclave at 150 for 8 hours. The solvent was removed in vacuo and the residue was triturated with water and collected. This was dissolved in dichloro-methane:methanol/4:1, absorbed onto silica gel and placed at the top of a silica gel column. Elution with the same solvent gave 2.27 9 (74%) of the title compound. A portion was converted to the dihydrochloride by recrystallization from 95% ethanol with conc. HCI; mp 228-230" (dec.). Anal. Calculated for C,5H2,N502.2HCI . H2O: C, 45.69; H, 6.39; N, 17.76; CI, 17.98. Found: C, 45.70; H, 6.40; N, 17.77; Cl, 17.86.

Claims

1. A method of preparing a compound of formula (III)

wherein R4 and R4" are the same or different and each is selected from hydrogen and C1 4alkyl, and R5 and R6 are selected from halogen, C1 4alkyl and C1 4alkoxy which comprises a reaction (sequence) involving a compound of formula (IV) and selected

from the group consisting of: a) reaction of a compound of formula (IV) with 2,4-diamino-5-hydroxy-methylpyrimidine or a C14 ether thereof, b) reaction of a compound of formula (IV) with formaldehyde and secondary amine R7, RS NH wherein R7 and R8 are both C1 4alkyl or R7, R8 NH represents morpholine or piperidine to give a compound of formula (V)

which is then reacted with a compound of formula (VI)

wherein R9 is hydrogen, hydroxy, C1-4 alkylthio or mercapto, to give a compound of formula (VII)

followed by reductive removal of the group R9 when R9 is other than hydrogen; and c) reaction of a compound of formula (IV) with 5-dimethylaminomethyluracil followed by sequential alkylation of the amino group (where desired) halogenation and amination.

2. A method according to claim 1 for preparing a compound of formula (III)

wherein R4 is selected from hydrogen and C1-4 alkyl, and R5 and R6 are selected from halogen, C1-4 alkyl and C14 alkoxy, which comprises the reaction of a compound of formula (IV)

with 2,4-diamino-5-hydroxymethylpyrimidine.

3. A method according to claim 1 for preparing a compound of formula (III)

wherein R4 is selected from hydrogen and C14 alkyl and R5 and R6 are selected from halogen, C1-

4 alkyl and C14 alkoxy, which comprises the reaction of a compound of formula (IV)

with formaldehyde and a secondary amine R7 R8NH, wherein R7 and Re are both C1-4 alkyl or R7R8NH represents morpholine or piperidine, to give a compound of formula (V)

which is then reacted with a compound of formula (VI)

wherein R9 is hydrogen, hydroxy, C1 -4 alkylthio or mercapto, to give a compound of formula (VII)

followed by reductive removal of the group R9 when R9 is other than hydrogen. 4.A method according to claim 1 for preparing a compound of formula (III)

wherein R4 is selected from hydrogen and C14 alkyl, and R5 amd Re are selected from halogen, C14 alkyl and C14 alkoxy, which comprises the reaction of a compound for formula (IV)

with 5-dimethylaminomethyluracil followed by sequential halogenation and amination.

5. A method according to claim 2 wherein said reaction is carried out in the presence of an acid.

6. A method according to claim 5 wherein said acid is selected from hydrochloric acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid.

7. A method according to claim 5 wherein said acid is hydrochloric acid.

8. A method according to claim 5 wherein said acid is selected from methanesulfonic acid and p-toluenesulfonic acid.

9. A method according to claim 1 for preparing a compound of formula (III)

wherein R4 is selected from hydrogen and C14 alkyl, and R5 and R6 are selected from halogen, C14 alkyl and C14 alkoxy, which comprises the reaction of a compound of formula (IV)

with formaldehyde and a secondary amine R7R8NH, wherein R7 and R8 are both C14 alkyl or R7R8NH represents morpholine or piperidine, to give a compound of formula (V)

which is then reacted with a compound of formula (VI)

wherein R9 is hydrogen, hydroxy or C1-4 alkylthio, to give a compound of formula (VII)

followed by reductive removal of the group R9 when R9 is other than hydrogen.

10. A compound of formula (VII)

wherein R4 is selected from hydrogen and C1-4 alkyl, R5 and Re are selected from halogen, C1-4 alkyl and C1-4 alkoxy, and R9 is selected from hydroxy, C1-4 alkylthio and mercapto, and acid addition salts thereof.

11. A compound of formula (VIII)

wherein R4 is selected from hydrogen and C14 alkyl, and R5 and R6 are selected from halogen, C14 alkyl and C14 alkoxy, and acid addition salts thereof.

12. A compound of formula (IX)

13. A method according to claim 3 wherein the reaction of a compound of formula (V) with a compound of formula (VI) is carried out in the presence of an acid.

14. A method according to claim 13 wherein the acid is p-toluenesulfonic acid.

15. A method according to claim 4 wherein the reaction is carried out in the presence of an acid.

16. A method according to claim 15 wherein the acid is hydrochloric acid.

17. A method of preparing a compound of formula (III) as defined in claim 1 which comprises the reaction of a compound of the formula (V) with a compound of the formula (Vl) followed by the reductive removal of the group R9 wherein this is other than hydrogen, wherein formulae (V) and (VI) and R9 are as defined in relation to claim 1.

18. A method of preparing a compound of formula (III) as defined in claim 1 which comprises the amination of a compound of the formula

wherein, R4, R4a, R5 and R6 are as defined in relation to claim 1.