WO2002088088A1

WO2002088088A1 - Process for preparing 1-methyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof

Info

Publication number: WO2002088088A1
Application number: PCT/GB2002/001951
Authority: WO
Inventors: Gary Francis Breen; Michael Anthony Forth; Matthew Edward Popkin
Original assignee: Sb Pharmco Puerto Rico Inc.
Priority date: 2001-04-27
Filing date: 2002-04-26
Publication date: 2002-11-07
Also published as: GB0110338D0; WO2002088088A9

Abstract

The invention provides a process for preparing 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (A), or a salt thereof, the process comprising: (i) reacting N-(2-chloroethyl)-α-methylbenzylamine of formula (B), or a salt thereof, with a Lewis acid such as AlCl3, and (ii) causing or allowing cyclisation to 1-methyl-1,2,3,4-tetrahydroisoquinoline. The invention also provides a process for preparing 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (A), or a salt thereof, the process comprising: (i) reacting a N-(2-haloethyl)-α-methylbenzylamine, or a salt thereof, with a Lewis acid and (ii) causing or allowing cyclisation to 1-methyl-1,2,3,4-tetrahydroisoquinoline at a temperature of ≤130°C. The use of N-(2-chloroethyl)-α-methylbenzylamine and/or lower cyclisation temperatures decreases the amount of certain impurities formed in the reaction. In other aspects of the invention, the 1-methyl-1,2,3,4-tetrahydroisoquinoline can be used in the synthesis of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (SB 641257, YH1885), a pharmaceutically active reversible proton pump inhibitor.

Description

PROCESS FOR PREPARING l-METHYL-1,2,3,4- TETRAHYDROISOQUINOLINE OR A SALT THEREOF

This invention relates to processes for preparing a pharmaceutically active compound or a salt thereof and to a process for preparing reaction intermediates, such as 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinoline or a salt thereof, usable in the synthesis of such pharmaceutically active compound or salt.

WO 96/05177 (Yuhan Corporation) discloses a series of pyrimidine derivatives having a tetrahydroisoquinoline (THIQ) group at the 2- or 4-position of the pyrimidine nucleus, and also discloses that these compounds are active as reversible proton pump inhibitors. One of the compounds disclosed as a racemate is 5,6-dimethyl-2-(4-fluorophenylamino)- 4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (SB 641257) and its hydrochloride salt known as YH1885 or SB 641257 A (see Example 15 for HCl salt and Example 1 for general method for formation of free base or HCl salt). The (R)- and (S)- enantiomers of this compound and their hydrochloride salts are also disclosed in Examples 16 and 17 of WO 96/05177. The structures and YH (Yuhan) and SB (SmithKline Beecham) numbers for these 3 compounds are shown below.

SB 641257 (racemate) SB 641258 (R-enantiomer) SB 641259 (S-enantiomer)

HCl salt is HCl salt is HCl salt is

YH 1885, SB 641257 A YH 2121 , SB 641258 A YH 2109, SB 641259 A

Because of their reversible proton pump inhibition properties, 5,6-dimethyl-2-(4- fluorophenylamino)-4-( 1 -methyl- 1,2,3 ,4-tetrahydroisoquinolin-2-yl)pyrimidine and salts thereof are expected to be useful in the treatment and prophylaxis of gastro-(o)esophageal reflux disease (GERD, reflux esophagitis, heartburn), including both erosive and symptomatic (non-erosive) GERD, as well as certain other gastric-acid-related disorders such as duodenal / gastric ulcers, and also in the eradication of Helicobacter pylori. Indeed the compound has undergone and/or is currently undergoing clinical trials for the treatment of GERD, in particular the treatment of the symptoms of GERD, the healing of erosive GERD and the maintenance of such healing, as well as the eradication of Helicobacter pylori. Improved processes for the preparation of the 3 compounds (racemate and (R)- and (S)- enantiomers, each enantiomer being substantially free of the other enantiomer), either as free bases or as the hydrochloride salts, were disclosed in WO 97/42186 and WO 98/18784 (Yuhan Corporation). These publications disclose the steps of making 1- methyl-l,2,3,4-tetrahydroisoquinoline (compound (A)) from compounds (V), (W) and (X), as shown in Scheme 1.

Scheme 1

(Y) 2% (Z) 2% (A)

l-methyl-l,2,3,4-tetrahydroisoquinoline (A) can be made in either racemic or chiral (R- or S-enantiomer) form using this synthesis, based on the commercial availability of both (S)-(-)- and (R )-(+)- enantiomers of α-methylbenzylamine. Compound (A) itself can be used as the final-stage intermediate in the synthesis of 5,6-dimethyl-2-(4- fluorophenylarnino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a salt thereof or other compounds disclosed in WO 96/05177.

In WO 97/42186, the Friedel-Crafts cyclisation of N-(2-bromoethyl)-α- methylbenzylamine hydrobromide (X) is carried out in the presence of a Lewis acid such as AICI3, and preferably in the presence of decalin at 140 or 150 °C (e.g. see Examples 5(3), 7, 8(3), 10, 11(3) and 13 of WO 97/42186). However, it has now been discovered that during this cyclisation of (X) to (A), unexpected by-products (Y) and (Z) containing ethyl substituents in the aromatic ring can be formed. For example about 2% of each of (Y) and (Z) are formed in the presence of decalin during reaction at 140-150 °C. These impurities in the 1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline are undesirable.

A similar process to prepare l-methyl-l,2,3,4-tetrahydroisoquinoline is described in (i) SU 768177A and (ii) N.M. Potapov et al., Chemistry Heterocyclic Compounds (Russia), 1987, 23 (9), pages 990-992 which is an English translation of V.M. Potapov et al., Khim.. Geterotsikl. Soedin., 1987, (9), 1238-40, document (ii) referring to V.M. Potapov et al., Zh. Org. Khim.(English translation), 1985, 21, pp. 1606-9 for the (N) to (W) conversion. Documents (i) and (ii) disclose a synthesis similar to that shown in Scheme 1 but converting (V) to (W) using ethylenechlorohydrin (2-chloroethanol). The conversion of bromo-derivative (X) to (A) is disclosed as being done in the presence of AICI3 and decalin at 145-150 °C, similarly to WO 97/42186, and thus would also form the same undesirable impurities (Y) and (Z).

R.D. Topsom, L.W. Deady, and N. Pirazada, J. Chem. Soc, Chem. Commun., 1971, 799 discloses a very similar process to make tetrahydroisoquinoline from N-(2-bromoethyl)- N-benzyl-amine using AICI3 at 150 °C in decalin for 1.5 hrs.

Surprisingly, it has now been found that the amount of impurities (Y) and (Z) formed during the synthesis of 1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline can be decreased by cyclising N~(2-c/z/<?roethyl)-α-methylbenzylamine (compound (B)) or a salt thereof instead of cyclising N-(2-bromoethyl)-α-methylbenzylamine hydrobromide (X).

A first aspect of the invention therefore provides a process for preparing 1-methyl- 1,2,3,4-tetrahydroisoquinoline of formula (A):

, or a salt thereof, the process comprising:

(i) reacting N-(2-chloroethyl)- -methylbenzylamine of formula (B):

, or a salt thereof, with a Lewis acid, and (ii) causing or allowing cyclisation (e.g. of the resulting complex) to 1 -methyl- 1,2,3, 4- tetrahydroisoquinoline.

(S)-l-methyl-l,2,3,4-tetrahydroisoquinoline or a salt thereof, e.g. substantially free of the (R)-enantiomer, can be prepared using (S)-N-(2-chloroethyl)- -methylbenzylamine or a salt thereof.

(R)-l-methyl-l,2,3,4-tetrahydroisoquinoline or a salt thereof, e.g. substantially free of the (S)-enantiomer, can be prepared using (R)-N-(2-chloroethyl)-α-methylbenzylamine or a salt thereof.

Preferably, the hydrochloride salt of N-(2-chloroethyl)-α-methylbenzylamine is used Advantageously, the Lewis acid comprises an aluminium trihalide such as AICI3 or AlBr3, preferably AICI3. Preferably, the compound of formula (B) or the salt thereof is mixed slowly with (e.g. added slowly to) the Lewis Acid such as AICI3 or AlBr3, preferably in portions allowing sufficient time between portions for HCl (or HBr) evolution to cease between each portion. "Slowly" here preferably means over a period of at least 20 or 30 or 40 minutes e.g. over a period of 20-240 or 20-120 or 20-90 or 30-120 or 30-90 minutes, preferably over about 45 minutes.

Preferably, in step (i), about 1.2 to about 4 mole equivalents of the Lewis acid, such as comprising an aluminium trihalide (e.g. AICI3 or AlBr3), are used based on the number of moles of the N-(2-haloethyl)-α-methylbenzylamine of formula (B) or of formula (BI) defined hereinafter. More preferably, about 1.4 to about 3 mole equivalents or about 1.5 to about 2.5 mole equivalents of the Lewis acid are used in step (i). Most preferably about 1.6 to about 2.5 mole equivalents or about 1.6 to about 1.8 mole equivalents of the Lewis acid are used in step (i).

The temperature in step (i) is preferably at least 70 °C, for example 70-150 °C but more preferably 70-100 °C or 70-90 °C, most preferably about 80 °C. Step (i) preferably lasts for from 20 minutes to 6 hours, more preferably 0.5 to 4 hours, for example about 0.75-1 hour or about 2-3 hours (e.g. Example 1: step (i) lasts 45 mins + 2 hours).

The temperature in the cyclisation step (ii) is preferably > 90 °C, more preferably >95 °C. The temperature in the cyclisation step (ii) is preferably <150 °C, more preferably preferably <130 °C or <125 °C, more preferably <120 °C, even more preferably <110 °C, still more preferably <105 °C. For example, the temperature in the cyclisation step (ii) is advantageously 90-150 °C, e.g. 95-125 °C, 95-120 °C, 95-110 °C, or 95-105 °C, most advantageously about 100 °C. Lower temperatures generally give lower amounts of impurities (Y) and (Z), as shown in the results given below.

Preferably, in step (ii), substantially complete cyclisation (e.g. of the resulting complex) to l-methyl-l,2,3,4-tetrahydroisoquinoline is caused or allowed. For example, the conditions (e.g. reaction time) of step (ii) are suitably such that substantially complete cyclisation is caused or allowed. In particular, especially in the presence of decalin or other biphasic-mixture-forming solvents (see later), the time of cyclisation at 95-105 °C or 95-110 °C (e.g.100 °C) is preferably about 1-3 days or more, e.g about 2 days or more; at 111-130 °C (e.g. about 120 °C) the cyclisation reaction time is preferably about 10-30 hours (e.g. ca. 15 hrs) or more; at 131-139 °C the cyclisation reaction time is preferably about 1-15 or 1.5-10 hours or more; at 140-160 °C (e.g. about 150 °C) the cyclisation reaction time is preferably about 0.5-6 hours (e.g. ca. 1-4 hours e.g. ca. 3 hrs) or more.

Preferably, steps (i) and/or (ii) are carried out in the presence of a suitable solvent.

Preferably, the suitable solvent comprises or is a hydrocarbon solvent or other non-polar organic solvent with a boiling point higher than the reaction temperature in steps (i) and and decalin at 140-150 °C, as disclosed in e.g. Examples 5(3), 7, 8(3), 10, 11(3) and 13 of WO 97/42186 and Comparative Examples A and B hereinafter. The results also unexpectedly show that reducing the cyclisation temperature has an advantageous effect on the impurity profile.

It has also been found that the impurities can also be further reduced by crystallising out a salt of the 1 -methyl- 1, 2,3, 4-tetrahydroisoquinoline. Thus, the impurities can remain in the mother liquor and can be separated from the product. Similarly, for the (R)- or (S)- isomer, the chiral impurity can be improved to >99 in some circumstances.

Thus, preferably, after formation of the l-methyl-l,2,3,4-tetrahydroisoquinoline, the process comprises the additional steps of:

(iii) reacting the l-methyl-l,2,3,4-tetrahydroisoquinoline with an acid (e.g. a mineral acid, e.g. HCl or HBr) to form a salt (e.g. hydrochloride or hydrobromide salt) of 1-methyl- 1,2,3, 4-tetrahydroisoquinoline in a suitable solvent; and

(iv) allowing or causing said salt to crystallise from solution.

Preferably, the crystalline salt of l-methyl-l,2,3,4-tetrahydroisoquinoline is separated from the reaction mixture, and preferably is dried.

Optionally, the salt of l-methyl-l,2,3,4-tetrahydroisoquinoline can be treated with base and the resulting l-methyl-l,2,3,4-tetrahydroisoquinoline then distilled.

In step (iii), preferably the suitable solvent is an organic solvent from which it is possible to crystallise said salt; preferably the suitable solvent comprises or is isopropanol.

The compound of formula (B) is novel. Therefore, a second aspect of the present invention provides N-(2-chloroethyl)-α-methylbenzylamine of formula (B):

, or a salt thereof.

Preferred features of the second aspect are as for the first and third aspects where relevant.

A third aspect of the invention provides a process for preparing l-methyl-1,2,3,4- tetrahydroisoquinoline of formula (A):

, or a salt thereof, the process comprising:

(i) reacting N-(2-haloethyl)- -methylbenzylamine of formula (BI):

, or a salt thereof, with a Lewis acid, and (ii) causing or allowing cyclisation (e.g. of the resulting complex) to 1 -methyl- 1,2,3, 4- tetrahydroisoquinoline at a temperature of <130 °C.

The halogen "Hal" in formula (BI) is preferably F, CI, Br or I, more preferably CI (a chlorine atom) or Br (a bromine atom).

The temperature in the cyclisation step (ii) is preferably <125 °C or <120 °C, more preferably <110 °C, even more preferably <105 °C; and or is preferably > 90 °C, more preferably >95 °C. For example, the temperature in the cyclisation step (ii) is advantageously 90-125 °C or 90-120 °C, e.g. 95-125 °C, 95-120 °C, 95-110 °C, or 95- 105 °C, and (especially where "Hal" is CI) is most advantageously about 100 °C.

As discussed above, temperatures lower than the 140-150 °C disclosed in WO 97/42186 generally give lower amounts of impurities (Y) and (Z). This advantage of lower cyclisation temperatures has been found to apply to cyclisation of the 2-bromo-ethyl as well as 2-chloro-ethyl compounds or salts (BI). For example, the total combined amount of 6/7-ethyl impurities (Y) and (Z) obtained with 120 °C bromo-ethyl cyclisation is normally about 1-2% (e.g. Example 2 hereinafter - ca. 1% total (Y) + (Z)), compared to about 3.5-4% impurities with 150 °C bromo-ethyl cyclisation (e.g. Comparative Examples A and B hereinafter).

Where the halogen "Hal" in formula (BI) is a bromine atom, the temperature in cyclisation step (ii) is advantageously 110-130 °C, 110-125 °C or more preferably about 120-125 °C; and or preferably the cyclisation time is preferably 15-48 hours, more preferably 18-36 or 19-30 hours. The bromo-intermediate (BI) generally reacts more slowly than the chloro-intermediate (B 1)/(B), in which case a reaction temperature of about 120 °C allows the reaction to be completed in a more reasonable time than at about 100 °C, thereby optimising throughput and use of reactor equipment.

In the first, third and other aspects of the invention, "the temperature in the cyclisation step (ii)" means the average reaction temperature for the majority of the time period (i.e. for >50% of the time period, or more preferably for >70% or >80% or >95% or substantially all of the time period) during which a significant amount of cyclisation takes place, the time period starting at the time when a significant amount of cyclisation starts to take place. For example, for Examples 3, 4, 8 and 9 hereinafter, in which "Hal" in formula (B 1) = Br and the reaction temperature is 120 °C for 20 to 25 hrs and then 140°C for 1 hr, then the temperature in the cyclisation step (ii) is deemed as being 120 °C as this is the temperature for >95% of the cyclisation time period. Similarly, for Example 5 hereinafter, in which "Hal" in formula (BI) = Br and the temperature used is 80 °C for 4 hrs and then 120 °C for 19 hrs and then 140 °C for 4 hrs, the temperature in the cyclisation step (ii) is deemed as being 120 °C as this is the temperature for ca. 82.6% of the time period during which a significant amount of cyclisation takes place (there is no significant cyclisation at 80 °C at least where "Hal" in formula (BI) is Br). For Example 7, using 120 °C for 22 hrs and then cooling to and remaining at room temperature for 24 hrs, the temperature in the cyclisation step (ii) is deemed as being 120 °C as this is the temperature for most or substantially all of the time period during which a significant amount of cyclisation takes place.

Optionally, in the first and third aspects, where the temperature in the cyclisation step (ii) - as defined above - is <130 °C or <125 °C or <120 °C, and especially where "Hal" in formula (B 1) is Br, the temperature at or near the end of the cyclisation step (ii) may be raised to 135 to 160 °C or preferably to about 140 to about 150 °C (e.g. about 140 °C). The temperature may be so raised: (a) for a period of about 0.5 to about 5 hours, or preferably for a period of about 0.5 to about 2 hours or about 0.5 hours to about 1 hour; and/or (b) for the last <30% or <20% or <5% of the time period during which a significant amount of cyclisation takes place, the time period starting at the time when a significant amount of cyclisation starts to take place. This optional temperature regime enables the reaction to go further to completion thereby increasing yield, but at the expense of slightly increased levels of the undesirable impurities (Y) and (Z). Examples 3, 4, 5, 8 and 9 hereinafter are examples of this.

In the first, second and third aspects of the invention, preferably, a hydrohalide (e.g. hydrochloride or hydrobromide) salt of the N-(2-haloethyl)-α-methylbenzylamine is used. Preferably the HCl salt is used where "Hal" is chlorine, and the HBr salt where "Hal" is bromine.

Other preferred features are as described above for the first aspect of the invention.

A fourth aspect of the invention provides a process for preparing 5,6-dimethyl-2-(4- fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, or a salt thereof, comprising:

(a) preparing l-methyl-l,2,3,4-tetrahydroisoquinoline or a salt thereof according to a process as defined in the first or third aspects of the invention, and

(b) reacting the resulting l-methyl-l,2,3,4-tetrahydroisoquinoline or salt thereof with 5,6- dimethyl-2-(4-fluorophenylamino)-4-(halo)pyrimidine.

The conditions of step (b) can be as disclosed in WO 97/42186, for example using one or more of the conditions disclosed in claims 2-8 and/or page 5 line 20 to page 7 line 17 of WO 97/42186, each of which conditions separately or together are hereby incorporated herein by reference as though fully set forth. For example, 5,6-dimethyl-2-(4- fluorophenylamino)-4-(chloro)pyrimidine can be used in step (b). Also provided according to a fifth aspect of the invention is a process for preparing 5,6- dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2- yl)pyrimidine or a pharmaceutically acceptable salt thereof, comprising:

(i) reacting l-methyl-l,2,3,4-tetrahydroisoquinoline with 5,6-dimethyl-2-(4- fluorophenylamino)-4-(halo)pyrimidine in a first solvent in the presence of base,

(ii) optionally mixing the product of the reaction (i) with a second solvent (e.g. heptane or similar),

(iii) removing substantially all of the first and/or second solvent from the resulting 5,6- dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2- yl)pyrimidine ("free base"),

(iv) thereafter optionally forming the pharmaceutically acceptable salt of 5,6-dimethyl-2- (4-fluorophenyl_ιmino)-4-( 1 -methyl- 1,2,3 ,4-tetrahydroisoquinolin-2-yl)pyrimidine by reaction of the free base with the appropriate acid in a third solvent.

The preferred features of the fifth aspect of the invention are as follows. Preferably, in steps (i), (ii) and/or (iv) the reaction mixture is stirred. The conditions of step (i) can be as disclosed in WO 97/42186, for example using one or more of the conditions disclosed in claims 2-8 and/or page 5 line 20 to page 7 line 17 of WO 97/42186, each of which conditions separately or together are hereby incorporated herein by reference as though fully set forth. For example, 5,6-dimethyl-2-(4-fluorophenylamino)-4-(chloro)pyrimidine can be used in step (i). Preferably, in step (i) the first solvent comprises or is 1,2- propylene glycol or more preferably ethylene glycol, or a mixture thereof. In step (i), the reaction temperature is preferably in the range of from 110 °C to 160 °C, and/or the reaction time is preferably in the range of from 16 hours to 72 hours. Preferably, in step (i), the base comprises or is triethylamine.

In step (ii), the second solvent preferably comprises or is an organic solvent, more preferably a hydrocarbon solvent. The second solvent preferably has a boiling point of >100 °C. Preferably, the second solvent is such as to keep the product of the reaction (i) mobile, that is stirable and dispersed. More preferably, the second solvent comprises or is a Cη_ιo hydrocarbon solvent, for example toluene, xylene or a C7_ιo straight chain, branched or cyclic alkane solvent such as heptane, octane, nonane, decane, or decalin. Most preferably the second solvent comprises, consists essentially of, or is heptane. Preferably, the reaction mixture resulting from step (i) is cooled to or maintained at below the boiling point of the second solvent before the second solvent is added in step (ii). Preferably, the reaction mixture resulting from step (i) is cooled to or maintained at >70 or >80 °C and or <110 or <100 or <90 °C, e.g. 70-100 °C or 80-100 °C or 70-90 °C, before the second solvent is added in step (ii). Preferably, the ratio of the first solvent : the second solvent is 4:1 to 1:2, more preferably 4:1 to 1:1. Preferably, the temperature of the second solvent before the mixing in step (ii) is 0-40 °C, preferably 15-30 °C. It has been found that when the reaction mixture from step (i) - for example containing ethylene glycol - is cooled without addition of a second solvent acording to WO 97/42186, the crude product [5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahydroisoquinolin-2-yl)pyrimidine] precipitates out of solution as a large non-stirrable lump. Similarly, if water is added to the reaction mixture at a safe temperature then the product precipitates as a non-crystalline mass.

In the fifth aspect of the present invention, the product from reaction (i) [5,6-dimethyl-2- (4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine] usually at least partly precipitates out of solution during step (ii) after addition of the second solvent and/or after cooling. But in comparison to the WO 97/42186 procedure, the second organic solvent such as heptane helps to provide an organic/hydrophobic environment in step (ii) and/or helps to ensure that the precipitated product remains mobile - that is stirable and dispersed. This improves the crystallisation, ease of isolation and or the quality of the product 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-2-yl)pyrimidine.

After addition of the second solvent, the resulting mixture is preferably treated with water and an organic extraction solvent (e.g. dichloromethane). The resulting organic phase is optionally washed and optionally dried. Preferably some or all of the organic solvent resulting from extraction, and/or some or all of the first and/or second solvent, is removed from the resulting organic phase in step (iii), for example by distillation or by reduction in vacuo. Preferably, the concentrated organic solution or solid product resulting from the solvent removal is treated with such an amount of isopropanol and at such a temperature that after cooling the product 5,6-dimethyl-2-(4-fluorophenylamino)- 4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine crystallises from solution.

Preferably in step (iii) the free base is isolated as a crystalline solid (for example by crystallisation or recrystallisation from added isopropanol or from an isopropanol- containing solvent), and said solid is separated from the first and/or second solvent. Preferably, said solid is dried.

Preferably in step (iv) the pharmaceutically acceptable salt is formed as a crystalline solid, and said solid is separated from the third solvent. Preferably, said solid is dried.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The various aspects of the invention are illustrated by the following non-limiting Descriptions and Examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. Description 1

Preparation of (S)-N-(2-hydroxyethyl)-α-methylbenzylamine hydrobromide

C_βH^N C₁₀H₁₆NO MW = 121.18 MW = 165.234

(S)-(-)- -Phenethylamine (α-methylbenzylamine) (98%, 95%ee, obtained from BASF) (40.0g, 0.324mol) and 2-bromoethanol (45.5g, 0.356mol) are heated to 45 - 55°C (e.g. 47- 53°C) in dichloromethane (40 ml) for 36 - 48 hours (or 27 hours). The reaction mixture is cooled to 30°C and diluted with further dichloromethane (20 ml). Ethyl acetate (30ml) is added slowly at the end of the reaction (in general, sufficient ethyl acetate is added to the reaction mixture to obtain a turbid solution). During stirring for a further 2 hours, cooling the suspension to 0 - 5°C and continued stirring for 3 hours, the product (S)-N-(2- hydroxyethyl)-α-methylbenzylamine hydrobromide crystallizes from solution as the hydrobromide salt. The product is filtered and washed with ethyl acetate (40ml) and is dried at room temperature in the open atmosphere. Yield: 61. Og at 99% = 60.0g at 100% (75% yield).

Descriptions 2 and 3

Description 2: (R)-N-(2-hydroxyethyl)-α-methylbenzylamine hydrobromide was obtained from (R)-(+)-α-phenethylamine (α-methylbenzylamine) using the same method as described in Description 1.

Description 3: Similarly, racemic material N-(2-hydroxyethyl)-α-methylbenzylamine hydrobromide was obtained from racemic α-phenethylamine.

Description 4

Preparation of (R)-N-(2-chloroethyl)-α-methyIbenzyIamine hydrochloride

C₁₀H₁₅NO C₁₀H₁₄NCI MW = 165.234 MW = 220.142

(R)-N-(2-hydroxyethyl)-α-methylbenzylamine hydrobromide (from D2, 98%, 50.0g, 0.203mol) is dissolved in dichloromethane (500ml) and washed with a concentrated aqueous solution of potassium carbonate (56. lg, 0.406mol in 125ml water) with stirring for 30min, in order to liberate the (R)-N-(2-hydroxyethyl)-α-methylbenzylamine free base. After allowing the layers to separate, the lower aqueous layer is removed. The dichloromethane solution is concentrated by distillation (distilling off 250 ml dichloromethane) and then diluted with toluene (250ml). This solution is then dryed by azeotropic distillation (distilling off 250 ml of dichloromethane-toluene; base temperature = 73°C; cool to room temperature). The resulting solution is diluted with dichloromethane (250ml) and filtered to remove inorganic residues. The solution is then heated to reflux, thionyl chloride (44.5ml, 0.609mol) is then added slowly over 30- 60 minutes, and the reaction mixture is maintained at reflux for 8 - 16 hours. The product crystallizes from solution during this reflux period. When the reaction is complete the reaction mixture is concentrated to half its volume by distillation (distilling off about 250ml solvent until base temperature = 55 - 60° C, not allowing the temperature to exceed 60° C to avoid partial decomposition). Isopropanol (250ml) is then added over 30min. at reflux. Any remaining dichloromethane is removed by distillation (distilling off solvent until base temperature = 80 - 81°C) and the volume of the distillate is replaced with isopropanol. The resultant slurry is cooled to room temperature and stir for 3 hours, then cooled to 0 - 5° C and stirred for 3 hours. The product, which crystallizes during the reaction, is filtered, washed with with cold isopropanol (2 x 75ml) and dryed in a vacuum filter. Yield = 39.9g (89%).

Note that extra thionyl chloride (15.0ml, 0.20mol) can be added during the reaction to drive the reaction further to completion if necessary.

Example 1

Preparation of (R)-l-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride, the penultimate-stage intermediate in the synthesis of SB-641258-A

SB-699757-A SB-643003-A

(C₁₀H₁₄NC1).HC1 220 gmol^" (C₁₀H₁₃N).HC1 183 g mo! •1

Process Summary for Example 1:

Granular aluminium chloride (13.7 g, 102 mmol, 1.6 mole equivalents) is stirred as a suspension in decalin (decahydronaphthalene) (80 mL, 5.7 volumes). The mixture is heated to 80°C and N-(2-chloroethyl)-α-methylbenzylamine hydrochloride (14.1 g, 64 mmol) is added in portions over 45 minutes allowing sufficient time for HCl evolution to cease between each portion. Following addition the system is heated at 80°C for a further 2 hours to ensure formation of an amine-aluminium chloride melt. This is then heated to 100°C and maintained at that temperature for 46 hours. The system is allowed to cool to 35-25 °C and water (160 mL, 11 vol) is added very slowly, resulting in a vigorous exotherm. After complete addition, the slurry is transferred to a separating funnel, and the decalin layer separated and discarded. The aqueous phase is washed with ethyl acetate (40 mL, 2.8 vol) to eliminate any remaining decalin. The pH is adjusted to 14 by the slow addition of 10M NaOH (52 mL, 520 mmol), and the subsequent free-flowing aqueous suspension is extracted twice with dichloromethane (2 x 200 mL, 28 volumes in total). The dichloromethane is replaced with isopropyl alcohol (160 mL, 11 vol) by a distillation-addition process (see below for details). Concentrated aqueous hydrochloric acid (6.80 mL, 78 mmol) is then added maintaining the temperature below 30°C, resulting in the formation of a slurry of the salt SB-643003-A. The water is removed azeotropically by distilling to dryness. Further isopropyl alcohol (100 mL, 7 vol) is then added, and the mixture is heated to reflux to ensure complete dissolution of the solid. The solution is cooled slowly to 0°C resulting in crystallization of the salt between 50°C and 40°C. After one hour at 0°C the solid is removed by filtration, washing with isopropyl alcohol (2 x 20 mL, 2.8 vol), to afford pure SB-643003-A (8.1 g, 44.3 mmol, 69% yield, 99.6 % e.e.).

Detailed Procedure for Example 1

1. The granular AICI3 (13.7 g, 102 mmol) is stirred as a suspension in decalin (80 mL), and this immiscible mixture is heated to 80°C. 2. The hydrochloride salt SB-699757-A (14.1 g, 64 mmol) is added in portions over 45 minutes, allowing five minute intervals between additions. Evolution of HCl gas is observed after each addition.

3. Following complete addition, the mixture is stirred at 80°C for 2 hours to form a biphasic system with the amine and aluminium chloride forming a free-flowing melt with an upper decalin layer. This mixture is then heated to 100°C.

4. The mixture is heated between 100 and 105 °C for 46 hours, during which time there is again HCl evolution which gradually eases as the reaction nears completion. The finished reaction is a deep-red biphasic mixture. The reaction is then cooled to between 35 and 25 °C, at which temperature the system is still a fully liquid biphase.

5. The reaction is quenched by a very slow addition of water (160 mL, 11 vols), a process which is highly exothermic. The rate is adjusted to maintain the temperature below 60 °C. Early in the addition, the lower layer partially solidifies.

6. After complete addition of the water, the reaction is stirred until all the red solid has dissolved or dissipated and the system forms a free-flowing milky mixture.

7. Stirring is halted, and the system allowed to settle. SB-643003-A is contained in the lower aqueous layer whilst the decalin forms an immiscible upper layer. The aqueous phase is removed, and the organic phase is discarded.

8. The aqueous phase is returned to the reactor where it is washed with ethyl acetate (40 mL, 2.8 vol), in order to remove any residual decalin. The organic phase is again discarded.

9. The aqueous layer is adjusted to pH 14 by the slow addition of 10M NaOH (52.0 mL, 520 mmol), resulting in an exotherm and the precipitation of some solid. The system is then allowed to cool to room temperature. 10. The aqueous suspension is extracted with twice with dichloromethane (2 x 200 mL, 28 vols total). Emulsion formation occurs, but this rapidly separates. 11. The dichloromethane solution is concentrated to 30 mL by atmospheric distillation. IPA (160 mL, 11 vol) is then added and the mixture is again distilled at atmospheric pressure to leave 100 mL of an IPA solution of SB-643003.

12. The solution is cooled to 25 °C and acidified by the dropwise addition of concentrated hydrochloric acid (6.80 mL, 78 mmol). The exothermic addition is controlled to maintain the temperature below 30 °C.

13. The solution is stirred at 25 °C for 15 minutes after which a slurry forms. The mixture is then concentrated to a minimum stirrable volume (near dryness, 2 volumes approx.) by atmospheric distillation of the IPA (head temperature still 81

°C).

14. IPA (100 mL, 7 vol) is added and the mixture is heated to reflux. After 30 minutes dissolution of the solid is complete and the system is allowed to cool slowly.

Crystallization of SB-643004-A occurs between 50 and 40 °C.

15. The mixture is cooled to 0 °C and stirring continued for a further hour. 16. The solid is filtered and the flask is rinsed twice with IPA at 0 °C (2 x 20 mL, 2.8 vol) the rinses being used to wash the collected solid.

17. The solid is dried overnight on a vacuum filter at room temp, to afford off-white

SB-643003-A.

Example 2: Preparation of (_R)-l-methyl-l,2,3,4-tetrahydroisoquinoline, SB-643003, by reduced temperature cyclisation of N-(2-bromoethyI)-α-methylbenzylamine hydrobromide

SB-672675-C SB-643003

(C₁₀H₁₄NBr).HBr 309 gmol^"1 C_I0H₁₃N 147 g mol^"1

Process Summary for Example 2:

Granular aluminium chloride (3.45 g, 25.9 mmol, 1.6 mole equivalents) is stirred as a suspension in decalin (20 mL, 4.0 vol). The mixture is heated to 80°C and N-(2- bromoethyl)-α-methylbenzylamine hydrobromide (SB-672675-C, (R)-isomer thereof, 5.00 g, 16.2 mmol) is added in portions over 45 minutes allowing sufficient time for HBr evolution to cease between each portion. Following addition the system is heated to about 120°C and maintained at that temperature for twenty-four hours. The system is allowed to cool to 25°C and water (40 mL, 8 vol) is added very slowly, resulting in a vigorous exotherm. After complete addition, the slurry is transferred to a separating funnel, and the decalin layer separated and discarded. The aqueous phase is washed with ethyl acetate (10 mL, 2 vol) to remove any remaining decalin. The aqueous phase is adjusted to pH 14 by the slow addition of 10M NaOH (13 mL, 2.6 vol), and the subsequent free-flowing aqueous suspension is extracted twice with dichloromethane (2 x 50 mL, 20 vols total). The combined organic extracts are dried over magnesium sulfate and the solvent removed in vacuo to leave a brown oil. The oil may be purified by kugelrohr distillation at 110°C, 2mmHg (lit. 75°C, 0.5mmHg) to afford the pure f -l-___ιethyl-l,2,3,4- tetrahydroisoquinoline, SB-643003, as a clear oil. Yield of SB-643003 with respect to SB-672675-C = 54%; 96.3% purity by assay; 94.2% e.e.

Detailed Procedure for Example 2

1. The granular A1C1₃ (3.45 g, 25.9 mmol) is stirred as a suspension in decalin (20 mL), and this immiscible mixture is heated to 80°C.

2. The (R)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide SB-672675-C (5.00 g, 16.2 mmol) is added in 0.5 g portions over 45 minutes, allowing five minute intervals between additions. Evolution of HBr gas is observed after each addition. 3. Following complete addition, the system is biphasic with the amine and aluminium chloride forming a free-flowing melt with an upper decalin layer. This mixture is then heated to 120°C.

4. The mixture is maintained at between 120 and 125 °C for 24 hours, during which time there is again HBr evolution which gradually eases as the reaction nears completion. The finished reaction is a deep-red biphasic mixture. The reaction is then cooled to between 45 and 25°C, at which temperature the system is still a fully liquid biphase.

5. The reaction is quenched by a very slow addition of water (40 mL, 8.0 vols), a process which is highly exothermic. The rate of addition is adjusted to maintain the temperature below 50°C. Early in the addition, the lower layer partially solidifies. 6. After complete addition of the water, the reaction is stirred until all the red solid has dissolved or dissipated and the system forms a free-flowing milky mixture. 7. Stirring is halted, and the system allowed to settle. SB643003 is contained in the lower aqueous layer whilst the decalin forms an immiscible upper layer. The aqueous phase is removed, and the organic phase is discarded. 8. The aqueous phase is returned to the reactor where it is washed with ethyl acetate (10 mL), in order to remove any residual decalin. The organic phase is again discarded. 9. The aqueous layer is adjusted to pH 14 by the slow addition of 10M NaOH (13.0 mL, 2.6 vols), resulting in an exotherm and the precipitation of some solid. The system is then allowed to cool. 10. The aqueous suspension is extracted with twice with dichloromethane (2 x 50 mL, 20 vols total). Emulsion fomation occurs, but rapidly separates.

11. The combined dichloromethane extracts are dried over magnesium sulfate and are concentrated by evaporation to give a brown oil of impure SB-643003.

12. The oil is distilled in a bulb-to-bulb apparatus (90°C, 2mmHg) to afford SB- 643003 as a clear oil (1.29 g, 8.8 mmol, 54%). Example 2 using about 120 °C, produced reduced quantities of the 6/7-ethyl-impurities (Y) and (Z) - about 1% in total as shown in the scheme below:

This impurity profile compares favourably to the total 3.5-4% of the impurities [(Y) + (Z)] obtained when cyclising the 2-bromo-ethyl compound at the higher 150 °C temperature disclosed in WO 97/42186 (see Comparative Examples A and B below).

Examples 3 to 9 - Cyclisations of N-(2-bromoethyl)-α-methylbenzyIamine hydrobromide

Further examples of cyclisation of N-(2-bromoethyl)-α-methylbenzylamine hydrobromide were performed using procedures similar to Example 2 but on a larger scale, as follows. Some of these are Comparative Examples, which are not according to the present invention, using the higher 150 °C temperatures roughly according to WO 97/42186. Other Examples - according to the present invention - used lower temperatures and gave a generally lower %age of 6/7-ethyl-substituted impurities (Y) and (Z); some of these reactions of the invention used a short ca. 1-4 hour period at higher temperatures at the end of the cyclisation reaction to maximise conversion/yield at the expense of slightly higher amounts of 6/7-ethyl-substituted impurities.

SB-672675-C SB-643003

Example number of Reaction conditions * Scale (mass Yield (%) Assay 6/7-ethyl e.e. number equivalents of SB- (total SB- (%) 2 impurities of AlX₃ 672675-C) 643003) (Y) + (Z); total %age

Comparative I.6 AICI3 B, 150°C for 4 hrs 50 g 56 91.0 3.71 97.0 Example A Comparative I.6 AICI3 B, 150°C for 5 hrs 100 g 24 94.1 3.56 95.1 Example B

Example 3 1.6 AlCl B, 120 °C for 24 hrs, then 10 g 80 98.2 0.51 97.2 140°C for 1 hr

Example 4 1.6 A1C1^ B, 120°C for 25 hrs, then 100 g 80 93.5 1.73 98.7 140 °C for 1 hr

Example 5 1.6 A1C1 B, 80 °C for 4 hrs, 20 g 71 96.7 1.33 98.3 then 120 °C for 19 hrs, then 140 °C for 4 hrs

Example 6 1.6 AlCl^ B, 130 °C for 22 hours 50 g 50 88.6 1.54 98.0

Example 7 1.6 A1C1-} B, 120 °C for 22 hrs, 50 g 80 94.7 1.13 99.0 then allowing to cool to and remain at room temperature for 24 hrs

Example 8 1.7 AlCl^ B, 120 °C for 23 hrs, 50 g 71 94.0 2.45 98.3 then 140 °C for 1 hr

Example 9 1.8 AlCl^ B, 120 °C for 20 hrs, 50 g 65 96.0 1.15 99.3 then 140 °C for 1 hr

1. Under "Reaction conditions", "B" = slow addition of HBr salt SB-672675-C to A1C1₃

2. Assay = % purity of SB-643003 after distillation. 3. PAR relative to SB-643003

Example 10 - Deuterium labelling to find the source of the ethyl impurity in SB- 641258: Part 1

In the Examples 1-9 and Comparative Examples A-B, it was supposed that the ethyl impurities (Y) and (Z) observed could have come from either the N-(2-haloethyl)-α- methylbenzylamine starting material or from the decalin solvent (decalin can liberate ethylene on pyrolysis: Bajus, M; Baxa, J. Collect. Czech. Chem. Commun. 1982, 47, 1838-1847). To clarify the source of the ethyl-impurities (Y) and (Z), a study was undertaken involving the Freidel-Crafts reaction of the b._.-deuterated bromide 5. The bromide 5 was made in 3 steps from (R)-methylbenzylamine, as shown in the following scheme. Alkylation with ethyl bromoacetate gave the ester 3 which was reduced with lithium aluminium deuteride to give the di-deutero alcohol 4. Treatment with thionyl bromide gave the primary bromide 5, which was then submitted to a Friedel-Crafts reaction. The use of A1C1₃ and decalin at 150°C was employed to maximise the amount of ethyl impurity formed.

HPLC of the crude reaction mixture suggested 4% of the 6/7 ethyl impurities had been formed relative to the MTQ 5. Normal work-up and isolation of the free base were undertaken and the resulting oil containing 6, 7 and 8 was purified by distillation and preparative HPLC. The two ethyl impurities 7 and 8 were isolated as a mixture and it was clear that no deuterium atoms were present in the ethyl moiety. The logical conclusion is that the bromoethylene chain of is not the origin of the ethyl impurities.

Example 11 - Deuterium labelling to find the source of the ethyl impurity in SB- 641258: Part 2

Further studies were undertaken to determine the source of the ethyl analogues (Y) and (Z) of SB-643003, formed during the Friedel-Crafts reaction of the present invention. Deuterium can be readily incorporated into the methyl group of acetophenone by equilibration in D2O (Hillier, I.H.; Smith, S.; Mason, S.C.; Whittleton, S.N.; Watt, C.I.F.; Willis, J. , J.Chem.Soc, Perkin Trans. 2, 1988, 1345). Subsequent reduction, mesylation, azide formation and hydrogenation furnished the racemic benzylamine 7 with the deuteriums now incorporated into the α-methyl group. The bromoethyl side chain was then added and the racemic product subjected to the Friedel-Crafts reaction, as shown in the following scheme.

LC/MS analysis of the reaction showed that 2% of the 6/7 ethyl impurities 9 and 10 had been formed. This time the ethyl side chains each contained 3 deuterium atoms. Without being bound to theory, this suggests that surprisingly an intermolecular Friedel-Crafts rearrangement is taking place (March's Advanced Organic Chemistry, M.B. Smith and J. March Eds., Wiley, New York, 2001, p. 730), as shown below:

The amine 12 has been previously isolated from the reaction mixture. Further evidence for this mechanism was gained when the reaction was run in perfluorodecalin - the intermediate 11 was detected and no 6/7 ethyl impurities were formed. This suggests that decalin is the H source for the last step. If this were the case one would expect to see decalin oxidation products in the reaction mixture i.e. tetralin or napthalene. Indeed, traces of napthalene adducts with SB-643003 are seen as by-products from this reaction but are easily removed during workup.

Example 12

i) Formation of racemate of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (SB-641257) (free base)

1. 1 -methyl- 1,2,3, 4-tetrahydroisoquinoline ("MeTHIQ", 4.5g, 30.5mmol), 5,6-dimethyl- 2-(4-fluorophenylamino)-4-(chloro)pyrimidine ("chloropyrimidine", 7g , 27.8mmol), and triethylamine (4.02g, 39.75mmol) are heated to 135°C in ethylene glycol (45mL) until the reaction is complete (this is determined as <0.5% chloropyrimidine by LC PAR).

2. The reaction mixture is cooled to 95°C and heptane (25mL) is added. On further cooling water (lOOrnL) is added at 85°C and dichloromethane (75mL) at 35°C. The mixture is finally cooled to 20°C.

3. The aqueous phase is further extracted with dichloromethane (20mL). 4. The combined organic extracts are washed successively with 60mL portions of 2N HCl, water, 2molar NaOH, and 20% brine solution.

5. The organic phase is subjected to distillation and distillate collected until an internal temperature of 62°C is reached. Heptane (60mL) is added and the distillation continued until an internal temperature of 98°C is reached; ~35mL of distillate will be collected.

6. The solution is cooled to 80°C and isopropanol (lOmL) added. On cooling the SB- 641257 crystallizes at about 58°C. The mixture is cooled to 0°C, stirred for l-2h and the product isolated by filtration. It can be dried under vacuum at 45°C for 3h to give 8.23g, 81.6% yield.

ii) Conversion of SB-641257 free base to hydrochloride salt SB-641257-A (from a sample of the above isolated base).

1. SB-641257 (2g) is dissolved in isopropanol (8mL) at reflux. 2. The solution is cooled to 75°C and conc.HCl (0.85mL) added. The solution is allowed to cool to 20°C; crystallization occurs almost immediately (-70 - 75°C). 3. After stirring at 20°C for 2-4h the product is filtered off, washed with isopropanol (5mL) and dried under vacuum at 45°C to give 2.07g of SB-641257 A, 94.1% yield.

Claims

1. A process for preparing 1 -methyl- 1,2,3, 4-tetrahydroisoquinoline of formula (A):

, or a salt thereof, the process comprising:

(i) reacting N-(2-chloroethyl)-α-methylbenzylamine of formula (B):

, or a salt thereof, with a Lewis acid, and

(ii) causing or allowing cyclisation to l-methyl-l,2,3,4-tetrahydroisoquinoline.

2. A process as claimed in claim 1 wherein the hydrochloride salt of N-(2- chloroethyl)-α-methylbenzylamine is used in step (i).

3. A process as claimed in claim 1 or 2 wherein the Lewis acid comprises AICI3 or AlBr₃.

4. A process as claimed in claim 1, 2 or 3 wherein in step (i) about 1.5 to about 2.5 mole equivalents of the Lewis acid are used based on the number of moles of the N-(2- haloethyl)-α-methylbenzylamine of formula (B).

5. A process as claimed in any preceding claim, wherein the temperature in the cyclisation step (ii) is 90-150 °C.

6. A process as claimed in any preceding claim, wherein the temperature in the cyclisation step (ii) is 95-110 °C.

7. A process as claimed in any preceding claim, wherein steps (i) and/or (ii) are carried out in the presence of a non-polar organic solvent with a boiling point higher than the reaction temperature in steps (i) and (ii).

8. A process as claimed in any preceding claim, wherein steps (i) and/or (ii) are carried out in the presence of a suitable solvent which allows formation of a biphasic mixture in steps (i) and/or (ii).

9. A process as claimed in any preceding claim, wherein steps (i) and/or (ii) are carried out in the presence of a suitable solvent comprising or being decalin or perfluorodecalin.

10. A process as claimed in any preceding claim, wherein, after the cyclisation step (ii), the reaction mixture is caused or allowed to cool; the reaction mixture is then mixed with water or an aqueous solution; and the resulting aqueous phase is then separated, adjusted to alkaline pH if necessary, and extracted with a organic solvent suitable for extraction.

11. A process as claimed in any preceding claim, wherein, after formation of the 1- methyl- 1,2,3, 4-tetrahydroisoquinoline, the process comprises the additional steps of:

(iii) reacting the 1 -methyl- 1,2,3, 4-tetrahydroisoquinoline with an acid to form a salt of 1- methyl- 1,2,3, 4-tetrahydroisoquinoline in a suitable solvent;

(iv) allowing or causing said salt to crystallise from solution; and

(v) separating the crystalline salt of l-methyl-l,2,3,4-tetrahydroisoquinoline from the reaction mixture.

12. A process as claimed in claim 11, wherein in step (iii) the suitable solvent comprises or is isopropanol.

13. N-(2-chloroethyl)-α-methylbenzylamine of formula (B):

, or a salt thereof.

14. A salt as claimed in claim 13, being the hydrochloride salt.

15. A process for preparing l-methyl-l,2,3,4-tetrahydroisoquinoline of formula (A):

, or a salt thereof, the process comprising:

(i) reacting N-(2-haloethyl)- -methylbenzylamine of formula (BI):

, or a salt thereof, with a Lewis acid, and

(ii) causing or allowing cyclisation to l-methyl-l,2,3,4-tetrahydroisoquinoline at a temperature of <130 °C.

16. A process as claimed in claim 15, wherein the halogen "Hal" in formula (BI) is a bromine atom.

17. A process as claimed in claim 16, wherein the temperature in cyclisation step (ii) is 110-130 °C.

18. A process as claimed in any of claims 5 to 6, or claims 7 to 12 as dependent on claims 5 to 6, or claims 15 to 16, wherein the temperature in the cyclisation step (ii) means the average reaction temperature for >80% of the time period during which a significant amount of cyclisation takes place, the time period starting at the time when a significant amount of cyclisation starts to take place.

19. A process for preparing 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, or a salt thereof, comprising:

(a) preparing 1 -methyl- 1,2,3, 4-tetrahydroisoquinoline or a salt thereof according to a process as defined in the first or third aspects of the invention, and

20. A process for preparing 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof, comprising:

(ii) optionally mixing the product of the reaction (i) with a second solvent, (iii) removing substantially all of the first and/or second solvent from the resulting 5,6- dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2- yl)pyrimidine ("free base"), and

(iv) thereafter optionally forming the pharmaceutically acceptable salt of 5,6-dimethyl-2- (4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine by reaction of the free base with the appropriate acid in a third solvent.

21. A process as claimed in claim 20, wherein in step (ii), the second solvent preferably comprises or is a C .jQ hydrocarbon solvent.

22. A process as claimed in claim 20, wherein the 'J.IQ hydrocarbon solvent comprises, consists essentially of, or is heptane.

23. A process as claimed in claim 20, 21 or 22, wherein the reaction mixture resulting from step (i) is cooled to or maintained at 70-90 °C, before the second solvent is added in step (ii).