Process for the preparation of anagrelide and analogues thereof

1. A process for the preparation of a compound of formula (A), or a salt thereof:

wherein:

R 1 and R 2 are each independently hydrogen or a blocking group which functions to directly or indirectly prevent metabolic reaction at the 3-position of substitution;

V and W are independently chosen from the group consisting of: H, F, Cl, I, Br, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkanoyl;

X and Y are independently selected halo's; and

R 7 is a C 1-6 alkyl group or aryl group, each of which can be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C 1-6 alkyl, C 1-6 haloalkyl, —SR 8 , —OR 9 , —NR 8 R 9 , —NO 2 , SCF 3 , halogen, —C(O)R 8 , —CN, and —CF 3 , where R 8 and R 9 are independently H or C 1-6 alkyl

the process comprising the steps of:

(a) reacting a compound of the formula (X):

with a glycine derivative of the formula (XI)

in the presence of a suitable base and a suitable solvent to form an imine compound of the formula (XII)

(b) reducing the imine compound of formula (XII) with a suitable reducing agent to form the compound of formula A; and

(c) optionally isolating the compound of formula A in the form of an acid addition salt by reacting the compound of formula A with an suitable acid.

2. A process for the preparation of a compound of formula (B), or a pharmaceutically acceptable salt thereof:

wherein:

R 1 , R 2 , V, W, X, and Y are all as defined in claim 1 ; and

R 5 is H, C 1-6 alkyl or OH;

the process comprising the steps of:

(a) forming a compound of formula A from a compound of formula (X) as defined in claim 1 ;

(b) reducing the compound of formula (A) to form a compound of formula (XIII):

(c) reacting the compound of formula (XIII) prepared in step (b) above with cyanogen bromide in a suitable solvent to form a compound of the formula (XIV)

(d) reacting the compound of formula (XIV) under cycloalkylation conditions to form the compound of formula (B); and

(e) optionally thereafter forming a pharmaceutically acceptable salt of the compound of formula (B).

3. The process according to claim 1 , wherein X and Y are chloro.

4. The process according to claim 1 , wherein W and V are hydrogen.

5. The process according to claim 1 , wherein R 1 and R 2 are both selected from hydrogen or methyl.

6. The process according to claim 1 , wherein R 1 and R 2 are both methyl.

7. The process according to claim 2 , wherein R 5 is hydrogen.

8. The process according to claim 1 , wherein R 7 is methyl or ethyl.

9. The process according to claim 2 , wherein X and Y are chloro; V and W are hydrogen, R 1 and R 2 are both methyl; and R 5 is hydrogen.

10. The process according to claim 1 , wherein X and Y are chloro; V and W are hydrogen, R 1 and R 2 are both hydrogen or methyl; and R 7 is methyl or ethyl.

11. The process according to claim 1 , wherein the compounds of formula (X) are prepared by nitrating a compound of the formula (IX) shown below: