Process for the preparation of N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-amine

1. Process for the preparation of a compound of the formula (I):

or pharmaceutically acceptable addition salts thereof,

comprising the following steps:

step a) oxidation of [3-(bromomethyl)oxetan-3-yl]methanol of formula (II) to form a compound of formula (III)

step b) conversion of carboxy group of a compound of formula (III) to carbamate to form a compound of formula (IV)

wherein R is C 1-6 alkyl, C 1-6 alkoxyphenyl-C x H 2x — or phenyl-C x H 2x —, wherein x is 1-6;

step c) amination of a compound of formula (IV) to form a compound of formula (V)

wherein R is as defined above;

step d) salt formation of a compound of formula (V) with an acid to form a compound of formula (VI)

wherein R is as defined above;

step e) substitution reaction of a compound of formula (VI) with a compound of formula (IX)

to give a compound of formula (VII)

wherein R is as defined above;

step f) substitution reaction of a compound of formula (VII) with a compound of formula (X)

to give a compound of formula (VIII)

wherein R is as defined above;

step g) comprises deprotection of a compound of formula (VIII) to give a compound of formula (I)

and if necessary, form a pharmaceutically acceptable addition salt.

2. A process according to claim 1 , wherein R is tert-butyl, 1,1-dimethylpropyl, benzyl or 4-methoxyphenylmethyl.

3. A process according to claim 1 , wherein step a) is performed with an oxidant at a reaction temperature range between 0° C. and 100° C.

4. A process according to claim 1 , wherein step a) is performed in a solvent comprising water, acetonitrile, dichloromethane, ethyl acetate or isopropyl acetate; or a co-solvent which is a mixture of two or more kinds of solvents comprising water, acetonitrile, dichloromethane, ethyl acetate or isopropyl acetate.

5. A process according to claim 3 , wherein the oxidant comprises sodium hypochlorite, potassium permanganate, 2,2,6,6-tetramethylpiperidinooxy or pyridinium chlorochromate; or a co-oxidant which is a mixture of two or more kinds of oxidants comprising sodium hypochlorite, potassium permanganate, 2,2,6,6-tetramethylpiperidinooxy or pyridinium chlorochromate.

6. A process according to claim 1 , wherein step b) is performed with an azide reagent and a base in an organic solvent and followed by adding an alcohol at temperature range of 0° C. and 100° C.

7. A process according to claim 6 , wherein the azide reagent used in step b) is diphenylphosphoryl azide.

8. A process according to claim 6 , wherein the base used in step b) is triethylamine, diisopropylethylamine or 4-methyl morpholine.

9. A process according to claim 6 , wherein the solvent used in step b) is acetonitrile, toluene, chlorobenzene or dichloromethane.

10. A process according to claim 6 , wherein the alcohol used in step b) is tert-butanol, 2-methyl-2-butanol, benzyl alcohol or 4-methoxyphenylmethanol.

11. A process according to claim 1 , wherein step c) is performed with an amination agent, at reaction temperature range of 0° C. and 60° C.

12. A process according to claim 11 , wherein the amination agent used in step c) is liquid ammonia.

13. A process according to claim 1 , wherein step d) is performed in a solvent with an organic or inorganic acid at a temperature range of 0° C. and 60° C.

14. A process according to claim 13 , wherein the solvent used in step d) is tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethylacetate or methyl tert-butyl ether.

15. A process according to claim 13 , wherein the acid used in step d) is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, L-tartaric acid, citric acid, L-lactic acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acid or 4-chlorobenzoic acid.

16. A process according to claim 1 , wherein step e) is performed in tetrahydrofuran at reaction temperature range between 10° C. and 30° C.

17. A process according to claim 1 , wherein step f) is performed in an organic solvent with acid catalyst in temperature range between 0° C. and 100° C.

18. A process according to claim 1 , wherein step g) is performed in an organic solvent with acid in temperature range between 0° C. and 100° C.

19. A process according to claim 3 , wherein step a) is performed with an oxidant at a reaction temperature range between 15° C. to 25° C.

20. A process according to claim 4 , wherein the solvent is a co-solvent of water and acetonitrile.

21. A process according to claim 5 , wherein the oxidant is a co-oxidant of 2,2,6,6-tetramethylpiperidinooxy and sodium hypochlorite.

22. A process according to claim 6 , wherein step b) is performed with an azide reagent and a base in an organic solvent and followed by adding an alcohol at temperature of 80° C.

23. A process according to claim 6 , wherein the base used in step b) is 4-methylmorpholine.

24. A process according to claim 6 , wherein the solvent used in step b) is toluene.

25. A process according to claim 6 , wherein the alcohol used in step b) is 4-methoxyphenylmethanol.

26. A process according to claim 1 , wherein step c) is performed with an amination agent, at reaction temperature range of 25° C. and 30° C.

27. A process according to claim 13 , wherein step d) is performed in a solvent with an organic or inorganic acid at a temperature range of 15° C. and 25° C.

28. A process according to claim 14 , wherein the solvent used in step d) is methyl tert-butyl ether.

29. A process according to claim 13 , wherein the acid used in step d) is 4-chlorobenzoic acid.

30. A process according to claim 17 , wherein step f) is performed in an organic solvent with acid catalyst in temperature range between 60° C. and 80° C.

31. A process according to claim 1 , wherein step g) is performed in an organic solvent with acid in temperature range between 10° C. and 40° C.