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

Patent metadata

Field	Value
Publication number	US-10005770-B2
Application number	US-201615216501-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	Jan 24, 2014
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

The present invention relates to a novel process for the preparation of a compound of the formula (I):

and pharmaceutically acceptable acid addition salts thereof, which is useful for prophylaxis and treatment of respiratory syncytial virus (RSV) infection in mammal or human being.

First claim

The invention claimed is:

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.

Assignees

• Hoffmann La Roche

Inventors

• Chen Junli
• Ren Yi
• She Jin
• Wang Lin
• Yu Jianhua
• Zhang Guocai

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07D305/06

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms · CPC title

• C07D305/08

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title