CA-3210678-C - NOVEL PROCESS FOR PREPARING 7-(4,7-DIAZASPIRO[2.5]OCTAN-7-YL)-2-(2,8-DIMETHYLIMIDAZO[1,2-B]PYRIDAZIN-6-YL)PYRIDO[1,2-A]PYRIMIDIN-4-ONE

Abstract

The present invention relates to a process for the preparation of 7-(4,7- diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2- a]pyrimidin-4-one derivatives useful as pharmaceutically active compounds.

Inventors

• Jean-Michel Adam
• Christophe Pfleger
• Georg WUITSCHIK

Assignees

• F. HOFFMANN-LA ROCHE AG

Dates

Publication Date

20260505

Application Date

20220316

Priority Date

20210318

Claims (1)

1. CA 3210678-50- Claims 1. 5 A process for the preparation of a compound of formula (I) or the HCl salt thereof: (I) which comprises reacting compound of formula (II): with a strong acid. 2. (II) ; The process according to claim 1, wherein the strong acid is HCl. 3. 10 The process according to claim 1 or 2, wherein the HCl is made in situ with n propanol and acetyl chloride. 4. A process for the preparation of a compound of formula (II): CA 3210678-51- (II) ; which comprises heating at a temperature above 70°C a mixture of a compound of formula (III) 5 in the presence of a solvent. 5. (III) The process according to claim 4, wherein the solvent is selected from isopropanol, n-propanol, t-butanol, n-butanol and isobutanol. 6. A process for the preparation of a compound of formula (III) CA 3210678-52- (III) which comprises reacting a compound of formula (IV) (IV) with a compound of formula (IVa) 5 7. (IVa) . A process for the preparation of a compound of formula (IV) CA 3210678-53- (IV) which comprises reacting a compound of formula (V) or its tautomer (V) with oxalyl chloride in presence of a solvent. 5 8. (V-tautomer) A process for the preparation of a compound of formula (V) (V) CA 3210678-54- which comprises reacting a compound of formula (VII) 5 (VII) with oxalyl chloride in presence of a solvent followed by the addition of 2,2 dimethyl-1,3-dioxane-4,6-dione, wherein DMAP is present, wherein 2.5 to 5.0 equivalents of DMAP is present with respect to the theoretical amount of compound of formula (VII). 9. A process for the preparation of a compound of formula (V) (V) which comprises reacting a compound of formula (VI) 10 (VI) CA 3210678-55- with 2,2-dimethyl-1,3-dioxane-4,6-dione, in presence of a solvent, wherein DMAP is present, wherein 2.0 to 2.5 equivalents of DMAP is present with respect to the theoretical amount of compound of formula (VI). 10. 5 10 11. A process for the preparation of a compound of formula (VI) (VI) which comprises reacting a compound of formula (VII) (VII) with oxalyl chloride in presence of a solvent wherein DMAP is present. The process according to any one of claims 1 to 3, which further comprises the preparation of a compound of formula (II) which comprises heating a compound of formula (III) (II) ; CA 3210678-56- 12. (III) . The process according to claim 11, which further comprises the preparation of a compound of formula (III) 5 which comprises reacting a compound of formula (IV) (III) ; CA 3210678-57- (IV) with a compound of formula (IVa) 13. 5 (IVa) . The process according to claim 6 or 12, wherein reacting a compound of formula (IV) with a compound of formula (IVa) is in the presence of a tertiary amine. 14. The process according to claim 12 or 13, which further comprises the preparation of a compound of formula (IV) (IV) which comprises reacting a compound of formula (V) or its tautomer CA 3210678-58- (V) with oxalyl chloride. 15. 5 (V-tautomer) The process according to claim 14, wherein the reaction is carried out in the presence of solvent selected from dichloromethane, 2-MeTHF, THF, DMF, and NMP. 16. The process according to claim 14 or 15, which further comprises the preparation of a compound of formula (V) (V) which comprises reacting a compound of formula (VI) (VI) ; CA 3210678-59- with 2,2-dimethyl-1,3-dioxane-4,6-dione. 17. The process according to claim 16, which further comprises the preparation of a compound of formula (VI) 5 (VI) which comprises reacting a compound of formula (VII) (VII) with oxalyl chloride in presence of a solvent, wherein DMAP is present, wherein 1.5 to 4.0 equivalents of DMAP is present with respect to the theoretical amount of compound of formula (VII). 10 18. The process according to claim 17, which further comprises the preparation of a compound of formula (VII) (VII) which comprises reacting a compound of formula (VIII) CA 3210678-60- 19. 5 (VIII) with carbon monoxide in the presence of a catalyst and in the presence of a base. The process according to claim 18, wherein the catalyst is Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, or PdCl2(dppp). 20. The process according to claim 18 or 19, which further comprises the preparation of a compound of formula (VIII) (VIII) which comprises: a) reacting a compound of formula (X) 10 (X) with NH4OH to obtain compounds of formula (IXa) b) reacting compounds of formula (IXa) CA 3210678-61- (IXa) with 1-bromo-2,2-dimethoxypropane, in the presence of pyridinium p toluenesulfonate, to obtain a compound of formula (VIII). 21. A compound of formula (II) 5 22. A compound of formula (III) (II) . 23. A compound of formula (IV) (III) . CA 3210678-62- (IV) 24. A compound of formula (V) 5 25. (V) . . A compound of formula (V-tautomer) (V-tautomer) . CA 3210678-63- 26. A compound of formula (VI) (VI) .

Description

NOVEL PROCESS FOR PREPARING 7-(4,7- DIAZASPIRO[2.5]OCTAN-7-YL)-2-(2,8-DIMETHYLIMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRIDO[1,2-A]PYRIMIDIN-4-ONE The present invention relates to a process for the preparation 7-(4,7- diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2- a]pyrimidin-4-one useful as pharmaceutically active compounds. In a first aspect, the present invention provides a process for the preparation of a compound 5 of formula (I) hydrates, solvates or the HCl salt thereof: (I) which comprises reacting compound of formula (II): (II) with a strong acid (to effect the decarboxylation and Boc-deprotection), in particular 10 sulfuric acid, methanesulfonic acid, triflic acid or hydrochloric acid, in particular methanesulfonic acid, triflic acid and HCl, more particularly HCl, most particularly wherein HCl is made in situ with an alcohol and acetyl chloride. The process according to the first embodiment, wherein the water free HCl is used. It can as well be made in situ with an alcohol and acetyl chloride, in particular, methanol, 15 ethanol, n-propanol, isopropanol or n-butanol and acetyl chloride in particular npropanol and acetyl chloride. ~N ~N~:I HN~ 0 In a particular embodiment, after strong acid addition and reaction (to effect Boe deprotection and decarboxylation), the pH of the resulting acid solution of I is adjusted via base addition to isolate the free base. In particular, the preparation of compound of formula (I) is being carried out in the 5 presence of an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol or nbutanol, in particular n-propanol or isopropanol, more particularly n-propanol. In a particular embodiment, the present invention provides a process as described herein, wherein 5 to 20 equivalents, more particularly 7 to 10 equivalents ofHCl with respect to the theoretical amount of compound of formula (II) is used. 10 In another embodiment, the present invention provides a process as described above for the preparation of compound of formula (I), wherein the reaction is carried out at a temperature between 80°C to 120°C, particularly between 85°C to 100°C, more particularly between 85°C and 95°C. In another embodiment, the present invention provides a process as described herein, 15 wherein HCl is made in situ with acetyl chloride in n-propanol at a temperature between 0- 60°C, particularly between 0-40°C during the addition of acetyl chloride then heated up to 60°C, more particularly between 10-20°C during the addition of acetyl chloride then heated up to 60°C at atmospheric pressure. In another embodiment, the present invention provides a process as described herein 20 wherein to reach a temperature higher than the boiling point would the solvent a pressurized reactor. The compounds of formula (I) are valuable pharmaceutical compounds, in particular 7- ( 4, 7-diazaspiro[2. 5]octan-7-yl)-2-(2,8-dimethylimidazo[ 1,2-b ]pyridazin-6-yl)pyrido[ 1,2- a ]pyrimidin-4-one as described in WO2015l73181. 25 Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: "(C1-C6)alkyl" refers to a branched or straight hydrocarbon chain of one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl. The term "(C3-Cs)cycloalkyl" denotes a saturated monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Examples for monocyclic (C3- Cs)cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl,cyclohexyl or cycloheptyl. "base" refers to a chemical compound that deprotonates another compound when reacted 5 with it. Suitable bases for use in accordance with this disclosure include but are not limited to, e.g., tertiary amines and basic alkali metal salts. In some embodiments, the tertiary amines include triethylamine, tributylamine, N-methylmorpholine and diisopropylethylamine. In some embodiments, the basic alkali metal salts include, e.g., lithium carbonate (Li2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 10 cesium carbonate (Cs2CO3), sodium bicarbonate (NaHCQ3), lithium, cesium, sodium and potassium hydroxide, sodium and potassium alkoxides including, but not limited to, sodium and potassium t-butoxide, npropoxide, i-propoxide, ethoxide, methoxide, and the like, sodium amide (NaNH2), potassium amide (KNH2), and the like. "crystallization" and "recrystallization" may be used interchangeably; referring to a 15 process wherein a chemical compound that is dissolved or suspended in a solvent system leads to a stable polymorph or crystalline form of a particular chemical compound. For example the crystallization steps can be done by forming a crystal with a solvent and an anti-solvent. "strong acid" refers to an acid that dissociates completely in an aqueous solution with a 20 pKa < -1.74. The strong acids include, but are not limited to: sulphuric acid (H2 SQ4), hydrohalogenic acid (i.e. HX" wherein X" is I, Br, Cl