CN-122010950-A - Process for preparing Li Sipu orchid

Abstract

The present invention relates to a process for preparing Li Sipu orchid. In particular, the present invention relates to a process for the preparation of 7- (4, 7-diazaspiro [2.5] oct-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
• Christopher Flig
• George Uitjic

Assignees

• 豪夫迈·罗氏有限公司

Dates

Publication Date

20260512

Application Date

20220316

Priority Date

20210318

Claims (5)

1. 1. A process for the preparation of a compound of formula (IV), Comprising reacting a compound of formula (V) or a tautomer thereof With oxalyl chloride, in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from the group consisting of 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane.
2. 2. A process for the preparation of a compound of formula (V), Comprising reacting a compound of formula (VII) With oxalyl chloride, in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, followed by the addition of 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, also known as Meldrum's acid, wherein DMAP is present, more particularly wherein 2.5 to 5.0 equivalents, more particularly 3.0 to 4.0 equivalents, most preferably about 3.2 equivalents of DMAP are present relative to the theoretical amount of compound of formula (VII).
3. 3. A process for the preparation of a compound of formula (V), Which comprises reacting a compound of formula (VI) ; With 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, also known as Meldrum's acid, in particular in the presence of a solvent, more particularly wherein the solvent is selected from dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF and dichloromethane, most particularly wherein the solvent is dichloromethane, wherein DMAP is present, more particularly wherein 2.0 to 2.5 equivalents, more particularly 2.2 to 2.4 equivalents, most preferably about 2.3 equivalents of DMAP relative to the theoretical amount of compound of formula (VI).
4. 4. A process for the preparation of a compound of formula (VI), Comprising reacting a compound of formula (VII) With oxalyl chloride, in particular in the presence of a solvent, more particularly wherein the solvent is selected from the group consisting of dichloromethane, 2-MeTHF, THF, DMF, NMP, more particularly from 2-MeTHF and THF, and dichloromethane, most particularly wherein the solvent is dichloromethane, in particular wherein DMAP is present, more particularly wherein 1.5 to 4.0 equivalents, more particularly 2.0 to 3.0 equivalents, most preferably about 2.0 equivalents of DMAP are present relative to the theoretical amount of compound of formula (VII).
5. 5. A compound of formula (IV), (V) or (V-tautomer): , Or (b) 。

Description

Process for preparing Li Sipu orchid The application is a divisional application of PCT International application No. PCT/EP2022/056778, china national application No. 202280021947.3, method for preparing Li Sipu blue, with PCT International application No. 2022, 3 months and 16 days. The present invention relates to a process for the preparation of 7- (4, 7-diazaspiro [2.5] oct-7-yl) -2- (2, 8-dimethylimidazo [1,2-b ] pyridazin-6-yl) pyrido [1,2-a ] pyrimidin-4-one, which is useful as a pharmaceutically active compound. In a first aspect, the present invention provides a process for preparing a compound of formula (I), a hydrate, solvate or hydrochloride thereof: comprising reacting a compound of formula (II): With strong acids, in particular sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid or hydrochloric acid, in particular methanesulfonic acid, trifluoromethanesulfonic acid and hydrochloric acid, more in particular hydrochloric acid, most in particular wherein hydrochloric acid is prepared in situ with alcohol and acetyl chloride, to achieve decarboxylation and Boc-deprotection. The method according to the first embodiment, wherein anhydrous hydrochloric acid is used. It can also be prepared in situ from alcohols and acetyl chloride, in particular methanol, ethanol, n-propanol, isopropanol or n-butanol and acetyl chloride, in particular n-propanol and acetyl chloride. In a particular embodiment, after addition and reaction of the strong acid (to achieve Boc deprotection and decarboxylation), the pH of the resulting acid solution of I is adjusted via addition of a base to isolate the free base. In particular, the preparation of the compounds of formula (I) is carried out in the presence of an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol, in particular n-propanol or isopropanol, more in particular 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 of hydrochloric acid are used relative to the theoretical amount of the compound of formula (II). In another embodiment, the present invention provides a process for preparing a compound of formula (I) as described above, wherein the reaction is carried out at a temperature between 80 ℃ and 120 ℃, in particular between 85 ℃ and 100 ℃, more in particular between 85 ℃ and 95 ℃. In another embodiment, the present invention provides a process as described herein, wherein hydrochloric acid is prepared in situ with acetyl chloride in n-propanol during the addition of acetyl chloride and then heating to up to 60 ℃, more particularly between 10 and 20 ℃ at atmospheric pressure during the addition of acetyl chloride and then heating to up to 60 ℃, between 0 and 60 ℃, particularly between 0 and 40 ℃. In another embodiment, the invention provides a process as described herein wherein the solvent requires a pressurized reactor in order to reach a temperature above the boiling point. The compounds of formula (I) are valuable pharmaceutical compounds, in particular 7- (4, 7-diazaspiro [2.5] oct-7-yl) -2- (2, 8-dimethylimidazo [1,2-b ] pyridazin-6-yl) pyrido [1,2-a ] pyrimidin-4-one as described in WO 2015173181. The following terms, as used in the specification and claims, have the meanings given below, unless otherwise indicated: "(C 1-C6) alkyl" means a branched or straight hydrocarbon chain having one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. The term "(C 3-C8) cycloalkyl" means a saturated monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Examples of monocyclic (C 3-C8) cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. "Base" refers to a compound that deprotonates another compound when reacted with the other compound. Suitable bases for use in the present disclosure include, but are not limited to, for example, tertiary amines and basic alkali metal salts. In some embodiments, tertiary amines include triethylamine, tributylamine, N-methylmorpholine, and diisopropylethylamine. In some embodiments, the alkali metal salts include, for example, lithium carbonate (Li 2CO3), sodium carbonate (Na 2CO3), potassium carbonate (K 2CO3), cesium carbonate (Cs 2CO3), sodium bicarbonate (NaHCO 3), lithium, cesium, sodium and potassium hydroxides, sodium and potassium alkoxides (including but not limited to sodium and potassium t-butoxides, n-propoxide, isopropoxide, ethoxide, methoxide, and the like), sodium amide (NaNH 2), potassium amide (KNH 2), and the like. "Crystallization" and "recrystallization" are used interchangeably and refer to the process by which a compound dissolved or suspended in a solvent system produces a stable polymorph or crystal form of a particular compound. For example, the crystallization step may be accomplished by forming crystals with a solvent and