WO2024003798A1 - A novel process for the preparation of 7 (4, 7- diazaspiro [2.5] octan-7-yl)-2-(2,8 dimethylimidazo[1,2-b] pyrid azin-6- yl) pyrido-4h-[1,2-a] pyrimidin-4-one with novel intermediates - Google Patents

A novel process for the preparation of 7 (4, 7- diazaspiro [2.5] octan-7-yl)-2-(2,8 dimethylimidazo[1,2-b] pyrid azin-6- yl) pyrido-4h-[1,2-a] pyrimidin-4-one with novel intermediates Download PDF

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WO2024003798A1
WO2024003798A1 PCT/IB2023/056733 IB2023056733W WO2024003798A1 WO 2024003798 A1 WO2024003798 A1 WO 2024003798A1 IB 2023056733 W IB2023056733 W IB 2023056733W WO 2024003798 A1 WO2024003798 A1 WO 2024003798A1
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formula
palladium
compound
risdiplam
solvents
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PCT/IB2023/056733
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French (fr)
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Kiran Kumar Kothakonda
Bhaskar Reddy Pitta
Suresh Babu NAMANA
Jagadeesh Babu Rangisetty
Manik Reddy Pullagurla
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Biophore India Pharmaceuticals Pvt. Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
    • B01J21/18—Carbon
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/44—Palladium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J25/00—Catalysts of the Raney type
    • B01J25/02—Raney nickel
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a process for the preparation of 7-(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) pyrido-4H-[l,2-a] pyrimidin-4-one represented by the following structural formula (1) by employing novel intermediates of formulae (5), (6), (7), (9) and (13).
  • Risdiplam is reported in US 9,969,754 by F Hoffmann La Roche AG.
  • the synthetic process for Risdiplam is reported in US’754 patent, which comprises amination of compound of formula (10) is reacted with aqueous ammonia in dichloromethane to provide compounds of formulae (11) and (11’) as a mixture of Regio isomers.
  • the Regio isomers of formula (11) and (11’) are reacted with l-bromo-2,2- dimethoxypropane in the presence of PPTS/2-propanol/DCM followed by chromatography purification to provide compound of formula (12).
  • the compound of formula (12) is reacted with bis (pinacolato) diborane in the presence of PdC12(dppf).CH2C12/potassium acetate to provide compound of formula (8).
  • the compound of formula (8) is reacted with compound of formula (16) in the presence of Pd (PPh3)4/potassium carbonate/acetonitrile to provide compound of formula (17)
  • the compound of formula (17) is reacted with compound of formula (18) in the presence of DIPEA/DMSO/DCM followed by purification using column chromatography to obtain Risdiplam (1).
  • the present invention aims at providing a novel process and purification of Risdiplam (1) by employing novel intermediates limiting the formation of impurities and yield enhancement of the final compound by using safe and commercially viable reagents under mild reaction conditions and in short time which are applicable at large scales.
  • one objective of the present invention is to provide a process for the preparation of Risdiplam (1) by using novel intermediates of formulae (5), (6), (7) and (9).
  • Yet, in another objective of the present invention is to provide a process for the purification of Risdiplam (1).
  • Risdiplam (1) so obtained is having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.
  • one aspect of the present invention is to provide a process for the preparation of Risdiplam (1) as shown in scheme 2, the process comprising: a) reacting compound of formula (2) or its salt with 5-bromo-2-nitro pyridine
  • step F adding water to the obtained solid in step E),
  • step F adding one or more solvent(s) to the obtained solid in step F),
  • Risdiplam (1) obtained by the above process is having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.
  • the present invention further provides process for the preparation of tartaric acid premix with pure Risdiplam of formula (1).
  • Figure 1 illustrates X-Ray Diffraction (XRD) pattern of premix of Risdiplam (1) with tartaric acid obtained according to example 19.
  • one embodiment of the present invention is to provide a process for the preparation of Risdiplam (1), which is illustrated in scheme 2:
  • P is an “amine protecting group” or “N-protecting group” can be selected from but not limited to alkoxy carbonyl such methoxycarbonyl (Moc), methoxycarbonyl, benzyloxy carbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), acyl, benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), tosyl, trityl, methanesulfonyl, benzene sulfonyl, triflate, trialkyl silyl, trifluoroacetyl, trichloro ethyl chloroformate (Troc) group and the like.
  • step a) of the present invention proceeds with reacting compound of formula (2) or its salt with 5-bromo-2-nitro pyridine (3) in the presence of a suitable base and potassium iodide in a suitable solvent to obtain compound of formula (4).
  • the reaction may be carried out at a temperature ranging from about 70°C to 95°C, preferably about 80°C to 85°C.
  • This step further provides a simple method for the purification of compound of formula (4) using suitable solvent.
  • the base as used in step a) is selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like.
  • the salts used in step a) is selected from acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane sulfonic, ethane di sulfonic, oxalic, iso thionic, and the like, preferably using oxalic acid.
  • step b) of the present invention proceeds with hydrogenating compound of formula (4) with a suitable hydrogenation catalyst in one or more suitable solvent(s) to obtain compound of formula (5).
  • the reaction may be carried out at temperature ranging from about 20°C to 45°C or about 25 °C to 35 °C.
  • the compound of formula (5) may be further isolated in the form of solid or proceeds to next step without isolation (in-situ).
  • the compound of formula (5) obtained in step b) is not isolated as a solid and proceeds to next step without isolation (in-situ).
  • the hydrogenation reaction as used in step b) is conducted using various catalysts, including but without limitation thereto: metal catalysts such as palladium, platinum, Raney nickel, iridium, ruthenium, rhodium, iron, zinc, and the like on a carbon or other Support; a transition metal catalyst in combination with an acid Such as iron/HCl, Zn/HCl, Sn/HCl, Zn/acetic acid, or Zn/ammonium formate; Raney nickel; and the like.
  • a catalyst may be a chemical reducing agent Such as Stannous chloride (SnCh), ferric chloride (FeCh), in the presence of an acid like acetic acid or hydrochloric acid, or a base like hydrazine.
  • a useful catalyst is Raney nickel.
  • concentrations of palladium on the support, such as carbon, that can be used for the hydrogenation reaction may range from about 1% to about 30%, or about 5% to 10%, or about 10% by weight.
  • step c) of the present invention proceeds with reacting compound of formula (5) with di-tert-butyl malonate in the presence of a suitable solvent to obtain compound of formula (6).
  • the reaction may be carried out at a temperature of about 130°C to 155°C, preferably about 140°C to 145°C.
  • step d) of the present invention proceeds with reacting compound of formula (6) with p-toluene sulfonyl chloride in the presence of a suitable base in one or more suitable solvent to provide compound of formula (7).
  • the reaction may be carried out at room temperature.
  • This step further provides a simple method for the purification of compound of formula (7) using suitable solvent.
  • step e) of the present invention proceeds with coupling compound of formula (7) with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) imidazo [1,2-b] pyridazine (8) in the presence of palladium catalyst and base in a suitable solvent, followed by purification in a suitable solvent or mixture thereof to obtain compound of formula (9).
  • the compound of formula (9) may be further isolated in the form of solid or proceeds to next step without isolation (in-situ).
  • step f) of the present invention proceeds with deprotecting compound of formula (9) with a suitable amine deprotecting agent and ammonium formate in one or more suitable solvent to provide crude Risdiplam (la).
  • the suitable amine deprotecting agent used in step f) is selected from palladium on carbon, palladium hydroxide, palladium, or palladium hydroxide mixture.
  • step 1) of the present invention proceeds with amination of
  • the suitable aminating agent used in step 1) is selected from aqueous ammonia or ammonium hydroxide.
  • the reaction may be carried out at a temperature of about 100°C to 120°C, preferably at a temperature of about 110 °C.
  • step 2) of the present invention proceeds with cyclizing 6- chloro-4-methylpyridazin-3-amine (11) with 1-bromo, 2,2-dimethoxy propane in the presence of a suitable acid in a suitable solvent to obtain 6-chloro-2,8- dimethylimidazo[l,2-b] pyridazine (12).
  • the suitable acid used in step 2) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, p- toluenesulfonic acid monohydrate, pyridinium p-toluene sulfonate, 10- camphorsulfonic acid, and the like,
  • step 3) of the present invention proceeds with reacting 6- chloro-2,8-dimethylimidazo[l,2-b] pyridazine (12) with ethyl propiolate in the presence of cupper iodide, palladium catalyst and a suitable base in a suitable solvent to obtain ethyl 3-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) propiolate (13),
  • step 4) of the present invention proceeds with reacting ethyl 3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)propiolate (13) with tert-butyl 7-(6- aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (14) in the presence of a suitable base in a suitable solvent to obtain tert-butyl 7-(2-(2,8- dimethylimidazo[l,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-7-yl)-
  • step 5 of the present invention proceeds with deprotecting tert-butyl 7-(2-(2,8-dimethylimidazo[ 1 ,2-b] pyridazin-6-yl)-4-oxo-4H-pyrido[ 1 ,2- a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (15) with a suitable acid in a suitable solvent to obtain crude Risdiplam (la).
  • the suitable acid used in step 5) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluene sulfonate, 10-camphorsulfonic acid and the like; and
  • step 6) of the present invention proceeds with purifying crude Risdiplam (la) from a suitable solvent or mixture of solvents to obtain Risdiplam (1).
  • the compound of formula (10) and ethyl propiolate which are utilized in the present invention can be synthesized by any of the known processes or they can be procured from any of the commercial sources.
  • step F adding water to the obtained solid in step E),
  • step F adding one or more solvent(s) to the obtained solid in step F),
  • Risdiplam (1) obtained in the present invention is in crystalline form.
  • Risdiplam (1) obtained in the present invention has moisture content less than 1% (w/w), preferably less than 0.5%.
  • Risdiplam (1) obtained in the present invention is anhydrous in nature. Further embodiment of the present invention is Risdiplam (1) obtained by the above process is having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene 5 glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate,
  • suitable base refers to inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert butoxide and the like; and organic bases such as Di isopropyl ethyl amine, Triethyl amine, pyridine, or mixtures thereof.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydro
  • palladium catalyst refers to 1 , 1'- bis(diphenyl phosphino) ferrocene] dichloro palladium(II)(Pd(dppf)C12), tetrakis (triphenylphosphine) palladium (0) (Pd(PPh3)4), palladium (Il)acetate (Pd(OAc)2), palladium(II)chloride (PdCh), bis(benzonitrile)palladium(II)dichloride (Pd(Ph CN)2Ch), bis(triphenylphosphine)palladium (II) dichloride (Pd(PPh3)2C12), allylpalladium(II) chloride dimer (Pd C1(C3H5)]2), (dppp), Cyclo penta dienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl)
  • the reaction mass was stirred and heated to 80-85°C until completion of the reaction, then distilled off the solvent.
  • the reaction mass was cooled to room temperature.
  • To this reaction mass 5 volumes of water and 5 volumes of dichloromethane were added and stirred for 10-15 minutes.
  • the aqueous layer was extracted with dichloromethane and distilled off.
  • the obtained crude was stripped out with 2 volumes of ethanol.
  • To this 1 volume ethanol was added and stirred, then 5 volumes of methyl t-butyl ether was added to the reaction mass and stirred.
  • the obtained solid was fdtered, washed with methyl t-butyl ether and dried to get the titled compound. Yield: 43-47g.
  • Example-19 Preparation of premix of Risdiplam (1) with tartaric acid.

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[l,2-b] pyridazin-6-yl) pyrido-4H-[1,2-a] pyrimidin-4-one represented by the following structural formula (1) by employing novel intermediates of formulae (5), (6), (7), (9) and (13). (1) The present invention further relates to process for the purification of 7-(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b] pyridazin-6-yl) pyrido-4H-[1,2-a] pyrimidin-4-one (1), is with purity greater than 99.5% by High-performance liquid chromatography.

Description

"A NOVEL PROCESS FOR THE PREPARATION OF 7 (4, 7- DIAZASPIRO [2.5] OCTAN-7-YL)-2-(2,8 DIMETHYLIMIDAZO[1,2-B] PYRID AZIN-6- YL) PYRIDO-4H-[1,2-A] PYRIMIDIN-4-ONE WITH NOVEL INTERMEDIATES"
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 7-(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) pyrido-4H-[l,2-a] pyrimidin-4-one represented by the following structural formula (1) by employing novel intermediates of formulae (5), (6), (7), (9) and (13).
Figure imgf000003_0001
It further relates to a process for the purification of 7-(4,7-diazaspiro [2.5] octan-7- yl)-2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) pyrido-4H-[l,2-a] pyrimidin-4- one (1), having purity greater than 99.5% by High-performance liquid chromatography .
BACKGROUND OF THE INVENTION
7-(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) pyrido-4H-[l,2-a] pyrimidin-4-one (1) is commonly known as Risdiplam (1). It is approved by USA Food and drug administration and by European Medicines Agency under the brand name of Evrysdi and it is a survival of motor neuron 2 (SMN2) splicing modifier indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.
Risdiplam is reported in US 9,969,754 by F Hoffmann La Roche AG. The synthetic process for Risdiplam is reported in US’754 patent, which comprises amination of compound of formula (10) is reacted with aqueous ammonia in dichloromethane to provide compounds of formulae (11) and (11’) as a mixture of Regio isomers. The Regio isomers of formula (11) and (11’) are reacted with l-bromo-2,2- dimethoxypropane in the presence of PPTS/2-propanol/DCM followed by chromatography purification to provide compound of formula (12). The compound of formula (12) is reacted with bis (pinacolato) diborane in the presence of PdC12(dppf).CH2C12/potassium acetate to provide compound of formula (8). The compound of formula (8) is reacted with compound of formula (16) in the presence of Pd (PPh3)4/potassium carbonate/acetonitrile to provide compound of formula (17) The compound of formula (17) is reacted with compound of formula (18) in the presence of DIPEA/DMSO/DCM followed by purification using column chromatography to obtain Risdiplam (1).
The above process is schematically shown in scheme 1 as below:
Figure imgf000004_0001
Scheme 1
The main drawback associated with the above said prior art process for the purification of Risdiplam (1) using column chromatography which is not feasible for industrial scale, lack of desired yield and purity of Active Pharmaceutical Ingredient (API) and impurities associated with final API. Hence, the present invention aims at providing a novel process and purification of Risdiplam (1) by employing novel intermediates limiting the formation of impurities and yield enhancement of the final compound by using safe and commercially viable reagents under mild reaction conditions and in short time which are applicable at large scales.
OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide a process for the preparation of Risdiplam (1) by using novel intermediates of formulae (5), (6), (7) and (9).
In another objective of the present invention is to provide another process for the preparation of Risdiplam (1) by using novel intermediate of formula (13).
In another objective of the present invention is to provide novel intermediates of formulae (5), (6), (7), (9) and (13).
Yet, in another objective of the present invention is to provide a process for the purification of Risdiplam (1).
In further objective, Risdiplam (1) so obtained is having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is to provide a process for the preparation of Risdiplam (1) as shown in scheme 2, the process comprising: a) reacting compound of formula (2) or its salt with 5-bromo-2-nitro pyridine
(3) to provide compound of formula (4), b) hydrogenating compound of formula (4) to provide compound of formula (5), c) reacting compound of formula (5) with di-tert-butyl malonate to provide compound of formula (6), d) reacting compound of formula (6) with p-toluenesulfonyl chloride to provide compound of formula (7), e) coupling compound of formula (7) with 2,8-dimethyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl) imidazo[l,2-b] pyridazine of formula (8) to provide compound of formula (9), f) deprotecting compound of formula (9) to obtain Risdiplam crude (la), and g) purifying crude Risdiplam (la) to obtain Risdiplam (1).
In another aspect of the present invention is to provide another process for the preparation of Risdiplam (1) as shown in scheme 3, the process comprising:
1. aminating 3,6-dichloro-4-methylpyridazine (10) to provide 6-chloro-4- methylpyridazin-3 -amine (11),
2. cyclizing 6-chloro-4-methylpyridazin-3-amine (11) with 1-bromo, 2,2- dimethoxy propane to provide 6-chloro-2,8-dimethylimidazo[l,2-b] pyridazine (12),
3. reacting 6-chloro-2,8-dimethylimidazo[l,2-b] pyridazine (12) with ethyl propiolate to provide ethyl 3-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) propiolate (13),
4. reacting ethyl 3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)propiolate (13) with tert-butyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (14) to provide tert-butyl 7-(2-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)-4-oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (15), and
5. deprotecting tert-butyl 7-(2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl)-4- oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4- carboxylate (15) to provide Risdiplam crude (la), and
6. purifying crude Risdiplam (la) to provide Risdiplam (1).
In another aspect of the present invention is to provide a process for the purification of Risdiplam (1), comprises of the following steps:
A. dissolving crude Risdiplam of formula (la) in one or more suitable solvents, B. passing the solution obtained in step A) through silica column,
C. collecting all the pure fractions and distilling off the solvent,
D. adding water and ascorbic acid to the crude,
E. adjusting pH of the aqueous layer to 9-10 with a suitable base,
F. adding water to the obtained solid in step E),
G. adding one or more solvent(s) to the obtained solid in step F),
H. distilling off the solvent completely,
I. adding one or more suitable solvents to the solid obtained in step H),
J. heating the reaction mixture for 5-6 hours at 80-85°C,
K. cooling the reaction mixture to room temperature; and
L. isolating pure Risdiplam of formula (1).
In further aspect of the present invention is Risdiplam (1) obtained by the above process is having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.
The present invention further provides process for the preparation of tartaric acid premix with pure Risdiplam of formula (1).
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 illustrates X-Ray Diffraction (XRD) pattern of premix of Risdiplam (1) with tartaric acid obtained according to example 19.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, one embodiment of the present invention is to provide a process for the preparation of Risdiplam (1), which is illustrated in scheme 2:
Figure imgf000008_0001
Scheme 2
Wherein “P” is an “amine protecting group” or “N-protecting group” can be selected from but not limited to alkoxy carbonyl such methoxycarbonyl (Moc), methoxycarbonyl, benzyloxy carbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), acyl, benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), tosyl, trityl, methanesulfonyl, benzene sulfonyl, triflate, trialkyl silyl, trifluoroacetyl, trichloro ethyl chloroformate (Troc) group and the like.
In another embodiment, the steps involved in the preparation of Risdiplam (1) as shown in scheme- 1 are as follows:
In some embodiment step a) of the present invention proceeds with reacting compound of formula (2) or its salt with 5-bromo-2-nitro pyridine (3) in the presence of a suitable base and potassium iodide in a suitable solvent to obtain compound of formula (4). The reaction may be carried out at a temperature ranging from about 70°C to 95°C, preferably about 80°C to 85°C. This step further provides a simple method for the purification of compound of formula (4) using suitable solvent. The base as used in step a) is selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like.
The salts used in step a) is selected from acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane sulfonic, ethane di sulfonic, oxalic, iso thionic, and the like, preferably using oxalic acid.
In another embodiment step b) of the present invention proceeds with hydrogenating compound of formula (4) with a suitable hydrogenation catalyst in one or more suitable solvent(s) to obtain compound of formula (5). The reaction may be carried out at temperature ranging from about 20°C to 45°C or about 25 °C to 35 °C. The compound of formula (5) may be further isolated in the form of solid or proceeds to next step without isolation (in-situ).
In an embodiment, the compound of formula (5) obtained in step b) is not isolated as a solid and proceeds to next step without isolation (in-situ).
The hydrogenation reaction as used in step b) is conducted using various catalysts, including but without limitation thereto: metal catalysts such as palladium, platinum, Raney nickel, iridium, ruthenium, rhodium, iron, zinc, and the like on a carbon or other Support; a transition metal catalyst in combination with an acid Such as iron/HCl, Zn/HCl, Sn/HCl, Zn/acetic acid, or Zn/ammonium formate; Raney nickel; and the like. A catalyst may be a chemical reducing agent Such as Stannous chloride (SnCh), ferric chloride (FeCh), in the presence of an acid like acetic acid or hydrochloric acid, or a base like hydrazine. A useful catalyst is Raney nickel.
The concentrations of palladium on the support, such as carbon, that can be used for the hydrogenation reaction may range from about 1% to about 30%, or about 5% to 10%, or about 10% by weight.
In another embodiment step c) of the present invention proceeds with reacting compound of formula (5) with di-tert-butyl malonate in the presence of a suitable solvent to obtain compound of formula (6). The reaction may be carried out at a temperature of about 130°C to 155°C, preferably about 140°C to 145°C.
In another embodiment step d) of the present invention proceeds with reacting compound of formula (6) with p-toluene sulfonyl chloride in the presence of a suitable base in one or more suitable solvent to provide compound of formula (7). The reaction may be carried out at room temperature. This step further provides a simple method for the purification of compound of formula (7) using suitable solvent.
In another embodiment step e) of the present invention proceeds with coupling compound of formula (7) with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) imidazo [1,2-b] pyridazine (8) in the presence of palladium catalyst and base in a suitable solvent, followed by purification in a suitable solvent or mixture thereof to obtain compound of formula (9). The compound of formula (9) may be further isolated in the form of solid or proceeds to next step without isolation (in-situ).
In an embodiment, the compound of formula (9) obtained in step e) is not isolated as a solid and proceeds to next step without isolation (in-situ). In another embodiment step f) of the present invention proceeds with deprotecting compound of formula (9) with a suitable amine deprotecting agent and ammonium formate in one or more suitable solvent to provide crude Risdiplam (la). The suitable amine deprotecting agent used in step f) is selected from palladium on carbon, palladium hydroxide, palladium, or palladium hydroxide mixture.
In another embodiment step g) of the present invention proceeds with purifying crude Risdiplam (la) from a suitable solvent or mixture thereof to obtain Risdiplam (1)
The compounds of formulae (2) and (3) which are utilized in the present invention can be synthesized by any of the known processes or they can be procured from any of the commercial sources. In another embodiment of the present invention is to provide another process for the preparation of Risdiplam (1), which is illustrated in scheme-3:
Figure imgf000011_0001
Scheme-3 In another embodiment, the steps involved in the preparation of Risdiplam (1) as shown in scheme-3 are as follows:
In some embodiment step 1) of the present invention proceeds with amination of
3.6-dichloro-4-methylpyridazine (10) with a suitable aminating agent in a suitable solvent to obtain 6-chloro-4-methylpyridazin-3-amine (11). The suitable aminating agent used in step 1) is selected from aqueous ammonia or ammonium hydroxide. The reaction may be carried out at a temperature of about 100°C to 120°C, preferably at a temperature of about 110 °C.
In another embodiment step 2) of the present invention proceeds with cyclizing 6- chloro-4-methylpyridazin-3-amine (11) with 1-bromo, 2,2-dimethoxy propane in the presence of a suitable acid in a suitable solvent to obtain 6-chloro-2,8- dimethylimidazo[l,2-b] pyridazine (12). The suitable acid used in step 2) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, p- toluenesulfonic acid monohydrate, pyridinium p-toluene sulfonate, 10- camphorsulfonic acid, and the like,
In another embodiment step 3) of the present invention proceeds with reacting 6- chloro-2,8-dimethylimidazo[l,2-b] pyridazine (12) with ethyl propiolate in the presence of cupper iodide, palladium catalyst and a suitable base in a suitable solvent to obtain ethyl 3-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) propiolate (13),
In another embodiment step 4) of the present invention proceeds with reacting ethyl 3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)propiolate (13) with tert-butyl 7-(6- aminopyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (14) in the presence of a suitable base in a suitable solvent to obtain tert-butyl 7-(2-(2,8- dimethylimidazo[l,2-b]pyridazin-6-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-7-yl)-
4.7-diazaspiro[2.5]octane-4-carboxylate (15). In another embodiment step 5) of the present invention proceeds with deprotecting tert-butyl 7-(2-(2,8-dimethylimidazo[ 1 ,2-b] pyridazin-6-yl)-4-oxo-4H-pyrido[ 1 ,2- a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (15) with a suitable acid in a suitable solvent to obtain crude Risdiplam (la). The suitable acid used in step 5) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluene sulfonate, 10-camphorsulfonic acid and the like; and
In another embodiment step 6) of the present invention proceeds with purifying crude Risdiplam (la) from a suitable solvent or mixture of solvents to obtain Risdiplam (1).
The compound of formula (10) and ethyl propiolate which are utilized in the present invention can be synthesized by any of the known processes or they can be procured from any of the commercial sources.
In another embodiment of the present invention is to provide a process for the purification of Risdiplam (1), comprises of the following steps:
A. dissolving crude Risdiplam of formula (la) in one or more suitable solvents,
B. passing the solution obtained in step A) through silica column,
C. collecting all the pure fractions and distilling off the solvent,
D. adding water and ascorbic acid to the crude,
E. adjusting pH of the aqueous layer to 9-10 with a suitable base,
F. adding water to the obtained solid in step E),
G. adding one or more solvent(s) to the obtained solid in step F),
H. distilling off the solvent completely,
I. adding one or more suitable solvents to the solid obtained in step H),
J. heating the reaction mixture for 5-6 hours at 80-85°C, K. cooling the reaction mixture to room temperature; and
L. isolating pure Risdiplam of formula (1).
In another embodiment of the present invention is to provide novel intermediates of form ulae.
Figure imgf000014_0001
In another embodiment, Risdiplam (1) obtained in the present invention is in crystalline form.
In another embodiment, Risdiplam (1) obtained in the present invention has moisture content less than 1% (w/w), preferably less than 0.5%.
In another embodiment, Risdiplam (1) obtained in the present invention is anhydrous in nature. Further embodiment of the present invention is Risdiplam (1) obtained by the above process is having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene 5 glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, 2-propanol, isopropanol, n-butanol, isobutanol, t- butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2- methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3 -pentanol, neopentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The term “suitable base” as used in the present invention refers to inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert butoxide and the like; and organic bases such as Di isopropyl ethyl amine, Triethyl amine, pyridine, or mixtures thereof.
The term “palladium catalyst” as used in the present invention refers to 1 , 1'- bis(diphenyl phosphino) ferrocene] dichloro palladium(II)(Pd(dppf)C12), tetrakis (triphenylphosphine) palladium (0) (Pd(PPh3)4), palladium (Il)acetate (Pd(OAc)2), palladium(II)chloride (PdCh), bis(benzonitrile)palladium(II)dichloride (Pd(Ph CN)2Ch), bis(triphenylphosphine)palladium (II) dichloride (Pd(PPh3)2C12), allylpalladium(II) chloride dimer (Pd C1(C3H5)]2), (dppp), Cyclo penta dienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl) 2, (2 -Butenyl) chloro palladium dimer, (2 -Methyl allyl) palladium (Il)chloride dimer, palladium(l 1- phenylallyl)chloride dimer, di di-p-chloro bis[2 2-(amino amino-N)[l,r-bi phenyl]-2-yl-C]dipalladium (II), di-p-chloro bis[2-(dimethylamino) methyl]phenyl-C,N]dipalladium(II), palladium hydroxide and dichloro[9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (Pd(Xant Phos)Ch).
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example 1: Preparation of benzyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (4) [wherein, P=benzyl].
100 g of benzyl 4,7-diazaspiro [2.5] octane-4-carboxylate (2), 73 g of 5-bromo-2- nitro pyridine (3), 500 ml of dimethyl sulfoxide and 36.36 g of triethyl amine was taken at room temperature. The reaction mixture was stirred for 12 to 14 hours at 80 to 85 °C, then cooled to room temperature and added 3.0 litres of water. The reaction mass was extracted with 10 volumes of ethyl acetate. The solution was dried with sodium sulphate and fdtered. The fdtrate was distilled off completely under vacuum to get the crude compound. Yield: 76%
Example 2: Preparation of benzyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (4) [wherein, P=benzyl]
100 g of benzyl 4,7-diazaspiro [2.5] octane -4-carboxy late oxalate (2) was dissolved in 500 ml of water at room temperature. To this 100 g of 30% sodium carbonate solution (prepared by dissolving 30 g of sodium carbonate in 100 ml of water) was added to the reaction mass for 15-20 minutes at room temperature. Both the layers were separated. The aqueous layer was extracted with di chloromethane and distilled off. 10 volumes of acetonitrile were added to the crude compound at room temperature. To this reaction mass, 1.7 g of potassium carbonate and 0.1 g of potassium iodide was added. The reaction mass was stirred and heated to 80-85°C until completion of the reaction, then distilled off the solvent. The reaction mass was cooled to room temperature. To this reaction mass 5 volumes of water and 5 volumes of dichloromethane were added and stirred for 10-15 minutes. The aqueous layer was extracted with dichloromethane and distilled off. The obtained crude was stripped out with 2 volumes of ethanol. To this 1 volume ethanol was added and stirred, then 5 volumes of methyl t-butyl ether was added to the reaction mass and stirred. The obtained solid was fdtered, washed with methyl t-butyl ether and dried to get the titled compound. Yield: 43-47g.
Example 3: Purification of benzyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (4) [wherein, P=benzyl]
45 g of benzyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (4) crude was dissolved in 9 volumes of ethanol. To this 1 volume of toluene was added at room temperature, then the reaction mass was heated for 30-45 minutes at 80- 85°C. The reaction mass was cooled to 0-5°C and stirred. Filtered the solid, washed with ethanol and dried to get the title compound. Yield: 26-30 g. Purity: 99.5% Example 4: Preparation of benzyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate of formula (5) [wherein, P=benzyl]
100 g of benzyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (4) was dissolved in 20 volumes of methanol. 30 g of Raney nickel was added to the reaction mixture. 6.0 to 7.0 kg of hydrogen gas was applied at room temperature. The reaction mass was stirred for 6-8 hours at room temperature, fdtered the catalyst, and washed with 200 ml of methanol. Filtrate was distilled off completely to get the title compound.
Example 5: Preparation of benzyl 7-(2-hydroxy-4-oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate of formula (6) [wherein, P=benzyl]
100 g of benzyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate of formula (5), 500 ml of anisole and 80 g of di t-butyl malonate were added at room temperature. The reaction mixture was heated for 4-5 hours at 140 to 145 °C. The reaction mass was cooled to room temperature. Filtered the solid and washed with 4x100 ml of toluene. The compound was dried under vacuum at room temperature to get the title compound. Yield: 67.0%.
Example 6: Preparation of benzyl 7-(2-hydroxy-4-oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate of formula (6) [wherein, P=benzyl]
100 g of benzyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (4) was dissolved in 2000 ml of methanol at room temperature. To this reaction mass, 2000 ml of ethyl acetate was added. 30 g of Raney nickel was added to the reaction mass and filled the vessel with hydrogen gas and stirred at room temperature. After completion of the reaction, the reaction mass was filtered and washed the hyflo bed with methanol and ethyl acetate (l: l).10 g of neutral carbon was added to the filtrate at room temperature and stirred. The carbon was filtered through hyflow and washed the bed with methanol. Distilled off the solvent at below 50°C to obtain benzyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro [2.5] octane- 4-carboxylate of formula (5). 80 g of the obtained compound was dissolved in 800 ml of anisole at room temperature, then 96 ml of di tertiary butyl malonate was added at room temperature. The reaction mass temperature was raised to 140-145°C and stirred until the reaction complete. After completion of the reaction, the reaction mass was cooled to room temperature. The obtained solid was filtered, washed with toluene, and dried to obtain title compound. Yield: 75-80 gm. Purity: 99.4%. Example 7: Preparation of benzyl 7-(4-oxo-2-((p-tolyl sulfinyl) oxy)-4H- pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (7).
100 g of benzyl 7-(2-hydroxy-4-oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7- diazaspiro [2.5] octane-4-carboxylate of formula (6), 600 mL of dichloromethane, 32.3 gm of triethyl amine and 52.5 g of para toluene sulfonyl chloride (pTSC) was added for 8-9 hours at room temperature and washed with 100 ml of 10 % HC1 solution. Layers were separated. Organic layer was washed with 200 ml of 5 % sodium hydroxide solution and distilled off the solvent completely. 500 ml of ethyl acetate and 500 ml of n-heptane was added for 3-4 hours at 0-5 °C. The obtained solid was filtered, washed with 100 ml of n-heptane, and dried under vacuum to get the title compound. Yield: 86%. Purity: 99.6%
Example 8: Preparation of benzyl 7-(4-oxo-2-((p-tolyl sulfinyl) oxy)-4H- pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (7) [wherein, P=benzyl]
100 g of benzyl 7-(2-hydroxy-4-oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7- diazaspiro [2.5] octane-4-carboxylate of formula (6), was dissolved in di chloromethane and acetone (1: 1) at room temperature. To this reaction mass 400 ml of triethyl amine and 120 g of para toluene sulfonyl chloride (pTSC) was added and stirred until reaction complete. After completion of the reaction, the reaction mass was distilled completely at below 45°C to get distilled crude. A mixture of methylene dichloride and water (1: 1) was added to the obtained crude and stirred for 10-15 minutes. The organic layer was separated, washed with 1200 ml of water and dried with sodium sulphate. The reaction mass was distilled completely at below 45 °C and cooled to room temperature. 500 ml of methyl -tert-butyl ether was added to the distilled crude at room temperature and stirred. Filtered the obtained solid, washed with methyl tert. Butyl ether and dried to get the title compound.
Yield: 80-85 g. Purity: 99.6%
Example 9: Preparation of benzyl 7-(2-(2,8-dimethylimidazo[l,2-b] pyridazin- 6-yl)-4-oxo-4H-pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4- carboxylate (9) [wherein, P=benzyl] 100 g of benzyl 7-(4-oxo-2-((p-tolylsulfinyl)oxy)-4H-pyrido[l,2-a]pyrimidin-7- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (7), 600 mb of acetonitrile and 65 g of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaboralan-2-yl)imidazo[l,2- b]pyridazine (8) was added at room temperature. To this 70 mL of 1% potassium carbonate solution was added. The reaction mass was heated for 3-4 hours at reflux temperature and cooled. The obtained solid was filtered and washed with 600 ml of acetonitrile. 1000 ml of tetrahydrofuran, 100 ml of methanol and 10% of sodium bicarbonate solution (prepared by dissolving 10 g sodium bicarbonate in 100 mL of water) was added to the wet solid. 5 g of activated charcoal was added to the organic layer at room temperature. Distilled off the solvent and 300 ml of heptane was added. The reaction mixture was stirred for 15-16 hours at room temperature, cooled to 0-5 °C and again stirred for 3-4 hours. Filtered the solid and dried under vacuum at 55 °C for 7-8 hours. The obtained compound was dissolved in 540 ml of toluene and 60 ml of ethanol at reflux. The reaction mass was stirred for 15-16 hours at room temperature. The reaction mass was stirred for 3-4 hours at 0-5 °C. The solid was fdtered and dried under vacuum at 55 °C for 7-8 hours to get the title compound. Yield: 67%.
Example 10: Preparation of Risdiplam of formula (1)
100 g of benzyl 7-(2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl)-4-oxo-4H- pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (9), 1000 ml of methanol and 10 g of palladium on carbon at room temperature and heated to 60-65 °C. 4-5 kg of hydrogen pressure was applied and maintained for 4-5 hours. Cooled the reaction mass to room temperature, fdtered the catalyst, take the fdtrate, and distilled off the methanol. The reaction mass was cooled to room temperature and 500 ml of methyl tert-butyl ether was added. The reaction mass was stirred to room temperature for 1-2 hours, fdtered the solid and dried under vacuum to get the title compound.
Example 11: Preparation of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaboralan-2-yl) imidazo [1,2-b] pyridazine (8)
70 g of 6-bromo-2,8-dimethylimidazo[l,2-b] pyridazine (19) was dissolved in 1000 ml of 1,4-dioxane. To this reaction mass 100 g of potassium acetate, 100 g of bis pinacolato diborane and 10 g of 1,1 -bis (diphenylphosphino)ferrocene) dichloro palladium dichloromethane was added at room temperature, then the reaction mass temperature was raised to 90-95 °C and stirred until reaction complete. After completion of the reaction, the reaction mass was cooled to room temperature, then filtered and washed the obtained solid with 1,4-dioxane. The obtained solution was directly used in the next step without isolation.
Example 12: Preparation of Risdiplam of formula (la)
100 g of benzyl 7-(4-oxo-2-((p-tolyl sulfinyl) oxy)-4H-pyrido[l,2-a] pyrimidin-7- yl)-4,7-diazaspiro [2.5] octane-4-carboxylate (7) was dissolved in 1000 ml of acetonitrile at room temperature. To this reaction mass 100 g of 2,8-dimethyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaboralan-2-yl) imidazo [1,2-b] pyridazine (8) solution obtained in Ex-11, potassium carbonate solution (prepared by dissolving 100 g of potassium carbonate in 150 ml of water) and 10 g of 1,1-bis (diphenylphosphino)ferrocene) dichloro palladium dichloromethane were added. The reaction mass temperature was raised to 80-85°C and stirred for 4-6 hours. After completion of the reaction, the reaction mass was distilled completely, then cooled to room temperature. 1000 ml of water was added to the distilled crude, stirred, and filtered to obtain wet solid.500 ml of methyl tert. Butyl ether was added to the wet solid and stirred. Filtered the solid and dried at below 50°C to get compound of formula (9) (Yield: 100-110 g). 100 g of compound of formula (9) was dissolved in 40 volumes of methanol and 10 volumes of tetrahydrofuran at room temperature. To this 25 g of palladium hydroxide and 250 g of ammonium formate were added, then the reaction mass was heated to 50-55°C and stirred for 1-2 hours. After completion of the reaction, the reaction mass was cooled to room temperature and filtered. The filtrate was distilled off at below 50°C and cooled the crude to room temperature. 20 volumes of dichloromethane were added to the crude, then 10 volumes of water were added to the reaction mass at room temperature. The organic layer was distilled off at below 50°C and cooled to room temperature . 5 volumes of methyl t-butyl ether were added to the crude and filtered. The obtained solid was washed with methyl t-butyl ether and dried to get the title compound. Weight: 50-55 g Example 13: Purification of Risdiplam of formula (1)
50 g of crude Risdiplam of formula (la) was dissolved in 10 volumes of 2.5% of methanol in methylene dichloride through silica column. The compound was collected as fractions. After completion of the solution, 3 volumes of 2.5% of methanol in methylene dichloride was passed for two times and collected as two fractions. All the fractions were combined and distilled off the solvent completely at below 40 °C. The distilled crude was cooled to room temperature, then 7 volumes of water and 15 g of ascorbic acid was added to the crude at. The reaction mass was stirred for 30- 40 minutes and washed with 3 volumes of methylene dichloride and 2 volumes of methyl t-butyl ether. pH of the aqueous layer was adjusted to 9-10 with sodium carbonate and stirred. The obtained solid was filtered. 4 volume of water was added to the wet solid at room temperature and stirred. The obtained solid was filtered and suck dried for 1-2 hours. 2 volumes of ethanol were added to the wet solid at room temperature and distilled off the solvent completely. To this reaction mass 5 Volumes of mixture of isopropyl alcohol and ethanol (1: 1) was added at room temperature. The reaction mass was heated to 80-85°C and maintained for 5-6 hours. Cooled the reaction mass to room temperature and stirred. The obtained solid was filtered, washed with 1 volume of 1 : 1 ethanol and isopropyl alcohol mixture and dried to get the pure Risdiplam of formula (1). Yield: 21-25 g.
Purity: 99.8%
Example 14: Preparation of 6-chloro-4-methyl-pyridazin-3-amine (11)
27 g of 3,6-dichloro-4-methylpyridazine (10) was suspended in 300 ml of 25% aqueous ammonia. The reaction mixture was heated at 110° C for 48 hours. After cooling to room temperature, the reaction was poured into dichloromethane, and the organic phase was separated, dried over sodium sulfate, and concentrated under vacuum, to give title compounds as a mixture of Regio isomers which were used directly in the next step.
Example 15: Preparation of 6-chloro-2,8-dimethylimidazo[l,2-b] pyridazine of formula (12)
22.4 g of the mixture of regioisomers 6-chloro-4-methyl-pyridazin-3-amine (11) and 6-chloro-5-methyl-pyridazin-3 -amine (11’) was suspended in 300 ml of 2- propanol. 36.0 g of l-bromo-2,2-dimethoxypropane and 2.96 g of pyridinium p- toluene sulfonate (PPTS) were added, and the resulting solution was heated at 105° C overnight. The solvent was removed under vacuum, and the residue was taken up in dichloromethane and washed with sodium bicarbonate. The organic phases were dried over sodium sulfate, concentrated in vacuo and the crude light brown solid was purified by column chromatography (EtOAc/Heptane 1/2-1/1) to give separately 6.1 g of 6-chloro-2,8-dimethyl-imidazo[l,2-b]pyridazine (21%) as a white solid and 5.9 g of 6-chloro-2,7-dimethyl-imidazo[l,2-b]pyridazine (20%) as a white solid.
Example 16: Preparation of ethyl 3-(2,8-dimethylimidazo[l,2-b] pyridazin-6- yl) propiolate of formula (13)
100 g of 6-chloro-2,8-di methyl imidazo [ 1,2-b] pyridazine (12), 500 ml of dimethyl formamide and 111 g of triethyl amine were added at room temperature. 10.47 g of copper(I) iodide (Cui), 5.0g of tetra kis (triphenyl phosphine) palladium and 53.9 g of ethyl propiolate were added to the reaction mixture at room temperature. After stirring for 12-14 hours, 3.0 litres of water were added to the reaction mass at room temperature. The compound was extracted with 2X500 m of ethylacetate. The compound was dried with sodium sulphate. Filtered and distilled off the solvent completely. The obtained crude was used directly in the next step.
Example 17: Preparation of tert-butyl 7-(2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl)-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate of formula (15) [wherein, Boc= tert-Butoxycarbonyl] 100 g of ethyl 3-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl) propiolate of formula (13), 124.6 g of Tert-butyl 7-(6-amino pyridine-3-yl)-4,7-di aza spiro [2,5] octane- 4-carboxylate (14), 1200 m of acetonitrile and 92 g of triethyl amine was added at room temperature. The reaction mass was heated for 6-8 hrs at 55-60°C and cooled to room temperature. 1000 ml of DM water was added. The compound was extracted with 2x1000 mb of ethyl acetate. Distilled of the solvent at below 50°C. 1000 mb of hexane was added at room temperature and stirred for 1-2 hours. Filtered the solid and dried under vacuum to get the title compound. Example 18: Preparation of Risdiplam of formula (1)
100 g of tert-butyl 7-(2-(2,8-dimethylimidazo[l,2-b] pyridazin-6-yl)-4-oxo-4H- pyrido[l,2-a] pyrimidin-7-yl)-4,7-diazaspiro [2.5] octane-4-carboxylate of formula (15), 500 m of methanol and 54.2 g of para toluene sulfonyl chloride (pTSC) was added at room temperature. The reaction mixture was heated for 4-5 hrs at 50-55°C. The reaction mass was cooled and distilled off the solvent at below 50°C. 600 m of methyl t-butyl ether was added. The obtained solid was filtered and dissolved in 1000 mb of water. 10% sodium carbonate solution was added to the aqueous solution and extracted with 1000 mb of ethyl acetate. Ethyl acetate was distilled off and 500 mb of hexane was added and stirred for 15-20 mins at room temperature. The obtained solid was filtered and dried under vacuum to get Risdiplam of formula
(1)
Example-19: Preparation of premix of Risdiplam (1) with tartaric acid.
To 1.0 g of Risdiplam (1), 200 ml of water was added at room temperature and cooled to 2-5 °C. and 370 mg of tartaric acid were added at the same temperature and stirred for 10 to 15 minutes. pH of the reaction mass was adjusted between 8 to 8.5 using 10 % sodium hydroxide solution and stirred for 10 to 15 minutes at 2- 5 °C. Reaction mass was transferred into petri dish. The petri plate was kept in freeze dryer for lyophilization to yield premix of Risdiplam (1) with tartaric acid. Yield: 92.8%; PXRD: Fig 1.

Claims

We Claim:
1. A process for the preparation of Risdiplam (1),
Figure imgf000025_0001
which comprises: a) reacting the compound of formula (2) or its salts
Figure imgf000025_0002
with 5-bromo-2-nitro pyridine (3)
Figure imgf000025_0003
to provide compound of formula
Figure imgf000025_0004
b) hydrogenating the compound of formula (4) to provide compound of formula (5),
Figure imgf000025_0005
c) reacting the compound of formula (5) with di-tert-butyl malonate to provide compound of formula (6),
Figure imgf000026_0001
d) reacting the compound of formula (6) with p-toluenesulfonyl chloride to provide compound of formula (7),
Figure imgf000026_0004
e) coupling the compound of formula (7) with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) imidazo[l,2-b] pyridazine of formula (8)
Figure imgf000026_0002
to provide compound of formula (9),
Figure imgf000026_0003
f) deprotecting the compound of formula (9) to obtain Risdiplam crude of formula (la), and g) purifying crude Risdiplam of formula (la) to obtain Risdiplam of formula (1). The process as claimed in claim 1, wherein the reaction in step a), step d) and step e) are carried out in presence of a base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and organic bases such as dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine (DIPEA), di isobutyl amine, trimethylamine, triethylamine, tri isopropylamine, tributylamine, tert, butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP), or mixtures thereof. The process as claimed in claim 1, wherein the reaction in step a) is carried out in presence of a metal iodide selected from sodium iodide or potassium iodide. The process as claimed in claim 1, wherein the reaction in step b) is carried out in the presence of hydrogenation catalyst selected from metal catalysts such as palladium, platinum, nickel, iridium, ruthenium, and the like on a carbon or other support; a transition metal catalyst in combination with an acid such as iron/HCl, Zn/HCl, Sn/HCl, Zn/acetic acid, or Zn/ammonium formate; Raney nickel; and the like; wherein the catalyst may be a chemical reducing agent selected from stannous chloride (SnCh), ferric chloride (FeCh), or zinc in the presence of an acid selected from acetic acid or hydrochloric acid, or a base, wherein the base is hydrazine. The process as claimed in claim 1, wherein the reaction in step e) is carried out in the presence of palladium catalyst selected from 1, l'-bis(diphenyl phosphino) ferrocene] dichloro palladium (II)(Pd(dppf)C12), tetrakis (triphenylphosphine) palladium (0) (Pd(PPh3)4), palladium (Il)acetate (Pd(OAc)2), palladium(II)chloride (PdCh), bis(benzonitrile)palladium(II)dichloride (Pd(Ph CN)2Ch), bis(triphenylphosphine)palladium (II) dichloride (Pd^Ph Ch), allylpalladium(II) chloride dimer (Pd C1(C3H5)]2), (dppp), Cyclo penta dienyl allyl palladium, allylpalladium(II) chloride dimer (Pd(allyl) 2, (2 -Butenyl) chloro palladium dimer, (2 - Methyl allyl) palladium (Il)chloride dimer, palladium(l l-phenylallyl)chloride dimer, di di- p-chloro bis[2 2-(amino amino-N)[I,I’-bi phenyl]-2-yl-C]dipalladium (II), di-p-chloro bis[2-(dimethylamino) methyl]phenyl-C,N]dipalladium(II), and dichloro [9, 9-dimethyl-4, 5- bis(diphenylphosphino)xanthene]palladium (Pd(Xant Phos)C12). The process as claimed in claim 1, wherein the reaction is step f) is carried out in the presence of amine deprotecting agent and ammonium formate. The process as claimed in claim 6, wherein amine deprotecting agent is selected from palladium on carbon, palladium hydroxide, palladium, or palladium hydroxide mixture. A process for the purification of Risdiplam of formula (1), comprising of:
A. dissolving crude Risdiplam of formula (la) in one or more suitable solvents,
B. passing the solution obtained in step A) through silica column,
C. collecting all the pure fractions and distilling off the solvent,
D. adding water and ascorbic acid to the crude,
E. adjusting pH of the aqueous layer to 9-10 with a suitable base,
F. adding water to the obtained solid in step E),
G. adding one or more solvent(s) to the obtained solid in step F), H. distilling off the solvent completely,
I. adding one or more suitable solvents to the solid obtained in step H),
J. heating the reaction mixture for 5-6 hours at 80-85°C,
K. cooling the reaction mixture to room temperature; and
L. isolating pure Risdiplam of formula (1). The process as claimed in claim 1 and 8, wherein the reaction in each step is carried out in presence of solvent selected from hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, ketone solvents, polar-aprotic solvents, nitrile solvents, alcoholic solvents, polar solvents, or its mixture thereof. . A compound of formula
Figure imgf000028_0001
. A compound of formula
Figure imgf000028_0002
. A compound of formula
Figure imgf000028_0003
. A compound of formula
Figure imgf000028_0004
. A process for the preparation of tartaric acid premix with pure Risdiplam of formula (1).
PCT/IB2023/056733 2022-06-29 2023-06-29 A novel process for the preparation of 7 (4, 7- diazaspiro [2.5] octan-7-yl)-2-(2,8 dimethylimidazo[1,2-b] pyrid azin-6- yl) pyrido-4h-[1,2-a] pyrimidin-4-one with novel intermediates WO2024003798A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019057740A1 (en) * 2017-09-22 2019-03-28 F. Hoffmann-La Roche Ag Process for the prepration 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
WO2020079203A1 (en) * 2018-10-19 2020-04-23 F. Hoffmann-La Roche Ag New forms of pyrido[1,2-a]pyrimidin-4-one derivatives, its formulation and its process of making

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019057740A1 (en) * 2017-09-22 2019-03-28 F. Hoffmann-La Roche Ag Process for the prepration 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
WO2020079203A1 (en) * 2018-10-19 2020-04-23 F. Hoffmann-La Roche Ag New forms of pyrido[1,2-a]pyrimidin-4-one derivatives, its formulation and its process of making

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