WO2016071382A1 - Synthèse d'un inhibiteur de pi3k et de ses sels - Google Patents

Synthèse d'un inhibiteur de pi3k et de ses sels Download PDF

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Publication number
WO2016071382A1
WO2016071382A1 PCT/EP2015/075670 EP2015075670W WO2016071382A1 WO 2016071382 A1 WO2016071382 A1 WO 2016071382A1 EP 2015075670 W EP2015075670 W EP 2015075670W WO 2016071382 A1 WO2016071382 A1 WO 2016071382A1
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compound
formula
reaction
optionally
solvent
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PCT/EP2015/075670
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English (en)
Inventor
Jan-Georg Peters
Philipp Rubenbauer
Kai Lovis
Juergen Stiehl
Martin Seyfried
Theodor Zweifel
Maurus Marty
Günter Weingärtner
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Bayer Pharma Aktiengesellschaft
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Publication of WO2016071382A1 publication Critical patent/WO2016071382A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel method of preparing A/-(8- ⁇ [(2R)-2- Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
  • the invention also relates to novel intermediate compounds, and to the use of said novel intermediate compounds for the preparation of said A/-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, or salts thereof. Further, the invention also relates to a novel method of purifying a compound of formula (I), or a salt thereof.
  • the present invention also relates to crystalline forms, form A of a compound of formula (I), pharmaceuticals uses thereof.
  • A/-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide (which is hereinafter referred to as compound of formula (I), compound (I), or (I), interchangeably), is a proprietary anticancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role in the transduction of cellular signals from surface receptors for survival and proliferation.
  • Compound of formula (I) exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo.
  • Compound of formula (I) may be synthesised according to the method given in international patent application PCT/EP201 1 /069637, published as WO 201 2/062748 A1 on May 18, 2012, (which is incorporated herein by reference in its entirety).
  • Compound of formula (I) may exist in one or more tautomeric forms : tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds.
  • Compound of formula (I) may for example exist in tautomeric form (la), tautomeric form (lb), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention.
  • Compound of formula (I) may exist as a solvate : a solvate for the purpose of this invention is a complex of a solvent and compound of formula (I) in the solid state.
  • Compound of formula (I) may exist as a hydrate : hydrates are a specific form of solvate wherein the solvent is water.
  • compound of formula (I) is, in WO 2012/062748, described on pp. 85, and may be synthesized according to the method given therein.
  • the present invention provides a method of preparing a compound of formula (I) (Step A10):
  • the reaction is carried out in a solvent, such as NMP, DMF, ethanol, ethylene glycol, pyridine or morpholine, or mixtures thereof.
  • a solvent such as NMP, DMF, ethanol, ethylene glycol, pyridine or morpholine, or mixtures thereof.
  • the solvent is NMP.
  • the reaction is carried at a temperature of about 90 ⁇ C to about 1 10 ⁇ C, preferably at a temperature between 90 ⁇ C and 1 10 ⁇ C.
  • the reaction is performed at a temperature of about 90 , preferably at 90 "C.
  • the reaction is performed at a temperature of about 1 1 0 , prefera bly at 1 10 ⁇ .
  • the reaction provides high yields and is performed under relatively mild conditions, e.g. no need to use microwave heating.
  • the reaction of compound (1 0) with morpholin takes place at about 90 to about 1 10 and no microwave irradiation at 140 *C is necessary.
  • Th e product can easily be isolated by filtration without the need of MPLC purification.
  • the product crystallizes directly out of the reaction mixture and can easly be isolated by filtration. No MPLC separation is necessary to purify the product.
  • the present invention relates to a method of preparing the above-mentioned compound of formula (1 0) (Step A9):
  • the compound of formula (9) is used as the TFA salt thereof compound (9a) :
  • the reaction of compound (9) or compound (9a) with (R)-(-)Glycidylnosylate or (R)-(-)Glycidyltosylate is carried out in a solvent, such as DMF.
  • the reaction is optionally carried with heating, such as at a temperature of about 45 ⁇ (e.g. at 45 ⁇ ).
  • the reaction is carried out in the presence of a base, such as potassium carbonate.
  • the compound of formula (1 0) is prepared by reaction of compound of formula (9a) with (R)-(-)Glycidylnosylate.
  • the reaction is regioselective for the -OH moiety, since the amine function is protected as an amide, and generates less side products. Surprisingly, no erosion of the enantiomeric excess can be detected, which is the case for a variety of other reagents such as (f?)-(-)-Epichlorohydrin or 4- ⁇ [(4R)-2-oxido-1 ,3,2-dioxathiolan-4-yl]methyl ⁇ morpholine hydrochloride. The product crystallizes directly out of the reaction mixture and no MPLC separation is necessary to purify the product.
  • the present invention relates to a method of preparing the above-mentioned compound of formula (9) (Step A8):
  • said compound of formula (9) is the TFA salt thereof, com ound (9a) :
  • the O-debenzylation of a compound of formula (8) is carried out in the presence of trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • the O-debenzylation is carried out with heating, preferably under reflux.
  • compound of formula (9) or (9a) is crystallized in ethyl acetate.
  • the present invention relates to a method of preparing the above-mentioned compound of formula (8) (Step A7), or salt thereof,
  • reaction of a compound of formula (7) with 2- methylnicotinic acid is carried out in the presence of a coupling agent, such as N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (EDC) or PyBOP, and optionally a catalyst, such as 4-Dimethylaminopyridine (DMAP).
  • a coupling agent such as N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (EDC) or PyBOP
  • EDC N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride
  • DMAP 4-Dimethylaminopyridine
  • the coupling agent is EDC.
  • reaction is carried out in a solvent, such as dimethylformamide (DMF).
  • compound of formula (7) can be coupled in the presence of EDC instead of PyBOP which is difficult to handel on scale.
  • the present invention relates to a method of preparing the above-mentioned compound of formula (7) (Step A6):
  • annelating agent such as cyanogen bromide (also known as bromocyanide)
  • a base such as triethylamine
  • a solvent such as acetonitrile or dichloromethane.
  • the solvent is acetonitrile.
  • compound of formula (7) is further stirred in acetone and water.
  • compound of formula (7) is further stirred in toluene.
  • compound of formula (6) can be annelated in acetonitrile thus avoiding the use of chlorinated solvents, such as dichloromethane, which are environmentally harmful and avoids need for distillation of dichloromethane. Also advantageously, stirring the crude compound of formula (7) in toluene removes relevant side products (i.e. low level of impurities are obtained, such as impurities below 0.1 %).
  • the present invention relates to a method of preparing the above-mentioned compound of formula (6) (Step A5):
  • a reducing agent such as hydrogen
  • a catalyst such as a bimetallic catalyst, such as platinum/iron on charcoal, particularly 1 % Pt/0.2% Fe/C in water, optionally dissolved in a solvent or in suspension in a solvent, such as tetrahydrofuran, water or methanol, or a mixture thereof.
  • the reaction is carried out in THF.
  • the reaction is carried out in THF/water.
  • the reduction is carried out in THF in the presence of 1 % Pt/0.2% Fe/C in water as a catalyst.
  • the reduction is carried out in THF in the presence of 1 % Pt/0.2% Fe/C in water as a catalyst.
  • the reduction is carried out in methanol in the presence of 1 % Pt/0.2% Fe/C in water as a catalyst.
  • the catalyst is 1 % Pt/0.2% Fe/C.
  • the compound of formula (6) is purified before proceeding to Step A6, comprising a step of stirring the compound of formula (6) in a solvent or mixture of solvents, preferably stirring the compound of formula (6) in a suspension in a solvent or in a mixture of solvents, such as, isopropanol and/or water, preferably stirring the compound of formula (6) in a suspension of water/isopropanol (1 /1 ).
  • the reduction of compound of formula (5) proceeded with negligible or no debenzylation with the catalyst devised (1 % Pt/0.2% Fe/C in water).
  • the use of THF improved the overall reaction volume (rapid hydrogenation in THF already at 3 bar pressure of H2) and kept compound (6) in solution, especially during catalyst filtration. Improved crystallization conditions and product isolation, as well as a significant higher yield and high product quality (over two steps) were obtained. Crystallisation and isolation of the product after solvent switch to iso-propanol and water in excellent yield (yield > 90%).
  • Previous process with Fe catalyst and acetic acid took 3 days and had a difficult work up since Fe generated a lot of salt waste and complete removal of the solvent was difficult on scale.
  • the present invention relates to a method of preparing the above-mentioned compound of formula (6) (Step A5):
  • the present invention relates to a method of preparing the above-mentioned compound of formula (5) (Step A4):
  • N-halosuccinimide such as N-bromosuccinimide (NBS)
  • N-bromosuccinimide optionally in a solvent, such as dichloromethane, methanol, acetonitrile or a mixture thereof, such as a mixture of methanol/acetonitrile.
  • the solvent is a mixture of methanol/acetonitrile.
  • the reaction of compound of formula (4) with ethylenediamine is quenched with NaHC03 and Na2S03, optionally in a solution in water.
  • the reaction of compound of formula (4) with ethylenediamine proceedes smoothly in the presence of NBS as an oxidizing reagent , which is easier to handle on scale than iodine.
  • Step A4 conducting Step A4 in methanol and acetonitrile lead to few side products, which made the process easier to conduct (dosing a NBS solution) and safer on scale.
  • the process conducted in methanol and acetonitrile allows removal of the wrong nitro regio isomer (e.g. those originated during the nitration of compound of formula (1 ), since in the nitration step A1 app. 10% of the wrong regioisomer is formed.
  • Step A4 the wrong isomer is removed to ⁇ 0.5%.) under the devised work-up conditions.
  • the process is reproducible and robust starting with isomeric or pure raw materials (yield 80- 94% depending on isomeric or pure starting material) with improved purity profile and aspect.
  • the product could be directly used in the hydrogenation step of compound of formula (5) as described above (low yielding recrystallization of compound (5) could be avoided).
  • a tedious purification was necessary since side products poison the bimetallic catalyst (1 % Pt/0.2% Fe/C in water).
  • the present invention relates to a method of preparing the above-mentioned compound of formula (4) (Step A3):
  • the work-up of compound of formula (4) is done in the presence of water or methanol, or a mixture thereof.
  • a solvent such as ⁇ , ⁇ -dimethylformamide (DMF)
  • a base such as potassium carbonate
  • heating such as under reflux or at a temperature of about 30 to about 40 ⁇ .
  • the work-up of compound of formula (4) is done in the presence of water or methanol, or a mixture thereof.
  • the present invention relates to a method of preparing the above-mentioned compound of formula (3) (Step A2):
  • the compound of formula (3) is recrystallized from dichloromethane/toluene.
  • the work-up of compound of formula (3) is done in the presence of water.
  • Step A3 using aqueous NaOH allowed a simple product crystallization, instead of a complex extractive work up using dichloromethane, with high product quality, high yield and producing aqueous waste only.
  • the subsequent benzylation (Step A3) could be run reproducibly independently of starting the method to prepare compound (3) with both isomeric or pure raw materials of compound (2).
  • the present invention relates to a method of preparing the above-mentioned compound of formula (2) (Step A1 ):
  • the method is carried continuously in a micro reactor, via flow nitration.
  • the work-up of compound of formula (2) is done in the presence of dichloromethane.
  • the continuous process via microreaction-technology, as exemplified in Example 1 allows kilogram-quantities to be prepared within days or a few weeks. There is no danger of a runaway-reaction and good yields are obtained.
  • the present invention relates to a method of preparing compound of formula (I) (Step A1 1 ), wherein the compound of formula (I) is further stirred in a mixture of morpholine and pyridine in NMP, optionally with heating, for example at a temperature of about 1 10 ⁇ (for example at 1 1 0 ), followed by addition of 1 ,8-dia zabicyclo[5.4.0]undec-7-ene (DBU), optionally in a solvent such as ethyl acetate.
  • DBU 1 ,8-dia zabicyclo[5.4.0]undec-7-ene
  • the present invention relates to a method of preparing compound of formula (I), wherein the compound of formula (I) is further crystalized from a solvent or mixture of solvents, such as a water/acetic acid mixture (solvent) and an ethanol/water/sodium bicarbonate mixture (antisolvent).
  • a solvent or mixture of solvents such as a water/acetic acid mixture (solvent) and an ethanol/water/sodium bicarbonate mixture (antisolvent).
  • Compound of formula (I) decomposes in acidic and basic media. Surprisingly, it has been found that with the described process, the compound (I) can be dissolved in acidic media and purified via filtration form macroscopic impurities, which is advantageous for a preparing a pharmaceutical composition. After crystallization with ethanol/water/sodium a crystalline product is obtained with a purity level equal to or higher than 99%.
  • the compound of formula (I) is crystalline form A as described hereinafter.
  • the present invention relates to a method, wherein the compound of formula (I) is prepared via the following steps, infra :
  • the present invention relates to a 5 method of preparing compound of formula (I), wherein each of said steps A3, A4, A5, A6, A7, A8, A9, A10 and A1 1 as shown supra, are undergone as described supra.
  • the present invention relates to a lo method of preparing compound of formula (I), wherein each of said steps A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10 and A1 1 as shown supra, are undergone as described supra.
  • Step A3 Using aqueous NaOH allowed a simple product crystallization, instead of a complex extractive work up using dichloromethane, with high product quality, high yield and producing aqueous waste only.
  • the subsequent benzylation (Step A3) could be run reproducibly independently of starting the method to prepare compound (3) with both isomeric or pure raw materials of compound (2).
  • Compound of formula (6) can be annelated in acetonitrile thus avoiding the use of chlorinated solvents, such as dichloromethane, which are environmentally harmful and avoids need for distillation of dichloromethane. Also advantageously, stirring the crude compound of formula (7) in toluene removes relevant side products (i.e. low level of impurities were obtained (below 0.1 %) and lead to a product in an excellent quality.
  • Step A7
  • the alkylation is regioselective for the -OH moiety, generates less side products and no erosion of the enantiomeric excess can be observed unlike for a variety of other alkylating reagents such as (R)-(-)-Epichlorohydrin or 4- ⁇ [(4R)-2-oxido-1 ,3,2-dioxathiolan-4-yl]methyl ⁇ morpholine hydrochloride.
  • the product crystallizes directly out of the reaction mixture and no MPLC separation is necessary to purify the product.
  • the reaction provides high yields and is performed under relatively mild conditions, e.g. no need to use microwave heating.
  • the reaction of compound (10) with morpholin takes place at about 90 C to about 1 10 and no microwave irradiation at 140 "C is necessary .
  • the product can easly be isolated by filtration without the need of MPLC purification.
  • the product crystallizes directly out of the reaction mixture and can easily be isolated by filtration. No MPLC separation is necessary to purify the product. ⁇ Step A1 1
  • the compound (I) can be dissolved in acidic media and purified via filtration form macroscopic impurities, which is advantageous for a preparing a pharmaceutical composition. After crystallization with ethanol/water/s odium a crystalline product is obtained with a purity level equal or higher than 99%.
  • the present invention relates to intermediate compounds which are useful in the preparation of compound of formula (I).
  • the present invention relates to a compound :
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  • the present invention relates to compound : , or a salt thereof.
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  • the present invention relates to the use of the intermediate compounds for preparing compound of formula (I), or a salt thereof.
  • the present invention relates to the use of :
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  • the present invention relates to the use of : for preparing compound of formula (I) , or a salt thereof.
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  • the present invention relates to a method of purifying a compound of formula (I) or a salt thereof, comprising a step of cristallizing a compound of formula (I), or a salt thereof, from a water/acetic acid mixture (solvent) and a water/ethanol/sodium bicarbonate mixture (antisolvent).
  • Compound of formula (I) decomposes in acidic and basic media. Surprisingly, under the acidic conditions applied removal of undesired impurities generated during the synthesis of the compound of formula (I) can be achieved without increasing the amount of other impurities (e.g. degradation products). A crystalline product is obtained with a purity level equal or higher than 99%.
  • the compound of formula (I), or a salt thereof is stirred in a mixture of morpholine and pyridine in NMP, optionally with heating, for example at a temperature of about 1 10 ⁇ C (for example at 1 10 ⁇ C), followed by addition of 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), optionally in a solvent such as ethyl acetate.
  • the compound of formula (I) is crystalline Form A as described hereinafter.
  • solvent as optionally present in any reaction step of the method of the invention, is understood, as is by the person skilled in the art, as meaning any substance in which other materials dissolve to form a solution, such as, without being limited to : a polar solvent, such as a polar protic solvent, such as water, n-butanol, isopropanol, n-propanol, ethanol, methanol, or formic acid or acetic acid, etc., for example ; a polar aprotic solvent, such as 1 ,4-dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, acetone, acetonitrile, dimethylformamide, sulfolane, pyridine or dimethylsulphoxide, etc., for example ; or a non-polar solvents, such as
  • a compound or mixture of compounds may not be soluble in a solvent or a mixture of solvents, thus not forming a (homogeneous) solution, but rather a suspension or a heterogeneous solution.
  • the compounds and intermediates of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the present invention covers all such stoichiometric and non-stoichiometric salts of the compounds and intermediates described herein.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • the present invention covers all such stoichiometric and non-stoichiometric hydrates and/or solvates of the compounds and intermediates described herein.
  • the present invention relates to crystalline polymorphs of A/-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, herein referred to as crystalline Form A, or simply Form A.
  • Crystalline Form A is a crystalline polymorph and, thus, characterizable by its powder X-ray diffraction (XRPD) pattern.
  • the diffraction pattern may either be experimentally recorded or calculated from the results of the measurement of the unit cell parameters of the crystal form.
  • characteristic peaks of the XRPDs of the polymorphs of the invention are given in degrees 2 ⁇ (Cu- ⁇ radiation).
  • the polymorphic forms are described as having an XRPD pattern with peaks at the positions listed in the respective Tables. It is to be understood that, in one embodiment, the polymorphic form has an XRPD pattern with peaks at the positions listed ⁇ 0.2 V. ⁇ ; or in another embodiment, an XRPD pattern with peaks at the positions listed ⁇ 0.1 ⁇ ⁇ .
  • the XRPD pattern may have further peaks at 5.8, 9.8, 1 3.2, 15.1 , 16.3, 1 7.5, 18.9, 20.2, 20.7, 21 .3, 21 .6, 22.6, 23.1 , 23.4, 23.9, 24.4, 24.9, 25.1 , 25.4, 25.8, 26.6, 27.2, 27.6, 28.1 , 28.6, 28.9, 29.2, 29.9, 30.4, 30.8, 32.0, 32.7, 33.9, 36.3, 37.4 « 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • Form A is characterised as having an XRPD pattern with one or more of the peaks presented in Table 1 .
  • Form A has an XRPD as shown in Figure 1 .
  • a pharmaceutical composition comprising a crystalline Form A as described herein, and a pharmaceutically acceptable diluent or carrier.
  • crystalline Form A as described herein, or a pharmaceutical composition as described herein, for use in the treatment or prophylaxis of a disease.
  • the invention relates to the use of a crystalline Form A as described herein, or a pharmaceutical composition as described herein, for the prophylaxis or treatment of a disease.
  • Another aspect of the present invention is the use of crystalline Form A as described herein or the use of a pharmaceutical composition comprising crystalline Form A as described herein, in the manufacture of a medicament for the treatment or prophylaxis of a disease.
  • Another aspect of the present invention relates to a method for using crystalline Form A of the present invention and compositions thereof, to treat a disease.
  • Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a crystalline Form A as described herein which is effective to treat the disorder.
  • said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the phosphotidylinositol-3-kinase (PI3K) pathway.
  • PI3K phosphotidylinositol-3-kinase
  • Stationary phase Eclipse Plus RRHD C18 (150 mm length, 3.1 mm ID, 1 .8 im particle size); mobile phase A: water + 0.1 vol. % trifluoroacetic acid; mobile phase B: acetonitrile + 0.1 vol. % trifluoroacetic acid: UV detection at 226 nm; column temperature: 20 C, injection volume: 7.0 ⁇ iL (at sample rack cooled at 2-8 ⁇ C), flow 0.90 mL / min; linear gradient in 3 steps: 3% B ⁇ 3% B (3 min.), 3% B ⁇ 15% B (1 5 min.), 15% ⁇ 80% B (30 min.), 5 min. holding time at 80% B;
  • Stationary phase Eclipse Plus RRHD C18 (150 mm length, 3.0 mm ID, 1 .8 ⁇ im particle size); mobile phase A: water + 0.1 vol. % trifluoroacetic acid; mobile phase B: acetonitrile + 0.1 vol. % trifluoroacetic acid: UV detection at 226 nm; column temperature: 20 C, injection volume: 7.0 ⁇ iL (in the sample rack cooled at 2-8 ⁇ C), flow 0.90 ml_ / min; linear gradient in 3 steps: 3% B ⁇ 3% B (3 min.), 3% B ⁇ 15% B (1 5 min.), 15% ⁇ 80% B (30 min.), 5 min. holding time at 80% B; LC-MS :
  • LC-MS trace analysis method for quantitation of (R)-Glycidyl-MDIC-nicotinate: stationary phase: Eclipse XDB-C18 (1 50 mm length, 3.0 mm ID, 3.5 ⁇ im particle size); mobile phase A: 0.1 % formic acid, mobile phase B: acetonitrile + 0.1 % formic acid; MS detection; column temperature: 45 ; injection vo lume: 3 ⁇ _; flow: 0.6 ml_ / min; linear gradient in 3 steps: 3% B ⁇ 3% B (4.5 min.), 3% ⁇ 15% B (22.5 min.), 15% ⁇ 80% B (25.0 min.), 10 min. holding time at 80% B.
  • the amount of Pt and Fe in the 1 % Pt/0.2% Fe/C catalyst should be understood throughout the specification as weight percent (wt.%).
  • Example 1 Step A1 and Step A2: Preparation of 4-acetoxy-3-methoxy-2- nitrobenzaldehyde (2) and 4-hydroxy -3-methoxy-2-nitrobenzaldehyde (2- nitro-vanillin) (3)
  • 2-Nitrovanilin (3) was synthesized via a flow nitration of vanillin acetate (1 ) in a micro reactor. 3.94 kg of nitric acid (65 w%) were added to 5.87 kg of concentrated sulfuric acid at 0 ⁇ (nitrating acid). 1 .5 kg of vanil lin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app.
  • Example 3B Step A3 : Preparation of 4-(benzyloxy)-3-methoxy-2- nitrobenzaldehyde (4) : 10 g of compound (3) were dissolved in 45 mL DMF at 25 ⁇ . This solution was charged with 14 g potassium carbonate and the temperature did rise to app. 30 ⁇ . Into this suspension 7.1 mL benzyl bromide was dosed in 15 minutes at a temperature of 30 ⁇ . The reaction mixture was stirred for 2 hours to complete the reaction. After cooling to 25 125 mL water was added. The suspension was filtered, washed twice with 50 mL water and once with water / methanol (10 mL / 1 0 mL) and dried at 40 ⁇ under reduced pressure. In this way 14.2 g (97 % yield) of (4) were obtained as a yellowish solid.
  • Example 4A Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5- dihydro-1 H-imidazole (5) : Method A
  • Example 5A Step A5 : 3-(benzyloxy)-6-(4,5-dihydro-1 H-imidazol-2-yl)-2- methoxyaniline (6) :
  • Example 6A Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-amine (7) : Method A
  • Example 6B Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-amine (7) : Method B
  • Example 7 Step A7 : preparation of N-[8-(benzyloxy)-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl]-2-methylpyridine-3-carboxamide (8) :
  • a vessel was charged with 13.8 kg 2-methylnicotinic acid, 14.3 kg DMAP and 356 kg DMF at 0 ⁇ . To this mixture 22.3 kg EDC were added and t he reaction was stirred for 30 minutes. Compound (7) (25.0 kg) was added and the reaction was stirred for 4 hours at 0 ⁇ . The vessel was heated to 20 and stirring was continued for 19 hours. The product was isolated on a centrifuge in 6 portions and each portion was washed with DMF (2 x 1 2 kg). The combined products were dried under reduced pressure and 29 kg of an almost white product (85% yield) were obtained.
  • Example 8 Step A8 : preparation of N-(8-hydroxy-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide trifluoroacetate (9a) :
  • Example 9 Step A9 : preparation of N- ⁇ 7-methoxy-8-[(2R)-oxiran-2- ylmethoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl ⁇ -2-methylpyridine-3- carboxamide (10)
  • a vessel was charged with 33 kg of compound (9a), 10.7 kg potassium carbonate and 313 kg DMF and stirred for 30 minutes at 20 ⁇ . An other portion of potassium carbonate (10.7 kg) was added and the reaction was stirred for 30 minutes. The last portion of 1 0.7 kg potassium carbonate was added and the reaction was stirred for one hour.
  • Into this suspension a solution of (R)-(- )Glycidylnosylate (24 kg) in 47 kg DMF was dosed and the reaction mixture was heated to 45 ⁇ . After stirring for 4 hours at this temperature the mixture was cooled 20 ⁇ C and stirred for one hour. The product was filtered of f and washed with DMF (1 x 99 kg) and water (6 x 230 kg). The solid was dried under reduced pressure and 17.5 kg (94% yield) of (10) were obtained as a white solid.
  • Example 10 Step A10 : preparation of compound of formula (I) : N-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide : A vessel was charged with 14.4 kg of compound (10), 59.7 kg morpholine, 310 kg N-methylpyrrolidone and heated to 90 . After the reaction m ixture was stirred for 3 h 144 kg ethyl acetate were added, the mixture was cooled to 20 ⁇ and stirred for another 30 minutes.
  • Example 11 Step A11 : purification of compound of formula (I) : N-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide :
  • a vessel was charged with 12.0 kg of compound (I), 58.7 kg pyridine, 5.3 kg morpholine, 1 1 8.6 kg N-methylpyrrolidone and heated to 1 10 .
  • the reaction mixture was stirred for 2 h 3.7 kg 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 54 kg ethyl acetate were added, the mixture was cooled to 20 ⁇ and stirred for another 60 minutes.
  • the product was isolated and washed with 27 kg ethyl acetate and 60 kg ethanol (2 x 30 kg). The solid was dissolved in 3.7 kg acetic acid and 95 kg water.
  • Example 12 X-Ray Powder Diffraction (XRPD) Sample treatment: Samples of crystal Form A were used as a powder without further preparation. Optionally grinding or milling of powder may be performed. Sample preparation: Approximatly 100mg of material was brought between two thin acetate foils. This sandwich was held in position by a clip in appropriate transmission sample holder. The sample holder was positioned in the diffractometer.
  • XRPD X-Ray Powder Diffraction
  • XRPD patterns were collected with a PANalytical X'Pert Pro diffractometer.
  • a incident beam of Cu Ka radiation (1 ,54056 A) was produced using a long, fine focus tube (40 kV, 40 mA).
  • Used slits were an antiscatter slit 1 /4° and a divergence slit 1 /2°.
  • the samples were analyzed in transmiss ion geometry in a measurement range between 2 and 38° 2Theta with a step size of 0 .013° 2Theta and 25s as time per step.
  • the sample holder was rotated with a spinner revolution time of 1 s.
  • the intensities of pattern were collected with a PixCel detector located 240 mm from the specimen and Data Collector software.
  • the powder pattern were evaluated with PANalytical HighScorePlus software.
  • the identification of the phase composition of an unknown sample by XRPD was usually based on the visual or computer-assisted comparison of a portion of its XRPD pattern to the experimental pattern of a reference material.
  • a crystalline substance was identified by its 2 ⁇ diffraction angles or d-spacings and by its relative intensities. The agreement in the 29-diffraction angles between specimen and reference was within 0.2°for the same crystal form.

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Abstract

La présente invention concerne un nouveau procédé de préparation d'un composé de formule (I) ou d'un sel de celui-ci, de nouveaux composés intermédiaires, ainsi que l'utilisation desdits nouveaux composés intermédiaires pour la préparation dudit composé de formule (I) ou d'un sel de celui-ci. La présente invention porte également sur des formes cristallines, la forme A, d'un composé de formule (I), des produits pharmaceutiques et leurs utilisations.
PCT/EP2015/075670 2014-11-07 2015-11-04 Synthèse d'un inhibiteur de pi3k et de ses sels WO2016071382A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018215282A1 (fr) 2017-05-26 2018-11-29 Bayer Pharma Aktiengesellschaft Combinaison d'inhibiteurs de bub1 et de pi3k
CN112824387A (zh) * 2019-11-21 2021-05-21 济南尚博生物科技有限公司 一种2-甲基烟酸酯及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012062748A1 (fr) * 2010-11-11 2012-05-18 Bayer Pharma Aktiengesellschaft Dérivés de 2,3-dihydroimidazo[1,2-c]quinazoléine substitués par un aminoalcool utiles pour traiter des troubles hyperprolifératifs et des maladies associées à l'angiogenèse

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012062748A1 (fr) * 2010-11-11 2012-05-18 Bayer Pharma Aktiengesellschaft Dérivés de 2,3-dihydroimidazo[1,2-c]quinazoléine substitués par un aminoalcool utiles pour traiter des troubles hyperprolifératifs et des maladies associées à l'angiogenèse

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018215282A1 (fr) 2017-05-26 2018-11-29 Bayer Pharma Aktiengesellschaft Combinaison d'inhibiteurs de bub1 et de pi3k
CN112824387A (zh) * 2019-11-21 2021-05-21 济南尚博生物科技有限公司 一种2-甲基烟酸酯及其制备方法和应用
CN112824387B (zh) * 2019-11-21 2023-03-21 济南尚博生物科技有限公司 一种2-甲基烟酸酯及其制备方法和应用

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