WO2016071380A1

WO2016071380A1 - Synthesis of pi3k inhibitor and salts thereof

Info

Publication number: WO2016071380A1
Application number: PCT/EP2015/075667
Authority: WO
Inventors: Jan-Gerog PETERS; Philipp Rubenbauer; Johannes Platzek; Juergen Stiehl; Kai Lovis; Martin Seyfried; Theodor Zweifel; Maurus Marty; Günter Weingärtner
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2014-11-07
Filing date: 2015-11-04
Publication date: 2016-05-12

Abstract

The present invention relates to a novel method of preparing a compound of formula (I) or salt thereof, to novel intermediate compounds, to the use of said novel intermediate compounds for the preparation of said compound of formula (I) or salt thereof and to a method of purifying a compound of formula (I), or salt thereof. The present invention also relates to crystalline forms, form A, of a compound of formula (I), pharmaceuticals and uses thereof.

Description

SYNTHESIS OF PI3K INHIBITOR AND SALTS THEREOF

FIELD OF THE INVENTION 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

(I),

or salts thereof, and a method for its purification. 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. The invention also relates to a method of purifying a compound of formula (I), or a salt thereof.

The present invention further relates to crystalline forms, form A of a compound of formula (I), pharmaceuticals and uses thereof.

BACKGROUND TO THE INVENTION

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 2012/062748 A1 on May 18, 2012, (which is incorporated herein by reference in its entirety).

Compound of formula (I) is published in WO 2012/062748 A1 as the compound of Example 14 : 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, on page 85.

Biological test data for said compound of formula (I) is given in WO 2012/062748 on pp. 120 to 129.

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.

As mentioned supra, compound of formula (I) is, in WO 2012/062748, described on pp. 85, and may be synthesized according to the method given therein. The processes described in WO 2012/062748, although effective, suffer from numerous disadvantages which pose especially problems at larger scale :

• Batchwise nitration of a molecule which is susceptible to oxidation is only possible at a very small scale due to safety-concerns.

• Conversion of the aldehyde-group into a nitrile with ammonia and iodine as reagents may be dangerous and/or require special conditions for safe operation, as ammonia and iodine may form nitrogen triiodide, a highly sensitive explosive substance.

• The cyclisation with ethylenediamine to the imidazoline-ring needs sulfur.

As sulfur is very difficult in cleaning processes in technical systems with fixed reactors and tubings, this cyclisation reaction is less suitable for scaleup.

• Reduction of the nitrogroup to the corresponding amine on larger scale is difficult with iron and acid (also large quantities of waste are generated). Standard catalytic reductions often suffer from side reactions which reduce the yield significantly (e.g. debenzylation) .

• After the alkylation with R-glycidyl methanesulfonate the epoxide is reacted with morpholine in the microwave at 140 Ό. The product is obtained in low yield and has to be purified by MPLC. This process is less suitable for scale up.

• In the final amide formation PyBOP (benzotriazol-1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate) is used as a coupling reagent. Due to safety concerns this reagent is less suitable for scale up and/or require special conditions for safe operation.

It was therefore desirable to devise a new synthesis, which circumvents some or all of these disadvantages and is suitable for production scale/industrial scale, providing benefits such as increased safety, easier to handle reagents/reactants and/or an increase in yields/selectivity. Other benefits which would be appropriate include those selected from reduction in number of process steps, reduction in number of unit operations, reduction of cycle-times, increased space yield, and/or increase in purity of the PI3K inhibitor especially when manufacture of larger quantities are envisaged.

DESCRIPTION OF THE INVENTION

According to a first aspect the present invention provides a method of preparing a compound of formula (I) (Step A1 0):

(I)

or a salt thereof, which com rises the reaction of a compound of formula 9, or a salt thereof,

9

with a com ound of formula (1 2)

(12)

or a salt thereof, such as the hydrochloride salt thereof. In a preferred embodiment the compound of formula (9) is used as the TFA salt thereof compound (9a) :

In another preferred embodiment the compound of formula (1 2) is used as the hydrochloride salt thereof, compound (1 2a) :

(12a)

In a more preferred embodiment, the compound of formula (9) is compound (9a) the compound of formula (12) is compound (12a).

According to an embodiment the reaction is carried out in the presence of a base, such as potassium carbonate.

According to an embodiment the reaction is carried out in a solvent, such as DMF, at a temperature of about 70 to about 80 Ό , preferably at about 75 Ό.

Advantageously, compound of formula (12) or (12a) can be handled and prepared on scale. Surprisingly and advantageously the alkylation of compound of formula (9) or (9a) already works at 70 to 80 without the need of microwave irradiation. The crude product can be directly used in the optional next purification step and no MPLC purification is necessary.

Optionally, the purity and enantiomeric purity of the crude compound (I) may be increased by stirring the crude product in a suspension with (S)-mandelic acid, in a solvent, such as methanol, optionally with heating, such as under reflux. Optionally, the compound of formula (I) is further crystallized from a solvent or mixture of solvents, such as a water/acetic acid mixture (solvent) and an ethanol/water/sodium bicarbonate mixture (antisolvent).

Surprisingly, after the stirring of compound (I) with mandelic acid and subsequent crystallization, the purity of compound (I) is equal or higher than 99%.This method also surprisingly allows an increase of the enantiomeric purity, affording an enantiomeric excess of compound (I) equal or higher than 99% ee.

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (9) (Step A8):

or salt thereof, by O-debenz lation of a compound of formula (8):

(8)

or salt thereof.

In a preferred embodiment said compound of formula (9) is the TFA salt thereof, compound (9a) :

According to an embodiment the O-debenzylation of a compound of formula (8) is carried out in the presence of trifluoroacetic acid (TFA). According to an embodiment the O-debenzylation is carried out with heating, preferably under reflux. According to an embodiment, compound of formula (9) or (9a) is crystallized in ethyl acetate.

Advantageously, debenzylation of compound of formula (8) using TFA as a reagent leads to a clean reaction (i.e. low level of impurities) and almost all side products are removed upon crystallization of compound of formula (9) or (9a) with ethyl acetate leading to a product with >99% purity.

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (8) (Step A7), or salt thereof,

(8)

reaction of a compound of formula (7), or a salt thereof,

<7)

with a compound of formula

or a salt thereof. According to an embodiment the 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). In a preferred embodiment the coupling agent is EDC. According to an embodiment the reaction is carried out in a solvent, such as dimethylformamide (DMF). Advantageously, compound of formula (7) can be coupled in the presence of EDC instead of PyBOP which is difficult to handel on scale.

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (7) (Step A6):

by reaction of compound of formula 6) :

(6) with an annelating agent, such as cyanogen bromide (also known as bromocyanide), optionally in the presence of a base, such as triethylamine, optionally in a solvent, such as acetonitrile or dichloromethane. In a preferred embodiment the solvent is acetonitrile. According to an embodiment, compound of formula (7) is further stirred in acetone and water. According to another embodiment, compound of formula (7) is further stirred in toluene.

Advantageously, 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 %).

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (6) (Step A5):

(6) by reaction of a compound of formula 5) :

(5) with a reducing agent, such as hydrogen, optionally in the presence of 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. In an embodiment the reaction is carried out in THF. In another embodiment the reaction is carried out in THF/water. In an embodiment, the reduction is carried out in THF in the presence of 1 % Pt/0.2% Fe/C in water as a catalyst. In a preferred embodiment, the reduction is carried out in THF in the presence of 1 % Pt/0.2% Fe/C in water as a catalyst. In another embodiment, the reduction is carried out in methanol in the presence of 1 % Pt/0.2% Fe/C in water as a catalyst. In a preferred embodiment the catalyst is 1 % Pt/0.2% Fe/C. In an embodiment, 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 ).

Surprisingly and advantageously, 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). Advantageously 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 isopropanol 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.

In an embodiment of the first aspect, the present invention relates to a method of preparing a compound of formula (I) :

or a salt thereof, which comprises the steps of:

a reacting a compound of formula (9),

lt thereof, such as compound (9a),

(9a)

with a com ound of formula (1 2)

s the hydrochloride salt (12a)

(1 2a) _j wherein the reaction is optionally carried out in the presence of a base, such as potassium carbonate and optionally carried out in a solvent, such as DMF, at a temperature of about 70 to about 80 Ό, preferably at about 75 (e.g. at 75 ^«C);

b) preparing said compound of formula (9) or salt thereof, such as compound (9a), by O-debenzylation of a com ound of formula (8):

(8)

or salt thereof, wherein the O-debenzylation of a compound of formula (8) is carried out in the presence of trifluoroacetic acid (TFA), optionally with heating, preferably under reflux; wherein said compound of formula (8), or salt thereof, c) preparing said compound of formula (8) by reacting a compound of formula (7 or a salt thereof,

(7)

with a compound of formula

or a salt thereof, optionally in the presence of a coupling agent, such as EDC, and optionally a catalyst, such as DMAP, wherein the reaction is optionally carried out in a solvent, such as DMF;

d) preparing said compound of formula (7) by reacting compound of formula (6) :

(6) with an annelating agent, such as cyanogen bromide, optionally in the presence of a base, such as triethylamine, optionally in a solvent, such as acetonitrile or dichloromethane, preferably acetonitrile;

e) preparing said compound of formula (6) by reacting a compound of formula

(5) :

(5) with a reducing agent, such as hydrogen, optionally in the presence of 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, methanol or water, or a mixture thereof, preferably in THF or in THF/water.

In a preferred embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (6) (Step A5):

(6) by reaction of a compound of formula (5)

(5) with hydrogen in the presence of a bimetallic catalyst, which is 1 % Pt/0.2% Fe/C in water, in suspension in tetrahydrofuran.

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned com ound of formula (5) (Step A4):

(5) is prepared by reaction of a compound of formula (4) :

(4) with ethylenediamine, optionally in the presence of a N-halosuccinimide, such as N-bromosuccinimide (NBS), optionally in a solvent, such as dichloromethane, methanol, acetonitrile or a mixture thereof, such as a mixture of methanol/acetonitrile. In a preferred embodiment the solvent is a mixture of methanol/acetonitrile.

According to an embodiment, the reaction of compound of formula (4) with ethylenediamine is quenched with NaHC03 and Na2S03, optionally in a solution in water.

Advantageously, 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.

Surprisingly, conducting Step A4 in methanol and acetonitrile lead to fewer side products, which made the process easier to conduct (dosing a NBS solution) and safer on scale. Surprisingly, the process conducted in methanol and acetonitrile allows removal of the wrong nitro regio isomer (e.g. originated during the nitration of compound of formula (1 )) under these 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.

Advantageously, after the quench with NaHC03 and Na2S03 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). Under a variety of conditions applied a tedious purification was necessary since side products poison the bimetallic catalyst (1 % Pt/0.2% Fe/C in water). Advantageously, it was also possible to use the wet crude product in the (subsequent) hydrogenation.

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (4) (Step A3):

(4), by reaction of a compound of formula (3) :

(3), with benzyl bromide,

optionally in a solvent, such as Ν,Ν-dimethylformamide (DMF), optionally in the presence of a base, such as potassium carbonate, optionally with heating, such as under reflux or at a temperature of about 30 to about 40 . According to an embodiment, the work-up of compound of formula (4) is done in the presence of water or methanol, or a mixture thereof.

Advantageously, no destination of DMF was necessary and less solvents were needed in the work up. After addition of water the product precipitated and could be filtered off.

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (3) (Step A2):

(3), is prepared by reaction of a compound of formula (2) :

(2), with K2CO3, optionally in a solvent, such as methanol, or with NaOH, optionally in a solvent, such as water. According to an embodiment, the compound of formula (3) is recrystallized from dichloromethane/toluene.

According to another embodiment, the work-up of compound of formula (3) is done in the presence of water.

Surprisingly and advantageously, 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).

In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (2) (Step A1 ):

(2), is prepared by reaction of a compound of formula (1 )

(1 ) with nitric acid in the presence of sulphuric acid, optionally in a solvent, such as dichloromethane (DCM). According to an embodiment, the method is carried continuously in a micro reactor, via flow nitration. According to an embodiment, the work-up of compound of formula (2) is done in the presence of dichloromethane. Advantageously, 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. In an embodiment of the first aspect, the present invention relates to a method of preparing the above-mentioned compound of formula (12) (Step A9):

(12) or salt thereof, such as the hydrochloride salt thereof, compound (12a) :

(12a)

by reaction of a compound of formula (1 1 )

(^{1 1} )

with thionyl chloride (SOCI2), optionally in a solvent, such as dichloromethane, optionally with heating, such as under reflux. According to an embodiment, compound (12), particularly compound (12a), is crystallized from dichloromethane and toluene.

Surprisingly and advantageously, compound (12a) is obtained as a stable solid after crystallization from dichloromethane and toluene. Compound (12a) can be handled and prepared on scale by the present method. By the known process compound (12a) was evaporated to dryness and this material was less stable due to remaining acidic impurities and was difficult to handle on scale.

In an embodiment of the first aspect, the present invention relates to a method of preparing the compound of formula (I), wherein the compound of formula (I) is further purified in a solution or in a suspension with (S)-mandelic acid, such as a suspension of compound of formula (I) in methanol with (S)-mandelic acid, optionally with sitirring. In an embodiment the stirring in methanol/(S)-mandelic acid is done with heating, such as under reflux.

In an embodiment 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).

Surprisingly and advantageously, the side products generated in the alkylation step (Step A10) could be removed upon stirring of compound (I) with mandelic acid in methanol and subsequent crystallization. The purification process affords a purity of compound (I) equal or to higher than 99%. This method also allows an increase of the enantiomeric purity, affording an enantiomeric excess of compound (I) equal or higher than 99% ee. Surprisingly and/or advantageously, a crystalline product is obtained with a purity level equal to or higher than 99%. In an embodiment of the first aspect, the compound of formula (I) is crystalline form A as described hereinafter.

5 In an embodiment of the first aspect, the present invention relates to a method, wherein the compound of formula (I) is prepared via the following steps, infra :

In a further embodiment of the first aspect, the present invention relates to a lo 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. In a further embodiment of the first aspect, the present invention relates to a 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.

Further aspects of the present invention are, independently of each other, steps A1 , A2, A3, A4, A5, A6, A7, A8, and A9 for the preparation of the intermediates 2, 3, 4, 5, 6, 7, 8, 9 and 12, respectively, each independent step being useful for the preparation of the compound of formula (I).

More particularly, the following further surprising effects and/or advantages of the specific steps of the synthesis of the present invention, as described and depicted supra, are given infra :

• Step AI :

A continuous process via microreaction-technology, as exemplified in Example 1 {vide infra) has been devised. The nitration reaction was performed in a microreactor system and kilogram-quantities could easily be prepared within days or a few weeks. There was no danger of a runaway- reaction. Good yields were obtained.

• Step A2 :

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). · Step A3 :

Simple alkylation mediated by a base like potassium carbonate afforded high yields. No phase separation was necessary, direct precipitation by addition of water followed by filtration. Diethyl ether can be avoided by the present process. Overall no distillation of DMF and fewer solvents in the work up were needed in the present process.

• Step A4 :

A one-pot reaction of cyclisation and oxidation of compound of formula (4) with ethylenediamine and NBS has been devised. Iodine (which is more difficult to handle on scale than NBS) and sulfur could be avoided. Conducting the process in methanol and acetonitrile leads to fewer side products, which makes 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 (in the nitration step A1 app. 10% of the wrong regioisomer is formed). In 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. After the quench with NaHCO3 and Na2SO3 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). Under a variety of conditions applied a tedious purification was necessary since side products poison the bimetallic catalyst (1 % Pt/0.2% Fe/C in water). It was also possible to use the wet crude product in the (subsequent) hydrogenation.

• Step A5 :

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). Advantageously 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.

• Step A6 :

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 :

Compound of formula (7) could be coupled in the presence of EDC instead of PyBOP which is difficult to handel on scale due to safety reasons.

• Step A8 :

Debenzylation of compound of formula (8) using TFA as a reagent leads to a clean reaction and a product in a very high purity. Almost all side products were removed upon crystallization of compound of formula (9) or (9a) with ethyl acetate leading to a product with >99% purity, (no impurity higher than 0.5%)

• Step A9 :

Compound (12a) could be obtained as a stable solid after crystallization from dichloromethane and toluene. Compound (12a) could be handled and prepared on scale. By the known process compound (1 2a) was evaporated to dryness and this material was not stable due to remaining acidic impurities and was difficult to be handled on scale. · Step AI O :

Surprisingly and advantageously the alkylation of compound of formula (9a) with compound (12a) was scalable to kg quantities and already worked at 70C to 80 without the need for microwave irradiat ion at 140 C. The crude product could be directly used in the optional next purification step and no MPLC purification was necessary. • Step A1 1 :

The side products generated in Step A10 could be removed under the acidic conditions applied without increasing the amount of other impurities (e.g. degradation products) by stirring the crude product and mandelic acid in methanol and subsequent crystallization. It was also possible to increase the enantiomeric excess via this method.

Crystallization of compound (I) could be achieved via dissolving in acetic acid/water and crystallization in ethanol/water/sodium bicarbonate.

In accordance with a second aspect, the present invention relates to intermediate compounds which are useful in the preparation of compound of formula (I).

In an embodiment of said second aspect, the present invention relates to a compound :

(9) , or a salt thereof.

, or a salt thereof

In an embodiment of said second aspect, the present invention relates to compound :

(6)

(5)

(4)

(3)

(2)

(1 )

In accordance with a third aspect, the present invention relates to the use of the intermediate compounds for preparing compound of formula (I), or a salt thereof.

In an embodiment of said third aspect, the present invention relates to the use of

(9)

, or a salt thereof,

for preparing compound of formula (I) , or a salt thereof. In an embodiment of said third aspect, the present invention relates to the use of

(9a)

for preparing compound of formula (I) , or a salt thereof.

, or a salt thereof, for preparing compound of formula (I) , or a salt thereof.

(12a) for preparing compound of formula (I) , or a salt thereof.

(8)

for preparing compound of formula (I) , or a salt thereof.

for preparing compound of formula (I) , or a salt thereof.

for preparing compound of formula (I), or a salt thereof.

(6),

for preparing compound of formula (I) , or a salt thereof.

(5),

for preparing compound of formula (I) , or a salt thereof.

(4), for preparing compound of formula (I) , or a salt thereof.

(3),

for preparing compound of formula (I) , or a salt thereof.

(2),

for preparing compound of formula (I) , or a salt thereof.

(1 )

for preparing compound of formula (I) , or a salt thereof.

In accordance with a fourth aspect, the present invention relates to a method of purifying a compound of formula (I), comprising the step of contacting the compound of formula (I) with a solution or a suspension with (S)-mandelic acid, such as a suspension in methanol with (S)-mandelic acid, optionally with sitirring.

In an embodiment of the fourth aspect, the compound of formula (I) is further crystalized from a solvent or mixture of solvents, such as a water/acetic acid mixture (solvent) and a water/ethanol/sodium bicarbonate mixture (antisolvent).

In an embodiment of the fourth aspect, the compound of formula (I) is crystalline form A as described hereinafter.

Surprisingly and advantageously, side products generated in the preparation of compound of formula (I) can be removed upon stirring of compound (I) with mandelic acid in methanol and subsequent crystallization. Surprisingly, under the acidic conditions applied removal of undesired impurities can be achieved without increasing the amount of other impurities (e.g. degradation products). The purification process affords a purity of compound (I) equal or higher than 99%. This method also allows an increase of the enantiomeric purity, affording an enantiomeric excess of compound (I) equal or higher than 99% ee.

Within the context of the present invention the term "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 pentane, hexane, benzene, toluene, diethyl ether, methyl ethyl ketone, dichoromethane, chloroform, tetrachloromethane, ethyl acetate, etc., for example ; or any mixture of the solvents listed above. As it is understood by the person skilled in the art, under certain conditions 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. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of 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.

In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.

Suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.

Suffixes to chemical names or structural formulae such as "dihydrochloride", "2 HCI", "2 CF3COOH", "1 Na+", for example, are to be understood as stoichiometric or as a not stoichiometric specification. 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.

This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.

The present invention covers all such stoichiometric and non-stoichiometric hydrates and/or solvates of the compounds and intermediates described herein. It is understood that any combination of the definitions given in the above- mentioned embodiments is possible within the context of the present invention.

In accordance with a fifth aspect, the present invention relates to a crystalline polymorph 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.

Processes for the preparation of crystalline Form A are given in the experimental section. 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. In the following, characteristic peaks of the XRPDs of the polymorphs of the invention are given in degrees 2Θ (Cu-Ka radiation).

In the following description of the present invention, the polymorphic form is 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. Θ ; or in another embodiment, an XRPD pattern with peaks at the positions listed ± 0.1 °2 Θ.

In an embodiment of the fourth aspect, there is provided a crystalline Form A of a compound of formula (I) having an XRPD pattern with peaks at 5.6, 7.5, 1 0.2, 1 1 .1 , 12.2, 15.5, 22.2 °2 Θ ± 0.2 °2 Θ. The XRPD pattern may have further peaks at 5.8, 9.8, 13.2, 15.1 , 16.3, 17.5, 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 Θ ± 0.2 °2 Θ.

In an embodiment, Form A is characterised as having an XRPD pattern with one or more of the peaks presented in Table 1 .

Form A

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

In an embodiment, Form A has an XRPD as shown in Figure 1 . According to another aspect, there is provided a pharmaceutical composition comprising a crystalline Form A as described herein, and a pharmaceutically acceptable diluent or carrier.

According to another aspect, there is provided a crystalline Form A as described herein or a pharmaceutical composition as described herein, for use in the treatment or prophylaxis of a disease.

According to another aspect, the invention relates to the use of a crystalline Form A 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.

According to one embodiment, 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.

It is understood that any combination of the definitions given in the above- mentioned embodiments is possible within the context of the present invention.

The invention will be better understood upon reading the Examples below, which are provided as an illustration of the present invention. The Examples below in no way whatsoever constitute a limitation of the present invention as described in the present text and as defined in the claims appended hereto.

Brief description of the figures

Figure 1 . XRPD of crystalline Form A

Figure 2. Embodiment of the process to prepare compound of formula (I) according to the present invention

EXPERIMENTAL SECTION

Abbreviations used : The following abbreviations used in the Examples have the following meanings: PI3K phosphotidylinositol-3-kinase

1 H-NMR proton nuclear magnetic resonance spectroscopy (chemical shifts

(δ) are given in ppm)

bm broad multiplet

bs broad singlet

d doublet

dd doublet of doublets

m mulitplet

br broad

s singulet

t triplet

NBS N-bromosuccinimide

EDC 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

PyBOP Benzotriazol-1 -yl-oxytripyrrolidinophosphonium

hexafluorophosphate

DMAP 4-Dimethylaminopyridine

TFA trifluoroacetic acid

DMF dimethylformamide

ACN acetonitrile

Ac or AcO acetate

THF tetrahydrofuran

DCM dichloromethane

DMSO dimethylsulfoxide

HOAc acetic acid

NMP N-Methyl-2-pyrrolidone

app. approximately

RT room temperature RRT relative retention time

HPLC high performance liquid chromatography

MPLC medium pressure liquid chromatography

ee enantiomeric excess

HPLC MS high performance liquid chromatography - mass spectrometry wt weight

The above abbreviations are provided for ease of reference only and do not depart from the commonly accepted meanings used in the technical field of the invention. Any abbreviations described herein not listed above take the meaning commonly used in the technical field of the invention.

EXAMPLES

Unless otherwise indicated, yields of the reactions, purity and enantiomeric purity of the compounds described herein have been determined by HPLC by the methods described herein or equivalent methods, or by methods available to the skilled person.

Methods:

HPLC

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: 45 C, injection volume: 7.0 \iL (in the sample rack cooled at 10 ^<C), flow 0.90 mL / min; linear gradient in 3 steps: 3% B→ 3% B (3 min.), 3% B→ 15% B (15 min.), 15%→80% B (30 min.), 5 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 vanillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5Ό. The reaction mixture was directly dosed into 8 kg of water at 3Ό. After 3h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L.

1 .25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30Ό for 3h. 7.3 kg of d ichloromethane and 12.8 kg of aqueous hydrochloric acid (1 0 w%) were added at < 30Ό (pH 0.5 - 1 ). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0Ό. After 90 min the sus pension was filtered. The collected solids were washed with cold toluene and dried to give 0.95 kg (62 % yield).

¹ H-NMR (400 MHz, de-DMSO): δ =3.84 (s, 3H), 7.23 (d, 1 H), 7.73 (d, 1 H), 9.74 (s, 1 H), 1 1 .82 (brs, 1 H). Example 2 : Step A2 : Preparation of 4-hydroxy -3-methoxy-2- nitrobenzaldehyde (2-nitro-vanillin) (3)

24 g acetyl-2-nitrovanilline were suspended in 300 ml water at 10-30 The mixture was heated to 40 - 45 and 40 g NaOH 30% (300 mmol, 3 equiv.) were added in 10-20 min. Stirring was continued for 30-45 min. The reaction was cooled to 25-30 and the pH was set to 2.0-2.5 by the addition of 10% sulfuric acid. Stirring was continued for 15 min at 20-25 Ό and the product was filtered off and washed with water (2 x 100 ml).

The product was dried at 45-50Ό under reduced pres sure and 1 8.7 g 2- nitrovanilline were obtained a white to yellow solid in 95% yield.

Example 3A : Step A3 : Preparation of 4-(benzyloxy)-3-methoxy-2- nitrobenzaldehyde (4) :

18 g 2-nitrovanilline (91 .3 mmol) were dissolved in 75 ml DMF at. 25Ό and 25.2 g K2C03 (182 mmol, 2 equiv.) were added. At a temperature of app. 30 - 40 18.0 g benzyl bromide (1 05 mmol, 1 .15 equiv.) were added in 15-30 min. The suspension was stirred for 45-60 min and 125 ml water were dosed in. The suspension was filtered and washed twice with 50 ml water. The obtained product was dried at 45 - 60 under reduced pressu re and 24.7 g of a light yellow solid were obtained 94.2%.

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 Ό. Into this suspension 7.1 mL benzyl bromide was dosed in 15 minutes at a temperature of 30 . The reaction mixture was stir red for 2 hours to complete the reaction. After cooling to 25 125 mL water w as added. The suspension was filtered, washed twice with 50 mL water and once with water / methanol (10 mL / 10 mL) and dried at 40 Ό under reduced pressu re. In this way 14.2 g (97% yield) of (4) were obtained as a yellowish solid.

1 H-NMR (500 MHz, d6-DMSO): 3.86 (s, 3H); 5.38 (s, 2 H); 7.45 (m, 5H); 7.62 (d, 2H); 7.91 (d, 2H); 9.81 (s, 1 H).

Example 4A : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5- dihydro-1H-imidazole (5) : Method A

10 g of of compound (4) were dissolved in 100 mL methanol and 2.5 g ethylenediamine were added at 20-25 . The reactio n mixture was stirred at this temperature for one hour, cooled to 0 and a solution of N- bromosuccinimide (8.1 g) in 60 mL acetonitrile was added. Stirring was continued for 1 .5 h and the reaction mixture was warmed to 20 and stirred for another 60 minutes. The reaction was quenched with a solution of 8.6 g NaHC03 and 2.2 g Na2S03 in 100 mL water. After 10 minutes 230 mL water was added, the product was filtered, washed with 40 mL water and dried at 40 Ό under reduced pressure. In this way 8.9 g (78% y ield) of (5) was obtained as an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.31 (s, 4H); 3.83 (s, 3H); 5.29 (s, 2 H); 6.88 (s, 1 H); 7.37 (t, 1 H); 7.43 (m, 3H); 7.50 (m, 3H).

Example 4B : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5- dihydro-1H-imidazole (5) : Method B

28.7 kg of compound (4) were dissolved in 231 kg dichloromethane at 20 Ό and 8.2 kg ethylenediamine were added. After stirring for 60 minutes N- bromosuccinimide was added in 4 portions (4 x 5.8 kg) controlling that the temperature did not exceed 25 . When the addition was completed stirring was continued for 90 minutes at 22 Ό. To the reaction mixture 9 kg potassium carbonate in 39 kg water was added and the layers were separated. From the organic layer 150 kg of solvent was removed via distillation and 67 kg toluene was added. Another 50 kg solvent was removed under reduced pressure and 40 kg toluene was added. After stirring for 30 minutes at 35-45 the reaction was cooled to 20 Ό and the product was isolated via fi Itration. The product was washed with toluene (19 kg), dried under reduced pressure and 26.6 kg (81 % yield) of a brown product (5) was obtained.

Example 5A : Step A5 : 3-(benzyloxy)-6-(4,5-dihydro-1 H-imidazol-2-yl)-2- methoxyaniline (6) :

8.6 g of compound (5) were suspended in 55 mL THF and 1 .4 g of 1 wt%Pt/0.2wt% Fe/C in 4 mL water was added. The mixture was heated to 45 Ό and hydrogenated at 3 bar hydrogen pressure for 30 minutes. The catalyst was filtered off and washed two times with THF. THF was removed via distillation and 65 mL isopropanol/water 1 /1 were added to the reaction mixture. The solvent remaining THF was removed via distillation and 86 mL isopropanol/water 1 /1 was added. The suspension was stirred for one hour, filtered, washed twice with isopropanol/water 1 /1 and dried under reduced pressure to yield 7.8g (99% yield) of an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.26 (t, 2H); 3.68 (s, 3H); 3.82 (t, 2H); 5.1 3 (s, 2 H); 6.35 (d, 1 H); 6.70 (s, 1 H); 6.93 (bs, 2 H); 7.17 (d, 1 H); 7.33 (t, 1 H); 7.40 (t, 2H); 7.45 (d, 2H). Example 5B : Step A5 : 3-(benzyloxy)-6-(4,5-dihydro-1 H-imidazol-2-yl)-2- methoxyaniline (6) :

2 g of compound (5) were suspended in 20 mL MeOH and 0.4 mL NaOH (30% in water) then 0.32 g of 1wt% Pt/0.2wt% Fe/C was added. The mixture was heated to 30 Ό and hydrogenated at 3 bar hydrogen pressure for 2 hours. The catalyst was filtered off and washed with MeOH. The reaction mixture was concentrated and 40 mL water was added. The suspension was stirred for one hour, filtered, washed twice with water and dried under reduced pressure to yield 1 .4 g (76% yield) of a white solid.

Example 6A : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-amine (7) : Method A 10 g of compound (6) were suspended in 65 mL acetonitrile and 6.1 mL triethylamine were added. At 5-1 0 Ό 8.4 mL bromocy anide 50% in acetonitrile were added over one hour and stirring was continued for one hour. 86 mL 2% NaOH were added and the reaction mixture was heated to 45 Ό and stirred for one hour. The suspension was cool to 10 , filter ed and washed with water/acetone 80/20. To further improve the quality of the material the wet product was stirred in 50 mL toluene at 20-25 Ό. T he product was filtered off, washed with toluene and dried under reduced pressure. In this way 8.8 g (81 % yield) of (7) was isolated as a white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.73 (s, 3H); 3.87 (m, 4H); 5.14 (s, 2 H); 6.65 (bs, 2 H); 6.78 (d, 1 H); 7.33 (m, 1 H); 7.40 (m, 3 H); 7.46 (m, 2H). Example 6B : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-amine (7) : Method B

20 kg of compound (6) were dissolved in 218 kg dichloromethane at 20 and the mixture was cooled to 5 Ό. At this temperature 23.2 kg triethylamine was dosed in 15 minutes and subsequently 25.2 kg bromocyanide (3 M in dichloromethane) was dosed in 60 minutes to the reaction mixture. After stirring for one hour at 22 Ό the reaction was concentrated and 188 kg of solvent were removed under reduced pressure. Acetone (40 kg) and water (50 kg) were added and another 100 kg of solvent were removed via distillation. Acetone (40 kg) and water (1 50 kg) were added and stirring was continued for 30 minutes at 36Ό. After cooling to 2 ^<C the suspension was stir red for 30 minutes, isolated, washed with 80 kg of cold water and dried under reduced pressure. With this procedure 20.7 kg (95% yield) of an off-white product was obtained.

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 wer e added and the reaction was stirred for 30 minutes. Compound (7) (25.0 kg) was added and the reaction was stirred for 4 hours at 0 C. The vessel was hea ted to 20 C 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 12 kg). The combined products were dried under reduced pressure and 29 kg of an almost white product (85% yield) were obtained.

HPLC MS RT = 0.69 min, MH⁺ = 442.2; 1 H-NMR (500 MHz, d6-DMSO): 2.80 (s, 3H); 3.94 (s, 3H); 4.03 (m, 4H); 5.28 (s, 2H); 7.18 (d, 1 H); 7.32 (dd, 1 H); 7.38 (d, 1 H); 7.44 (m, 2H); 7.52 (m, 2H); 7.62 (d, 1 H); 8.33 (dd, 1 H); 8.52 (dd, 1 H); 12.77 (s, 1 H).

¹ H-NMR (400 MHz, de-DMSO): δ = 3.72 (s, 3H), 3.85 (m, 4H), 6.47 (d, 1 H), 6.59 (bs, 1 H), 7.29 (d, 1 H), 9.30 (bs, 1 H).

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) :

Compound (8) (18.5 kg) was added to 185 kg trifluoroacetic acid (TFA) and heated to reflux. After stirring for 2 hours the reaction mixture was cooled to 20 Ό and the pressure was reduced to 120mbar. At this pressure the reaction was heated to 50 and 151 kg trifluoroacetic acid were removed via distillation. To the reaction mixture 167 kg ethyl acetate were added and 85 kg were removed via distillation. Another 85 kg ethyl acetate were added and the reaction was cooled to 0 Ό and stirred for 90 minutes. The prod uct was isolated on a centrifuge in four portions and each portion was washed with ethyl acetate (2 x 10 kg). The product was dried under reduced pressure and 22.2 kg (91 % yield) of a white solid were obtained. HPLC MS RT = 0.35 min, MH+ = 352.2; 1 H-NMR (500 MHz, d6-DMSO): 2.90 (s, 3H); 3.98 (s, 3H); 4.20 (t, 2H); 4.50 (m, 2H); 7.19 (d, 1 H); 7.61 (m, 1 H); 7.90 (d, 1 H); 8.72 (m, 2H); 13.35 (bs, 1 H). Example 9 : Step A9 : preparation of 4-{[(4R)-2-oxido-1 ,3,2-dioxathiolan-4- yl]methyl}morpholine hydrochloride (12a)

27.7 kg of (1 1 , (2R)-3-(morpholin-4-yl)propane-1 ,2-diolwas dissolved in 1 18 kg dichloromethane and 24.5 kg thionyl chloride was added at 30Ό over 30 minutes. The solution was heated to reflux and stirred for 4 hours. The reaction mixture was cooled to 30 , seeded and stirred for 30 minutes. 25 kg toluene was added and the reaction mixture was heated to reflux. After 30 minutes the suspension was cooled to 20 Ό and stirred for one hour. The product was isolated, washed with dichloromethane (2 x 36 kg) and dried under reduced pressure. 21 kg of (12a) (50% yield) were obtained as an almost 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

1 1 .4 kg of (9a) were dissolved in 109 kg DMF at 22 Ό. Potassium carbonate (16.2 kg) was added and the suspension was stirred for one hour. The reaction mixture was heated to 75 Ό, 4.8 kg of (12a) were a dded and stirring was continued for three hours. The reaction mixture was charged with overall six portions of 1 .37 kg potassium carbonate and 1 .37 Kg (12a) every 3 hours. After addition of the last potassium carbonate / (1 2a) portions the reaction was stirred for another 16 hours. The reaction was cooled to 20Ό, 1 14 kg water were added and stirred for one hour. The product was filtered off and washed with 45 kg of DMF. The product was washed with water (5 x 58 kg) and dried under reduced pressure at 50 Ό. The isolated product (6 kg) was optionally directly used in the final purification. (62% yield and 93% ee).

HPLC: stationary phase: Eclipse Plus RRHD C18 (150 mm length, 3.0 mm ID, 1 .8 μπι 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: 45 Ό, injection volume: 7. 0 μΙ_ (in the sample rack cooled at 10 Ό), flow 0.90 ml_ / min; linear gradie nt in 3 steps: 3% B→ 3% B (3 min.), 3% B→ 1 5% B (1 5 min.), 1 5%→80% B (30 min.), 5 min. holding time at 80% B; purity: typically 82.2 % (Rt = 10.3 min.), potential by-products: N-(8-{[1 - hydroxy-3-(morpholin-4-yl)propan-2-yl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)-2-methylpyhdine-3-carboxamide at RRT 0.98: typically 15.43 %(10.1 min.), N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl)-2-methylpyridine-3-carboxamide at RRT 1 .20: typically 1 .12 % (12.4 min.)

Example 11 : Step A11 : purification and crystallization of compound of formula (I) The vessel was charged with 9.4 kg crude (I), 4.2 kg (S)-mandelic acid and 149 kg methanol. The suspension was stirred under reflux for five days. The product was filtered off, washed with 42 kg methanol and 63 kg water. The product was dissolved in 93 kg water and 2.9 kg acetic acid at 50 Ό. This solution was dosed into a mixture of 77 kg water, 4.52 kg sodium bicarbonate and 1 1 kg ethanol at 50 Ό. The suspension was cooled to 21 ° C, stirred for one hour and filtered. The product was washed with 28 kg water and 26 kg ethanol. The final product was dried under reduced pressure and 5.9 kg (63% yield; >98% ee) of a white solid were obtained. HPLC: stationary phase: Eclipse Plus RRHD C18 (150 mm length, 3.0 mm ID, 1 .8 μπι 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: 45 Ό, injection volume: 7. 0 μΙ_ (in the sample rack cooled at 10 Ό), flow 0.90 ml_ / min; linear gradie nt in 3 steps: 3% B→ 3% B (3 min.), 3% B→ 1 5% B (1 5 min.), 1 5%→80% B (30 min.), 5 min. holding time at 80% B; purity: > 97.0 % (Rt = 10.3 min.), potential by-products: mandelic acid at RRT (relative retention time) of 0.64: typically < 0.05% (6.6 min.), N-(8-{[1 - hydroxy-3-(morpholin-4-yl)propan-2-yl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide at RRT 0.98: typically 0.07 %(10.1 min.), N-[3-(2-aminoethyl)-7-{[(2R)-2-hydroxy-3-(morpholin-4- yl)propyl]oxy}-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl]-2-methylpyridine-3- carboxamide at RRT 1 .14: typically 0.36 % (1 1 .7 min.), N-(8-hydroxy-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide at RRT 1 .20: typically 0.23 % (12.4 min.)

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. Measurement Conditions:

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 transmission geometry in a measurement range between 2 and 38° 2Theta with a s tep 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 2Θ 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.

Claims

1 . A method of preparing a compound of formula (I) :

or a salt thereof, which comprises the reaction of a compound of formula 9,

(9)

r a salt thereof such as compound (9a),

(9a)

with a com ound of formula (1 2)

or a salt thereof, such as the hydrochloride salt (12a) thereof.

2. The method according to claim 1 , wherein the reaction is carried out in the presence of a base, such as potassium carbonate.

3. The method according to claim 1 or 2, wherein the reaction is carried out in a solvent, such as DMF, at a temperature of about 70 to 80 , preferably at about 75 ^«C.

4. The method according to any one of claims 1 to 3, wherein said compound of formula (9) :

(9)

or salt thereof, such as compound (9a), is prepared by O-debenzylation of a compound of formula (8 :

(8)

or salt thereof.

5. The method according to claim 4, wherein the O-debenzylation of a compound of formula (8) is carried out in the presence of trifluoroacetic acid (TFA).

6. The method according to any one of claims 4 to 5, wherein the O- debenzylation is carried out with heating, preferably under reflux.

7. The method according to any one of claims 4 to 6, wherein said compound of formula (9) is further crystallized with ethyl acetate.

8. The method according to any one of claims 4 to 7, wherein said compound of formula (8), or salt thereof,

(8)

is repared by reaction of a compound of formula (7), or a salt thereof,

<7)

with a compound of formula

or a salt thereof.

9. The method according to claim 8, wherein the reaction is carried out in the presence of a coupling agent, such as EDC, and optionally a catalyst, such as DMAP.

10. The method according to claim 8 or 9, wherein the reaction is carried out in a solvent, such as DMF.

1 1 . The method according to any one of claims 8 to 10, wherein said compound of formula (7) :

<7) is prepared by reaction of compound of formula (6) :

(6) with an annelating agent, such as cyanogen bromide (also known as bromocyanide),

optionally in the presence of a base, such as triethylamine, optionally in a solvent, such as acetonitrile or dichloromethane, preferably acetonitrile.

12. The method according to claim 1 1 , wherein said compound of formula (6) :

is prepared by reaction of a compound of formula (5)

13. The method according to claim 1 1 or 12, wherein said compound of formula

(6) :

(6) is prepared by reaction of a com ound of formula (5) :

14. The method according to any one of claims 1 1 to 13, wherein said compound of formula (5) :

(5) is prepared by reaction of a compound of formula (4)

(4) with ethylenediamine, optionally in the presence of a N-halosuccinimide, such as N-bromosuccinimide, optionally in a solvent, such as dichloromethane methanol, acetonitrile or a mixture thereof, preferably in methanol/acetonitrile.

15. The method according to claim 14, wherein the reaction of compound of formula (4) with ethylenediamine is quenched with NaHC03 and Na2S03, optionally in a solution in water.

16. The method according to claims 14 or 1 5, wherein said compound of formula (4) :

(4), is prepared by reaction of a compound of formula (3) :

(3), with benzyl bromide,

optionally in a solvent, such as Ν,Ν-dimethylformamide, optionally in the presence of a base, such as potassium carbonate, optionally with heating, such as under reflux.

17. The method according to any one claim 16, wherein said compound of formula (3) :

(3), is prepared by reaction of a compound of formula (2) :

(2), with K2CO3, optionally in a solvent, such as methanol, or with NaOH, optionally in a solvent, such as water or methanol, or a mixture thereof.

18. The method according to claim 1 7, wherein the compound of formula (3) is recrystallized from dichloromethane/toluene.

19. The method according to claim 17 or 18, wherein the work-up of compound of formula (3) is done in the presence of water.

20. The method according to any one of claims 17 to 19, wherein said compound of formula (2) :

(2), is prepared by reaction of a compound of formula (1 ) :

(1 ) with nitric acid in the presence of sulphuric acid, optionally in a solvent, such as dichloromethane (DCM) in a micro reactor, via flow nitration.

21 . The method according to claim 20, wherein the work-up of compound of formula (2) is done in the presence of dichloromethane.

22. The method according to any one of claims 1 to 21 , wherein said compound of formula (1 2), or salt thereof, such as the hydrochloride salt (12a) thereof, is prepared by reaction of a com ound of formula (1 1 )

(1 1 )

with thionyl chloride.

23. The method according to claim 22, wherein the reaction is carried out in a solvent, such as dichloromethane, optionally with heating, such as under reflux.

24. The method according to claim 22 or 23, wherein compound (12), particularly compound (12a), is crystallized from dichloromethane and toluene. 25. The method according to any one of claims 1 to 24, wherein the compound of formula (I) is further purified in a solution or in a suspension with (S)-mandelic acid, such as a suspension in methanol with (S)-mandelic acid, optionally with sitirring. 26. The method according to any one of claims 1 to 25, wherein the compound of formula (I) is crystallized from a solvent or mixture of solvents, such as a water/acetic acid mixture (solvent) and a water/ethanol/sodium bicarbonate mixture (antisolvent). 27. The method according to any one of claims 1 to 26, wherein the compound of formula (I) is prepared via the following steps, infra :

purified (I)

28. A compound selected from

(9) , or a salt thereof,

(3),

for preparing a compound of formula (I)

(I)

or a salt thereof.

30. Method of purifying a compound of formula (I), comprising contacting a compound of formula (I) with a solution or a suspension with (S)-mandelic acid, such as a suspension in methanol with (S)-mandelic acid, optionally with sitirring.

31 . The method according to claim 30, 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 a water/ethanol/sodium bicarbonate mixture (antisolvent).

32. Crystalline Form A 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. 33. Form A according to claim 32 having an XRPD pattern with peaks at 5.6, 7.5, 10.2, 1 1 .1 , 12.2, 15.5, 22.2 ¾ θ ± 0.2 °2 Θ.

34. Form A according to claim 33 having an XRPD pattern with further peaks at 5.8, 9.8, 13.2, 15.1 , 16.3, 17.5, 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 Θ ± 0.2 °2 Θ.

35. Form A according to any one of claims 32 to 34 having an XRPD as shown in Figure 1 .

36. Pharmaceutical composition comprising a crystalline form A according to any one of claims 32 to 35, and a pharmaceutically acceptable diluent or carrier.

37. A crystalline form A according to any one of claims 32 to 35, or a pharmaceutical composition according to claim 36, for use in the treatment or prophylaxis of a disease. 38. Use of a crystalline form A according to any one of claims 32 to 35, or a pharmaceutical composition according to claim 36, for the prophylaxis or treatment of a disease.

39. Use according to claim 37 or 38, wherein 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.

40. The method of claim 30 or 31 , wherein the compound of formula (I) is a crystalline form A according to any one of claims 32 to 35.