HK1245774B - Synthesis of copanlisib and its dihydrochloride salt - Google Patents

Description

Synthesis of Copanlisib and its dihydrochloride

Field of the Invention

The present invention relates to the preparation of 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (10), 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (11), a novel method for preparing 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride hydrate I and 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride hydrate II, a novel intermediate compound, and the use of the novel intermediate compound in preparing the 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide. (10) 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (11) Uses of 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride hydrate I and 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride hydrate II:

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,

COPANLISIB,

(10);

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride,

(11).

The present invention also relates to copanlisib dihydrochloride hydrate as a compound.

Background of the Invention

2-Amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (10) (hereinafter referred to as "copanlisib") is a proprietary cancer drug with a novel mechanism of action, inhibition of class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target because PI3Ks play a central role in cellular signaling through surface receptors for survival and proliferation. Copanlisib has demonstrated broad activity against a variety of tumor histological types both in vitro and in vivo.

Copanlisib can be synthesized according to the method given in International Patent Application PCT/EP2003/010377, published on April 8, 2004 as WO 04/029055 A1, pages 26 et seq., which is incorporated herein by reference in its entirety.

Copanlisib is disclosed as Example 13, compound 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, in International Patent Application PCT/US2007/024985, published on June 12, 2008 as WO 2008/070150 A1, the entirety of which is incorporated herein by reference.

Copanlisib can be synthesized according to the methods given in WO 2008/070150, pages 9 et seq. and 42 et seq. The biological test data of the compound of formula (I) are given in WO 2008/070150, pages 101 to 107.

2-Amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (11) (hereinafter referred to as "copanlisib dihydrochloride") is disclosed as the compound 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride of Examples 1 and 2 in International Patent Application PCT/EP2012/055600 published on October 11, 2012 as WO2012/136553 (the entire content of which is incorporated herein by reference), and can be synthesized according to the methods given in Examples 1 and 2.

Copanlisib may exist in one or more tautomeric forms: Tautomers (sometimes called prototropic tautomers) are two or more compounds related by the migration of a hydrogen atom along with the migration of one or more single bonds and one or more adjacent double bonds.

Copanlisib may exist, for example, in tautomeric form (Ia), tautomeric form (Ib), or tautomeric form (Ic), or may exist as a mixture of any of these forms as depicted below. All such tautomeric forms are intended to be included within the scope of the present invention.

Copanlisib may exist as a solvate: a solvate for the purposes of the present invention is a complex of a solvent and copanlisib in a solid state. Exemplary solvates include, but are not limited to, complexes of copanlisib with ethanol or methanol.

Copanlisib and copanlisib dihydrochloride can exist as hydrates. Hydrates are a special form of solvates in which the solvent is water, wherein the water is a structural element of the crystal lattice of copanlisib or copanlisib dihydrochloride. The amount of water can be present in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric hydrates, hemi-, (half-), mono-, sesqui-, di-, tri-, tetra- or penta-hydrates of copanlisib or copanlisib dihydrochloride are possible. Water may also be present on the surface of the crystal lattice of copanlisib or copanlisib dihydrochloride. The present invention includes all such hydrates of copanlisib or copanlisib dihydrochloride, particularly copanlisib dihydrochloride hydrates referred to as "Hydrate I" prepared and characterized as described in the experimental section herein or as "Hydrate II" prepared and characterized as described in the experimental section herein.

As mentioned above, copanlisib is described in WO 2008/070150 on pages 9 et seq. and can be synthesized according to the method given on pages 42 et seq. therein, namely:

Reaction Scheme 1:

In reaction scheme 1, vanillin acetate can be converted to intermediate (III) via nitrating conditions, such as pure fuming nitric acid or nitric acid in the presence of another strong acid such as sulfuric acid. It is expected that the acetate in intermediate (III) will hydrolyze in a protic solvent such as methanol in the presence of a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide. Protecting intermediate (IV) to produce a compound of formula (V) can be accomplished by standard methods (Greene, TW; Wuts, PGM; Protective Groups in Organic Synthesis ; Wiley & Sons: New York, 1999). The conversion of the compound of formula (V) to the compound of formula (VI) can be achieved using ammonia in an aprotic solvent such as THF or dioxane in the presence of iodine. The reduction of the nitro group in formula (VI) can be accomplished using iron or hydrogen in acetic acid in the presence of a suitable palladium, platinum or nickel catalyst. The conversion of the compound of formula (VII) to the imidazoline of formula (VIII) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur under heating. The cyclization of compounds of formula (VIII) to compounds of formula (IX) is accomplished using cyanogen bromide in a halogenated solvent such as DCM or dichloroethane in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine. Removal of the protecting group in formula (IX) will depend on the group chosen and can be accomplished by standard methods (Greene, TW; Wuts, PGM; Protective Groups in Organic Synthesis ; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (X) can be accomplished using a base such as cesium carbonate, sodium hydride, or potassium tert-butoxide in a polar aprotic solvent such as DMF or DMSO, accompanied by the introduction of a side chain with an appropriate leaving group such as a halide or sulfonate group. Finally, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides, or alternatively using a carboxylic acid and an appropriate coupling agent such as PYBOP, DCC, or EDCI in a polar aprotic solvent.

Reaction Scheme 2:

In Reaction Scheme 2, the compound of formula (IV) prepared as described above can be converted to the structure of formula (XII) using ammonia in an aprotic solvent such as THF or dioxane in the presence of iodine. Alkylation of the phenol in formula (XII) can be achieved using a base such as cesium carbonate, sodium hydride or potassium tert-butoxide in a polar aprotic solvent such as DMF or DMSO, accompanied by the introduction of a side chain with an appropriate leaving group such as a halide or sulfonate group. Reduction of the nitro group in formula (XIII) can be achieved using iron or hydrogen in acetic acid in the presence of a suitable palladium, platinum or nickel catalyst. The conversion of the compound of formula (XIV) to the imidazoline of formula (XV) is best achieved using ethylenediamine in the presence of a catalyst such as elemental sulfur under heating. The cyclization of the compound of formula (XV) to the compound of formula (XVI) is achieved using cyanogen bromide in a halogenated solvent such as DCM or dichloroethane in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine. Finally, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides, or alternatively using carboxylic acids and a suitable coupling agent such as PYBOP, DCC or EDCI in a polar aprotic solvent.

The two known synthetic routes above - Reaction Schemes 1 and 2 - have a number of disadvantages that are particularly problematic on a larger scale:

• Batch nitration of molecules susceptible to oxidation can be problematic for scale-up due to safety concerns. To this end, we developed a continuous process via microreaction technology, as exemplified in Example 1 (vide infra).

•The use of ammonia and iodine as reagents for the conversion of aldehyde groups to nitriles is dangerous because ammonia and iodine can form nitrogen triiodide, a highly sensitive explosive substance.

• Cyclization to the imidazoline ring using ethylenediamine requires sulfur. Since sulfur is extremely difficult to remove during cleaning in technical systems with fixed reactors and pipelines, this cyclization reaction is not suitable for scale-up.

• Reduction of the nitro group to the corresponding amine using iron and acid is difficult on a larger scale. Standard catalytic reductions often result in side reactions, such as imidazoline ring opening, which significantly reduce the yield.

It is therefore desirable to design new syntheses which avoid these disadvantages and which are suitable for production/industrial scale.

It has been found quite surprisingly and provides the basis for the present invention that compounds of the following structural type, in particular copanlisib, can be synthesized according to the following scheme, see reaction scheme 3 below:

Reaction Scheme 3:

The following advantages of a specific step of the synthesis of the present invention as depicted in Reaction Scheme 3 above are given below:

• Step A1: The nitration reaction can be carried out in a flow reactor system. This allows for easy control of the exothermic reaction without the risk of a runaway reaction. Kilogram quantities of 2-nitrovanillin can be readily prepared within days or weeks. The isolated material contains similar amounts (approximately 10%) of the undesired positional isomer 6-nitrovanillin as the material produced by batch nitration.

• Step A3: The alkylation is mediated by a base such as potassium carbonate and the product is easily isolated in high yield by filtration after addition of water to the reaction mixture. Concentration of the reaction mixture and aqueous workup with phase separation are not necessary.

• Step A4: One-pot cyclization and oxidation reaction using ethylenediamine and N-bromosuccinimide ("NBS"). The new procedure solves two problems because it avoids:

a) using ammonia/iodine to convert the aldehyde to the nitrile (safety concerns), and

b) Use of sulfur during imidazoline synthesis (scaling issues). Carrying out the process in methanol and acetonitrile results in fewer by-products, making the process easier to perform (given the NBS solution) and safer on the scale. An additional unexpected advantage is the removal of the wrong nitro position isomer under these process conditions.

• Step A5: Reduction using hydrogen and a specially prepared catalyst. The catalyst consists of platinum and iron on carbon. Surprisingly, no debenzylation was observed with this catalyst. The product was crystallized and isolated in excellent yield from isopropanol and water. Rapid hydrogenation in THF at 3 bar has been performed.

• Step A6: Dichloromethane can be exchanged for acetonitrile. Stirring of the product in toluene leads to a product of excellent quality.

• Step A7: The benzyl protecting group is removed by simple hydrogenation over palladium on carbon. The product is easily isolated by filtration.

• Step A8: Alkylation in n-butanol or a mixture of n-butanol with other solvents, such as DMF and water, allows for easy workup and isolation of the product via crystallization from n-butanol-tert-butyl methyl ether ("MTBE"). Recrystallization from water removes inorganic impurities and produces a product of excellent quality.

• Step A9: N-[3-(Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride ("EDCI") is used as a coupling reagent. Copanlisib is isolated by simple filtration.

• Step A11: Copanlisib is easily purified via its dihydrochloride salt (dihydrochloride salt is the final product).

Thus, in a first aspect, the present invention relates to a process for preparing copanlisib (10) via the following steps shown in the following Reaction Scheme 3:

Reaction Scheme 3:

In one embodiment of the first aspect, the present invention relates to a method for preparing copanlisib (10):

It includes the following steps:

Step A9:

wherein the compound of formula (9):

With the compound of formula (9b):

optionally in the presence of a catalyst such as N,N-dimethyl-4-aminopyridine, optionally in the presence of a coupling agent such as N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride, optionally in a solvent such as N,N-dimethylformamide,

Copanlisib (10) is provided hereby:

The compound of formula (9):

Prepared by following the steps A8:

wherein the compound of formula (8):

With the compound of formula (8a):

optionally in the presence of a base such as potassium carbonate, in a solvent such as n-butanol, N,N-dimethylformamide and water, optionally under heating such as under reflux,

This provides a compound of formula (9);

The compound of formula (8):

Prepare A7 by following the steps below:

wherein the compound of formula (7):

reacting with a reducing agent such as hydrogen, optionally in the presence of a catalyst such as a metal catalyst, optionally dissolved in a solvent such as N,N-dimethylformamide or in suspension in a solvent such as N,N-dimethylformamide, thereby providing a compound of formula (8);

The compound of formula (7):

Prepared by following the steps A6:

wherein the compound of formula (6):

optionally in the presence of a base such as triethylamine with an annelating agent such as cyanogen bromide (also known as bromine cyanide), optionally in a solvent such as acetonitrile or dichloromethane,

This provides a compound of formula (7);

The compound of formula (6):

Prepare A5 by following the steps below:

wherein the compound of formula (5):

reacting with a reducing agent such as hydrogen, optionally in the presence of a catalyst such as a bimetallic catalyst, such as platinum iron on carbon, particularly 1% Pt/0.2% Fe/C, optionally water wetted, optionally dissolved in a solvent such as tetrahydrofuran or in suspension in a solvent such as tetrahydrofuran, thereby providing a compound of formula (6);

The copanlisib of formula (10) is:

optionally reacting it with hydrogen chloride and optionally hydrochloric acid to form copanlisib dihydrochloride (11),

This provides copanlisib dihydrochloride (11):

.

In one embodiment of the first aspect, the present invention relates to a method for preparing copanlisib dihydrochloride (11):

It includes the following steps A11:

wherein copanlisib of formula (10) is:

reacting with hydrogen chloride and optionally hydrochloric acid,

This provides copanlisib dihydrochloride (11):

.

In one embodiment of the first aspect, the present invention relates to a process for preparing copanlisib dihydrochloride hydrate I:

It includes the following steps A11:

wherein copanlisib of formula (10) is:

reacting with hydrogen chloride and optionally hydrochloric acid,

This provides copanlisib dihydrochloride hydrate I.

In one embodiment of the first aspect, the present invention relates to a process for preparing copanlisib dihydrochloride hydrate II,

It includes the following steps A11:

wherein copanlisib of formula (10) is:

reacting with hydrogen chloride and optionally hydrochloric acid,

This provides copanlisib dihydrochloride hydrate II.

In one embodiment of the first aspect, the present invention relates to a method for preparing copanlisib (10):

It includes the following steps A9:

wherein the compound of formula (9):

With the compound of formula (9b):

optionally in the presence of a catalyst such as N,N-dimethyl-4-aminopyridine, optionally in the presence of a coupling agent such as N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride, optionally in a solvent such as N,N-dimethylformamide,

Copanlisib (10) is provided hereby:

.

In one embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (9b) above:

It includes the following steps A10:

wherein the compound of formula (9a):

a) reacting with a base such as sodium methoxide, optionally in a solvent such as 1,4-dioxane, with heating, such as under reflux, and then,

b) After cooling, for example to room temperature, methyl formate is added, and then

c) adding guanidine hydrochloride, followed by heating, for example under reflux, and then,

d) adding water and an aqueous solution of a base such as sodium hydroxide, followed by heating, and then,

e) adding an aqueous solution of a mineral acid such as hydrochloric acid,

f) Add an amine such as dicyclohexylamine and filter, then

g) Add a strong base such as an aqueous solution of sodium hydroxide, then

h) adding an aqueous solution of a mineral acid such as hydrochloric acid,

This provides compounds of formula (9b):

.

In one embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (9) above:

It includes the following steps A8:

wherein the compound of formula (8):

With the compound of formula (8a):

optionally in the presence of a base such as potassium carbonate, in a solvent such as n-butanol, optionally under heating such as under reflux,

This provides compounds of formula (9).

In one embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (8) above:

It includes the following steps A7:

wherein the compound of formula (7):

Reaction with a reducing agent such as hydrogen, optionally in the presence of a catalyst such as a metal catalyst, optionally dissolved in a solvent such as N,N-dimethylformamide or in suspension in a solvent such as N,N-dimethylformamide, optionally in the presence of an acid such as trifluoroacetic acid, thereby providing a compound of formula (8).

In one embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (7) above:

It includes the following steps A6:

wherein the compound of formula (6):

optionally in the presence of a base such as triethylamine with a ring-enhancing agent such as cyanogen bromide (also known as bromine cyanide), optionally in a solvent such as acetonitrile or dichloromethane,

This provides compounds of formula (7).

In one embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (6) above:

It includes the following steps A5:

wherein the compound of formula (5):

Reaction with a reducing agent such as hydrogen, optionally in the presence of a catalyst such as a bimetallic catalyst, for example platinum iron on carbon, particularly water wet 1% Pt/0.2% Fe/C, optionally dissolved in a solvent such as tetrahydrofuran or in suspension in a solvent such as tetrahydrofuran, provides a compound of formula (6).

In a specific embodiment of the first aspect, the present invention relates to a method for preparing the compound of formula (6) above:

It includes the following steps A5:

wherein the compound of formula (5):

Reaction with hydrogen in the presence of a bimetallic catalyst, 1% Pt/0.2% Fe/C wet with water, in suspension in tetrahydrofuran provides compounds of formula (6).

In one embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (5) above:

It includes the following steps A4:

wherein the compound of formula (4):

with ethylenediamine, optionally in the presence of N-bromosuccinimide, optionally in a solvent mixture such as methanol and acetonitrile,

This provides compounds of formula (5).

In a particular embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (4) above:

It includes the following steps A3,

wherein the compound of formula (3):

optionally in a solvent such as N,N-dimethylformamide, optionally in the presence of a base such as potassium carbonate,

with benzyl bromide, optionally with heating, for example under reflux,

This provides compounds of formula (4).

In a particular embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (3) above:

It includes the following steps A2,

wherein the compound of formula (2):

with a base such as potassium carbonate in a solvent such as methanol,

This provides compounds of formula (3).

In a particular embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (2) above:

It includes the following steps A1:

wherein the compound of formula (1):

reacting with nitric acid and sulfuric acid in a solution in a solvent such as dichloromethane,

This provides compounds of formula (2).

In another embodiment of the first aspect, the present invention relates to a method for preparing copanlisib (10) or copanlisib dihydrochloride (11) or copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II, wherein each of steps A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 as shown in Scheme 3 above is performed as described above.

In another embodiment of the first aspect, the present invention relates to a process for the preparation of copanlisib dihydrochloride (11) in the form of copanlisib dihydrochloride hydrate I as prepared and characterized in the experimental section.

In another embodiment of the first aspect, the invention relates to copanlisib dihydrochloride hydrate I as prepared and characterized in the experimental section.

In another embodiment of the first aspect, the present invention relates to copanlisib dihydrochloride hydrate I.

In another embodiment of the first aspect, the present invention is directed to copanlisib dihydrochloride hydrate I having an XRPD peak maximum [°2θ] (copper (Cu)) of 5.6.

In another embodiment of the first aspect, the present invention is directed to copanlisib dihydrochloride hydrate I having an XRPD peak maximum [°2θ] (copper (Cu)) of 7.0.

In another embodiment of the first aspect, the present invention is directed to copanlisib dihydrochloride hydrate I having an XRPD peak maximum [° 2θ] (copper (Cu)) of 15.4.

In another embodiment of the first aspect, the present invention is directed to copanlisib dihydrochloride hydrate I having an XRPD peak maximum [°2θ] (copper (Cu)) of 26.4.

In another embodiment of the first aspect, the present invention is directed to copanlisib dihydrochloride hydrate I having XRPD peak maxima [°2θ] (copper (Cu)) of 5.6, 7.0, 15.4, and 26.4.

In another embodiment of the first aspect, the present invention relates to a process for the preparation of copanlisib dihydrochloride (11) in the form of copanlisib dihydrochloride hydrate II as prepared and characterized in the experimental section.

In another embodiment of the first aspect, the invention relates to copanlisib dihydrochloride hydrate II as prepared and characterized in the experimental section.

In another embodiment of the first aspect, the present invention relates to copanlisib dihydrochloride hydrate II.

In another embodiment of the first aspect, the present invention is directed to copanlisib dihydrochloride hydrate II having an XRPD peak maximum [°2θ] (copper (Cu)) of 5.7.

In another embodiment of the first aspect, the present invention relates to copanlisib dihydrochloride hydrate II having an XRPD peak maximum [°2θ] (copper (Cu)) of 7.3.

In another embodiment of the first aspect, the present invention relates to copanlisib dihydrochloride hydrate II having XRPD peak maxima [°2θ] (copper (Cu)) of 5.7 and 7.3.

According to a second aspect, the present invention relates to intermediate compounds for preparing copanlisib (10) and copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I and copanlisib dihydrochloride hydrate II.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

In one embodiment of said second aspect, the invention relates to the following compounds:

.

According to a third aspect, the present invention relates to the use of the intermediate compound of the second aspect for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10) or copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10) or copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In one embodiment of the third aspect, the present invention relates to

Use for preparing copanlisib (10), copanlisib dihydrochloride (11), copanlisib dihydrochloride hydrate I or copanlisib dihydrochloride hydrate II.

In the context of the present invention, the term "solvent", as optionally present in any reaction step of the process of the present invention, is understood to mean any substance in which other materials are dissolved to form a solution, as understood by those skilled in the art, such as, but not limited to: polar solvents, such as polar protic solvents such as water, n-butanol, isopropanol, n-propanol, ethanol, methanol or formic acid or acetic acid, etc.; polar aprotic solvents, such as 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, acetone, acetonitrile, dimethylformamide, sulfolane, pyridine or dimethyl sulfoxide, etc.; or non-polar solvents, such as pentane, hexane, benzene, toluene, diethyl ether, methyl ethyl ketone, dichloromethane, chloroform, tetrachloromethane, ethyl acetate, etc.; or any mixture of the solvents listed above.

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

The present invention will be better understood upon reading the following examples which are provided as illustrations of the invention.The following examples are in no way intended to limit the invention as described herein and as defined in the claims appended hereto.

Experimental part

Abbreviations used:

The following abbreviations used in the examples have the following meanings:

1H-NMR proton nuclear magnetic resonance spectroscopy

(Chemical shifts (δ) are given in ppm)

Ac acetyl

Boc tert-Butoxycarbonyl

bm wide multiplet

br broad peak

bs broad singlet

c- ring-

d Doublet

dd doublet

DCM dichloromethane

DME 1,2-dimethoxyethane

DIPE diisopropyl ether

DIPEA N,N-Diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EDCI N-[3-(Dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride

Eq equivalent

ESI electrospray ionization

HATU N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-

[methyl]-N-methylmethylammonium hexafluorophosphate

Hünig's base N,N-diisopropylethylamine

m multiplet

m.p. melting point in °C

MS

MTBE tert-butyl methyl ether

MW molecular weight

NaOtBu sodium tert-butoxide; sodium 2-methylpropan-2-ol

NMP N-Methylpyrrolidone

NMR Nuclear Magnetic Resonance Spectroscopy: Chemical shifts (δ) are given in ppm

q quartet

quin quintet

Rac racemic

Rt Room temperature

r.t. room temperature

RT retention time in minutes

s single peak

t Triplet

TBAF Tetrabutylammonium fluoride

TBTU N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanium tetrakis

Fluoborate

TEA triethylamine

TFA trifluoroacetic acid

THF Tetrahydrofuran

TMS trimethylsilyl

Ts p-Toluenesulfonyl; (Toluenesulfonyl)

UPLC ultra-performance liquid chromatography.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: X-ray diffraction pattern of copanlisib dihydrochloride hydrate II of Example 12.

Figure 2: X-ray diffraction pattern of copanlisib dihydrochloride hydrate II of Example 13.

Figure 3: X-ray diffraction pattern of copanlisib dihydrochloride hydrate II of Example 14.

Figure 4: X-ray diffraction pattern of copanlisib dihydrochloride hydrate I of Example 15.

Figure 5: X-ray diffraction pattern of copanlisib dihydrochloride hydrate I of Example 16.

Example

Example 1: Step A1: Preparation of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2)

At 0 ° C, 3.94 kg nitric acid (65w%) was added to 5.87 kg of concentrated sulfuric acid (nitrating acid). 1.5 kg of vanillin acetate was dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). The two solutions were reacted at 5 ° C in a microreactor with a flow rate of about 8.0 mL/min (nitrating acid) and about 4.0 mL/min (vanillin acetate solution). At 3 ° C, the reaction mixture was directly added to 8 kg of water. After 3 hours, the flow rate was increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After another 9 hours, the mobile reaction was complete. The layers were separated at room temperature and the aqueous phase was extracted with 2L of dichloromethane. The combined organic phase was washed with 2L of saturated sodium bicarbonate and then with 0.8L of water. The dichloromethane solution was concentrated to about 3L in a vacuum, 3.9L of methanol was added and roughly the same volume was removed again by distillation. An additional 3.9 L of methanol was added, and the solution was concentrated to a volume of approximately 3.5 L. This solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) was used directly in the next step.

Example 2: Step A2: Preparation of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (2-nitro-vanillin) (3)

To a solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) prepared as described in Example 1 (see above) was added 1.25 kg of methanol followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30°C for 3 hours. 7.3 kg of dichloromethane and 12.8 kg of aqueous hydrochloric acid (10 w %) (pH 0.5-1) were added at <30°C. The mixture was stirred for 15 minutes and the layers were separated. The organic layer was filtered and the filter cake was 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 vacuo to approximately 4 L. 3.41 kg of toluene was added and the mixture was concentrated to a final volume of approximately 4 L. The mixture was cooled to 0°C. After 90 minutes, the suspension was filtered. The collected solids were washed with cold toluene and dried to obtain 0.95 kg (62%).

The NMR spectrum also contains signals of the positional isomer 6-nitrovanillin (about 10%):

.

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

10 g of 3 was dissolved in 45 mL of DMF at 25 ° C. 14 g of potassium carbonate was added to the solution, and the temperature was raised to approximately 30 ° C. Within 15 minutes, at a temperature of 30 ° C, 7.1 mL of benzyl bromide was added to the suspension. The reaction mixture was stirred for 2 hours to complete the reaction. After being cooled to 25 ° C, 125 mL of water was added. The suspension was filtered, washed twice with 50 mL of water, and once with water/methanol (10 mL/10 mL), and tested under reduced pressure at 40 ° C. In this way, 14.2 g (97% yield) of 4 as a light yellow solid was obtained.

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

10 g of 4 is dissolved in 100 mL of methanol, and 2.5 g of ethylenediamine is added at 20-25 ° C. The reaction mixture is stirred for 1 hour at this temperature, cooled to 0 ° C, and a solution of N-bromosuccinimide (8.1 g) in 60 mL of acetonitrile is added. Stirring is continued for 1.5 hours, and the reaction mixture is warmed to 20 ° C, and stirred for another 60 minutes. The reaction is quenched with 8.6 g of NaHCO ₃ and 2.2 g of Na ₂ SO ₃ in a solution of 100 mL of water. After 10 minutes, 230 mL of water is added, the product is filtered, washed with 40 mL of water, and tested under reduced pressure at 40 ° C. In this way, 8.9 g (78% yield) of 5 as a white solid are obtained.

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

28.7kg compound 4 is dissolved in 231kg dichloromethane at 20 ℃, and 8.2kg ethylenediamine is added. After stirring for 60 minutes, N-bromosuccinimide is added with 4 parts (4 x 5.8 kg), and the temperature is controlled to be no more than 25 ℃. When the addition is completed, stirring is continued for 90 minutes at 22 ℃. In the reaction mixture, 9kg potassium carbonate/39kg water is added, and each layer is separated. From the organic layer, 150kg solvent is removed via distillation, and 67kg toluene is added. Another 50kg solvent is removed under reduced pressure, and 40kg toluene is added. After stirring for 30 minutes at 35-45 ℃, the reaction is cooled to 20 ℃, and the product is separated by filtration. The product is washed with toluene (19kg), tested under reduced pressure, and 26.6kg (81% yield) of brown product are obtained.

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

8.6g compound 5 is suspended in 55mL THF, and 1.4g 1%Pt/0.2%Fe/C/4mL water is added.The mixture is heated to 45 ℃, and hydrogenated 30 minutes under 3 bar hydrogen pressure.The catalyst is filtered out and washed twice with THF.THF is removed via distillation, and 65mL isopropyl alcohol/water 1/1 is added to the reaction mixture.The solvent of THF is removed via distillation, and 86mL isopropyl alcohol/water 1/1 is added.The suspension is stirred 1 hour, filtered, washed twice with isopropyl alcohol/water 1/1, and dried under reduced pressure, to obtain 7.8g (99% productive rate) 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 6 was suspended in 65 mL of acetonitrile and 6.1 mL of triethylamine was added. At 5-10 ° C, 8.4 mL of 50% bromine cyanide in acetonitrile was added over 1 hour and stirring continued for 1 hour. 86 mL of 2% NaOH was added and the reaction mixture was heated to 45 ° C and stirred for 1 hour. The suspension was cooled to 10 ° C, filtered and washed with water/acetone 80/20. In order to further improve the quality of the material, the wet product was stirred in 50 mL of toluene at 20-25 ° C. The product was filtered, washed with toluene and dried under reduced pressure. In this way, 8.8 g (81% yield) of 7 as a white solid were isolated.

Example 6b: Step A6: 8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (8): Method B

20kg compound 6 is dissolved in 218kg dichloromethane at 20 ℃, and the mixture is cooled to 5 ℃.At this temperature, 23.2kg triethylamine is added to the reaction mixture in 15 minutes, followed by 25.2kg bromine cyanide (3M in dichloromethane) in 60 minutes.After stirring at 22 ℃ for 1 hour, the reaction is concentrated and 188kg solvent is removed under reduced pressure.Acetone (40kg) and water (50kg) are added, and 100kg solvent is removed again via distillation.Acetone (40kg) and water (150kg) are added, and stirring is continued for 30 minutes at 36 ℃.After being cooled to 2 ℃, the suspension is stirred for 30 minutes, separated, washed with 80kg cold water and tested under reduced pressure.With this procedure, 20.7kg (95% yield) of off-white product is obtained.

Example 7a: Step A7: Method A: Preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (8):

A mixture of 2 kg 8- (benzyloxy) -7-methoxy -2,3- dihydroimidazo [1,2-c] quinazoline -5- amine, 203 g 5% palladium on carbon (50% water-wetted) and 31.8 kg N, N- dimethylformamide was stirred at 60 ° C under 3 bar of hydrogen for 18 hours. The mixture was filtered and the residue was washed with 7.5 kg N, N- dimethylformamide. The filtrate (38.2 kg) was concentrated in a vacuum (collecting and discarding about 27 L of distillate). The remaining mixture was cooled from 50 ° C to 22 ° C in 1 hour. During this cooling stage, 14.4 kg of water was added in 30 minutes. The resulting suspension was stirred at 22 ° C for 1 hour and then filtered. The collected solid was washed with water and dried in a vacuum to obtain 0.94 kg (65%).

Example 7b: Step A7 Method B: Preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (8):

222.8g trifluoroacetic acid is added to a mixture of 600g 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline-5-amine and 2850g DMF. Add 18g 5% carbon-supported palladium (50% water-moistened). The mixture is stirred overnight under 3 bar of hydrogen. Remove the catalyst by filtration and wash with 570g DMF. The filtrate is concentrated in a vacuum (collecting and discarding 432g distillate). Add 4095ml of 0.5M sodium hydroxide aqueous solution within 2 hours. The gained suspension is stirred overnight. Use a centrifuge to separate the product. The collected solid is washed with water. The isolated material (480.2g; containing approximately 25w% water) can be directly used in the next step (Example 8b).

Example 8a: Step A8: Method A: Preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (9):

2.5 kg of potassium carbonate was added to a mixture of 1.4 kg of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol, 14 L of n-butanol, 1.4 L of N,N-dimethylformamide and 1.4 L of water. 1.57 kg of 4-(3-chloropropyl)morpholine hydrochloride was added. The resulting suspension was heated to 90 ° C and stirred at this temperature for 5 hours. The mixture was cooled to room temperature. 8.4 kg of water was added at 50 ° C. The mixture was stirred at room temperature for 15 minutes. After phase separation, the aqueous phase was extracted with 12 L of n-butanol. The combined organic phases were concentrated in vacuo to a volume of approximately 11 L. 10.7 L of tert-butyl methyl ether was added at 50 ° C. The resulting mixture was cooled to 0 ° C within 2 hours and stirred at this temperature for 1 hour. The suspension was filtered, and the collected solids were washed with tert-butyl methyl ether and dried to obtain 1.85 kg (86%).

The separated 1.85 kg was combined with an additional 0.85 kg of material produced according to the same method. 10.8 L of water was added, and the mixture was heated to 60°C. The mixture was stirred at this temperature for 10 minutes, then cooled to 45°C over 30 minutes and then to 0°C over 1 hour. The suspension was stirred at 0°C for 2 hours and then filtered. The solid was washed with cold water and dried to obtain 2.5 kg.

HPLC: Stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 µm particle size): Mobile phase A: 0.5 mL trifluoroacetic acid / 1 L water; Mobile phase B: 0.5 mL trifluoroacetic acid / L acetonitrile; UV detection at 256 nm; Oven temperature: 40°C; Injection volume: 2.0 µL; Flow rate: 1.0 mL/min; Linear gradient in 4 steps: 0% B-> 6% B (20 min), 6 % B -> 16 % B (5 min), 16 % B -> 28 % B (5 min), 28 % B ->80 % B (4 min), retention time at 80 % B 4 minutes; Purity: >99.5 % (Rt=11.0 min), Related potential by-products: Degradation product 1, RRT (relative retention time) of 0.60 (6.6 min) Typically <0.05 %, 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol RRT 0.71 (7.8 min): Typically <0.05 %, Degradation product 2 RRT 1.31 (14.4 min): Typically <0.05 %, 7-methoxy-5-{[3-(morpholin-4-yl)propyl]amino}-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol RRT 1.39 (15.3 min): Typically <0.05 %, 9-methoxy-8-[3-(morpholin-4-yl)propyloxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine RRT 1.43 (15.7 min): Typically <0.05 %, Degradation product 3 RRT 1.49 (16.4 min): Typically <0.05 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine RRT 1.51 (16.7 min): typically <0.10 %, 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine RRT 2.56 (28.2 min): typically <0.05 %, 8-(benzyloxy)-7-methoxy-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine RRT 2.59 (28.5 min): typically <0.05 %.

Example 8b: Step A8 (Method B): Preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (9):

13.53g 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (containing about 26w% water) was suspended in 110g n-butanol. The mixture was concentrated in vacuo (13.5g distillate was collected and discarded). 17.9g potassium carbonate and 11.2g 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting mixture was heated to 90°C and stirred at this temperature for 4 hours. The reaction mixture was cooled to 50°C and 70g water was added. The layers were separated. The organic layer was concentrated in vacuo (54g distillate was collected and discarded). 90g tert-butyl methyl ether was added at 65°C. The resulting mixture was cooled to 0°C. The mixture was filtered, and the collected solid was washed with tert-butyl methyl ether and then dried in vacuo to obtain 13.4g (86%).

13.1 g of the isolated material was suspended in 65.7 g of water. The mixture was heated to 60° C. The resulting solution was slowly cooled to 0° C. The precipitated solid was isolated by filtration, washed with water and dried in vacuo to give 12.0 g (92%).

Example 9: Step A10: Preparation of 2-aminopyrimidine-5-carboxylic acid (9b)

1 kg of methyl 3,3-dimethoxypropionate was dissolved in 7 L of 1,4-dioxane. 1.58 kg of sodium methoxide solution (30 w % in methanol) was added. The mixture was heated to reflux and about 4.9 kg of distillate was removed. The resulting suspension was cooled to room temperature and 0.5 kg of methyl formate was added. The reaction mixture was stirred overnight, then 0.71 kg of guanidine hydrochloride was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then heated to reflux and stirred for 2 hours. 13.5 L of water was added, followed by 0.72 kg of sodium hydroxide aqueous solution (45 w %). The reaction mixture was heated under reflux for another 0.5 hour and then cooled to 50 ° C. 0.92 kg of hydrochloric acid aqueous solution (25 w %) was added until pH 6 was reached. Seed crystals were added, and 0.84 kg of hydrochloric acid aqueous solution (25 w %) was added at 50 ° C until pH 2 was reached. The mixture was cooled to 20 ° C and stirred overnight. The suspension was filtered and the collected solid was washed twice with water and then twice with methanol to yield 0.61 kg (65%).

The four batches produced according to the above procedure were combined (a total of 2.42 kg). 12 L of ethanol was added and the resulting suspension was stirred at room temperature for 2.5 hours. The mixture was filtered. The collected solid was washed with ethanol and dried in vacuo to obtain 2.38 kg.

2.5L dichloromethane and 4L water are added to 800 g of this material, followed by 1375 mL dicyclohexylamine. The mixture is stirred at room temperature for 30 minutes and filtered. The collected solid is discarded. Each phase of the separated filtrate is separated, and the organic phase is discarded. 345 mL of sodium hydroxide aqueous solution (45w%) is added to the aqueous phase. The aqueous phase is extracted with 2.5L of ethyl acetate. Each phase is separated and the organic phase is discarded. The pH value of the aqueous phase is adjusted to pH 2 using approximately 500 mL of hydrochloric acid (37w%). The mixture is filtered, and the collected solid is washed with water and dried to obtain 405 g.

The 405 g was combined with a second batch (152 g) of comparable quality. 2 L of ethyl acetate and 6 L of water were added, followed by 480 mL of aqueous sodium hydroxide solution (45 w %). The mixture was stirred at room temperature for 30 minutes. Each phase was separated. The pH of the aqueous phase was adjusted to pH 2 with approximately 770 mL of aqueous hydrochloric acid solution (37 w %). The mixture was filtered, and the collected solids were washed with water and dried to obtain 535 g.

Example 10: Step A9: Preparation of copanlisib (10)

A mixture of 1250 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine, 20.3 kg of N,N-dimethylformamide, 531 g of 2-aminopyrimidine-5-carboxylic acid, 425 g of N,N-dimethylaminopyridine, and 1000 g of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride was stirred at room temperature for 17 hours. The reaction mixture was filtered. The collected solid was washed with N,N-dimethylformamide, then with ethanol, and dried at 50°C to give 1.6 kg (96%). The isolated material was directly converted to the dihydrochloride salt.

Example 11: Step A11: Preparation of copanlisib dihydrochloride (11)

To a mixture of 1.6 kg copanlisib and 4.8 kg water was added 684 g of aqueous hydrochloric acid (32 w %) while maintaining the temperature between 20 and 25 ° C until a pH of 3 to 4 was reached. The resulting mixture was stirred for 10 minutes and the pH was checked (pH 3.5). The mixture was filtered and the filter cake was washed with 0.36 kg of water. 109 g of aqueous hydrochloric acid was added to the filtrate until the pH was 1.8 to 2.0. The mixture was stirred for 30 minutes and the pH was checked (pH 1.9). At 20 to 25 ° C, 7.6 kg of ethanol was slowly added over 5 hours, and the addition was paused for 1 hour after 20 minutes, at which point crystallization began. After the ethanol was completely added, the resulting suspension was stirred for 1 hour. The suspension was filtered. The collected solid was washed with an ethanol-water mixture and finally with ethanol, and then dried in a vacuum to obtain 1.57 kg of copansilib dihydrochloride (85%).

HPLC: Stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 µm particle size): Mobile phase A: 2.0 mL trifluoroacetic acid / 1 L water; Mobile phase B: 2.0 mL trifluoroacetic acid / L acetonitrile; UV detection at 254 nm (switch to 282 nm after 1 minute); Oven temperature: 60°C; Injection volume: 2.0 µL; Flow rate: 1.7 mL/min; Linear gradient after 1 minute isocratic run in 2 steps: 0% B -> 18% B (9 min), 18 % B -> 80% B (2.5 min), hold time at 80% B 2.5 minutes; Purity: >99.8% (Rt=6.1 min), Related potential by-product: 2-aminopyrimidine-5-carboxylic acid, RRT (relative retention time) of 0.10 (0.6 min), typically <0.01 %, 4-dimethylaminopyrimidine RRT 0.26 (1.6 min): typically <0.01 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine RRT 0.40 (2.4 min): typically <0.03 %, by-product 1 RRT 0.93 (5.7 min): typically <0.05 %, by-product 6 RRT 1.04 (6.4 min): typically <0.05 %, 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide RRT 1.12 (6.9 min): typically <0.10 %, 2-Aminopyrimidine-5-carboxylic acid 5-{[(2-aminopyrimidin-5-yl)carbonyl]amino}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl ester RRT1.41 (8.6 min): typically <0.01 %.

Example 12: Step A11: Further example of the preparation of copanlisib dihydrochloride (11)

99ml hydrochloric acid (37w%) was added to a mixture of 300g copanlisib and 1450ml water at 24-30°C and stirred at 30°C for 10 minutes. The mixture was filtered and the filter residue was washed twice with 25mL water. 6.0L ethanol was added to the filtrate at room temperature over 18 minutes. The resulting suspension was heated to 76°C and stirred at 76-78°C for 1 hour. The mixture was cooled to 22°C and stirred at this temperature for 1 hour. The suspension was filtered and the collected solid was washed with a mixture of 120ml water and 480ml ethanol. The suspension was filtered and the collected crystals were dried in a vacuum at 40°C to obtain 295g of copanlisib dihydrochloride as Hydrate II.

Water (Karl-Fisher): 7.9%

Chloride (ion chromatography): 11.7%

XRPD: Hydrate II

Measurement conditions:

Scan axis 2θ-ω

Starting position [°2θ] 2.0000

End position [°2θ] 37.9900

K-α1 [Å] 1.54060

Generator environment 35 mA, 45 kV

Diffractometer type Transmission diffractometer

Incident beam monochromator Yes

Rotate No

The X-ray diffraction pattern is given in FIG1 .

Example 13: Step A11: Further example of the preparation of copanlisib dihydrochloride (11)

9.10 g of hydrochloric acid (25 w %) was added to a mixture of 15 g of copanlisib in 37.5 g of water. The mixture was stirred for 10 minutes and filtered. The filter residue was washed with 7.0 g of water. The filtrate was added to 70.6 g of ethanol at 40 ° C over 1 hour. An additional 2.0 g of water was used to rinse the addition equipment. The resulting suspension was cooled to 23 ° C over 1 hour and stirred at this temperature for 1 hour. The suspension was filtered and the collected crystals were washed twice with a mixture of 17.9 g of ethanol and 7.5 g of water and then air-dried to obtain 17.0 g of copanlisib dihydrochloride as Hydrate II.

Purity by HPLC: 99.9%, <0.06% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Loss on drying (120°C, 30 minutes): 12.9 w%

Ethanol (Headspace-GC): < 0.1 %

XRPD: Hydrate II

Measurement conditions:

Note Configuration = Reflection-Transmission Rotator Stage,

Scan Axis Gonio

Starting position [°2θ] 2.0066

End position [°2θ] 37.9906

Anode material Cu

K-α1 [Å] 1.54060

K-α2 [Å] 1.54443

K-β [Å] 1.39225

K-A2 / K-A1 ratio 0.50000

Generator environment 40 mA, 40 kV

Incident beam monochromator Focusing X-ray mirror

Rotation Yes

The X-ray diffraction pattern is given in FIG2 .

Example 14: Step A11: Further example of the preparation of copanlisib dihydrochloride (11)

17 g of copanlisib dihydrochloride was dissolved in 66 g of water. The clear solution was added to 127.5 g of ethanol at 40°C over 1 hour. The addition apparatus was rinsed with 2 g of water. The mixture was stirred at 40°C for 30 minutes and then cooled to 0°C over 3 hours. The suspension was filtered. The collected crystals were washed three times with 20 ml of a 3:1 ethanol:water mixture (v/v) and then air-dried to obtain 15.8 g of copanlisib dihydrochloride as Hydrate II.

Purity by HPLC: 99.9%, 0.06% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Mass loss (thermogravimetric analysis): 12.3 w%

Water (Karl-Fisher): 12.0 w%

Ethanol (Headspace-GC): < 0.1 %

XRPD: Hydrate II

Measurement conditions:

Note Scan 2-80 Trans (STOE - Small Slot for Sheet Metal)

Scan Axis Gonio

Starting position [°2θ] 2.0066

End position [°2θ] 37.9906

Anode material Cu

K-α1 [Å] 1.54060

K-α2 [Å] 1.54443

K-β [Å] 1.39225

K-A2 / K-A1 ratio 0.50000

Generator environment 40 mA, 40 kV

Incident beam monochromator Focusing X-ray mirror

Rotation Yes

The X-ray diffraction pattern is given in FIG3 .

Example 15: Step A11: Further example of the preparation of copanlisib dihydrochloride (11)

7.3 g of hydrochloric acid was added to a mixture of 12 g of copanlisib and 33 g of water at a maximum temperature of 30°C. The resulting mixture was stirred at 25°C for 15 minutes and filtered. The filter residue was washed with 6 g of water. 11.5 g of ethanol was added to the filtrate over 1 hour at 23°C. After the addition was complete, the mixture was stirred at 23°C for 1 hour. An additional 59 g of ethanol was added to the mixture over 3 hours. After the addition was complete, the mixture was stirred at 23°C for 1 hour. The resulting suspension was filtered. The collected crystals were washed three times with a mixture of 11.9 g of ethanol and 5.0 g of water and air-dried to obtain 14.2 g of copanlisib dihydrochloride as Hydrate I.

Purity by HPLC: > 99.8%; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Mass loss (thermogravimetric analysis): 14.5 w%

Water (Karl-Fisher): 14.1%

Ethanol (Headspace-GC): < 0.1 %

Chloride (ion chromatography): 11.9%

XRPD: Hydrate I

Measurement conditions:

Note Configuration = Reflection-Transmission Rotator Stage,

Original data source: XRD measurement (*.XRDML)

Scan Axis Gonio

Starting position [°2θ] 2.0066

End position [°2θ] 37.9906

Anode material Cu

K-α1 [Å] 1.54060

K-α2 [Å] 1.54443

K-β [Å] 1.39225

K-A2 / K-A1 ratio 0.50000

Generator environment 40 mA, 40 kV

Incident beam monochromator Focusing X-ray mirror

Rotation Yes

The X-ray diffraction pattern is given in FIG4 .

Example 16: Step A11: Further example of the preparation of copanlisib dihydrochloride (11)

At a maximum temperature of 28°C, 9.1 kg of hydrochloric acid (25 w %) was added to a mixture of 14.7 kg of copanlisib and 41.9 kg of water. The resulting mixture was stirred at 23°C for 80 minutes until a clear solution was formed. The solution was transferred to a second reaction vessel and the transfer line was rinsed with 6 kg of water. 14.1 kg of ethanol was slowly added at 23°C over 70 minutes. After the addition of ethanol was complete, the mixture was stirred at 23°C for 1 hour. An additional 72.3 kg of ethanol was slowly added at 23°C over 3.5 hours, and the resulting mixture was stirred at this temperature for 1 hour. The suspension was filtered, and the collected solids were washed twice with 31 kg of an ethanol-water mixture (2.4:1 (w/w)). The product was dried in a vacuum at a maximum jacket temperature of 40°C for 3.5 hours to obtain 15.0 kg of copanlisib dihydrochloride as Hydrate I.

Purity by HPLC: >99.9%; <0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Loss on drying: 14.7 w%

Chloride (titration): 10.8%

Water (Karl-Fisher): 14%

XRPD: Hydrate I

Measurement conditions:

Scan Axis Gonio

Starting position [°2θ] 2.0066

End position [°2θ] 37.9906

Anode material Cu

K-α1 [Å] 1.54060

K-α2 [Å] 1.54443

K-β [Å] 1.39225

K-A2 / K-A1 ratio 0.50000

Generator environment 40 mA, 40 kV

Incident beam monochromator Focusing X-ray mirror

Rotation Yes

The X-ray diffraction pattern is given in FIG5 .

XRPD (Table)

Claims (50)

1. Method for preparing copanlisib(10): It includes the following steps A9: Among them, the compounds of formula (9) are: Compounds of formula (9b): The reaction may be carried out in the presence of a catalyst, in the presence of a coupling agent, or in a solvent. This provides copanlisib(10): The compound of formula (9): Prepared by the following steps (A8): Among them, the compounds of formula (8) are: Compounds of formula (8a): The reaction may be carried out in the presence of a base, in a solvent, or optionally under heating. This provides a compound of formula (9); The compound of formula (8): Prepared via the following steps (A7): Among them, the compounds of formula (7) are: The compound of formula (8) is provided by reacting with a reducing agent, optionally in the presence of a catalyst, optionally dissolved in a solvent or in a suspension of a solvent, optionally in the presence of an acid; The compound of formula (7): Prepared via the following step A6: Among them, the compounds of formula (6) are: The reaction can be carried out optionally in the presence of a base, or optionally in a solvent with a ring-increasing agent. This provides the compound of formula (7); The compound of formula (6): Prepared using the following steps (A5): Among them, the compounds of formula (5) are: The compound of formula (6) is obtained by reacting with a reducing agent, optionally in the presence of a catalyst, optionally dissolved in a solvent or in a suspension of a solvent. 2. The method according to claim 1, wherein the catalyst in step A9 is N,N-dimethyl-4-aminopyridine. 3. The method according to claim 1, wherein the coupling agent in step A9 is N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride. 4. The method according to claim 1, wherein the solvent in step A9 is N,N-dimethylformamide. 5. The method according to claim 1, wherein the base in step A8 is potassium carbonate. 6. The method according to claim 1, wherein the solvent in step A8 is n-butanol. 7. The method of claim 1, wherein step A8 is performed under reflux. 8. The method according to claim 1, wherein the reducing agent in step A7 is hydrogen. 9. The method according to claim 1, wherein the catalyst in step A7 is a metal catalyst. 10. The method according to claim 9, wherein the metal catalyst is carbon-supported palladium. 11. The method of claim 10, wherein the carbon-supported palladium is water-wetted and is 5% carbon-supported palladium. 12. The method according to claim 1, wherein the solvent in step A7 is N,N-dimethylformamide. 13. The method according to claim 1, wherein the acid in step A7 is trifluoroacetic acid. 14. The method according to claim 1, wherein the base in step A6 is triethylamine. 15. The method according to claim 1, wherein the ring-increasing agent in step A6 is cyanogen bromide, also known as bromide cyanide. 16. The method according to claim 1, wherein the solvent in step A6 is acetonitrile or dichloromethane. 17. The method according to claim 1, wherein the reducing agent in step A5 is hydrogen. 18. The method according to claim 1, wherein the catalyst in step A5 is a bimetallic catalyst. 19. The method according to claim 18, wherein the bimetallic catalyst is carbon-supported platinum-iron. 20. The method of claim 19, wherein the carbon-supported platinum-iron is water-wetted 1% Pt/0.2% Fe/C. 21. The method according to claim 1, wherein the solvent in step A5 is tetrahydrofuran. 22. The method according to claim 1, wherein the compound of formula (6) is: Prepared using the following steps (A5): Among them, the compounds of formula (5) are: The reaction involves hydrogen in a suspension in tetrahydrofuran in the presence of a bimetallic catalyst, wherein the bimetallic catalyst is a water-wetted 1% Pt/0.2% Fe/C mixture. This provides the compound of formula (6). 23. The method according to claim 1, wherein the compound of formula (5) is: Prepared using the following steps (A4): Among them, the compounds of formula (4) are: Reacts with ethylenediamine, optionally in the presence of N-bromosuccinimide, optionally in a solvent mixture. This provides the compound of formula (5). 24. The method of claim 23, wherein the solvent mixture in step A4 is methanol and acetonitrile. 25. The method according to claim 23, wherein the compound of formula (4) is: Prepared via the following step A3. Among them, the compounds that make up formula (3) are: Optionally in a solvent, or optionally in the presence of a base. The reaction with benzyl bromide can optionally be carried out under heating. This provides the compound of formula (4). 26. The method of claim 25, wherein the solvent in step A3 is N,N-dimethylformamide. 27. The method according to claim 25, wherein the base in step A3 is potassium carbonate. 28. The method of claim 25, wherein step A3 is performed under reflux. 29. The method according to claim 25, wherein the compound of formula (3) is: Prepared via step A2 Among them, the compounds that make up formula (2) are: Reaction with base in solvent This provides the compound of formula (3). 30. The method according to claim 29, wherein the base in step A2 is potassium carbonate. 31. The method of claim 29, wherein the solvent in step A2 is methanol. 32. The method according to claim 29, wherein the compound of formula (2) is: Prepared via the following step A1 Among them, the compounds of formula (1) are: It reacts with nitric acid and sulfuric acid in solution in a solvent. This provides the compound of formula (2). 33. The method according to claim 32, wherein the solvent in step A1 is dichloromethane. 34. The method according to claim 1, wherein the compound of formula (9b) is prepared as follows: It includes the following steps A10: Among them, the compounds of formula (9a) are: a) React with a base, optionally in a solvent, under heating, and then... b) After cooling, add methyl formate, then c) Add guanidine hydrochloride, then heat, and then... d) Add an aqueous solution of water and alkali, then heat, and then... e) Add an aqueous solution containing an inorganic acid. f) Add amine and filter, then g) Add a strong alkali aqueous solution, then h) Add an aqueous solution of inorganic acid. This provides the compound of formula (9b): 35. The method according to claim 34, wherein the base in step A10, a) is sodium methoxide. 36. The method of claim 34, wherein the solvent in step A10, a) is 1,4-dioxane. 37. The method of claim 34, wherein step A10, a) is under reflux. 38. The method of claim 34, wherein step A10, b) is cooling to room temperature. 39. The method of claim 34, wherein step A10, c) is performed under reflux. 40. The method according to claim 34, wherein the base in step A10, d) is sodium hydroxide. 41. The method according to claim 34, wherein the inorganic acid in step A10, e) is hydrochloric acid. 42. The method according to claim 34, wherein the amine in step A10, f) is dicyclohexylamine. 43. The method according to claim 34, wherein the strong base in step A10, g) is sodium hydroxide. 44. The method according to claim 34, wherein the inorganic acid in step A10, h) is hydrochloric acid. 45. The method according to any one of claims 1 to 44, further comprising the step A11: Wherein, copanlisib in equation (10) is: Reacts with hydrogen chloride and, optionally, hydrochloric acid. This provides copanlisib dihydrochloride (11): 46. The method according to claim 45, wherein copanlisib (10) or copanlisib dihydrochloride (11) is prepared via the steps shown in reaction scheme 3 below: Reaction scheme 3: 47. The method according to claim 45, wherein the copanlisib dihydrochloride (11) is in the form of copanlisib dihydrochloride hydrate I, the copanlisib dihydrochloride hydrate I having a maximum XRPD peak value of 2θ 5.6° for copper (Cu) radiation, or having a maximum XRPD peak value of 2θ 7.0° for copper (Cu) radiation, or having a maximum XRPD peak value of 2θ 15.4° for copper (Cu) radiation, or having a maximum XRPD peak value of 2θ 26.4° for copper (Cu) radiation, or having maximum XRPD peak values of 2θ 5.6°, 7.0°, 15.4° and 26.4° for copper (Cu) radiation. 48. The method according to claim 45, wherein the copanlisib dihydrochloride (11) is in the form of copanlisib dihydrochloride hydrate II, the copanlisib dihydrochloride hydrate II having a maximum XRPD peak value of 2θ 5.7° for copper (Cu) radiation, or a maximum XRPD peak value of 2θ 7.3° for copper (Cu) radiation, or a maximum XRPD peak value of both 2θ 5.7° and 7.3° for copper (Cu) radiation. 49. Compounds selected from: 50. Selected from the following compounds: Used for the preparation of copanlisib (10): or Copanlisib dihydrochloride (11): Or copanlisib dihydrochloride hydrate I, The use of copanlisib dihydrochloride hydrate II, wherein copanlisib dihydrochloride hydrate I has a maximum XRPD peak value at 2θ 5.6° for copper (Cu) radiation, or has a maximum XRPD peak value at 2θ 7.0° for copper (Cu) radiation, or has a maximum XRPD peak value at 2θ 15.4° for copper (Cu) radiation, or has a maximum XRPD peak value at 2θ 26.4° for copper (Cu) radiation, or has maximum XRPD peak values at 2θ 5.6°, 7.0°, 15.4° and 26.4° for copper (Cu) radiation; wherein copanlisib dihydrochloride hydrate II has a maximum XRPD peak value at 2θ 5.7° for copper (Cu) radiation, or has a maximum XRPD peak value at 2θ 7.3° for copper (Cu) radiation, or has maximum XRPD peak values at 2θ 5.7° and 7.3° for copper (Cu) radiation.