HK40096314A - New process for the synthesis of 5-{5-chloro-2-[(3s)-3- [(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1h)-carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-carboxylic acid derivatives and its application for the production of pharmaceutical compounds - Google Patents

Description

A novel method for synthesizing 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylic acid derivatives and their application in the production of pharmaceutical compounds.

This invention relates to a novel method for preparing 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylic acid derivatives and their application in the production of pharmaceutical compounds.

More specifically, the present invention relates to a novel method for preparing ethyl 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylic acid and 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylic acid and their application in the production of pharmaceutical compounds.

More specifically, the present invention relates to a novel method for preparing 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylic acid and its use in the production of 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (hereinafter referred to as ‘compound A’).

In particular, the present invention relates to a method for preparing compound (V) using 1,5-dimethyl-1H-pyrrole derivatives and compounds of formula (IV):

Wherein: -Z is a group selected from -COOR and -CN, and

-R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl.

In the compounds of formula (IV):

Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

In some embodiments, the compound of formula (IV) is synthesized using a 4-chlorobenzoic acid derivative (the compound of formula (II)) and (3S)-3-[(morpholino-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (the compound of formula (I)) as starting materials.

In another embodiment, the compound of formula (V) is further hydrolyzed to prepare the carboxylic acid of formula (VI):

In some embodiments, the present invention relates to a method for preparing N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide of formula (VIII):

The following compounds are used as raw materials: (VI) and (VII) as defined above.

The compounds of formulas (IV), (V), (VI), (VII) and (VIII) obtained according to the method of the present invention are used to synthesize compound A and its structurally similar analogues.

In particular, compound A has pro-apoptotic properties, specifically, it can inhibit the anti-apoptotic Bcl-2 protein overexpressed in various types of cancer, making compound A usable in pathological conditions involving apoptosis defects, such as for the treatment of cancer and immune and autoimmune diseases.

Given the pharmaceutical value of compound A, it is important that it be obtained through an efficient synthetic method that is easily transferable to an industrial scale and produces compound A from economical and readily available starting materials in good yield and with excellent purity.

On the other hand, the present invention relates to a method for preparing 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile of formula (VII) and its use in the production of compounds of formula (VIII).

The structure of compound A is:

5-(5-chloro-2-{[(3S)3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrolo-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrolo-3-carboxamide. The preparation of compound A and its structurally similar analogs, their use as Bcl-2 inhibitors in the treatment of cancer, and pharmaceutical formulations thereof are described in WO 2015/011400, the contents of which are incorporated herein by reference. The preparation is specifically disclosed in Example 386 of WO 2015/011400, and its hydrochloride and hydrogen sulfate forms are also described in WO 2020/089281. Furthermore, WO 2020/089286 shows cyclodextrin-based formulations comprising compound A.

Specifically, the method for synthesizing compound A, as disclosed in WO 2015/011400, comprises the following steps, summarized in Scheme 1 below:

(a) C-H activation of ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate with 2-bromo-4-chlorobenzaldehyde;

(b) Oxidation step;

(c) Peptide coupling;

(d) Saponification step;

(e) N-acylation step with secondary amines;

(f) Deprotection step.

Option 1

Compound A was obtained in six steps using (3S)-3-[(morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline, 2-bromo-4-chlorobenzaldehyde, ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate and 4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H-pyrrole-2-carboxynitrile as starting materials. When scaled up to industrial operation, the difficulties of implementing this method quickly become apparent: particularly the risks of using potentially explosive agents such as hydroxybenzotriazole (HOBt) during peptide coupling between (3S)-3-[(morpholino-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline and 4-chloro-2-[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]benzoic acid, and the risks of using toxic solvents such as N,N-dimethylacetamide (DMAc) and potentially carcinogenic solvents such as 1,2-dichloroethane. Furthermore, the coupling step (e) with 4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H-pyrrole-2-carboxynitrile requires long contact times at high temperatures and generates several byproducts (e.g., acid anhydride derivatives), as follows:

Attempts to limit its formation need to be limited. Furthermore, the significant variability in yield observed for step (e) suggests that the experimental conditions for this coupling step, as described in WO 2015/011400, are not sufficiently stable for industrial applications. Finally, the use of Ghosez's reagent (1-chloro-N,N,2-trimethyl-prop-1-en-1-amine) on an industrial scale may be complicated due to some stability issues.

Therefore, the exploration of new and efficient synthetic routes is ongoing, and the applicant continues its research to develop a new synthetic method for the large-scale production of compound A. This synthetic method produces compounds of formulas (IV), (V), (VI), (VII), and (VIII) in a reproducible manner, with excellent yields and purity compatible with its use as a pharmaceutically acceptable intermediate. Finally, this new method enables the acquisition of compound A in good yields (32% based on the chemical route detailed in Scheme 2 below) and with purity compatible with its use as a pharmaceutical active ingredient (above 98%, preferably above 99%).

More specifically, the applicant has developed a novel synthetic method that allows for the reproducible acquisition of compounds of formulas (IV), (V), and (VI) without the need for laborious purification. Similar to the synthetic method disclosed in WO 2015/011400, (3S)-3-[(morpholino-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline and ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate are used as starting materials. However, a 4-chlorobenzoic acid derivative of formula (II) is used as a novel starting material:

In a preferred embodiment, the compound of formula (II) is 2-bromo-4-chlorobenzoic acid. This novel starting material has the advantages of being simple and readily available in large quantities at low cost. Therefore, the method of the present invention is based on a novel chemical route involving the compound of formula (IV) as an intermediate. More specifically, it allows for the acquisition of compound A in five steps, one fewer step than the disclosure in WO 2015/011400. Finally, benzyl is substituted for tert-butyldimethylsilyl as the protecting group of the hydroxyl functional group of the N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-N-(4-hydroxyphenyl) moiety. Accordingly, the coupling reaction between the secondary protected amine and the compound of formula (VII) yields higher and is reproducible on a large scale (lower variability is observed due to stable experimental conditions). Advantageously, this novel coupling reaction also avoids the formation of anhydride derivative impurities discussed above. The purity of the compound of formula (VIII) thus obtained is easier to control.

The synthesis method of the present invention is summarized in Scheme 2 below.

Option 2

Invention Details

In the first embodiment (E1), the present invention provides a method for preparing compound of formula (V):

Where: -Z is a group selected from -COOR and -CN, and

-R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl.

The following steps are included to make the compound of formula (III):

Where Z is as defined above,

With compounds of formula (IV):

Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

In a solvent or solvent mixture, at a temperature exceeding 70°C, at:

(i) Palladium catalyst;

(ii) optional phosphine; and

(iii) Reaction in the presence of a base.

This document describes further enumerated embodiments (E) of the invention. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the invention.

E2. According to the method of E1, where Z is -COOR and R represents methyl, ethyl, isopropyl, tert-butyl, benzyl, or p-methoxybenzyl. In a preferred embodiment, R represents ethyl.

E3. According to the method of E1, where W represents a bromine atom.

E4. According to the methods of E1-E3, wherein the palladium catalyst is palladium acetate (II) (Pd(OAc) ₂ ).

E5. According to the methods of E1-E3, the reaction mixture further comprises phosphine selected from tert-butylphosphine, XPhos, CyJohnPhos and tris(o-tolyl)phosphine, preferably CyJohnPhos.

E6. According to the methods of E1-E3, wherein the solvent is a proton-free solvent.

E7. According to the method of E6, the solvent is selected from dimethyl sulfoxide (DMSO), N-butylpyrrolidone (NBP), 2-methyltetrahydrofuran and toluene, preferably dimethyl sulfoxide.

E8. According to the methods of E1-E3, wherein the temperature exceeds 90°C, preferably T = 100°C.

_E9 . According to the methods _of E1-E3, the base is _{a carbonate} , preferably _Na2CO3 , _Cs2CO3 or _K2CO3 , and even more preferably _K2CO3 .

E10. According to the methods of E1-E3, the reaction mixture further comprises neopentanoic acid.

In the method of the first embodiment, the reaction between formulas (III) and (IV) can be carried out using other non-palladium analog catalyst systems, which may be mentioned:

-Sodium hydrosulfite (J.Org.Chem.2019, 84, 9946-9956);

-Cadmium sulfide and zinc selenide (as described in Chemistry of Materials (2017), 29(12), 5225-5231, photo-oxidation-reduction catalysis);

- Copper/nickel catalysts (such as photo-redox catalysis described in Organic Letters (2017), 19(13), 3576-3579);

- Nickel catalysts (such as coupling of Negishi as described in Tetrahedron (2006), 62(32), 7521-7533);

- Copper/palladium catalyst (Organic Letters (2004), 6(20), 3649-3652);

- Lithium/nickel catalyst (ChemSusChem (2017), 10(10), 2242-2248);

- Nickel or iron catalysts (as described in the Kumada reaction), provided that the mechanism requires an additional step to functionalize (iodide) the pyrrole group.

E11. According to any one of E0-E10, the compound of formula (IV) or its addition salt with a pharmaceutically acceptable acid:

Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

Compounds derived from formula (I):

Or its addition salt with a pharmaceutically acceptable acid.

Compounds of formula (II):

It is obtained by coupling reaction in a proton-free solvent in the presence of an amine base and a coupling agent.

E12. According to the method of E11, the compound of formula (II) is 2-bromo-4-chlorobenzoic acid, thereby leading to the formation of a compound of formula (IV-a):

E13. According to the method of E11 or E12, wherein compound (I) is in the form of a dihydrochloride salt.

E14. According to the method of E11 or E12, wherein the coupling agent is selected from propionic anhydride, cyanuric chloride, methyl propionate, tetraethyl orthosilicate, neopentylamine, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isobutyl chloroformate, thionyl chloride and oxalyl chloride, preferably propionic anhydride.

E15. According to the method of E11 or E12, wherein the amine base is selected from triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, N-ethylmorpholine, pyridine, and 2,6-rutidine. In a preferred embodiment, the amine base is triethylamine.

E16. According to the method of E11 or E12, the temperature includes 20-50°C.

E17. According to the method of E11 or E12, wherein the aprotic solvent is selected from ethyl acetate, dichloromethane and isopropyl ether, preferably ethyl acetate.

E18. According to the method of E11 or E12, wherein the compound of formula (IV) is isolated as a free base.

E19. According to the method of E11 or E12, wherein the compound of formula (IV) is isolated in the form of an addition salt of a pharmaceutically acceptable acid selected from oxalic acid, methanesulfonic acid and hydrochloric acid.

E20. The method according to any one of E1-E19, wherein the ester or nitrile functional group of the compound of formula (V) is:

Wherein: -Z is a group selected from -COOR and -CN, and

-R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl.

Further hydrolysis in a protic solvent yields the compound of formula (VI):

The compound of formula (VI) is further separated into zwitterions or as an addition salt of a pharmaceutically acceptable acid, and then peptide-coupled with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile of formula (VII) in a proton-free solvent, in the presence of a coupling agent, and optionally in the presence of an amine base:

The compound of formula (VIII) is obtained:

The compound of formula (VIII) was deprotected under acidic conditions to give compound A:

The compound can be isolated and further converted into its addition salt with a pharmaceutically acceptable acid or base.

E21. According to the method of E20, where Z is -COOR and R represents methyl, ethyl, isopropyl, tert-butyl, benzyl or p-methoxybenzyl.

E22. According to the method of E20, the compound of formula (V) is:

This allows the compound to undergo further hydrolysis under alkaline conditions.

E23. According to the method of E20, the compound of formula (V) is:

This allows the compound to undergo further hydrolysis under acidic conditions.

E24. According to the method of E20, the proton medium used for hydrolyzing compound (V) is methanol, ethanol, isopropanol, DMSO/water or a mixture of ethanol/water, preferably ethanol.

E25. The method according to E24, wherein the proton medium used is ethanol/water, and the hydrolysis of compound (V) is carried out at a temperature of 60-80°C.

E26. According to the method of E20, the compound of formula (VI) is separated as an addition salt of a pharmaceutically acceptable acid selected from hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, succinic acid, maleic acid, phosphoric acid, and boric acid. In a preferred embodiment, the pharmaceutically acceptable acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, phosphoric acid, and boric acid. Even more preferably, the compound of formula (VI) is separated as a hydrochloride salt.

E27. According to the method of E20, the coupling agent is selected from thionyl chloride, isobutyl chloroformate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and propionic anhydride. In a preferred embodiment, the coupling agent is propionic anhydride.

E28. According to the method of E20, the aprotic solvent used for peptide coupling is selected from dichloromethane, acetonitrile, toluene, ethyl acetate, isobutyl acetate, propyl acetate, isopropyl acetate, ammoniabenzene, N,N-dimethylformamide, and pyridine. In a preferred embodiment, a high-boiling-point solvent is used; it is selected from toluene, butyl acetate, isobutyl acetate, propyl acetate, isopropyl acetate, chlorobenzene, N,N-dimethylformamide, and pyridine.

E29. According to the method, wherein the coupling agent is N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and the solvent is toluene.

E30. According to the method of E20, where the amine base is used for peptide coupling.

E31. According to the method of E30, the amine base used for peptide coupling of the compound of formula (VI) and the compound of formula (VII) is selected from pyridine, N,N-diisopropylethylamine and triethylamine. In a preferred embodiment, the amine base is pyridine.

E32. According to the method of E20, wherein the coupling agent is propionic anhydride and the amine base is pyridine.

E33. The method according to E20, wherein the coupling agent is phosphonic anhydride, the amine base is pyridine, and the aprotic solvent is selected from: acetonitrile, toluene, chlorobenzene, ethyl acetate, butyl acetate and propyl acetate, more preferably the aprotic solvent is selected from toluene, chlorobenzene and butyl acetate, and even more preferably the aprotic solvent is chlorobenzene.

E34. The method according to E33, wherein the peptide coupling is carried out at a temperature of 60-135°C, preferably 110-135°C, and even more preferably 120°C.

E35. According to the method of E20, the deprotection of the compound of formula (VIII) is carried out in the presence of a mixture of hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrochloric acid and acetic acid or a mixture of hydrobromic acid and acetic acid, more preferably in the presence of a mixture of hydrobromic acid and acetic acid.

E36. According to the method of E35, the solvent used for deprotection of the compound of formula (VIH) is selected from dichloromethane, chlorobenzene, dioxane and ethyl acetate, more preferably ethyl acetate.

E37. According to the method of E35 or E36, wherein the temperature is maintained below 40°C.

E38. According to the method of E20, the deprotection of the compound of formula (VIII) is carried out by hydrogenation under acidic conditions in the presence of a catalyst.

E39. According to the method of E38, where:

- The palladium catalyst is Pd(OH) _₂ carbon or palladium-coated carbon.

The hydrogenation reaction is carried out in hydrochloric acid ethanol at a temperature of 40-65°C, preferably 45-60°C.

E40. According to any one of E20-E39, the compound of formula (VII):

Compounds of formula (SM1-VIII):

Where W' represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

Compounds of formula (SM2-VIII):

It is obtained by reacting in the presence of a palladium-phosphine complex catalyst and a base in a polar aprotic solvent at a temperature ranging from 40 to 85 °C.

The palladium-phosphine complex catalyst is prepared in situ or in-situ using palladium catalyst and phosphine as raw materials.

E41. Method for preparing compound A:

Its characteristic is that it makes the compound of formula (I):

Or its addition salt with a pharmaceutically acceptable acid.

To carry out a coupling reaction with the compound of formula (II):

Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

The reaction is carried out in a proton-free solvent, in the presence of an amine base and a coupling agent, at a temperature ranging from 20 to 50 °C.

The compound of formula (IV) is obtained:

Make the compound of formula (IV) and the compound of formula (III):

Wherein: -Z is a group selected from -COOR and -CN, and

-R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl.

In a solvent or solvent mixture, at a temperature exceeding 70°C, at:

(i) Palladium catalyst;

(ii) optional phosphine; and

(iii) Alkali

The following reaction occurs to give a compound of formula (V):

Further hydrolysis of the ester or nitrile functional groups of the compound of formula (V) in a proton medium yields the compound of formula (VI):

The compound of formula (VI) is further separated into zwitterions or as an addition salt of a pharmaceutically acceptable acid, and then peptide-coupled with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile of formula (VII) in a proton-free solvent, in the presence of a coupling agent, and optionally in the presence of an amine base:

The compound of formula (VIII) is obtained:

The compound of formula (VIII) was deprotected under acidic conditions to give compound A:

The compound can be isolated and further converted into its addition salt with a pharmaceutically acceptable acid or base.

E42. According to the method of E41, compound A is isolated in solution.

E43. According to the method of E41, the compound of formula (VII):

Compounds of formula (SM1-VIII):

Where W' represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

Compounds of formula (SM2-VIII):

It is obtained by reacting in the presence of a palladium-phosphine complex catalyst and a base in a polar aprotic solvent at a temperature ranging from 40 to 85 °C.

The palladium-phosphine complex catalyst is prepared in situ or in-situ using palladium catalyst and phosphine as raw materials.

E44. Compounds of formula (IV) or their addition salts with pharmaceutically acceptable acids:

Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

Compounds of formula (V) E45:

Wherein: -Z is a group selected from -COOR and -CN, and

-R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl.

The condition is that ( _C1 - _C6 ) alkyl does not represent ethyl.

Compounds of formula (VIII) E46:

E47. Compounds of formula (VII):

E48. A method for preparing compounds of formula (VII), comprising the following steps: making compounds of formulas (SM1-VIII):

Where W' represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

Compounds of formula (SM2-VIII):

The reaction takes place in the presence of a palladium-phosphine complex catalyst and a base, in a polar aprotic solvent, at a temperature ranging from 40 to 85 °C.

The palladium-phosphine complex catalyst is prepared in situ or in-situ using palladium catalyst and phosphine as raw materials.

E49. According to the method of E48, where W’ represents a bromine atom.

E50. According to the method of E48 or E49, wherein the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide and 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran.

E51. According to the method of E48 or E49, wherein the palladium-phosphine complex catalyst is selected from tBuXPhos Pd G1, tBuXPhos Pd G3, BrettPhos G3, tBuXPhosPd(allyl)OTf, more preferably tBuXPhosPd(allyl)OTf.

E52. According to the method of E48 or E49, wherein the palladium-phosphine complex catalyst is prepared in situ _{from Pd₂dba₃} and tBuXPhos.

E53. According to the method of E48 or E49, wherein the base is selected from tBuONa, tBuOK, _{K3PO4 and K2CO3 ,} more preferably tBuONa.

One specific embodiment of the present invention relates to a method for preparing a compound of formula (IV) or an addition salt thereof with a pharmaceutically acceptable acid:

Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups.

The compound is derived from a compound of formula (I):

Or its addition salt with a pharmaceutically acceptable acid.

Compounds of formula (II):

It is obtained by coupling reaction in a proton-free solvent, in the presence of an amine base and a coupling agent, at a temperature of 20-50°C.

Specific implementation details of compounds of formula (IV) are described in E12-E19 and are applicable to the stand-alone method steps.

This invention also relates to a method for preparing compounds of formula (VIII):

The compound is derived from compounds of formula (VI):

The peptide is obtained by coupling with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile of formula (VII) in a proton-free solvent, in the presence of a coupling agent and optionally in the presence of an amine base.

Specific implementation details of compounds of formula (VIII) are described in E27-E34 and are applicable to the stand-alone method steps.

The present invention is particularly advantageous for the following reasons:

- It enables the reproducible and industrial-scale production of compound A from simple and low-cost raw materials in excellent yields;

- It enables the reproducible and high-yield production of compounds of formulas (IV), (V), (VI), and (VII) on an industrial scale from simple and low-cost starting materials without the need for laborious purification.

This allows for the avoidance of using highly flammable and toxic reagents;

This allows for the use of standard crystallization techniques to achieve high levels of purity.

The present invention also relates to the use of the compound of formula (IV) in the synthesis of compound A.

The present invention also relates to the use of compounds of formulas (VII) and (VIII) in the synthesis of compound A.

In another embodiment, the present invention relates to the use of some compounds of formula (V) as defined below in the synthesis of compound A:

Wherein: -Z is a group selected from -COOR and -CN, and

-R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl.

The condition is that ( _C1 - _C6 ) alkyl does not represent ethyl.

definition

Various terms used throughout the specification and claims relate to various aspects of the specification. Unless otherwise stated, these terms shall be given their ordinary meaning in the art. Other specifically defined terms shall be interpreted in a manner consistent with the definitions provided herein.

As used herein, the term "aryl" refers to a phenyl group optionally substituted with methoxy, naphthyl, biphenyl, or indene.

As used herein, the term "halogen atom" preferably refers to iodine, bromine, and chlorine.

The term "medium" refers to a phase (and the composition of the phase) in which a chemical reaction takes place. As used herein, it refers to a solvent or a mixture of solvents.

Some abbreviations are defined as follows:

tBuONa: Sodium tert-butoxide

tBuOK: Potassium tert-butoxide

tBuXPhos Pd G3: [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

tBuXPhos Pd G1: [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride

BrettPhos Pd G3: [(2-Dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

tBuXPhosPd(allyl)OTf: Allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium trifluoromethanesulfonate(II)

DCM: Dichloromethane or dichloromethane

DMAc: N,N-dimethylacetamide

DMAP: 4-Dimethylaminopyridine

EDC: 1-Ethyl-3-(3′-dimethylaminopropyl)-carbodiimide

HOBt: Hydroxybenzotriazole

XPhos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

CyJohnPhos: 2-(Dicyclohexylphosphino)biphenyl

Pd ₂ dba ₃ : Tris(dibenzylacetone)dipalladium(0)

THF: Tetrahydrofuran

Preferably, the reactants are stirred using a suitable mechanical stirrer or agitator during the reaction. The reaction can proceed for about 2 to about 24 hours or longer, depending on the temperature, dilution volume, catalyst, concentration, and/or the nature of the materials in the reaction mixture. The term "about" as used herein refers to +/- 5%, particularly +/- 2%, and even more particularly +/- 1%.

The structure of the compound was confirmed using conventional spectroscopic techniques. For example, ^¹H NMR data were given in the form of delta values in parts per million (ppm), using residual peaks of the solvent (7.24 ppm for _CDCl₃ , 2.49 _ppm for DMSOd₆, or 33.1 ppm for _CD₃OD ) as internal standards. Splitting modes were represented as: s (singleton), d (doublet), t (triplet), m (multiplex), br or brs (broad singlet).

The preparation examples below illustrate the present invention, but are by no means intended to limit the invention in any way.

Step A1: Preparation of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carboxynitrile

1,5-Dimethyl-1H-pyrrolo-2-carboxynitrile (1.00 kg) was dissolved in acetonitrile (3.13 kg), and then cooled to 0 ± 5 °C. A solution of N-bromosuccinimide (1.52 kg) in acetonitrile (8.86 kg) was added over 2–3 hours while maintaining the temperature at 0 ± 5 °C. Once the conversion was complete, the reaction mixture was transferred to cold water. The product was filtered and then washed twice with water. After drying at 40 °C, 4-bromo-1,5-dimethyl-1H-pyrrolo-2-carboxynitrile was separated as a yellowish-brown powder in 92% yield (≥99.0% purity according to HPLC).

Step: Preparation of A2-4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile

Method 1

4-(benzyloxy)aniline, HCl (1.00 kg), and sodium tert-butoxide (1.22 kg) were suspended in 2-methyltetrahydrofuran (6.00 kg) at 20 °C, and then heated to 60 °C. After contacting for 1 hour, tBuXPhosPd(allyl)OTf (0.15 kg) was added, followed by a solution of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carboxynitrile (0.84 kg) in 2-methyltetrahydrofuran (3.20 kg) for approximately 1 hour. After a 30-minute contact, the reaction mixture was cooled to 20 °C. 1 N HCl solution was added until a pH of 3.0 ± 0.5 was obtained. The aqueous phase was removed, and the organic phase was washed twice with an aqueous solution of N-acetyl-L-cysteine, followed by washing with 1 N HCl solution. The organic phase was subjected to vacuum to reduce its volume, and isobutanol was added at 20 °C. The product precipitated during the addition. The suspension was cooled to 5 °C and then filtered. The cake was washed with isobutanol and then with heptane, and then dried in a vacuum oven at 40°C. 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile was isolated as a white powder in 70% yield (≥98.0% purity according to HPLC).

Method 2

Sodium tert-butoxide (1.22 kg), 4-(benzyloxy)aniline HCl (1.00 kg), tris(dibenzylacetone)dipalladium (0) (97.1 g), and tBuXPhos (90.8 g) were suspended in 2-methyltetrahydrofuran (6.34 kg) at 20 °C under an argon atmosphere, and then heated to 40 °C. After contacting for 1 hour, a solution of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carboxynitrile (0.836 kg) in 2-methyltetrahydrofuran (2.72 kg) was added for approximately 1 hour, not exceeding 55 °C. After contacting for 30 minutes, the reaction mixture was cooled to 20 °C. 1 N HCl solution was added until the pH reached 2.0 ± 0.5. The aqueous phase was removed, and the organic phase was washed twice with 7.5 w% N-acetyl-L-cysteine aqueous solution, followed by washing with 1 N HCl solution. The organic phase was reduced in volume under vacuum, and then isobutanol was added at 50°C. The product precipitated during evaporation. The suspension was cooled to 0-5°C and filtered. The cake was washed with isobutanol and heptane, and then dried in a vacuum oven at 40°C. 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile was separated as a yellow powder in 85% yield (≥98.0% purity according to HPLC).

7, 20-7, 50 (m, 5H, 7, 8, 9).

¹³ C NMR (DMSOd ₆ ): δ9.30(1), δ32, 55(2), δ69, 73(3), δ99, 43(15), δ113, 79(4), δ114, 35(16), δ114, 71(5), δ115, 68(6), δ12 4, 35(14), δ127, 43(7), δ127, 49(8), δ128, 22(9), δ130, 36(13), δ137, 62(10), δ141, 79(12), δ150, 33(11).

Step 1: (2-Bromo-4-chloro-phenyl)[(3S)-3-[9-morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)- Preparation of [base] methyl ketone

2-Bromo-4-chlorobenzoic acid (1.000 kg) and (3S)-3-[(morpholino-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline 2HCl (1.296 kg) were suspended in ethyl acetate (7.216 kg) at 35 °C. Triethylamine (2.148 kg) was then added while maintaining the temperature at 35 °C. 50% propionic anhydride in ethyl acetate (4.595 kg) was added to the reaction mixture over 2.5 hours, and the contact was then maintained at 35 °C for another 1.5 hours. The reaction mixture was hydrolyzed at 35 °C by adding water and sodium hydroxide until a pH of 7.0 ± 0.2 was achieved. The biphase mixture was cooled to 20 °C, and the aqueous phase was removed. The organic phase was washed twice with water and then concentrated until all residual triethylamine was removed. The solution was cooled to 20 °C, and isopropyl ether (1.095 kg) was added. Once crystallization occurred, the suspension was cooled to 0 °C. After a contact time, the product was filtered, washed with isopropyl ether, and dried in an oven. 2-Bromo-4-chloro-phenyl)[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-yl] ketone was separated as a white powder in 80% yield (≥99.0% purity according to HPLC).

Alternatively, crystallization can be initiated by adding seed crystals.

31.40(2), δ40.56, 44.40 and 44.64(8), δ43.23, 44.29 and 49.94(1), δ53.41, 53.49 and 53.74(4,5), δ57.83, 58.02, 59.12 and 59.25(3), δ65.91, 66.19 and 66.34(6,7), δ 119.03 and 109,08(16), δ120.00-127.00(9,10,11,12), δ127.00-133.00(13,14 , 15, 19, 20), δ134.00-138.00 (17, 18), δ166.07, 166.19, 166.25 and 166.72 (21).

Step 2: 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl] Preparation of ethyl phenyl-1,2-dimethyl-1H-pyrrole-3-carboxylate

(2-Bromo-4-chloro-phenyl)[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-yl] methyl ketone (1.00 kg), potassium carbonate (0.68 kg), palladium acetate (0.05 kg), and ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate (0.28 kg) were dissolved in DMSO (5.51 kg), and the mixture was then heated at 100 °C for 24 hours. At the end of the conversion, the reaction mixture was cooled to 50 °C, purified with Clarcel, and then washed with DMSO and ethyl acetate. The filtrate was cooled to 20 °C and then hydrolyzed with water. The product was extracted with ethyl acetate, and the organic phase was washed twice with N-acetyl-L-cysteine solution to remove residual palladium, and then the pH was adjusted to 8.0 ± 0.2 with potassium carbonate aqueous solution. The aqueous phase was then removed, and the organic phase was washed with water for the final time limit. Vacuum volume reduction was performed, and isopropyl ether was added at 50 °C. The suspension was cooled to 5°C. The product was filtered, and the cake was washed with isopropyl ether and then dried in a vacuum oven. Ethyl 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylate was separated as a brown powder in approximately 70% yield (≥96.0% purity according to HPLC).

^13C NMR ( _CDCl3 ): δ11, 15, 11, 45 and 11, 73 (2), δ14, 50 (1), δ29, 74 and 31, 00 (5), δ31, 74 and 32, 22 (4), δ43, 31, 45, 32 and 49, 99 (6), δ42, 38, 45, 02 and 45, 77 (9), δ53, 82 and 54, 02 (7, 8), δ58, 07 (18), δ58, 95 and 59, 28 (10), δ66, 83 and 67, 25 (11, 12), δ111, 08 (13), δ11 1, 73 (15), δ125-131 (23, 24, 25, 29, 30, 31, 32), δ128-138, 00 (19, 20, 21, 22, 26, 27, 28), δ164, 92 (16), δ168, 61 (17).

Step 3: 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl] Preparation of phenyl-1,2-dimethyl-1H-pyrrole-3-carboxylate

Method 1

1.000 kg of 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylate was dissolved in 4.734 kg of ethanol at 20 °C, followed by the addition of 0.876 kg of 10 N sodium hydroxide (3.5 eq.). The mixture was heated at 75 °C until conversion was complete. After cooling, dilute hydrochloric acid solution was added to pH 1.3. The suspension was cooled to 5 °C and then filtered. The product was washed with water and then dried. 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylate was isolated as a white powder in 85% yield (≥98.0% purity according to HPLC).

Alternatively, crystallization can be initiated by adding seed crystals.

Method 2

1.000 kg of 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylate was dissolved in a mixture of ethanol (2.370 kg) and water (2.000 kg) at 20 °C, and then 0.876 kg; 3.5 eq. of 10 N sodium hydroxide was added. The mixture was heated and maintained at 80 °C until complete conversion. The ethanol was removed by distillation, and the volume was adjusted to 5 L with water. At 25 °C, the mixture was added to a mixture of isopropanol, water, and concentrated hydrochloric acid solution (0.992 kg; 5 eq.). After precipitation, the suspension was filtered, washed with water (2 x 4.000 L/ kg), and then dried. 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylate salt was isolated with a yield of 97%.

5, 36 (m, 1H, 3), δ6, 15 (s, 1H, 11), δ6, 85 (m, 1H, 16), δ6, 96 (m, 1H, 12), δ7, 07 (m, 2H, 13 and 14), δ7, 43 (d, 1H , J=2.0Hz, 17), δ7,54 (dd, 1H, J=8.3Hz, J=2.0Hz, 15), δ7,86 (d, 1H, J=8.3HZ, 18), δ11,60 (s, 1H, COOH).

¹³ C NMR (DMSOd ₆ ): δ10, 58(1), δ29, 26(4), δ31, 31(2), δ41, 20(3), δ43, 91(5), δ49, 89(6), δ52, 28(7), δ54,78 (8), δ62, 53 and 62, 60 (9, 10), δ111, 03 (11), δ111, 16 (19), δ125, 52 (12), 125, 72 (13), 126, 12 (14 ), δ127, 07(20), δ127, 60(15), δ128, 60(16), δ128, 82(17), δ130, 12(21), δ130, 39(22), δ130, 48(23), δ130, 63(18), δ133, 30(24), δ135, 65(25), δ136, 68(26), δ165, 62(27), δ168, 93(28).

Step 4: N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydro Isoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrolo-3-yl)-1,2-dimethyl-1H-pyrrolo Preparation of 3-carboxamide

Method 1

5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylic acid HCl (1.000 kg) and 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile (0.549 kg) were suspended in chlorobenzene (11.10 kg), and the mixture was then heated to 120 °C. Pyridine (0.547 kg) and 50% propionic anhydride in ethyl acetate (1.650 kg) were added sequentially. After conversion, the mixture was cooled to 20 °C and then hydrolyzed with water. The aqueous phase was removed, and the organic phase was washed with an aqueous sodium hydroxide solution. The organic phase was concentrated under vacuum and then purified by silica gel column chromatography using a toluene/ethanol mixture (93/7) as the eluent. The eluent was then removed by concentration. The purified product was dissolved in a mixture of toluene and methyl tert-butyl ether (MTBE) (w/w 35/65) at 20 °C. The product was precipitated by adding this solution to a large excess of cyclohexane. The suspension was then filtered, and the cake was washed with cyclohexane. The product was dried over a temperature gradient of 20–40 °C to give N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide as a white solid in 75% yield (≥96.0% purity according to HPLC).

Method 2

5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxylate (1.000 kg) and 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile (0.583 kg) were suspended in chlorobenzene (8.0 L), and the mixture was then heated to 120 °C. Pyridine (0.581 kg) and 50% propionic anhydride in ethyl acetate (1.753 kg) were slowly added. After conversion, the mixture was cooled to 20 °C and then hydrolyzed with water. The aqueous phase was removed, and the organic phase was washed with an aqueous solution of sodium hydroxide (1N). The organic phase was concentrated under vacuum to 3 L and finally diluted with 20 L of ethyl acetate. N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide was stored in solution until the next step, with a theoretical yield of 100%.

1), δ5,38 and 5,65 (s, 1H, 16), δ6,34, 6,42 and 6,59 (s, 1H, 21), δ6,75-6,95 (m, 5H, 12, 22, 23), δ7,00-7,20 (m, 2H, 9, 10), δ7,20-7,60 (m, 9H, 11, 13, 14, 15, 25, 26, 27).

¹³ C NMR (CD ₃ 1 7 (4, 5), δ 58, 95 (3), δ 67, 82 and 68, 11 (6, 7), δ 71, 09 and 71, 25 (24), δ 102, 73 and 102, 86 (39), δ 111, 82 and 112, 51 (16), δ 114, 66 (34), δ115,53(40), δ116,21 and 116,30(23), δ117,74 and 117,94(21), 126,00-132,00(9,10,11,12,13,14,15,22,25,26,27,33,37), δ131,00-140,00(28,29,31,32,35,38,41,43,44), δ158,18 and 158,39(42), δ168,82 and 169,20(36), δ170,83 and 171,58(30).

Step 5: Preparation of 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-=methyl-1H-pyrrole-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

Method 1

The N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (1.000 kg) obtained in step 4 (method 1) was dissolved in ethyl acetate (9.02 kg) at 25 °C, followed by the addition of a 33% hydrobromic acid-acetic acid solution (2.800 kg). The reaction mixture was maintained at 25 °C until the conversion was complete. The mixture was hydrolyzed with water, and the pH was adjusted to 8.5 ± 0.5 by adding 10 N sodium hydroxide solution. After contact for a certain period of time, the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined and concentrated under vacuum. The product was then purified by silica gel column chromatography using a toluene/ethanol mixture of (95/5)–(93/7) as the eluent. The eluent was then removed by concentration, yielding a residual volume of 3.5 L. This yielded a toluene solution of 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide in approximately 90% yield (based on HPLC purity ≥98.0%).

Method 2

Acetyl chloride (77.8 g) was added to ethanol (1.0 L), and after 30 minutes, N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (100 g) obtained in step 4 (Method 1) was added at 20 °C. Palladium hydroxide on carbon 20% (10 g) was suspended, and the mixture was then heated to 55 °C. Deprotection was performed using hydrogen at atmospheric pressure. After conversion, the suspension was purified at 20 °C, and the palladium was washed with ethanol (200 mL). The pH of the mother liquor was adjusted to 8 with sodium hydroxide solution. Solvent exchange from ethanol to ethyl acetate was performed, the organic layer was washed with water (850 mL), concentrated under vacuum, and then purified by silica gel column chromatography using a toluene/ethyl acetate mixture (95/5)–(93/7) as the eluent. The eluent was then removed by concentration to give 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide as a pink solid in 80% yield.

Method 3

A solution of 33% hydrobromic acid in acetic acid (4.15 kg) was added to a solution of N-[4-(benzyloxy)phenyl]-5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (1.483 kg) obtained in step 4 (method 2) at 20 °C. The reaction mixture was maintained at 20 °C until the conversion was complete. The mixture was hydrolyzed with water and then with 10N sodium hydroxide solution (approximately 8.3 kg). After contact for a certain period of time, the aqueous phase was back-extracted with ethyl acetate. The organic phases were combined and concentrated under vacuum. The product was then purified by silica gel column chromatography using a toluene/ethanol mixture as the eluent. The eluent was then removed by concentration to give a residual volume of 3.5 L. This yielded 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide in 85% yield (yield from two consecutive steps).

34), δ5, 29, 5, 45 and 5, 52 (s, 1H, 18), δ6, 30-7, 70 (m, 12H, 3, 9, 10, 20, 22, 23, 28, 29, 30, 31), δ9, 31 (d, 1H, J=14.3Hz, OH).

¹³ C NMR (DMSOd ₆ ): δ9, 21, 9, 50 and 9, 69(6), δ11, 16 and 11, 70(15), δ30, 20(33), δ31, 01 and 31, 48(16), δ32, 62(7), δ42, 52(34) ), δ44, 28(26), δ53, 23 and 53, 58(36), δ55, 96(35), δ65, 92, 66, 18 and 66, 33(37), δ100, 19 and 100, 32(2), 109 , 99 and 110, 48(18), δ113, 82(1), δ114, 58(13), δ115, 19(10), δ116, 85(3), δ125, 00-140, 00(4, 5, 8, 9, 1 4, 17, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 31, 32), δ154, 94 and 155, 10(11), δ165, 64(12), δ167, 38(25).

Claims (49)

1. Method for preparing compounds of formula (V): Wherein: -Z is a group selected from -COOR and -CN, and -R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl. The following steps are included to make the compound of formula (III): Where Z is as defined above, With compounds of formula (IV): Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups. In a solvent or solvent mixture, at a temperature exceeding 70°C, at: (i) Palladium catalyst; (ii) optional phosphine; and (iii) Alkali, The following reaction exists. 2. The method of claim 1, wherein Z is -COOR and R represents methyl, ethyl, isopropyl, tert-butyl, benzyl or p-methoxybenzyl. 3. The method according to claim 1, wherein W represents a bromine atom. 4. The method according to claims 1-3, wherein the palladium catalyst is palladium(II) acetate (Pd(OAc) ₂ ). 5. The method according to claims 1-3, wherein the reaction mixture further comprises phosphine selected from tert-butylphosphine, XPhos, CyJohnPhos and tris(o-tolyl)phosphine, preferably CyJohnPhos. 6. The method according to claims 1-3, wherein the solvent is a proton-free solvent. 7. The method of claim 6, wherein the solvent is selected from dimethyl sulfoxide (DMSO), N-butylpyrrolidone (NBP), 2-methyltetrahydrofuran, and toluene, preferably dimethyl sulfoxide. 8. The method according to claims 1-3, wherein the temperature exceeds 90°C, preferably 100°C. 9. _The method according to claims 1-3, wherein the base is a _carbonate , preferably _Na₂CO₃ , _Cs₂CO₃ or _K₂CO₃ , and even more _{preferably K₂CO₃} . 10. The method according to claims 1-3, wherein the reaction mixture further comprises neopentanoic acid. 11. The method according to any one of claims 1-10, wherein the compound of formula (IV) or its addition salt with a pharmaceutically acceptable acid is obtained: Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups. The compound of formula (I) is prepared by the following steps: Or its addition salt with a pharmaceutically acceptable acid. Compounds of formula (II): The reaction takes place in a proton-free solvent in the presence of an amine base and a coupling agent. 12. The method according to claim 11, wherein the compound of formula (II) is 2-bromo-4-chlorobenzoic acid, thereby resulting in the formation of a compound of formula (IV-a): 13. The method according to claim 11 or 12, wherein compound (I) is in the form of a dihydrochloride salt. 14. The method according to claim 11 or 12, wherein the coupling agent is selected from propionic anhydride, cyanuric chloride, methyl propionate, tetraethyl orthosilicate, neopentanoyl chloride, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isobutyl chloroformate, thionyl chloride and oxalyl chloride, preferably propionic anhydride. 15. The method according to claim 11 or 12, wherein the amine base is selected from triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, N-ethylmorpholine, pyridine, and 2,6-rutidine. 16. The method of claim 11 or 12, wherein the temperature comprises 20-50°C. 17. The method according to claim 11 or 12, wherein the aprotic solvent is selected from ethyl acetate, dichloromethane and isopropyl ether, preferably ethyl acetate. 18. The method according to claim 11 or 12, wherein the compound of formula (IV) is isolated as a free base. 19. The method according to any one of claims 1-18, wherein the ester or nitrile functional group of the compound of formula (V) is: Wherein: -Z is a group selected from -COOR and -CN, and -R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl. Further hydrolysis in a proton-rich medium yields the compound of formula (VI): The compound of formula (VI) is further separated into zwitterions or as an addition salt of a pharmaceutically acceptable acid, and then reacted with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile of formula (VII): Peptide coupling is performed in a proton-free solvent, in the presence of a coupling agent, and optionally in the presence of an amine base, to give the compound of formula (VIII): The compound of formula (VIII) was deprotected under acidic conditions to give compound A: The compound can be isolated and further converted into its addition salt with a pharmaceutically acceptable acid or base. 20. The method of claim 19, wherein Z is -COOR and R represents methyl, ethyl, isopropyl, tert-butyl, benzyl or p-methoxybenzyl. 21. The method according to claim 19, wherein the compound of formula (V) is: The compound is further hydrolyzed under alkaline conditions. 22. The method according to claim 19, wherein the compound of formula (V) is: This allows the compound to be further hydrolyzed under acidic conditions. 23. The method of claim 19, wherein the proton medium used for hydrolyzing compound (V) is methanol, ethanol, isopropanol, DMSO/water, or a mixture of ethanol and water. 24. The method of claim 23, wherein the proton medium used is ethanol/water, and the hydrolysis of compound (V) is carried out at a temperature of 60-80°C. 25. The method of claim 19, wherein the compound of formula (VI) is separated in the form of an addition salt of a pharmaceutically acceptable acid selected from hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, succinic acid, maleic acid, phosphoric acid, and boric acid. 26. The method of claim 19, wherein the coupling agent is selected from thionyl chloride, isobutyl chloroformate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and propionic anhydride. 27. The method of claim 19, wherein the aprotic solvent used for peptide coupling is selected from dichloromethane, acetonitrile, toluene, ethyl acetate, butyl acetate, isobutyl acetate, propyl acetate, isopropyl acetate, chlorobenzene, N,N-dimethylformamide, and pyridine. 28. The method of claim 19, wherein the coupling agent is N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and the solvent is toluene. 29. The method of claim 19, wherein the amine base is used for peptide coupling. 30. The method of claim 29, wherein the amine base used for peptide coupling of the compound of formula (VI) and the compound of formula (VII) is selected from pyridine, N,N-diisopropylethylamine and triethylamine. 31. The method of claim 19, wherein the coupling agent is phosphonic anhydride and the amine base is pyridine. 32. The method of claim 19, wherein the coupling agent is phosphonic anhydride, the amine base is pyridine, and the aprotic solvent is selected from acetonitrile, toluene, chlorobenzene, ethyl acetate, butyl acetate, and propyl acetate. 33. The method of claim 32, wherein the peptide coupling is carried out at a temperature of 60-135°C, preferably 110-135°C, and even more preferably 120°C. 34. The method according to claim 19, wherein the deprotection of the compound of formula (VIII) is carried out in a mixture of hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrochloric acid and acetic acid or a mixture of hydrobromic acid and acetic acid, more preferably in a mixture of hydrobromic acid and acetic acid. 35. The method of claim 34, wherein the solvent used for deprotection of the compound of formula (VIII) is selected from dichloromethane, chlorobenzene, dioxane and ethyl acetate, more preferably ethyl acetate. 36. The method of claims 34 and 35, wherein the temperature is maintained below 40°C. 37. The method of claim 19, wherein the deprotection of the compound of formula (VIII) is carried out by hydrogenation under acidic conditions in the presence of a catalyst. 38. The method of claim 37, wherein: - The palladium catalyst is Pd(OH) _₂ carbon or palladium-coated carbon. The hydrogenation reaction is carried out in hydrochloric acid ethanol at a temperature of 40-65°C, preferably 45-60°C. 39. Method for preparing compound A: Its characteristic is that it makes the compound of formula (I): Or its addition salt with a pharmaceutically acceptable acid. Compounds of formula (II): Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups. The coupling reaction is carried out in a proton-free solvent, in the presence of an amine base and a coupling agent, at a temperature ranging from 20 to 50 °C. To obtain compounds of formula (IV) or their addition salts with pharmaceutically acceptable acids: Make the compound of formula (IV) and the compound of formula (III): Wherein: -Z is a group selected from -COOR and -CN, and -R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl. In solvents or solvent mixtures, at temperatures exceeding 70°C, and in: (iv) Palladium catalyst; (v) optional phosphine; and (vi) Reactions in the presence of a base. The compound of formula (V) is obtained: Further hydrolysis of the ester or nitrile functional groups of the compound of formula (V) in a proton medium yields the compound of formula (VI): The compound of formula (VI) is further separated into zwitterions or as an addition salt of a pharmaceutically acceptable acid, and then reacted with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carboxynitrile of formula (VII): Peptide coupling is performed in a proton-free solvent, in the presence of a coupling agent, and optionally in the presence of an amine base, to obtain the compound of formula (VIII): The compound of formula (VIII) was deprotected under acidic conditions to give compound A: The compound can be isolated and further converted into its addition salt with a pharmaceutically acceptable acid or base. 40. Compounds of formula (IV) or their addition salts with pharmaceutically acceptable acids: Where W represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups. 41. Compounds of formula (V): Wherein: -Z is a group selected from -COOR and -CN, and -R indicates ( _C1 - _C6 ) alkyl, allyl, or _-CH2 -aryl. The condition is that ( _C1 - _C6 ) alkyl does not represent ethyl. 42. Compounds of formula (VIII): 43. Compounds of formula (VII): 44. A method for preparing compounds of formula (VII), comprising the following steps: making compounds of formulas (SM1-VIII): Where W' represents a leaving group, which is selected from halogen atoms, trifluoromethanesulfonate groups, methanesulfonate groups, and p-toluenesulfonate groups. Compounds of formula (SM2-VIII): The reaction takes place in the presence of a palladium-phosphine complex catalyst and a base, in a polar aprotic solvent, and at a temperature ranging from 40 to 85 °C. The palladium-phosphine complex catalyst is prepared in situ or in-situ using palladium catalyst and phosphine as raw materials. 45. The method of claim 44, wherein W’ represents a bromine atom. 46. The method of claim 44 or 45, wherein the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, and 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran. 47. The method according to claim 44 or 45, wherein the palladium-phosphine complex catalyst is selected from tBuXPhos Pd G1, tBuXPhos Pd G3, BrettPhos G3, tBuXPhosPd(allyl)OTf, more preferably tBuXPhosPd(allyl)OTf. 48. The method according to claim 44 or 45, wherein the palladium-phosphine complex catalyst is prepared in situ _{from Pd₂dba₃} and tBuXPhos. 49. The method according to claim 44 or 45, wherein the base is selected from tBuONa, tBuOK, _{K3PO4 and K2CO3 ,} more preferably tBuONa.