Novel 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 preparation of pharmaceutical compounds

Abstract

The present invention relates to a novel process 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 its application for preparing pharmaceutical compounds.

Description

[Technical field]

[0001] The present invention relates to a novel process 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 its application for preparing pharmaceutical compounds.

[0002] More specifically, the present invention relates to a novel process 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-carboxylate 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 its application for preparing pharmaceutical compounds.

[0003] Even more specifically, the present invention relates to a novel process 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 application for preparing 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, herein referred to as "Compound A".

[0004] In particular, the present invention relates to a compound of formula (V): [ka] [In the formula, -Z is a group selected from -COOR and -CN; -R is (C 1 ~C 6 ) an alkyl group, an aryl group or -CH 2 -represents an aryl group] The compound represented by the formula (IV): [ka] [wherein W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group] The present invention relates to a method for producing a compound of the formula:

[0005] In some embodiments, the compound represented by formula (IV) is synthesized starting from 4-chlorobenzoic acid derivative (compound represented by formula (II)) and (3S)-3-[(morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (compound represented by formula (I)).

[0006] In another embodiment, the compound of formula (V) is further hydrolyzed to give a compound of formula (VI): [ka] A carboxylic acid represented by the formula:

[0007] In some embodiments, the present invention provides a compound of formula (VIII): [ka] The compound (VI) and the compound (VII) represented by the formula (VII) are prepared by the reaction 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide represented by the formula (VII): [ka] The present invention relates to a method for producing a compound of the formula:

[0008] The compounds of formulae (IV), (V), (VI), (VII) and (VIII) obtained according to the process of the present invention are useful for the synthesis of compound A and its structurally close analogues.

[0009] In particular, Compound A has pro-apoptotic properties and is capable of inhibiting, in particular, the anti-apoptotic Bcl-2 protein, which is overexpressed in various cancers, allowing Compound A to be used in pathologies involving defects in apoptosis, such as, for example, in the treatment of cancer and immune and autoimmune diseases.

[0010] Considering the pharmaceutical value of compound A, it is important to be able to obtain it by an efficient synthetic method, starting from economical and readily available starting materials, which is easily transferable to industrial scale and which gives compound A in good yield and excellent purity.

[0011] In another aspect, the present invention relates to a process for preparing 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carbonitrile of formula (VII) and its application for preparing a compound of formula (VIII).

[0012] The structure of compound A is as follows: [ka] 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide The preparation of Compound A and its structurally close analogues, their use as Bcl-2 inhibitors for the treatment of cancer, and their pharmaceutical formulations are described in WO 2015 / 011400, the contents of which are incorporated by reference. Its preparation is specifically disclosed in Example 386 of WO 2015 / 011400 in the form of a hydrochloride salt, and its hydrogen sulfate salt is also described in WO 2020 / 089281. In addition, a cyclodextrin-based formulation containing Compound A is shown in WO 2020 / 089286.

[0013] In particular, the method for synthesizing compound A disclosed in WO 2015 / 011400 included the following steps summarized in Scheme 1 below: (a) CH activation of ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate with 2-bromo-4-chlorobenzaldehyde (b) Oxidation process (c) Peptide coupling (d)Saponification process (e) N-acylation step using a secondary amine (f) Deprotection step

[0014] [ka]

[0015] Compound A is 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-carbonitrile as starting materials. Difficulties in carrying out the process quickly became apparent when moving to an industrial scale. In particular, in the peptide coupling between (3S)-3-[(morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline and 4-chloro-2-[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic acid, there is a risk of using potentially explosive reagents such as hydroxybenzotriazole (HOBt), toxic solvents such as N,N-dimethylacetamide (DMAc) and potentially carcinogenic solvents such as 1,2-dichloroethane. In addition, in the coupling step (e) with 4-({4-[(tert-butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H-pyrrole-2-carbonitrile, long contact times at high temperatures are required and several by-products (e.g. anhydride derivatives) are generated, as shown below. [ka]

[0016] Efforts to limit their formation are necessary. Furthermore, for step (e), considerable variability in yield was observed, suggesting that the experimental conditions for this coupling step described in WO 2015 / 011400 are not robust enough for industrial application. Finally, the use of Ghosez's reagent (1-chloro-N,N,2-trimethyl-prop-1-en-1-amine) on an industrial scale can be complicated by some stability issues.

[0017] As a result, the search for new efficient synthetic routes is still ongoing, and the applicant is continuing to work to develop a new synthetic method for compound A aimed at producing large batches. This synthetic method reproducibly produces compounds of formulae (IV), (V), (VI), (VII) and (VIII) in good yield and purity suitable for use as pharmaceutically acceptable intermediates. Finally, this new manufacturing method makes it possible to obtain compound A in good yield (32% based on the chemical route detailed in Scheme 2 below) and in purity suitable for use as a pharmaceutical active ingredient (greater than 98%, preferably greater than 99%).

[0018] In particular, the Applicant has now developed a novel synthesis method which makes it possible to reproducibly obtain the compounds of formulae (IV), (V) and (VI) without the need for laborious purification. Analogous to the synthesis method disclosed in WO 2015 / 011400, (3S)-3-[(morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline and ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate are used as starting materials, except that the 4-chlorobenzoic acid derivative of formula (II) is used as the new starting material. [ka]

[0019] In a preferred embodiment, the compound of formula (II) is 2-bromo-4-chlorobenzoic acid. This new starting material has the advantage of being simple and readily available in large quantities at low cost. For this reason, the preparation method of the present invention is based on a new chemical route that includes the compound of formula (IV) as an intermediate. More comprehensively, it is possible to obtain compound A in five steps, i.e. one step less compared to the disclosure of WO 2015 / 011400. Finally, tert-butyldimethylsilyl was replaced by a benzyl group as a protecting group for the hydroxy function of the N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl) moiety. In doing so, the coupling reaction between the secondarily protected amine and the compound of formula (VII) has a high yield and is reproducible in large batches (little variability is observed due to the robust experimental conditions). Advantageously, this new coupling reaction also avoids the formation of the impurity of anhydride derivatives discussed above. The purity of the compound of formula (VIII) thus obtained is more easily controlled.

[0020] The synthetic method of the present invention is outlined below in Scheme 2. [ka]

[0021] Detailed Description of the Invention In a first embodiment (E1), the present invention provides a compound of formula (V): [ka] [In the formula, -Z is a group selected from -COOR and -CN; -R is (C 1 ~C 6 ) an alkyl group, an aryl group or -CH 2 -represents an aryl group] A process for preparing a compound of the formula Formula (III): [ka]

[0023] wherein Z is as defined above. The compound represented by formula (IV): [ka] [wherein W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group] in a solvent or mixture of solvents at a temperature above 70° C. (i) a palladium catalyst; (ii) optionally, phosphine and (iii) Base In one embodiment, a method for producing the compound is provided, comprising the step of reacting in the presence of

[0022] Further enumerated embodiments (E) of the invention are described herein. It will be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0023] E2. The process according to E1, wherein Z is -COOR and R represents a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a benzyl group, or a para-methoxybenzyl group. In a preferred embodiment, R represents an ethyl group.

[0024] E3. The process according to E1, wherein W represents a bromine atom.

[0025] E4. The palladium catalyst is palladium(II) acetate (Pd(OAc) 2 The method according to any one of E1 to E3, wherein

[0026] E5. The process according to any one of E1 to E3, wherein the reaction mixture further contains a phosphine selected from tri-tert-butylphosphine, XPhos, CyJohnPhos and tri(o-tolyl)phosphine, preferably CyJohnPhos.

[0027] E6. The process according to any one of E1 to E3, wherein the solvent is an aprotic solvent.

[0028] E7. The process according to E6, wherein the solvent is selected from dimethylsulfoxide (DMSO), N-butylpyrrolidinone (NBP), 2-methyltetrahydrofuran and toluene, preferably dimethylsulfoxide.

[0029] E8. The process according to any one of E1 to E3, wherein the temperature is greater than 90°C, preferably T=100°C.

[0030] E9. The base is a carbonate, preferably Na 2 CO 3 , Cs 2 CO 3 Or K 2 CO 3 , and even more preferably, K 2 CO 3 The method according to any one of E1 to E3,

[0031] E10. The process according to any one of E1 to E3, wherein the reaction mixture further contains pivalic acid.

[0032] In the preparation method of the first embodiment, the reaction between the compound represented by formula (III) and the compound represented by formula (IV) can be carried out using a catalyst system other than palladium. -Rongalit (J. Org. Chem. 2019, 84, 9946-9956); - cadmium sulfide and zinc selenide (photoredox catalysts as described in Chemistry of Materials (2017), 29(12), 5225-5231); - copper / nickel catalysts (photoredox catalysts as described in Organic Letters (2017), 19(13), 3576-3579); - nickel catalysis (Negishi coupling 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 catalysis (as described in the Kumada reaction) (however, this mechanism requires an additional step to functionalize (iodinate) the pyrrole group) can be mentioned.

[0033] E11. A compound of formula (IV) or an addition salt thereof with a pharma- ceutically acceptable acid: [ka] wherein W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group. is represented by formula (I): [ka] or an addition salt thereof with a pharma- ceutically acceptable acid, [ka] and reacting the compound represented by the formula (I) with an amine base in an aprotic solvent in the presence of a coupling agent to obtain a compound represented by the formula (I):

[0034] E12. The compound represented by formula (II) is 2-bromo-4-chlorobenzoic acid, and therefore, the compound represented by the following formula (IV-a): [ka] The process according to E11, wherein a compound represented by the formula:

[0035] E13. The process according to E11 or E12, wherein compound (I) is in the form of a dihydrochloride salt.

[0036] E14. The process according to E11 or E12, wherein the coupling agent is selected from propylphosphonic anhydride, cyanuric chloride, methyl propiolate, tetraethyl orthosilicate, pivalyl chloride, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isobutyl chloroformate, thionyl chloride and oxalyl chloride, preferably propylphosphonic anhydride.

[0037] E15. The process according to 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-lutidine. In a preferred embodiment, the amine base is triethylamine.

[0038] E16. The method according to E11 or E12, wherein the temperature is comprised between 20 and 50°C.

[0039] E17. The process according to E11 or E12, wherein the aprotic solvent is selected from ethyl acetate, methylene chloride and isopropyl ether, preferably ethyl acetate.

[0040] E18. The process according to E11 or E12, wherein the compound of formula (IV) is isolated as the free base.

[0041] E19. The process according to E11 or E12, wherein the compound of formula (IV) is isolated in the form of an addition salt with a pharma- ceutically acceptable acid selected from oxalic acid, methanesulfonic acid and hydrochloric acid.

[0042] E20. Formula (V): [ka] [In the formula, -Z is a group selected from -COOR and -CN, -R is (C 1 ~C 6 ) an alkyl group, an aryl group or -CH 2 -represents an aryl group] The ester or nitrile functionality of the compound of formula (VI): [ka] To produce a compound represented by the formula: The compound of formula (VI) is further isolated as a zwitterion or in the form of its addition salt with a pharma- ceutically acceptable acid, and then reacted with a compound of formula (VII): [ka] to obtain a peptide having the formula (VIII): [ka] To produce a compound represented by the formula: The compound represented by formula (VIII) is deprotected under acidic conditions to give compound A: [ka] Generate The process according to any one of E1-E19, wherein the compound can be isolated and further converted into an addition salt thereof with a pharma- ceutically acceptable acid or base.

[0043] E21. The process according to E20, wherein Z is -COOR and R represents a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a benzyl group, or a para-methoxybenzyl group.

[0044] E22. The compound represented by formula (V) [ka] and This compound is further hydrolyzed under basic conditions, a process as described in E20.

[0045] E23. The compound represented by formula (V) [ka] and This compound is further hydrolyzed under basic conditions, a process as described in E20.

[0046] E24. The process according to E20, wherein the protic medium used for the hydrolysis of compound (V) is methanol, ethanol, isopropanol, a mixture of DMSO / water or ethanol / water, preferably ethanol.

[0047] E25. The process according to E24, wherein the protic medium used is ethanol / water and the hydrolysis of compound (V) is carried out at a temperature comprised between 60 and 80°C.

[0048] E26. The process according to E20, wherein the compound of formula (VI) is isolated in the form of an addition salt with a pharma- ceutically acceptable acid selected from hydrochloric acid, sulfuric acid, hydrobromic acid, para-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 pharma-ceutically acceptable acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, para-toluenesulfonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, phosphoric acid and boric acid. Even more preferably, the compound of formula (VI) is isolated in the form of a hydrochloride salt.

[0049] E27. The process according to E20, wherein the coupling agent is selected from thionyl chloride, isobutyl chloroformate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and propylphosphonic anhydride. In a preferred embodiment, the coupling agent is propylphosphonic anhydride.

[0050] E28. The process according to E20, wherein the aprotic solvent used for the peptide coupling is selected from dichloromethane, acetonitrile, toluene, ethyl acetate, butyl acetate, isobutyl acetate, propyl acetate, isopropyl acetate, chlorobenzene, 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.

[0051] E29. The process according to claim 1, wherein the coupling agent is N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the solvent is toluene.

[0052] E30. A process according to E20, in which an amine base is used for peptide coupling.

[0053] E31. The process according to E30, wherein the amine base used in peptide coupling of the compound of formula (VI) with the compound of formula (VII) is selected from pyridine, N,N-diisopropylethylamine and triethylamine. In a preferred embodiment, the amine base is pyridine.

[0054] E32. The process according to E20, wherein the coupling agent is propylphosphonic anhydride and the amine base is pyridine.

[0055] E33. The process according to E20, wherein the coupling agent is propylphosphonic 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, even more preferably the aprotic solvent is chlorobenzene.

[0056] E34. The process according to E33, wherein the peptide coupling is carried out at a temperature comprised between 60°C and 135°C, preferably between 110°C and 135°C, even more preferably at 120°C.

[0057] E35. The process according to E20, wherein the deprotection of compound of formula (VIII) is carried out in the presence of hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, a mixture of 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.

[0058] E36. The process according to E35, wherein the solvent used for the deprotection of compound of formula (VIII) is selected from dichloromethane, chlorobenzene, dioxane and ethyl acetate, more preferably ethyl acetate.

[0059] E37. The process according to E35 or E36, wherein the temperature is maintained below 40°C.

[0060] E38. The process according to E20, wherein the deprotection of the compound of formula (VIII) is carried out via a hydrogenation reaction in the presence of a catalyst under acidic conditions.

[0061] E39. -Palladium catalyst is Pd(OH) supported on carbon 2 or palladium on carbon, The process according to E38, wherein the hydrogenation reaction is carried out in ethanolic hydrochloric acid at a temperature comprised between 40 and 65°C, preferably between 45 and 60°C.

[0062] E40. Formula (VII): [ka] With the compound represented by formula (SM1-VIII): [ka] wherein W' represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group. The compound represented by formula (SM2-VIII): [ka] with a compound represented by the formula: The process according to any one of E20 to E39, wherein the palladium-phosphine complex catalyst is ready to use or is prepared in situ starting from the palladium catalyst and the phosphine.

[0063] E.41 Compound A: [ka] A method for producing Formula (I): [ka] or an addition salt thereof with a pharma- ceutically acceptable acid, [ka] [wherein W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group] and a compound represented by the formula (IV): [ka] To produce a compound represented by the formula: The compound represented by formula (IV) is reacted with a compound represented by formula (III): [ka] [In the formula, -Z is a group selected from -COOR and -CN; -R is (C 1 ~C 6 ) an alkyl group, an aryl group or -CH 2 -represents an aryl group] in a solvent or mixture of solvents at a temperature above 70° C. (i) a palladium catalyst; (ii) optionally, phosphine and (iii) Base in the presence of formula (V): [ka] To produce a compound represented by the formula: The ester or nitrile functionality of the compound of formula (V) may be further hydrolyzed in a protic medium to give a compound of formula (VI): [ka] To produce a compound represented by the formula: The compound of formula (VI) is further isolated as a zwitterion or in the form of its addition salt with a pharma- ceutically acceptable acid, and then reacted with a compound of formula (VII): [ka] to obtain a peptide having the formula (VIII): [ka] To produce a compound represented by the formula: The compound represented by formula (VIII) is deprotected under acidic conditions to give compound A: [ka] Generate The compound can be isolated and further converted into its addition salt with a pharma- ceutically acceptable acid or base. Manufacturing method.

[0064] E42. The process according to E41, wherein compound A is isolated in solution.

[0065] E43. Formula (VII): [ka] With the compound represented by formula (SM1-VIII): [ka] wherein W' represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group. The compound represented by formula (SM2-VIII): [ka] with a compound represented by the formula: The process according to E41, wherein the palladium-phosphine complex catalyst is either ready-to-use or prepared in situ starting from the palladium catalyst and the phosphine.

[0066] E44. Formula (IV): [ka] [wherein W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group] or an addition salt thereof with a pharma- ceutically acceptable acid.

[0067] E45. Formula (V): [ka] [In the formula, -Z is a group selected from -COOR and -CN; -R is (C 1 ~C 6 ) an alkyl group, an aryl group or -CH 2 -aryl group, However, (C 1 ~C 6 ) the alkyl group does not represent an ethyl group. A compound represented by the formula:

[0068] E46. Formula (VIII): [ka] A compound represented by the formula:

[0069] E47. Formula (VII): [ka] A compound represented by the formula:

[0070] E48. A process for preparing a compound of formula (VII), comprising the steps of: Formula (SM1-VIII): [ka] [Wherein W' represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group] The compound represented by formula (SM2-VIII): [ka] with a compound represented by the formula: wherein the palladium-phosphine complex catalyst is either ready to use or prepared in situ starting from a palladium catalyst and a phosphine, Manufacturing method.

[0071] E49. The process according to E48, wherein W' represents a bromine atom.

[0072] E50. The process according to E48 or E49, wherein the solvent is selected from N,N-dimethylformamide, dimethylsulfoxide and 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran.

[0073] E51. The process according to 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.

[0074] E52. Palladium-phosphine complex catalyst, Pd 2 dba 3and the process according to E48 or E49, prepared in situ starting from tBuXPhos.

[0075] E53. The bases are tBuONa, tBuOK, and K 3 PO 4 and K 2 CO 3 , more preferably tBuONa.

[0076] A particular embodiment of the present invention is a compound of formula (IV): [ka] [wherein W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a para-toluenesulfonate group] or an addition salt thereof with a pharma- ceutically acceptable acid, comprising the steps of: The compound has the formula (I): [ka] or an addition salt thereof with a pharma- ceutically acceptable acid, [ka] and subjecting the compound represented by the formula (I) to a coupling reaction in an aprotic solvent in the presence of an amine base and a coupling agent at a temperature ranging from 20 to 50° C.

[0077] Specific embodiments for the preparation of compounds of formula (IV) are detailed in E12 to E19 and apply to this separate preparation process.

[0078] The present invention also relates to a compound of formula (VIII): [ka] The preparation of a compound represented by This compound is reacted in an aprotic solvent in the presence of a coupling agent, and optionally in the presence of an amine base, to form a compound of formula (VI): [ka] and a compound represented by formula (VII): [ka] The compound is obtained by peptide coupling between 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carbonitrile represented by the formula:

[0079] Specific embodiments for the preparation of compounds of formula (VIII) are detailed in E27 to E34 and apply to this separate preparation process.

[0080] This manufacturing method is advantageous for the following reasons: - Compound A can be obtained reproducibly and in excellent yields on an industrial scale, starting from simple, low-cost starting materials. It is possible to obtain the compounds of formulae (IV), (V), (VI) and (VII) in good yields and reproducibly on an industrial scale, starting from simple, low-cost starting materials, without the need for laborious purification. - Avoidance of the use of highly flammable and toxic reagents - High purity can be achieved using standard crystallization techniques This is particularly advantageous.

[0081] The present invention also relates to the use of the compound of formula (IV) for the synthesis of compound A.

[0082] The present invention also relates to the use of the compounds of formulae (VII) and (VIII) for the synthesis of compound A.

[0083] In another embodiment, the present invention provides a method for the synthesis of compound A, comprising the steps of formula (V) as defined below: [ka] [In the formula, -Z is a group selected from -COOR and -CN; -R is (C 1 ~C 6 ) an alkyl group, an aryl group or -CH 2 -aryl group, However, (C 1 ~C 6 ) the alkyl group does not represent an ethyl group. The present invention relates to the use of certain compounds represented by the formula:

[0084] definition Throughout the specification and claims, various terms are used in connection with the aspects of the present specification. Such terms are given their ordinary meaning in the art unless otherwise specified. Other specifically defined terms are to be interpreted in a manner consistent with the definition provided herein.

[0085] As used herein, the term "aryl" refers to phenyl optionally substituted with a methoxy, naphthyl, biphenyl, or indenyl group.

[0086] As used herein, the term "halogen atom" preferably refers to iodine, bromine and chlorine.

[0087] The term "medium" refers to the phase (and composition of the phase) in which a chemical reaction takes place. As used herein, it refers to a solvent or mixture of solvents.

[0088] Some abbreviations are defined below. 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-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhos Pd(allyl)OTf: Allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate DCM: dichloromethane or methylene chloride 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(dibenzylideneacetone)dipalladium(0) THF: tetrahydrofuran

[0089] Preferably, the reactants are stirred for the duration of the reaction using a suitable mechanical stirrer or stirrer. The reaction can be carried out for about 2 to about 24 hours or more depending on the temperature, amount of dilution, catalyst, concentration and / or nature of the materials in the reaction mixture. As used herein, the term "about" means + / - 5%, particularly + / - 2%, and especially + / - 1%.

[0090] The structures of the compounds described were confirmed by conventional spectroscopic techniques. 1 H NMR data shows residual peaks of the solvent (CDCl 3 7.24 ppm for DMSOd6, 2.49 ppm for CD 3 The format is delta values ​​given in parts per million (ppm) using 33.1 ppm for OD as an internal standard. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), m (multiplet), br or brs (broad singlet).

[0091] The following preparations are illustrative of the invention but are not intended to limit it in any way.

[0092] Step A1 Preparation of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile [ka] 1,5-Dimethyl-1H-pyrrole-2-carbonitrile (1.00 kg) is 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) is added over 2-3 hours, while maintaining the temperature at 0±5°C. Once the conversion is complete, the reaction mixture is transferred to cold water. The product is filtered and then washed twice with water. After drying at 40°C, 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile is isolated in the form of a beige powder with a yield of 92% (purity by HPLC >99.0%).

[0093] [ka] 1 H NMR (DMSOd 6 ): δ 2,21 (s, 3H, 1), δ 3,64 (s, 3H, 2), δ 7,03 (s, 1H, 8). 13 C NMR (DMSOd 6 ): δ 10,54 (1), δ 33,44 (2), δ 94,50 (5), δ 102,69 (6), δ 113,07 (7), δ 119,73 (8), δ 134,46 (9).

[0094] Step A2 Preparation of 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carbonitrile [ka] Method 1 4-(benzyloxy)aniline, HCl (1.00 kg) and sodium tert-butoxide (1.22 kg) are suspended in 2-methyltetrahydrofuran (6.00 kg) at 20° C. and then heated to 60° C. After 1 hour of contact, tBuXPhos Pd(allyl)OTf (0.15 kg) is added, followed by a solution of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile (0.84 kg) in 2-methyltetrahydrofuran (3.20 kg) over about 1 hour. After 30 minutes of contact, the reaction mixture is cooled to 20° C. 1N HCl solution is added until a pH of 3.0±0.5 is obtained. The aqueous phase is removed and then the organic phase is washed twice with a solution of N-acetyl-L-cysteine ​​in water and then again with 1N HCl solution. The organic phase is subjected to reduction in volume in a vacuum and then isobutanol is added at 20° C. During this addition the product precipitates. The suspension is cooled to 5° C. and then filtered. The cake is 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-carbonitrile is isolated in the form of a white powder with a yield of 70% (purity by HPLC >98.0%).

[0095] Method 2 Sodium tert-butoxide (1.22 kg), 4-(benzyloxy)aniline,HCl (1.00 kg), tris(dibenzylideneacetone)dipalladium(0) (97.1 g) and tBuXPhos (90.8 g) are suspended in 2-methyltetrahydrofuran (6.34 kg) under argon at 20° C. and then heated to 40° C. After 1 hour of contact, a solution of 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile (0.836 kg) in 2-methyltetrahydrofuran (2.72 kg) is added over about 1 hour, without exceeding a temperature of 55° C. After 30 minutes of contact, the reaction mixture is cooled to 20° C. 1N HCl solution is added until the pH is 2.0±0.5. The aqueous phase is removed, then the organic phase is washed twice with a 7.5 w% N-acetyl-L-cysteine ​​solution in water and then again with a 1N HCl solution. The organic phase is subjected to volume reduction in vacuum and then isobutanol is added at 50°C. During evaporation, the product precipitates. The suspension is cooled to 0-5°C and filtered. The cake is 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-carbonitrile is isolated in the form of a yellow powder with a yield of 85% (purity by HPLC >98.0%).

[0096] [ka] 1 H NMR (DMSOd 6 ): δ 2,08 (s, 3H, 1); δ 3,60 (s, 3H, 2), δ 4,95 (s, 2H, 3), δ 6,55 (d, 2H, J=8.9 Hz ,4), δ 6,70 (s, 1H, 5), δ 6,78 (d, 2H, J=8.9 Hz ,6), δ 6,83 (s, 1H, NH), δ 7,20-7,50 (m, 5H, 7, 8, 9). 13 C NMR (DMSOd 6): δ 9.30 (1), δ 32,55 (2), δ 69,73 (3), δ 99,43 (15), δ 113,79 (4), δ 114,35 (16), δ 114,71 (5), δ 115,68 (6), δ 124,35 (14), δ 127,43 (7), δ 127,49 (8), δ 128,22 (9), δ 130,36 (13), δ 137,62 (10), δ 141,79 (12), δ 150,33 (11).

[0097] Step 1 Preparation of (2-bromo-4-chlorophenyl)[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone [ka] 2-Bromo-4-chlorobenzoic acid (1.000 kg) and (3S)-3-[(morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline, 2HCl (1.296 kg) are suspended in ethyl acetate (7.216 kg) at 35° C. Triethylamine (2.148 kg) is then added while maintaining the temperature at 35° C. 50% propylphosphonic anhydride in ethyl acetate (4.595 kg) is added to the reaction mixture over 2.5 hours and the contact is then maintained at 35° C. for an additional 1.5 hours. The reaction mixture is hydrolyzed at 35° C. by the addition of water and sodium hydroxide until a pH of 7.0±0.2 is reached. The biphasic mixture is cooled to 20° C. and the aqueous phase is then removed. The organic phase is washed twice with water and then concentrated until all residual triethylamine is removed. The solution is cooled to 20° C. and then isopropyl ether is added (1.095 kg). Once crystallized, the suspension is cooled to 0° C. After the contact time, the product is filtered, washed with isopropyl ether and dried in an oven. (2-Bromo-4-chlorophenyl)[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone is isolated in the form of a white powder with a yield of 80% (purity by HPLC >99.0%).

[0098] Alternatively, crystallization can be initiated by seeding.

[0099] [ka] 1 H NMR (DMSOd 6 ): δ 2.00-2.60 (m, 6H, 3, 4, 5), δ 2.80-3.12 (m, 2H, 2 / 2'), δ 3.40-3.70 (m, 4H, 6, 7), δ 3.80, δ 5.10 and δ 5.20 (m, 1H, 1), δ 4.10-4.40 and δ 5.25 (m, 2H, 8 / 8'), δ 6.90-8.00 (m, 7H, 9, 10, 11, 12, 13, 14, 15). 13 C NMR (DMSOd 6 ) : δ 29.77, 30.08, 30.29 and 31.40 (2), δ 40.56, 44.40 and 44.64 (8), δ43.23, 44.29 and 49.94 (1), δ 53.41, 53.49 and 53.74 (4, 5), δ 57.83, 58.02, 59.12 and 59.25 (3), δ 65.91, 66.19 and 66.34 (6, 7), δ 119.03 and 109,08 (16), δ120.00-127.00 (9, 10, 11, 12), δ 127.00-133.00 (13, 14, 15, 19, 20), δ 134.00-138.00 (17, 18), δ166.07, 166.19, 166.25 and 166.72 (21)

[0100] Step 2 Preparation of 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 [ka] (2-Bromo-4-chlorophenyl)[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]methanone (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) are dissolved in DMSO (5.51 kg) and the mixture is then heated at 100° C. for 24 hours. At the end of the conversion, the reaction mixture is cooled to 50° C., clarified with Clarcel and then rinsed with DMSO and ethyl acetate. The filtrate is cooled to 20° C. and then hydrolyzed with water. The product is extracted with ethyl acetate. The organic phase is washed twice with N-acetyl-L-cysteine ​​solution to remove residual palladium and the pH is then adjusted to 8.0±0.2 with aqueous potassium carbonate solution. The aqueous phase is then removed and the organic phase is finally washed with water. It is subjected to volume reduction in a vacuum and isopropyl ether is added at 50° C. The suspension is cooled to 5° C. The product is filtered and the cake is then 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 is isolated in the form of a brown powder with a yield of about 70% (purity by HPLC >96.0%).

[0101] [ka] 1 H NMR (CDCl 3) : δ 1,20 (t, 3H, J=7.0 Hz, 1), δ 1,90-2,70 (m, 6H, 7, 8, 18), 2,24 (s, 3H, 2), δ 2,45, 2,80 and 2,90 (m, dd, J=16.5 Hz, J=5.7 Hz and m, 2H, 5 / 5'), δ 3,23 (s, 3H, 4), δ 3,50-3,80 (m, 4H, 11 / 12), δ 4,00-4.40 (m, 4H, 9 and 10), δ 5,24 (m, 1H, 6), δ 6,18, 6,53 and 6.54 (s, 1H, 13), 6,70-7,60 (m, 7H, 23, 24, 25, 29, 30, 31, 32). 13 C NMR (CDCl 3 ): δ 11,15, 11,45 and 11,73 (2), δ 14,50 (1), δ 29,74 and 31,00 (5), δ 31,74 and 32,22 (4), δ 43,31, 45,32 and 49,99 (6), δ 42,38, 45,02 and 45,77 (9), δ53,82 and 54,02 (7, 8), δ 58,07 (18), δ 58,95 and 59,28 (10), δ 66,83 and 67,25 (11, 12), δ111,08 (13), δ 111,73 (15), δ 125-131 (23, 24, 25, 29, 30, 31, 32), δ 128-138,00 (19, 20, 21, 22, 26, 27, 28), δ 164,92 (16), δ 168,61 (17).

[0102] Step 3 Preparation 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, hydrochloride [ka] 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-carboxylate (1.000 kg) is dissolved in ethanol (4.734 kg) at 20° C., then 10N sodium hydroxide is added (0.876 kg, 3.5 eq.). The mixture is heated at 75° C. until conversion is complete. After cooling, a dilute hydrochloric acid solution is added to pH=1.3. The suspension is cooled to 5° C., then filtered. The product is 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-carboxylic acid, hydrochloride is isolated in the form of a white powder with a yield of 85% (purity by HPLC >98.0%).

[0103] Alternatively, crystallization can be initiated by seeding.

[0104] 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) is dissolved in a mixture of ethanol (2.370 kg) and water (2.000 kg) at 20° C., then 10N sodium hydroxide solution is added (0.876 kg, 3.5 eq.). The mixture is heated and maintained at 80° C. until complete conversion. Ethanol is removed by distillation and the volume is adjusted to 5 L with water. At 25° C., the mixture is added to a mixture of isopropanol, water and concentrated hydrochloric acid solution (0.992 kg, 5 eq.). After precipitation, the suspension is filtered, washed with water (2×4.000 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-carboxylic acid, hydrochloride is isolated in 97% yield.

[0105] [Chemical formula] 1 H NMR (DMSO-d 6 ): δ 1.89 (s, 3H, 1), δ 2.39 (d, 1H, J = 16.7 Hz, 4’), δ 2.74 (dd, 1H, J = 16.8 Hz, J = 6.8 Hz, 4), δ 2.97 (m, 1H, 7’), δ 3.08 (s, 3H, 2), δ 3.12 (m, 2H, 6’ and 8’), δ 3.39 (m, 2H, 7 and 8), δ 3.71 (d, 1H, J = 11.7 Hz, 6), δ 3.85 (d, 1H, J = 11.5 Hz, 9), δ 4.00 (m, 3H, 9’, 10), δ 4.06 (d, 1H, J = 18.5 Hz, 5’), δ 4.65 (d, 1H, J = 18.5 Hz, 5), δ 5.36 (m, 1H, 3), δ 6.15 (s, 1H, 11), δ 6.85 (m, 1H, 16), δ 6.96 (m, 1H, 12), δ 7.07 (m, 2H, 13 and 14), δ 7.43 (d, 1H, J = 2.0 Hz, 17), δ 7.54 (dd, 1H, J = 8.3 Hz, J = 2.0 Hz, 15), δ 7.86 (d, 1H, J = 8.3 Hz, 18), δ 11.60 (s, 1H, COOH). 13 C NMR (DMSO-d 6): δ 10,58 (1), δ 29,26 (4), δ 31,31 (2), δ 41,20 (3), δ 43,91 (5), δ 49,89 (6), δ 52,28 (7), δ 54,78 (8), δ 62,53 and 62,60 (9, 10), δ 111,03 (11), δ 111,16 (19), δ 125,52 (12), 125,72 (13), 126,12 (14), δ 127,07 (20), δ 127,60 (15), δ 128,60 (16), δ 128,82 (17), δ 130,12 (21), δ 130,39 (22), δ 130,48 (23), δ 130,63 (18), δ 133,30 (24), δ 135,65 (25), δ 136,68 (26), δ 165,62 (27), δ 168,93 (28).

[0106] Step 4 Preparation 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] 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-carbonitrile (0.549 kg) are suspended in chlorobenzene (11.10 kg) and the mixture is then heated to 120° C. Pyridine (0.547 kg) and 50% propylphosphonic anhydride in ethyl acetate (1.650 kg) are added successively. After complete conversion, the mixture is cooled to 20° C. and then hydrolyzed with water. The aqueous phase is removed and the organic phase is washed with aqueous sodium hydroxide solution. The organic phase is concentrated in a vacuum and then purified by chromatography on a silica gel column using a toluene / ethanol mixture (93 / 7) as eluent. The elution solvent is then removed by concentration. The purified product is dissolved in a mixture of toluene and methyl tert-butyl ether (MTBE) (w / w 35 / 65) at 20° C. The product is precipitated by adding the solution to a large excess of cyclohexane. The suspension is then filtered and the cake is then washed with cyclohexane. The product is dried in a temperature gradient from 20° C. to 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide in the form of a white solid with a yield of 75% (purity by HPLC >96.0%).

[0107] 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-carboxylic acid, hydrochloride (1.000 kg) and 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carbonitrile (0.583 kg) are suspended in chlorobenzene (8.0 L) and the mixture is then heated to 120° C. 50% propylphosphonic anhydride in pyridine (0.581 kg) and ethyl acetate (1.753 kg) is slowly added. After complete conversion, the mixture is cooled to 20° C. and then hydrolyzed with water. The aqueous phase is removed and the organic phase is washed with aqueous sodium hydroxide (1N). The organic phase is concentrated in 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide is obtained in 100% theoretical yield and is stored in solution until the next step.

[0108] [ka] 1 H NMR (CD 3OD) : δ 2,04 (s, 3H, 19), δ 2,11 (s, 3H, 18), δ 2,25 (dd, 1H, J=12.8 Hz, J=5.6 Hz, 3’), δ 2,48 (m, 1H, 3), δ 2,60 (m, 1H, 2’), δ 2,80 (dd, 1H, J=16.5 Hz, J=5.8 Hz, 2), δ 2,30-2,70 (m, 4H, 4, 5), δ 3,11 and δ 3,43 (s, 3H, 17), δ 3,59 (s, 3H, 20), δ 3,67 (m, 4H, 6, 7), δ 4,07 (d, 1H, J=17.4 Hz, 8), δ 4,28 (d, 1H, J=17.4 Hz, 8’), δ 5,03 (s, 2H, 24), δ 5,16 (m, 1H, 1), δ 5,38 and 5,65 (s, 1H, 16), δ 6,34, 6,42 and 6,59 (s, 1H, 21), δ 6,75-6,95 (m, 5H, 12, 22, 23), δ 7,00-7,20 (m, 2H, 9, 10), δ 7,20-7,60 (m, 9H, 11, 13, 14, 15, 25, 26, 27)。 13 C NMR (CD 3OD): δ 10,00 and 10,15 (19), δ 11,78 and 12,29 (18), δ 31,22 (2), δ 31,79 (17), δ 33,17 (20), δ 45,03 (1), δ 46,18 (8), δ 54,94 and 55,17 (4, 5), δ58,95 (3), δ67,82 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), δ 115,53 (40), δ 116,21 and 116,30 (23), δ 117,74 and 117,94 (21), 126,00-132,00 (9, 10, 11, 12, 13, 14, 15, 22, 25, 26, 27, 33, 37), δ 131,00-140,00 (28, 29, 31, 32, 35, 38, 41, 43, 44), δ 158,18 and 158,39 (42), δ 168,82 and 169,20 (36), δ170,83 and 171,58 (30).

[0109] 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-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide [ka] Method 1 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (1.000 kg) obtained in step 4 (method 1) is dissolved in ethyl acetate (9.02 kg) at 25° C., then a 33% solution of hydrobromic acid in acetic acid (2.800 kg) is added. The reaction mixture is maintained at 25° C. until the conversion is complete. The mixture is hydrolyzed with water, then the pH is adjusted to 8.5±0.5 by adding 10N sodium hydroxide solution. After the contact time, the aqueous phase is counter extracted with ethyl acetate. The organic phases are combined and concentrated in a vacuum. The product is then purified by chromatography on a silica gel column using a toluene / ethanol mixture (95 / 5) to (93 / 7) as eluent. The elution solvent is then removed by concentration until a residual volume of 3.5 L remains. Thereby, 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide is obtained in a yield of about 90% in solution in toluene (purity by HPLC >98.0%).

[0110] Method 2 Acetyl chloride (77.8 g) is added to ethanol (1.0 L) and after 30 min, 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (100 g) obtained in step 4 (method 1) is added at 20° C. 20% palladium hydroxide on carbon (10 g) is suspended and the mixture is then heated to 55° C. Deprotection is carried out with hydrogen under atmospheric pressure. After complete conversion, the suspension is clarified at 20° C. and the palladium is washed with ethanol (200 mL). The pH of the mother liquor is adjusted to 8 with sodium hydroxide solution. A solvent exchange from ethanol to ethyl acetate is carried out, the organic layer is washed with water (850 mL), concentrated in vacuum and then purified by chromatography on a silica gel column using a toluene / ethyl acetate mixture (95 / 5) to (93 / 7) as eluent. The elution solvent is 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-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide in the form of a pink solid with a yield of 80%.

[0111] Method 3 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-pyrrol-3-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (1.483 kg) obtained in step 4 (method 2) in a mixture of chlorobenzene and ethyl acetate, a 33% solution of hydrobromic acid in acetic acid (4.15 kg) is added at 20° C. The reaction mixture is maintained at 20° C. until the conversion is complete. The mixture is hydrolyzed with water and then with 10N sodium hydroxide solution (amount of about 8.3 kg). After the contact time, the aqueous phase is counter-extracted with ethyl acetate. The organic phases are combined and concentrated in vacuo. The product is then purified by chromatography on a silica gel column using a toluene / ethanol mixture as eluent. The elution solvent is then removed by concentration until a residual volume of 3.5 L is obtained, thereby obtaining 5-{5-chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide in 85% yield (yield for two successive steps) in toluene.

[0112] [ka] 1 H NMR (DMSOd 6) : δ 1.74 and 2.01 (s, 3H, 6), δ 2.01 and 2.36 (s, 3H, 15), δ 1.80-2.50 (m, 4H, 36), δ 2.10-2.40 (m, 2H, 35), δ 2.55 (m, 1H, 33), 2.73 (d, 1H, J=16.3 Hz, J=5.5 Hz, 33'), δ 3.08 and 3.30 (s, 3H, 16), δ 3.55 (s, 3H, 7), 3.40-3.60 (m, 4H, 37), δ 4.00, 4.20 and 4.94 (d, 2H, J=17.5 Hz, 26 / 26'), d 4.80 and 5.03 (m, 1H, 34), δ 5.29, 5.45 and 5.52 (s, 1H, 18), δ 6.30-7.70 (m, 12H, 3, 9, 10, 20, 22, 23, 28, 29, 30, 31), δ 9.31 (d, 1H, J=14.3 Hz, OH)。 13 C NMR (DMSOd 6 ): δ 9.21, 9.50 and 9.69 (6), δ 11.16 and 11.70 (15), δ 30.20 (33), δ 31.01 and 31.48 (16), δ 32.62 (7), δ 42.52 (34), δ 44.28 (26), δ 53.23 and 53.58 (36), δ 55.96 (35), δ 65.92, 66.18 and 66.33 (37), δ 100.19 and 100.32 (2), 109.99 and 110.48 (18), δ 113.82 (1), δ 114.58 (13), δ 115.19 (10), δ 116.85 (3), δ 125.00-140.00 (4, 5, 8, 9, 14, 17, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 31, 32), δ 154.94 and 155.10 (11), δ 165.64 (12), δ 167.38 (25).

Claims

1. Formula (V): 【Chemistry 1】 [In the formula, -Z is a group selected from -COOR and -CN, -R is (C １ ~C ６ ) Alkyl group, allyl group or -CH ２ - Represents an aryl group. A method for producing the compound shown in, Formula (III): 【Chemistry 2】 [In the formula, Z is as defined above.] The compound represented by formula (IV): 【Transformation 3】 [In the formula, W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a p-toluenesulfonate group.] In a compound represented by and a solvent or a mixture of solvents, at a temperature above 70°C, (i) Palladium catalyst, (ii) Depending on the case, phosphine and (iii) base The process includes carrying out the reaction in the presence of, Manufacturing method.

2. The manufacturing method according to claim 1, wherein Z is -COOR and R represents a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a benzyl group, or a para-methoxybenzyl group.

3. The manufacturing method according to claim 1, wherein W represents a bromine atom.

4. The palladium catalyst is palladium(II) acetate (Pd(OAc) ２ The manufacturing method according to any one of claims 1 to 3.

5. The method for producing a product according to any one of claims 1 to 3, wherein the reaction mixture further contains a phosphine selected from tri-tert-butylphosphine, XPhos, CyJohnPhos, and tri(o-tolyl)phosphine, preferably CyJohnPhos.

6. The manufacturing method according to any one of claims 1 to 3, wherein the solvent is an aprotic solvent.

7. The production method according to claim 6, wherein the solvent is selected from dimethyl sulfoxide (DMSO), N-butylpyrrolidinone (NBP), 2-methyltetrahydrofuran, and toluene, preferably dimethyl sulfoxide.

8. A manufacturing method according to any one of claims 1 to 3, wherein the temperature exceeds 90°C, preferably 100°C.

9. The base is a carbonate, preferably Na ２ CO ３ , Cs ２ CO ３ or K ２ CO ３ , even more preferably K ２ CO ３ , and the production method according to any one of claims 1 to 3

10. The method for producing a reaction mixture according to any one of claims 1 to 3, wherein the reaction mixture further contains pivalic acid.

11. Compounds represented by formula (IV) or their addition salts with pharmaceutically acceptable acids: 【Chemistry 4】 [In the formula, W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a p-toluenesulfonate group.] However, equation (I): 【Transformation 5】 The compound represented by or its addition salt with a pharmaceutically acceptable acid is given by formula (II): 【Transformation 6】 A method for producing a compound according to any one of claims 1 to 10, obtained by coupling a compound represented by in a non-protic solvent in the presence of an amine base and a coupling agent.

12. The compound represented by formula (II) is 2-bromo-4-chlorobenzoic acid, and therefore, the following formula (IV-a): 【Transformation 7】 The manufacturing method according to claim 11, wherein the compound represented by is formed.

13. The method for producing a compound (I) according to claim 11 or 12, wherein the compound (I) is in the form of a dihydrochloride salt.

14. The production method according to claim 11 or 12, wherein the coupling agent is selected from propylphosphonic anhydride, cyanuryl chloride, methylpropiolate, tetraethyl orthosilicate, pivalyl chloride, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isobutylchloroformate, thionyl chloride, and oxalyl chloride, preferably propylphosphonic anhydride.

15. The method for producing the product 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]unde-7-ene, N-methylmorpholine, N-ethylmorpholine, pyridine, and 2,6-lutidine.

16. The manufacturing method according to claim 11 or 12, wherein the temperature is within the range of 20 to 50°C.

17. The method for producing the product according to claim 11 or 12, wherein the aprotic solvent is selected from ethyl acetate, methylene chloride, and isopropyl ether, preferably from ethyl acetate.

18. The method for producing a compound represented by formula (IV) as a free base, according to claim 11 or 12.

19. Formula (V): 【Transformation 8】 [In the formula, -Z is a base selected from -COOR and -CN, -R is (C １ ~C ６ ) Alkyl group, allyl group or -CH ２ - Represents an aryl group. Further hydrolysis of the ester or nitrile functional group of the compound shown in formula (VI): 【Chemistry 9】 The compound shown is produced, The compound represented by formula (VI) is further isolated as a zwitterion or in the form of its addition salt with a pharmaceutically acceptable acid, and then, in an aprotic solvent, in the presence of a coupling agent, and optionally in the presence of an amine base, formula (VII): 【Chemistry 10】 When subjected to peptide coupling with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carbonitride, formula (VIII): 【Chemistry 11】 The compound shown is produced, The compound represented by this formula (VII) is deprotected under acidic conditions, and compound A: 【Chemistry 12】 Generate, A method for producing the compound according to any one of claims 1 to 18, comprising isolating the compound and, optionally, further converting it to an addition salt thereof with a pharmaceutically acceptable acid or base.

20. The manufacturing method according to claim 19, wherein Z is -COOR and R represents a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a benzyl group, or a para-methoxybenzyl group.

21. The compound represented by formula (V) 【Chemistry 13】 And, The manufacturing method according to claim 19, further hydrolyzing the compound under basic conditions.

22. The compound represented by formula (V) 【Chemistry 14】 And, The manufacturing method according to claim 19, further hydrolyzing the compound under acidic conditions.

23. The production method according to claim 19, wherein the protic medium used for hydrolysis of compound (V) is methanol, ethanol, isopropanol, DMSO / water, or a mixture of ethanol / water.

24. The manufacturing method according to claim 23, wherein the protic medium used is ethanol / water, and the hydrolysis of compound (V) is carried out at a temperature within 60 to 80°C.

25. The method for producing the compound represented by formula (VI) in the form of an addition salt with 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, according to claim 19.

26. The production method according to claim 19, wherein the coupling agent is selected from thionyl chloride, isobutyl chloroformate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and propylphosphonic anhydride.

27. The production method according to 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 manufacturing method according to claim 19, wherein the coupling agent is N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the solvent is toluene.

29. The manufacturing method according to claim 19, wherein an amine base is used for peptide coupling.

30. The method for producing the product according to claim 29, wherein the amine base used to peptide-couple the compound represented by formula (VI) with the compound represented by formula (VII) is selected from pyridine, N,N-diisopropylethylamine, and triethylamine.

31. The manufacturing method according to claim 19, wherein the coupling agent is propylphosphonic anhydride and the amine base is pyridine.

32. The manufacturing method according to claim 19, wherein the coupling agent is propylphosphonic anhydride, the amine base is pyridine, and the aprotic solvent is selected from the group consisting of acetonitrile, toluene, chlorobenzene, ethyl acetate, butyl acetate, and propyl acetate.

33. The manufacturing method according to claim 32, wherein the peptide coupling is performed at a temperature between 60°C and 135°C, preferably within the range of 110°C and 135°C, and more preferably at 120°C.

34. The method for producing the compound represented by formula (VIII) according to claim 19, wherein the deprotection is carried out in the presence of hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, a mixture of 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.

35. The method for producing a compound represented by formula (VII) according to claim 34, wherein the solvent used for deprotection is selected from dichloromethane, chlorobenzene, dioxane, and ethyl acetate, and more preferably the solvent is ethyl acetate.

36. The manufacturing method according to claim 34 or 35, wherein the temperature is maintained below 40°C.

37. The production method according to claim 19, wherein the deprotection of the compound represented by formula (VIII) is carried out via a hydrogenation reaction under acidic conditions in the presence of a catalyst.

38. Palladium catalyst, carbon-supported Pd(OH) ２ or carbon-supported palladium, The manufacturing method according to claim 37, wherein the hydrogenation reaction is carried out in hydrochloric acid ethanol at a temperature of 40 to 65°C, preferably 45 to 60°C.

39. Compound A: 【Chemistry 15】 A method for manufacturing, Equation (I): 【Chemistry 16】 The compound represented by or its addition salt with a pharmaceutically acceptable acid is given by formula (II): 【Chemistry 17】 [In the formula, W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a p-toluenesulfonate group.] The compound shown by is subjected to a coupling reaction in an aprotic solvent in the presence of an amine base and a coupling agent at a temperature ranging from 20 to 50°C to form an addition salt of the compound shown by formula (IV) or a pharmaceutically acceptable acid: [Chemistry 18] Generate, The compound represented by formula (IV) is represented by formula (III): 【Chemistry 19】 [In the formula, -Z is a group selected from -COOR and -CN, -R is (C １ ~C ６ ) Alkyl group, allyl group or -CH ２ - Represents an aryl group. In a compound represented by and a solvent or a mixture of solvents, at a temperature above 70°C, (iv) Palladium catalyst; (v) Depending on the circumstances, phosphine and (vi) base The reaction occurs in the presence of equation (V): 【Chemistry 20】 The compound shown is produced, Further hydrolysis of the ester or nitrile functional group of the compound represented by formula (V) in a protic medium yields formula (VI): 【Chemistry 21】 The compound shown is produced, The compound represented by formula (VI) is further isolated as a zwitterion or in the form of its addition salt with a pharmaceutically acceptable acid, and then, in an aprotic solvent, in the presence of a coupling agent, and optionally in the presence of an amine base, formula (VII): 【Chemistry 22】 When subjected to peptide coupling with 4-[4-(benzyloxy)anilino]-1,5-dimethyl-1H-pyrrole-2-carbonitride, formula (VIII): 【Chemistry 23】 The compound shown is produced, The compound represented by this formula (VIII) is deprotected under acidic conditions to obtain compound A: 【Chemistry 24】 Generate, This method is characterized by isolating the compound and, optionally, converting it to an addition salt thereof with a pharmaceutically acceptable acid or base. Manufacturing method.

40. Formula (IV): 【Chemistry 25】 [In the formula, W represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a p-toluenesulfonate group.] The compound represented by or its addition salt with a pharmaceutically acceptable acid.

41. Formula (V): 【Chemistry 26】 [In the formula, -Z is a group selected from -COOR and -CN, -R is (C １ ~C ６ ) Alkyl group, allyl group or -CH ２ - Represents an aryl group, However, (C １ ~C ６ [The condition is that the alkyl group does not represent an ethyl group.] The compound shown by [this symbol].

42. Formula (VIII): 【Chemistry 27】 The compound shown by [this symbol].

43. Formula (VII): 【Chemistry 28】 The compound shown by [this symbol].

44. A method for producing a compound represented by formula (VII) as described in claim 43, Formula (SM1-VIII): 【Chemistry 29】 [In the formula, W' represents a leaving group selected from a halogen atom, a trifluoromethanesulfonate group, a methanesulfonate group, and a p-toluenesulfonate group.] The compound represented by formula (SM2-VIII): 【Transformation 30】 The process includes reacting the compound shown with a palladium-phosphine complex catalyst and a base in a polar aprotic solvent at a temperature within 40 to 85°C. Here, the palladium-phosphine complex catalyst is either readily available or prepared in situ starting from a palladium catalyst and phosphine. Manufacturing method.

45. The manufacturing method according to claim 44, wherein W' represents a bromine atom.

46. The manufacturing method according to claim 44 or 45, wherein the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, and 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran.

47. The manufacturing method according to claim 44 or 45, wherein the palladium-phosphine complex catalyst is selected from tBuXPhosPd G1, tBuXPhosPd G3, BrettPhos G3, tBuXPhosPd(allyl)OTf, and more preferably tBuXPhosPd(allyl)OTf.

48. Palladium-phosphine complex catalyst, Pd ２ dba ３ The manufacturing method according to claim 44 or 45, which is prepared in situ starting from tBuxPhos.

49. The bases are tBuONa, tBuOK, and K. ３ PO ４ and K ２ CO ３ The manufacturing method according to claim 44 or 45, more preferably selected from tBuONa.

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