SI26182A - Process for the preparation of upadacitinib and its crystalline salts - Google Patents

Abstract

The present invention relates to processes for the preparation of upadacitinib and its key intermediates. Additionally, the present invention relates to crystalline salts of upadacitinib and processes for their preparation.

Description

A process for the preparation of upadacitinib and its crystalline salts

Technical field

The present invention relates to processes for the preparation of upadacitinib and its key intermediates. Additionally, the present invention relates to crystalline salts of upadacitinib and processes for their preparation.

State of the art

A compound of formula (I) known as upadacitinib or chemically as (3S,4R)-3-ethyl-4-(3H-imidazo[1,2a]pyrrolo[2,3-e]pyrazin-8-yl)-N -(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide is a Janus kinase inhibitor used to treat rheumatoid arthritis.

The compound of formula (I) was first disclosed in patent application WO 2011/068881 Al. However, the process for its preparation involves the use of toxic and hazardous reagents such as trimethylsilyldiazomethane or diazomethane, which should be avoided when scaled up. Even the processes disclosed in the patent applications WO 2017/066775 Al, WO 2019/016745 Al, CN 109369659 A, WO 2020/043033 A2, CN 111217819 A, WO 2020/202183 Al have some shortcomings, e.g. poor yield in key steps, toxic or hazardous reagents, lengthy work-ups and long reaction times. Consequently, there is a need for an improved process for the preparation of a compound of formula (I) that follows modern standards of chemical reagents, solvents and reaction conditions suitable for industrial production.

Several solid forms of the compound of formula (I) or its salts are known, described in patent applications WO 2017/066775 Al, WO 2020/115212 Al, WO 2020/115213 Al, WO 2020/063939 Al, WO 2020/177645 Al, WO 2020/224633 Al, CZ 33762 Ul. Many of them are thermodynamically unstable/metastable, hygroscopic, require strictly limited water content, or their preparation process has poor purification potential. Thus, there is a need for an improved solid state compound of formula (I) or its salt, which is pharmaceutically acceptable, stable and the process for its preparation is suitable for industrial production.

Summary of the invention (1) A process for preparing a compound of formula (I) or a salt thereof, preferably a crystalline salt thereof,

(I) comprising the following steps:

a) preparation of the compound with formula (V)

ΗΝ (V)

b) conversion of a compound of formula (V) into a compound of formula (I) and

c) optionally converting the compound of formula (I) into its salt, preferably its crystalline salt, whereby:

R is an amine protecting group (PG) or -CO-NH-CH2-CF3, preferably R is an amine protecting group (PG); and

P is an indole protecting group.

(2) The process according to point (1), where the process of step a) for the preparation of the compound of formula (V) comprises the following steps:

al) conversion of a compound of formula (IX) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (VIII)

OH (IX) (Vlil) a2) reduction of the compound with the formula (VIII) in the presence of a reducing reagent and acid to the compound with the formula (VII) by ₂ n

About ®

AH ₃ N (Vlil) (VII) a3) coupling a compound of formula (VI) with a compound of formula (VII) in the presence of a palladium catalyst or precatalyst, a ligand and a base to form a compound of formula (V) or a salt thereof

whereby:

R is an amine protecting group (PG) or -CO-NH-CH2-CF3, preferably R is an amine protecting group (PG);

A is the anion of a strong acid;

P is an indole protecting group; and

X is halogen or pseudohalogen.

(3) The process according to point (1) or point (2), where R is PG and where the process of step a) for the preparation of the compound of formula (Va) comprises the following steps:

al -a) conversion of a compound of formula (IXa) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (Vlila)

a2-a) reduction of the compound with the formula (Vila) in the presence of a reducing reagent and acid to the compound with the formula (Vila)

(Vlila) (Vila) a3-a) coupling a compound of formula (VI) with a compound of formula (Vila) in the presence of a palladium catalyst or precatalyst, a ligand and a base to form a compound of formula (Va) or a salt thereof

PG

(Fairy house) whereby:

PG is an amine protecting group;

A is the anion of a strong acid;

P is an indole protecting group; and X is halogen or pseudohalogen.

(4) The process according to point (1) or point (2), where R is -CO-NH-CH2-CF3 and where the process of step a) for the preparation of the compound of formula (Vb) comprises the following steps:

al-b) conversion of a compound of formula (IXb) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (VHIb)

a2-b) reduction of the compound with the formula (Vlllb) in the presence of a reducing reagent and acid to the compound with the formula (Vllb)

a3-b) coupling a compound of formula (VI) with a compound of formula (Vllb) in the presence of a palladium catalyst or precatalyst, a ligand and a base to form a compound of formula (Vb) or a salt thereof

(Vllb)

whereby:

A is the anion of a strong acid;

P is an indole protecting group; and X is halogen or pseudohalogen.

(5) The process according to any of items (1) to (4), wherein R is PG and wherein the process of step b) for the preparation of the compound of formula (I) comprises the following steps:

bi-a) cyclodehydration and deprotection of the compound with the formula (Va) or its salt to the compound with the formula (IVa) b2-a)

(IVa) b3-a) converts compounds of formula (IVa) into compounds of formula (lila)

(Hla) whereby:

PG is an amine protecting group; P is an indole protecting group; and HA is a strong acid.

(6) The process according to point (1) or point (5), where R is -CO-NH-CH2-CF3 and where the process of step b) for the preparation of the compound of formula (I) comprises the following steps:

bl-b) b2-b) cyclodehydration of the compound with the formula (Vb) or its salt to the compound with the formula (IVb)

(IVb) whereby:

P is an indole protecting group.

(7) The process according to any one of (1) to (6), wherein the amine protecting group (PG) is selected from the group consisting of tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), and benzyl (Bn), preferably carboxybenzyl (Cbz), and the strong acid anion (A) is a strong acid anion selected from the group consisting of hydrochloric acid (HCl), hydrobromic acid (HBr), p-toluenesulfonic acid (pTsOH), trifluoroacetic acid (TFA) and phosphoric acid (H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1), and the protecting group for indole (P) is selected from the group consisting of tert-butoxycarbonyl (Boc) , carboxybenzyl (Cbz), propellant (Ts), mesyl (Ms), pivaloxymethyl (POM) and 2(trimethylsilyl)ethoxymethyl (SEM), preferably tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), propellant (Ts), mesyl ( Ms), more preferably a propellant (Ts) and a halogen or pseudohalogen (X) is selected from the group consisting of Cl, Br, I, triflate (OTf) and this zylate (OTs), preferably Cl or Br, more preferably Br, and the strong acid (HA) is selected from the group consisting of hydrochloric acid (HCl), hydrobromic acid (HBr), p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and phosphoric acid (H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1).

Detailed description of the invention

The abbreviation 2-Me THF refers to 2-methyl tetrahydrofuran.

The abbreviation ACN refers to acetonitrile.

The abbreviation AcOH refers to acetic acid.

The abbreviation BINAP refers to 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene.

The abbreviation Bn refers to benzyl.

The abbreviation Boc refers to tert-butoxycarbonyl.

The abbreviation BrettPhos refers to 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'biphenyl.

The abbreviation BrettPhos Pd G3 refers to [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1 '-biphenyl)]palladium(II) methanesulfonate.

The abbreviation Cbz refers to carboxybenzyl.

The abbreviation CDI refers to carbonyldiimidazole.

The abbreviation CPME refers to cyclopentyl methyl ether.

The abbreviation DBU” refers to 1,8 diazabicyclo[5.4.0]undec-7-ene.

The abbreviation DCM refers to dichloromethane.

The abbreviation DIPEA refers to diisopropylethylamine.

The abbreviation DMF refers to dimethylformamide

The abbreviation EtOH refers to ethanol.

The abbreviation iPrOH refers to isopropanol.

The abbreviation LHMDS refers to lithium bis(trimethylsilyl)amide

The abbreviation MeOH refers to methanol.

The abbreviation MIBK refers to methyl isobutyl ketone.

The abbreviation Ms refers to mezyl.

The abbreviation MTBE refers to tert-butyl methyl ether.

The abbreviation NaH refers to sodium hydride.

The abbreviation NaOtBu refers to sodium tert-butoxide.

The abbreviation nPrOH refers to 1-propanol.

The abbreviation OTf refers to the triflate.

The abbreviation OTs refers to tosylate.

The abbreviation Pd2(dba)3 refers to tris(dibenzylideneacetone)dipalladium(0).

The abbreviation Pd(OAc)2 refers to palladium(II) acetate.

The abbreviation PFPAA refers to pentafluoropropionic anhydride.

The abbreviation POM refers to pivaloxymethyl.

The abbreviation PPTS refers to pyridinium p-toluenesulfonate.

The abbreviation p-TsOH refers to p-toluenesulfonic acid.

The abbreviation RuPhos refers to 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl.

The abbreviation SEM refers to 2-(trimethylsilyl)ethoxymethyl.

The abbreviation tAmOK refers to potassium tert-amylate.

The abbreviation tBuOH refers to tert-butanol.

The abbreviation tBuOK refers to potassium tert-butoxide.

The abbreviation tBuONa refers to sodium tert-butoxide.

The abbreviation tBuBrettPhos Pd G3 refers to [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'triisopropyl-1,1'-biphenyl)-2-(2'-amino-1 ,1'-biphenyl)]palladium(II) methanesulfonate.

The abbreviation TEA refers to triethylamine.

The abbreviation TFA refers to trifluoroacetic acid.

The abbreviation TFAA refers to trifluoroacetic anhydride.

The abbreviation THF refers to tetrahydrofuran.

The abbreviation Ts refers to the prosecutor.

The abbreviation XantPhos refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

The invention relates to a process for the preparation of a compound of formula (I), comprising the following steps:

al -a) conversion of a compound of formula (IXa) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (Vlila)

(IXa)

(Vlila) a2-a) reduction of the compound with the formula (Vlila) in the presence of a reducing reagent and acid to the compound with the formula (Vila)

(Infused)

(Vila) a3-a) coupling a compound of formula (VI) with a compound of formula (Vila) in the presence of a palladium catalyst or precatalyst, Uganda and a base to form a compound of formula (Va) or a salt thereof

bl-a) cyclodehydration and deprotection of the compound of formula (Va) or its salt to the compound of formula (IVa)

reads the compound with the formula (IVa) into the compound with the formula (lila) b2-a)

(IVa) (IHa) b3-a) conversion of the compound with the formula (lila) into the compound with the formula (I)

(I) (Hla) whereby:

PG is an amine protecting group;

A is the anion of a strong acid;

P is an indole protecting group; and X is halogen or pseudohalogen. HA is a strong acid.

The amine protecting group (PG) is selected from the group consisting of tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz) and benzyl (Bn), preferably carboxybenzyl (Cbz).

The strong acid anion (A) is selected from the group consisting of hydrochloric acid (HC1), hydrobromic acid (HBr), p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and phosphoic acid (H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1).

The protecting group for the indole (P) is selected from the group consisting of tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), propellant (Ts), mesyl (Ms), pivaloxymethyl (POM) and 2-(trimethylsilyl)ethoxymethyl (SEM ), preferably tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), sustenance (Ts), mesyl (Ms), more preferably sustenance (Ts).

Halogen or pseudohalogen (X) is selected from the group consisting of Cl, Br, I, triflate (OTf) and tosylate (OTs), preferably Cl or Br, more preferably Br.

The strong acid (HA) is selected from the group consisting of hydrochloric acid (HC1), hydrobromic acid (HBr), p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and phosphoic acid (H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1).

In one embodiment of the invention, in step al-a), a compound of formula (IXa) or a pharmaceutically acceptable salt thereof is converted with nitromethane to a compound of formula (Vlla). The reaction of step al-a) can be carried out in the presence of a coupling reagent and a strong base. A suitable coupling reagent can be selected from the group consisting of, but not limited to, CDI, 1, Γ-thiocarbonyldiimidazole, oxalyl chloride, thionyl chloride, and phosphoryl chloride. Preferably, the coupling reagent is CDI. The strong base may be selected from the group consisting of, but not limited to, DBU, tBuOK, tBuONa, NaOMe, and NaH. A strong DBU base is preferred.

The reaction of step al-a) can be carried out in a suitable organic solvent, which can be, but is not limited to, THF, DCM, DMF, 2-MeTHF and CPME, preferably THF.

In one preferred embodiment of the invention, the reaction of step al-a) is carried out in THF in the presence of CDI and DBU.

Specifically, in certain embodiments of the invention, the coupling reagent is added to a solution or suspension of a compound of formula (IXa) in a solvent and the resulting mixture is stirred. In a certain preferred embodiment of the invention, 0.9 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, more preferably 1.1 equivalents of coupling reagent is added to a solution or suspension of a compound of formula (IXa).

Separately, a strong base is slowly added to a solution of nitromethane in a suitable solvent. Specifically, in certain embodiments of the invention, 2.0 to 4.0 equivalents, preferably 1.5 to 3.0 equivalents, more preferably 1.7 to 2.5 equivalents, most preferably 2.0 equivalents of a strong base is added slowly to a solution of 1 .0 to 3.0 equivalents, preferably 1.3 to 2.0 equivalents, more preferably 1.5 equivalents of nitromethane in a suitable solvent.

In a certain embodiment of the invention, the reaction mixture is cooled to room temperature, the reaction is stopped and the compound of formula (Vlila) is isolated.

In one embodiment of the invention, in step a2-a), the reduction of the compound with the formula (VIla) to the compound with the formula (VIla) can be carried out in the presence of a reducing reagent and an acid. Preferably, the reducing reagent can be a one-electron reducing agent selected from the group consisting of zinc powder, iron powder or stannous chloride, preferably iron powder. The acid may be selected from the group consisting of, but not limited to, ammonium chloride, acetic acid, or aqueous hydrochloric acid. Preferably, the acid is aqueous hydrochloric acid. The reaction of step a2-a) can be carried out in a suitable solvent, which can be, but not limited to, EtOH, MeOH, THF, iPrOH, H2O or a combination thereof, preferably EtOH, MeOH, H2O or a combination thereof, more preferably EtOH or MeOH, most preferably EtOH.

In one preferred embodiment of the invention, the reaction of step a2-a) is carried out in EtOH in the presence of iron powder and aqueous hydrochloric acid.

Specifically, in certain embodiments of the invention, 3.0 to 10.0 equivalents, preferably 4.0 to 8.0 equivalents, more preferably 4.5 to 6.0 equivalents, most preferably 5.0 equivalents of reducing reagent are added to the solution or suspension, containing a mixture of a compound of formula (Vlila) and 1.5 to 4.0 equivalents, preferably 2.0 to 3.0 equivalents, more preferably 2.5 equivalents of acid. In a particular embodiment of the invention, a strong acid is optionally added. In a particular embodiment of the invention, activated carbon is optionally added. In a specific embodiment of the invention, the mixture is filtered, cooled to room temperature and the compound of formula (Vila) is isolated.

In one alternative embodiment of the invention, in step a2-a), in particular where the amine protecting group (PG) is tert-butoxycarbonyl (Boc), the reduction of the compound of formula (VIla) to the compound of formula (VIla) can be carried out in the presence of hydrogen, a catalyst for hydrogenation and acids. The hydrogenation catalyst can be, but is not limited to, Pd/C, sulfided Pt/C, Pt/C and Raney Ni, preferably Pd/C, or sulfided Pt/C, more preferably Pd/C. Suitable acids may include, but are not limited to, ammonium chloride, acetic acid or aqueous hydrochloric acid, preferably acetic acid. The reaction of step a2-a) can be carried out in a suitable solvent, which can be, but is not limited to, EtOH, MeOH, THF, iPrOH, water or a combination thereof.

More specifically, in certain embodiments of the invention, 1.5 to 4.0 equivalents, preferably 2.0 to 3.0 equivalents, more preferably 2.5 equivalents of acid are added to a suspension consisting of a compound of the formula (Vlila) and 4 wt% to 10% by weight, preferably 5% by weight of hydrogenation catalyst in a suitable solvent at room temperature. The resulting mixture is placed in a hydrogen atmosphere from 1.0 bar to 5.0 bar, preferably 3.5 bar. In a particular embodiment of the invention, the reaction mixture is then filtered, concentrated and the compound of formula (Vila) is isolated.

In one embodiment of the invention, in step a3-a), the coupling of the compound with the formula (VI) and the compound with the formula (Vila) into the compound with the formula (Va) or its salt can be carried out under a nitrogen or argon atmosphere in the presence of a palladium catalyst or precatalyst, a ligand and bases. The palladium catalyst or precatalyst can be selected from the group consisting of, but not limited to, Pd(OAc) 2 , BrettPhos Pd G 3 , /BuBrettPhos Pd G 3 , or Pd 2 (dba) 3 . Preferably, the palladium catalyst or precatalyst is Pd(OAc)2 or BrettPhos Pd G3, more preferably Pd(OAc)2. The ligand may be selected from the group consisting of, but not limited to, BrettPhos, XantPhos, /BuBrettPhos, BINAP, and RuPhos, preferably BrettPhos or XantPhos. More preferably, the ligand is BrettPhos. The base may be selected from the group consisting of, but not limited to, K 2 CO 3 , CS 2 CO 3 , NaO/Bu, and LHMDS. Preferably the base is K2CO3 or NaO/Bu, more preferably NaO/Bu. The reaction of step a3-a) can be carried out in a suitable solvent, which can be, but is not limited to, THF, dioxane, toluene, EtOH, nPrOH, tBuOH, MeOH or a combination thereof, preferably THF, tBuOH or toluene, more preferably toluene.

In one preferred embodiment of the invention, the reaction is carried out in toluene in the presence of Pd(OAc)2, BrettPhos and NaO/Bu.

Specifically, in certain embodiments of the invention, a solution or suspension of a compound of formula (VI), 1.0 to 1.5 equivalents, preferably 1.0 to 1.3 equivalents, more preferably 1.1 equivalents of a compound of formula (Vila), palladium catalyst or precatalyst and ligand are degassed and heated in a suitable solvent. Preferably, 0.01 to 0.1 equivalents, more preferably 0.01 to 0.05 equivalents, most preferably 0.02 equivalents of palladium catalyst or precatalyst are used. Preferably 0.02 to 0.2 equivalents, more preferably 0.03 to 0.06 equivalents, most preferably 0.04 equivalents of ligand are used. 3.5 to 5.0 equivalents, preferably 4.0 to 5.0 equivalents, more preferably 4.5 equivalents of base are added portionwise to this mixture (over about 1 hour) and the mixture is stirred. In a certain embodiment of the invention, the reaction mixture is filtered through celite and cooled to room temperature. If desired, add strong acid. In a certain embodiment of the invention, the compound of formula (Va) or its salt is isolated from the mixture.

In one embodiment of the invention, cyclodehydration of the compound of formula (Va) or its salt in the presence of perfluoro anhydride and an organic base can be carried out in step bi-a). Preferably, the perfluoro anhydride can be selected from the group consisting of TFAA and PFPAA, preferably TFAA. The organic base may be selected from the group consisting of, but not limited to, pyridine, TEA, DIPEA, 2-methylpyridine and 2,6-lutidine, preferably pyridine. The subsequent readout can be carried out in the presence of a strong acid selected from the group consisting of, but not limited to, HBr and HI, preferably HBr. The reaction of step bi-a) can be carried out in a suitable organic solvent, which can be, but is not limited to, acetonitrile, dioxane, THF, toluene or a combination thereof, preferably acetonitrile.

In one preferred embodiment of the invention, the reaction of step bi-a) is carried out in acetonitrile in the presence of TFAA and pyridine.

More specifically, in certain embodiments of the invention, 2.0 to 5.0 equivalents, preferably 3.0 to 4.5 equivalents, more preferably 4.0 equivalents of perfluoro anhydride are added at room temperature to a solution or suspension consisting of compound (V) and 1.0 to 4.0 equivalents, preferably 2.0 to 3.5 equivalents, more preferably 3.0 equivalents of the organic base in the solvent. 4.0 to 10.0 equivalents, preferably 4.0 to 7.0 equivalents, more preferably 4.5 equivalents of strong acid and solvent are added at room temperature and the mixture is stirred for about 1 hour to about 5 hours, preferably about 1 hour to 3 hours, preferably Ih. In a specific embodiment of the invention, the reaction is stopped, the compound of formula (IV a) is concentrated and isolated.

In one embodiment of the invention, in step b2-a), the deprotection of the compound of formula (IVa) can be carried out in the presence of an aqueous base. Preferably, the aqueous base can be selected from the group consisting of NaOH and KOH, preferably NaOH. The reaction of step b2-a) can be carried out in a suitable solvent, which can be, but is not limited to, THF, 2-MeTHF, CPME, dioxane, water or a combination thereof, preferably a combination of THF and water.

In one preferred embodiment of the invention, the reaction of step b2-a) is carried out in THF and water in the presence of NaOH. Specifically, in certain embodiments of the invention, 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, more preferably 2.0 equivalents of aqueous base are added to a solution or suspension of compound (IV) in a solvent at room temperature. In a particular embodiment of the invention, the reaction mixture is cooled, the reaction is stopped, the compound of formula (lila) is concentrated and isolated.

In one embodiment of the invention, in step b3-a), the compound of formula (I) or its pharmaceutically acceptable salt can be prepared from the compound of formula (lila) or its salt and 2,2,2-trifluoroethylamine. The process of step b3-a) can be carried out in the presence of a coupling reagent and a base. A suitable coupling reagent can be selected from the group consisting of, but not limited to, CDI, Ι,Γ-thiocarbonyldiimidazole, oxalyl chloride, thionyl chloride, and phosphoryl chloride. Preferably, the coupling reagent is CDI. The base can be selected from the group consisting of, but not limited to, KOH, NaOH, TEA, and DIPEA. Preferably the base is DIPEA. The reaction of step b3-a) can be carried out in a suitable organic solvent, which can be, but is not limited to, THF, DCM, DMF, 2-MeTHF and CPME, preferably THF.

In one preferred embodiment of the invention, the reaction of step b3-a) is carried out in THF in the presence of CDI and DIPEA. Specifically, in certain embodiments of the invention, 0.9 to 1.5 equivalents, preferably 0.9 to 1.2 equivalents, more preferably 1.0 equivalents of coupling reagent is added to a solution or slurry containing 0.9 to 1.5 equivalents, preferably 0.9 to 1.2 equivalents, more preferably 1.0 equivalents of 2,2,2trifluoroethylamine and 2.0 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents, more preferably 2.5 equivalents of base in the solvent . In a certain embodiment of the invention, the reaction mixture is cooled to room temperature, the reaction is stopped and the compound of formula (I) is isolated.

One preferred embodiment of the invention is shown in Scheme 1:

1) TFAA, pridin

2) 33% HBr and AcOH

aq. NaOH

1) CDI

2) H ₂ N ^/ ^CF ₃

Scheme 1

In one embodiment, the invention relates to a process for the preparation of a compound of formula (I), comprising the following steps:

al-b) conversion of a compound of formula (IXb) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (VHIb)

(VII Ib) a2-b) reduction of the compound with the formula (Vlllb) in the presence of a reducing reagent and acid to the compound with the formula (Vllb)

a3-b) coupling a compound of formula (VI) with a compound of formula (Vllb) in the presence of a palladium catalyst or precatalyst, a ligand and a base to form a compound of formula (Vb) or a salt thereof

bl-b) cyclodehydration of the compound of formula (Vb) or its salt into the compound of formula (IVb)

(IVb) O wherein: A is the anion of a strong acid;

P is an indole protecting group; and

X is halogen or pseudohalogen.

The protecting group for the indole (P) is selected from the group consisting of tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), propellant (Ts), mesyl (Ms), pivaloxymethyl (POM) and 2-(trimethylsilyl)ethoxymethyl (SEM ), preferably tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), sustenance (Ts), mesyl (Ms), more preferably sustenance (Ts).

Halogen or pseudohalogen (X) is selected from the group consisting of Cl, Br, I, triflate (OTf) and tosylate (OTs), preferably Cl or Br, more preferably Br.

The strong acid (HA) is selected from the group consisting of hydrochloric acid (HC1), hydrobromic acid (HBr), p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and phosphoic acid (H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1).

In one embodiment of the invention, in step al-b), a compound of formula (IXb) or a pharmaceutically acceptable salt thereof is converted with nitromethane to a compound of formula (VIllb). The reaction of step al-b) can be carried out in the presence of a coupling reagent and a strong base. A suitable coupling reagent can be selected from the group consisting of, but not limited to, CDI, Ι,Γ-thiocarbonyldiimidazole, oxalyl chloride, thionyl chloride, and phosphoryl chloride. Preferably, the coupling reagent is CDI. The strong base may be selected from the group consisting of, but not limited to, DBU, tBuOK, tBuONa, NaOMe, and NaH. A strong DBU base is preferred.

The reaction of step al-b) can be carried out in a suitable organic solvent which can be, but is not limited to, THF, DCM, DMF, 2-MeTHF and CPME, preferably THF.

In one preferred embodiment of the invention, the reaction of step al-b) is carried out in THF in the presence of CDI and DBU. Specifically, in certain embodiments of the invention, the coupling reagent is added to a solution or suspension of a compound of formula (IXb) in a solvent and the resulting mixture is stirred. In a certain preferred embodiment of the invention, 0.9 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, more preferably 1.1 equivalents of coupling reagent is added to a solution or suspension of a compound of formula (IXb).

Separately, a strong base is slowly added to a solution of nitromethane in a suitable solvent. Specifically, in certain embodiments of the invention, 2.0 to 4.0 equivalents, preferably 1.5 to 3.0 equivalents, more preferably 1.7 to 2.5 equivalents, most preferably 2.0 equivalents of a strong base is added slowly to a solution of 1 .0 to 3.0 equivalents, preferably 1.3 to 2.0 equivalents, more preferably 1.5 equivalents of nitromethane in a suitable solvent. In a certain embodiment of the invention, the reaction mixture is cooled to room temperature, the reaction is stopped and the compound of formula (Vlllb) is isolated .

In one embodiment of the invention, in step a2-b), the reduction of the compound of the formula (Vllb) to the compound of the formula (Vllb) can be carried out in the presence of a reducing reagent and an acid. Preferably, the reducing reagent can be a one-electron reducing agent selected from the group consisting of zinc powder, iron powder or stannous chloride, preferably iron powder. The acid may be selected from the group consisting of, but not limited to, ammonium chloride, acetic acid, or aqueous hydrochloric acid. Preferably, the acid is aqueous hydrochloric acid. The reaction of step a2-b) can be carried out in a suitable solvent, which can be, but not limited to, EtOH, MeOH, THF, iPrOH, H2O or a combination thereof, preferably EtOH, MeOH, H2O or a combination thereof, more preferably EtOH or MeOH, the most preferably EtOH.

In one preferred embodiment of the invention, the reaction of step a2-b) is carried out in EtOH in the presence of iron powder and aqueous hydrochloric acid.

Specifically, in certain embodiments of the invention, 3.0 to 10.0 equivalents, preferably 4.0 to 8.0 equivalents, more preferably 4.5 to 6.0 equivalents, most preferably 5.0 equivalents of reducing reagent are added to the solution or suspension, containing a mixture of a compound of formula (VIllb) and 1.5 to 4.0 equivalents, preferably 2.0 to 3.0 equivalents, more preferably 2.5 equivalents of acid. In a particular embodiment of the invention, a strong acid is optionally added. In a particular embodiment of the invention, activated carbon is optionally added. In a certain embodiment of the invention, the mixture is filtered, cooled to room temperature and the compound of formula (Vllb) is isolated.

In one alternative embodiment of the invention, in step a2-b), the reduction of the compound of formula (Vllb) to the compound of formula (Vllb) can be carried out in the presence of hydrogen, a hydrogenation catalyst and an acid. The hydrogenation catalyst can be, but is not limited to, Pd/C, sulfided Pt/C, Pt/C and Raney Ni, preferably Pd/C, or sulfided Pt/C, more preferably Pd/C. Suitable acids may include, but are not limited to, ammonium chloride, acetic acid or aqueous hydrochloric acid, preferably acetic acid. The reaction of step a2-b) can be carried out in a suitable solvent, which can be, but is not limited to, EtOH, MeOH, THF, iPrOH, water or a combination thereof.

More specifically, in certain embodiments of the invention, 1.5 to 4.0 equivalents, preferably 2.0 to 3.0 equivalents, more preferably 2.5 equivalents of acid are added to a suspension consisting of a compound of formula (VIllb) and 4 wt% to 10% by weight, preferably 5% by weight of hydrogenation catalyst in a suitable solvent at room temperature. The resulting mixture is placed in a hydrogen atmosphere from 1.0 bar to 5.0 bar, preferably 3.5 bar. In a particular embodiment of the invention, the reaction mixture is then filtered, concentrated and the compound of formula (VIllb) is isolated.

In one embodiment of the invention, in step a3-b), the coupling of the compound with the formula (VI) and the compound with the formula (Vllb) into the compound with the formula (Vb) or its salt can be carried out under a nitrogen or argon atmosphere in the presence of a palladium catalyst or precatalyst, a ligand and bases. The palladium catalyst or precatalyst can be selected from the group consisting of, but not limited to, Pd(OAc) 2 , BrettPhos Pd G 3 , /BuBrettPhos Pd G 3 , or Pd 2 (dba) 3 . Preferably, the palladium catalyst or precatalyst is Pd(OAc)2 or BrettPhos Pd G3, more preferably Pd(OAc)2. The ligand can be selected from the group consisting of, but not limited to, BrettPhos, XantPhos, ZBuBrettPhos, BINAP, and RuPhos, preferably BrettPhos or XantPhos. More preferably, the ligand is BrettPhos. The base may be selected from the group consisting of, but not limited to, K 2 CO 3 , CS 2 CO 3 , NaO/Bu and LHMDS. Preferably the base is K2CO3 or NaO/Bu, more preferably NaO/Bu. The reaction of step a3-a) can be carried out in a suitable solvent, which can be, but is not limited to, THF, dioxane, toluene, EtOH, nPrOH, tBuOH, MeOH or a combination thereof, preferably THF, tBuOH or toluene, more preferably toluene.

In one preferred embodiment of the invention, the reaction is carried out in toluene in the presence of Pd(OAc)2, BrettPhos and NaO/Bu.

Specifically, in certain embodiments of the invention, a solution or suspension of a compound of formula (VI), 1.0 to 1.5 equivalents, preferably 1.0 to 1.3 equivalents, more preferably 1.1 equivalents of a compound of formula (Vllb), palladium catalyst or precatalyst and ligand are degassed and heated in a suitable solvent. Preferably, 0.01 to 0.1 equivalents, more preferably 0.01 to 0.05 equivalents, most preferably 0.02 equivalents of palladium catalyst or precatalyst are used. Preferably 0.02 to 0.2 equivalents, more preferably 0.03 to 0.06 equivalents, most preferably 0.04 equivalents of ligand are used. 3.5 to 5.0 equivalents, preferably 4.0 to 5.0 equivalents, more preferably 4.5 equivalents of base are added portionwise to this mixture (over about 1 hour) and the mixture is stirred. In a certain embodiment of the invention, the reaction mixture is filtered through celite and cooled to room temperature. If desired, add strong acid. In a certain embodiment of the invention, the compound of formula (Vb) or its salt is isolated from the mixture.

In one embodiment of the invention, cyclodehydration of the compound of formula (Vb) or its salt in the presence of perfluoro anhydride and an organic base can be carried out in step bl-b). Preferably, the perfluoro anhydride can be selected from the group consisting of TFAA and PFPAA, preferably TFAA. The organic base may be selected from the group consisting of, but not limited to, pyridine, TEA, DIPEA, 2-methylpyridine and 2,6-lutidine, preferably pyridine. The subsequent readout can be carried out in the presence of a strong acid selected from the group consisting of, but not limited to, HBr and HI, preferably HBr. The reaction of step bl-b) can be carried out in a suitable organic solvent, which can be, but is not limited to, acetonitrile, dioxane, THF, toluene or a combination thereof, preferably acetonitrile.

In one preferred embodiment of the invention, the reaction of step bl-b) is carried out in acetonitrile in the presence of TFAA and pyridine.

More specifically, in certain embodiments of the invention, 2.0 to 5.0 equivalents, preferably 3.0 to 4.5 equivalents, more preferably 4.0 equivalents of perfluoro anhydride are added at room temperature to a solution or suspension consisting of compound (V) and 1.0 to 4.0 equivalents, preferably 2.0 to 3.5 equivalents, more preferably 3.0 equivalents of the organic base in the solvent. 4.0 to 10.0 equivalents, preferably 4.0 to 7.0 equivalents, more preferably 4.5 equivalents of strong acid and solvent are added at room temperature and the mixture is stirred for about 1 hour to about 5 hours, preferably about 1 hour to 3 hours, preferably lh. In a particular embodiment of the invention, the reaction is stopped, the compound of formula (IVb) is concentrated and isolated.

In one embodiment of the invention, in step b2-b), the deprotection of the compound of formula (IVb) can be carried out in the presence of an aqueous base. Preferably, the aqueous base can be selected from the group consisting of NaOH and KOH, preferably NaOH. The reaction of step b2-b) can be carried out in a suitable solvent, which can be, but is not limited to, THF, 2-MeTHF, CPME, dioxane, water or a combination thereof, preferably a combination of THF and water.

In one preferred embodiment of the invention, the reaction of step b2-b) is carried out in THF and water in the presence of NaOH. Specifically, in certain embodiments of the invention, 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, more preferably 2.0 equivalents of aqueous base are added to a solution or suspension of compound (IV) in a solvent at room temperature. In a certain embodiment of the invention, the reaction mixture is cooled, the reaction is stopped, the compound of formula (I) is concentrated and isolated.

One preferred embodiment of the invention is shown in Scheme 2:

TFAA, pyridine

Scheme 2

One preferred embodiment of the invention is shown in Scheme 3:

Cbz

I

____1)CDI____

2) MeNO ₂ DBU

p-TsOH

Fe, ag. NHJSI

Pd(OAc) ₂ BrettPhos, K ₂ CO ₃

1) TFAA, pyridine.

2) 33% HBr and AcOH

ag. NaOH

1) CDI

2) H ₂ N^CF ₃

Scheme 3

The compound of formula (I) can be converted into its crystalline salts.

The invention additionally relates to crystalline pharmaceutically acceptable salts of compounds of formula (I) and a process for their preparation.

In this context, pharmaceutically acceptable salts refer to salts of compounds of formula (I) where the counterion is, but is not limited to, a range of inorganic and organic acids, preferably hydrochloric acid, hydrobromic acid, phosphoric acid, hydroiodic acid, sulfuric acid, acetic acid, propionic acid, formic acid, caprylic acid, dichloroacetic acid, trifluoroacetic acid, butyric acid, mandelic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, maleic acid, mono-lactic acid, lactic acid, tartaric acid, aspartic acid, citric acid, malonic acid, mono-malic acid, firmic acid, succinic acid, glutamic acid, adipic acid, gluconic acid, methylmalonic acid, stearic acid, palmitic acid, saccharic acid, methanesulfonic acid, ethanesulfonic acid acid, p-toluenesulfonic acid, benzenesulfonic acid, o-hydroxybenzoic acid a acid, p-hydroxybenzoic acid, l-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, (+)-camphor-10 sulfonic acid and naphthalene -2-sulfonic acid, more preferably glutamic acid, sulfuric acid, malonic acid, citric acid, adipic acid, fumamic acid, lactic acid, nicotinic acid, methylmalonic acid, benzoic acid, methanesulfonic acid, gluconic acid, malic acid, even more preferably malonic acid, citric acid, fumamic acid and malic acid, mono-malic acid, most preferably mono-malic acid.

In one embodiment, the invention relates to a process for the preparation of a crystalline salt of a compound of formula (I), comprising the following steps:

cl-a) dissolving or suspending the compound of formula (I) in a solvent, c2-a) combining the reaction mixture obtained in step cl-a) with an acid in solid or liquid form or dissolved or suspended in a solvent, c3-a) adjusting the temperature of the reaction mixture obtained in step c2-a) to the temperature range from 0 °C to the reflux temperature as a suspension or a clear solution to form a salt, c4-a) optionally isolating a crystalline salt of the compound of formula (I).

In one embodiment, the invention relates to a process for the preparation of a crystalline salt of a compound of formula (I), comprising the following steps:

cl-b) dissolving or suspending the compound of formula (I) in a solvent, c2-b) combining the reaction mixture obtained in step cl-a) with an acid in solid or liquid form or dissolved or suspended in a solvent, c3-b) adjusting the temperature of the reaction mixture obtained in step c2-a) to the temperature range from 0 °C to the reflux temperature as a suspension or clear solution to form a salt, c4-b) optionally combining the reaction mixture from C3-a) with an antisolvent c5 -b) optionally isolate the crystalline salt of the compound with formula (I).

Examples

1) CDI

THF, rt, 1 h 2) MeNO ₂ , DBU 10-65 °C, 5 h

CDI (1.286 g, 7.93 mmol, 1.1 eq.) was added to a three-necked flask containing a suspension of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid (2.00 g, 7.21 mmol) in THF (15 mL) and stirred vigorously at room temperature for 1 h. Prepare a solution of nitromethane (0.58 mL, 10.82 mmol, 1.5 equiv) in THF (5 mL) in a separate flask. DBU (2.16 mL, 14.42 mmol, 2.0 equiv) was added dropwise. The reaction mixture containing the activated carboxylic acid is added to the nitromethane mixture. After the addition is complete, the reaction mixture is heated to slight reflux and stirred for 5 hours. After disappearance of starting material, 15 mL of EtOAc and HCl (2 M, 7.5 mL) were added. The aqueous phase was separated and discarded, the organic phase was washed with brine (15 mL) and concentrated to give benzyl (3S,4R)-3-ethyl-4-(2nitroacetyl)pyrrolidine-1-carboxylate, which was used in the next step without further cleaning. 'H NMR (400 MHz, chloroform-tZ) δ 7.33 (s, 5H), 5.57 (s, 2H), 5.02 (s, 2H), 3.81-3.56 (m, 2H), 3.52 3.27 (m, 2H), 2.55 (m, 1H), 1.91 (m, 1H), 1.55 (m, 2H), 0.99 (m, 3H); ¹³ C NMR (101 MHz, chloroform-d) δ 210.2, 155.1, 136.1, 128.9, 127.6, 127.1,84.2, 67.1,56.0,45.5,44.2, 29.9,22.7, 11.6.

Fe, aq. HCl EtOH, rt - reflux, 2 Ti (Vllla-1)

Cbz i

(Vlla-1)

Iron powder (2.21 g, 36.05 mmol, 5.0 equiv) was added to a solution of benzyl (3S,4R)-3-ethyl-4-(2nitroacetyl)pyrrolidine-1-carboxylate (2.54 g, 7 .92 mmol) and aq. HCl (3 M, 6.6 mL) in EtOH (51 mL). After the addition, the mixture is heated to a slight reflux and stirred for 2 hours and filtered while hot. Celite (10 g) was added, the suspension was stirred at reflux for 30 minutes, filtered and the reaction mixture was concentrated. The residue was purified by silica gel chromatography (eluent DCM:MeOH = 9:1) and triturated in heptane to give 2-((3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidin-3-yl)- 2 -oxoethane-1-amine chloride as a pale crystalline solid (1.04 g, 3.17 mmol, 40%). 1 H NMR (400 MHz, DMSO-<76) δ 8.70 (s, 3H), 7.33 ( s, 5H), 5.02 (s, 2H), 3.81-3.56 (m, 4H), 3.52 - 3.27 (m, 2H), 2.55 (m, IH), 1.91 (m, IH), 1.55 (m, 2H) , 0.99 (m, 3H); ¹³ C NMR (101 MHz, DMSO-J) δ 210.2, 155.1, 136.1, 128.9, 127.6, 127.1, 67.1, 56.0, 46.1, 45.2, 45.0, 30.9, 22.7, 11.6.

Example 3

(Vlla-1)

Pd(OAc) _2i BrettPhos, NadjBu toluene, rt -100 °C, 8 h

(Va-1)

To a suspension of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.98 g, 2.78 mmol) and 2-((3R,4S)-1-(( Benzyloxy)carbonyl)-4-ethylpyrrolidin-3-yl)-2-oxoethane-1-aminium chloride (1.00 g, 3.06 mmol, 1.1 equiv) in toluene (35 mL), Pd(OAc) 2 (0.012 g, 0.053 mmol, 0.02 eq.) and BrettPhos (0.06 g, 0.11 mmol, 0.04 eq.) and the reaction mixture was purged with nitrogen. NaO/Bu (1.32 g, 13.8 mmol, 4.5 equiv) was then added, the mixture was heated to 100 °C and stirred for 8 h. After completion, the mixture was cooled to room temperature and aqueous HCI (0.1 M) was added to adjust the pH to 8.0. The aqueous phase is then separated, extracted with toluene (18 mL), the organic phases are combined, washed with brine (18 mL), filtered through celite and concentrated. The residue was then chromatographed on silica gel (EtOAc in hexane - 10% to 50%) to give benzyl (3S,4R)-3-ethyl-4-((5-tosyl-5H-pyrrolo[2,3b]pyrazine). -2-yl)glycyl)pyrrolidine-1-carboxylate as a yellow vapor (0.94 g, 1.67 mmol, 60%). 1 H NMR (400 MHz, DMSO-J6) δ 8.36 (s, 1H), 7.75 (m, 2H), 7.44 (m, 2H), 7.39 (m, IH), 7.33 (m, 5H), 7.26 (m, IH), 6.33 (m, IH), 5.02 (s, 2H), 4.22 ( s, 2H), 3.81-3.56 (m, 2H), 3.52-3.27 (m, 2H), 2.55 (m, IH), 2.43 (s, 3H), 1.91 (m, IH), 1.55 (m, 2H) , 0.99 (m, 3H); ¹³ C NMR (101 MHz, DMSO-cZ) δ 210.2, 156.2,147.8,139.4,155.1,136.1,134.8,130.0,128.9,128.2,127.6,127.1,121.5,120.7,107.0, 67.1, 60.2, 46.1, 56.0 45.3, 45.2, 30.9, 22.7, 21.3 11.6.

Example 4

1) TFAA, pyridine ACN, 75 °C, 2 h

2) 33% HBr and AcOH 1,4-dioxane, rt, 4 h

(IVa-1)

To a solution of benzyl (3S,4R)-3-ethyl-4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)pyrrolidine-lcarboxylate (0.80 g, 1, 43 mmol) in ACN (5 mL), added TFAA (0.80 mL, 5.70 mmol, 4.0 equiv) and pyridine (0.31 mL, 4.38 mmol, 2.7 equiv). The reaction mixture is then heated to 75 °C and stirred for 2 hours. After completion, add water (10 mL) and ethyl acetate (10 mL). The aqueous phase is discarded and the organic phase is concentrated to an oil. The residue was then dissolved in 1,4-dioxane (24 mL) and 33% HBr in acetic acid (2.3 mL, 14.2 mmol, 10.0 equiv.) was added dropwise at room temperature. After 4 hours MTBE (15 mL) was added, the suspension was decanted and the cake was dried in a vacuum desiccator to give 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[l,2- a]pyrrolo[2,3-e]pyrazine bis hydrobromide as an orange solid (0.65 g, 1.14 mmol, 80%). 1H NMR (400 MHz, DMSO-i/6) δ 8.63 (s, 1H), 7.75 (m, 2H), 7.44 (m, 2H), 7.33 (s, 1H), 7.26 (m, 1H), 6.33 (m, IH), 3.21-2.81 (m, 2H), 2.81-2.56 (m, 3H), 2.43 (s, 3H), 2.84-2.59 (m, 2H), 1.87 (m, IH), 1.55 (m , 2H), 0.99 (m, 3H); ¹³ C NMR (101 MHz, DMSO-i/) δ 147.8, 143.0, 139.4, 138.7, 134.8, 130.0, 128.2, 121.5, 120.7, 119.9, 107.0, 55.2, 51.7, 54.6, 44.3, 37.0, 11.9, 22.8. .

Example 5

20% NaOH THF, 16 h, 60 °C

(IVa-1) ( ^|lla )

To a suspension of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine bis hydrobromide (0.5 g 0 .88 mmol) in THF (5 mL), add 20% NaOH (0.7 mL) and heat the mixture to 60 °C. After 16 hours, the mixture was cooled to room temperature and aqueous HC1 (0.1 M) was added to adjust the pH to 12.0. After the addition, the mixture was concentrated to remove most of the THF and the suspension was stirred at room temperature for 1 hour. The suspension is then decanted, the cake is washed 3x with water (1 mL) and dried in a vacuum drier to obtain 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2a]pyrrole [2 ,3-e]pyrazine as a yellow solid (0.19 g, 0.74 mmol, 85%). 1 H NMR (400 MHz, DMSOd 6 ) δ 11.12 (s, 1H), 8.61 (s, 1H), 7.92 (s, IH), 7.33 (s, IH), 7.33 (s, IH), 3.21-2.81 (m, 2H), 2.81-2.56 (m, 3H), 2.84-2.59, 1.87 (m, IH), 1.55 (m, 2H), 0.99 (m, 3H); ¹³ C NMR (101 MHz, DMSO-J) δ 144.9, 143.0, 138.7, 134.8, 126.1, 119.9, 118.1, 100.2, 55.2, 51.7, 44.3, 37.0, 22.8, 11.9.

Example 6

(la)

1) CDI, Et ₃ N THF, 3 h, 65 °C 2) NH ₂ CH ₂ CF ₃ h, 65 °C

To a solution of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.15 g, 0.78 mmol) in THF (5 mL) was added triethylamine (0.44 mL, 3.13 mmol, 4 equiv.), followed by CDI (0.13 g, 0.78 mmol, 1 equiv.) at room temperature. The resulting mixture is heated to 65 °C and stirred for 3 hours. Then 2,2,2-trifluoroethan-1-amine (0.09 ml, 1.18 mmol, 1.5 equiv.) was added and the mixture was stirred for 3 h at 65 °C. After completion, the reaction mixture was cooled to room temperature and ethyl acetate (5 mL) and aqueous NaHCCl solution (saturated, 5 mL) were added. The aqueous phase was discarded, the organics were concentrated under reduced pressure and the inuparin was purified by silica gel chromatography (eluent EtOAc in hexane gradient 0-10%) to give upadacitinib as a yellow solid (0.11 g, 0.39 mmol, 80%). 1H NMR (400 MHz, DMSO-J6) δ 12.24 (s, 1H), 8.54 (s, 1H), 7.47-7.35 (m, 2H), 7.02-6.85 (m, 2H), 4.31 (m, 1H) , 3.91-3.68 (m, 4H), 3.65 (m, IH), 3.23 (m, IH), 2.59-2.48 (m, IH), 1.06 (m, IH), 0.84-0.70 (m, IH), 0.60 (m, 3H); ¹³ C NMR (101 MHz, DMSO-J) δ 155.7, 144.9, 143.0, 138.7, 134.8, 126.1, 124.2, 119.9, 100.2, 56.7, 54.6, 41.8, 41.1, 33.8, 22.4, 11.9.

Example 7

(I) zones. H ₂ SO ₄ acetone, 0 °C

(la)

Upadacitinib (50 mg, 0.131 mmol) was dissolved in acetone (1 mL). Cool the solution to 0 °C. A concentrated aqueous solution of H2SO4 (18 M, 0.041 mL) was dissolved in acetone (1 mL) at 0 °C. This solution was added to the upadacitinib solution. The precipitate was collected to give upadacitinib hemisulfate (25 mg, 0.052 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 8.63 (s, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 6, 02 (s, IH), 3.87-3.62 (m, 3H), 3.52-3.27 (m, 2H), 2.97 (m, IH), 2.07 (m, IH) , 1.55 (m, 2H), 0.99 (m, 3H); ¹³ C NMR (101 MHz, DMSO-d) δ 155.7, 144.9, 143.0, 138.7, 134.8, 126.1, 124.2, 119.9, 118.1, 100.2, 56.7, 54.6, 41.8, 41.1, 33.8, 22.4, 11.9.

Claims (7)

Patent claims 1. Process for the preparation of a compound of formula (I) or its salt, preferably its crystalline salt, (I) comprising the following steps: a) preparation of the compound with formula (V) (V) b) conversion of a compound of formula (V) into a compound of formula (I) and c) optionally converting the compound of formula (I) into its salt, preferably its crystalline salt, whereby: R is an amine protecting group (PG) or -CO-NH-CH2-CF3, preferably R is an amine protecting group (PG); and P is an indole protecting group. 2. The process according to claim 1, where the process of step a) for the preparation of the compound of formula (V) comprises the following steps: al) conversion of a compound of formula (IX) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (VIII) a2) reduction of the compound with formula (VIII) in the presence of a reducing reagent and acid to the compound with formula (VII) R ι 0 ₂ N (Vlil) R i (VII) a3) coupling a compound of formula (VI) with a compound of formula (VII) in the presence of a palladium catalyst or precatalyst, Uganda and a base to form a compound of formula (V) or a salt thereof R i (Fairy) (V) whereby: R is an amine protecting group (PG) or -CO-NH-CH2-CF3, preferably R is an amine protecting group (PG); A is the anion of a strong acid; P is an indole protecting group; and X is halogen or pseudohalogen. 3. The process according to claim 1 or claim 2, where R is PG and where the process of step a) for the preparation of the compound of formula (Va) comprises the following steps: al-a) conversion of a compound of formula (IXa) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (Vlila) PG 1 (IXa) PG 1 O ₂ N (Vlila) a2-a) reduction of the compound with the formula (Vlila) in the presence of a reducing reagent and acid to the compound with the formula (Vila) (Infused) (Vila) a3-a) coupling a compound of formula (VI) with a compound of formula (Vila) in the presence of a palladium catalyst or precatalyst, a ligand and a base to form a compound of formula (Va) or a salt thereof PG (Fairy) whereby: PG is an amine protecting group; A is the anion of a strong acid; P is an indole protecting group; and X is halogen or pseudohalogen. 4. The process according to claim 1 or claim 2, where R is -CO-NH-CH2-CF3 and where the process of step a) for the preparation of the compound of formula (Vb) comprises the following steps: al-b) conversion of a compound of formula (IXb) with nitromethane in the presence of a coupling reagent and a strong base into a compound of formula (VHIb) a2-b) reduction of the compound of the formula (VHIb) in the presence of a reducing reagent and acid to the compound of the formula (Vllb) (VHIb) ( ^Vllb ) a3-b) coupling a compound of formula (VI) with a compound of formula (Vllb) in the presence of a palladium catalyst or precatalyst, Uganda and a base to form a compound of formula (Vb) or a salt thereof whereby: A is the anion of a strong acid; P is an indole protecting group; and X is halogen or pseudohalogen. 5. The process according to any one of claims 1 to 4, wherein R is PG and wherein the process of step b) for the preparation of the compound of formula (I) comprises the following steps: bi-a) cyclodehydration and deprotection of the compound of formula (Va) or its salt to the compound of formula (IVa) b3-a) conversion of the compound with the formula (lila) into the compound with the formula (I) (l) (Hla) whereby: PG is an amine protecting group; P is an indole protecting group; and HA is a strong acid. 6. The process according to claim 1 or claim 4, where R is -CO-NH-CH2-CF3 and where the process of step b) for the preparation of the compound of formula (I) comprises the following steps: bl-b) cyclodehydration of the compound of formula (Vb) or its salt into the compound of formula (IVb) (Vb) (IVb) b2-b) deprotection of the compound with the formula (IVb) into the compound with the formula (I) (i) (IVb) whereby: P is an indole protecting group. 7. The method according to any one of claims 1 to 6, characterized by: - the protecting group for the amine (PG) is selected from the group consisting of tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz) and benzyl (Bn), preferably carboxybenzyl (Cbz), and - strong acid anion (A) is a strong acid anion selected from the group consisting of hydrochloric acid (HC1), hydrobromic acid (HBr), p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and phosphoric acid ( H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1), and - the protecting group for indole (P) is selected from the group consisting of tert-butoxycarbonyl (Boc), carboxybenzyl ( Cbz), Sustainer (Ts), Mesyl (Ms), Pivaloxymethyl (POM) and 2-(trimethylsilyl)ethoxymethyl (SEM), preferably tert-butoxycarbonyl (Boc), Carboxybenzyl (Cbz), Sustainer (Ts), Mesyl (Ms) , sued more preferably (Ts) and - halogen or pseudohalogen (X) is selected from the group consisting of Cl, Br, I, triflate (OTf) and tosylate (OTs), preferably Cl or Br, more preferably Br, and - the strong acid (HA) is selected from the group consisting of hydrochloric acid (HC1), hydrobromic acid (HBr), p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and phosphoic acid (H3PO4), preferably hydrochloric acid (HC1), hydrobromic acid (HBr), more preferably hydrochloric acid (HC1).