Process for the preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 s,3 r)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1 h-isoquinolin-2-yl]ethanone monohydrate

Abstract

Process for the preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3- (hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethanone monohydrate

Description

[0001] Process for the preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 S,3 / ?)-3- (hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro-1 H-isoquinolin-2- yljethanone monohydrate

[0002] The present invention provides a process for the preparation of 2-(3,5-dichloro-1-methyl- indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro- 1 / 7-isoquinolin-2-yl]ethanone monohydrate, as well as key intermediates thereof.

[0003] Background

[0004] 2-(3,5-dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 - methylethyl)-1-methyl-3,4-dihydro-1 / 7-isoquinolin-2-yl]ethanone is described in international patent application WO 2021 / 001288 as a Positive Allosteric Modulator (PAM) of D1 receptor. Having a high selectivity towards the D1 receptor, 2-(3,5-dichloro-1 -methyl-indazol-4-yl)-1- [(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro-1 H-isoquinolin-2- yl]ethanone (I) is considered to be a therapeutic advancement to the symptomatic treatment of Parkinson’s Disease and is currently in clinical development.

[0005] Example 2 of WO 2021 / 001288 describes a process forthe synthesis of 2-(3,5-dichloro-1-methyl- indazol-4-yl)-1-[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro- 1 H-isoquinolin-2-yl]ethanone, and in particular its monohydrate form, represented herein by formula (I),

[0006] However, due inter alia, to the number of synthetic intermediates and associated reaction steps, including several protections and deprotections of amino groups, low overall yield due to the number of steps, but also to separations by chromatography, low diastereoselectivity of reactions involving tetrahydroisoquinoline moiety bearing both the hydroxymethyl and the methyl in trans configuration, scaling-up of this process on an industrial scale is not possible. As compound of formula (I) progresses into clinical development, there is therefore a need to develop an alternative process of synthesis of compound of formula (I) which is cost-effective, can be performed on industrial scale, but equally is environmentally friendly.

[0007] Summary of the invention

[0008] The present invention provides an improved process of synthesis of 2-(3,5-dichloro-1-methyl- indazol-4-yl)-1-[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro- 1 H-isoquinolin-2-yl]ethanone monohydrate, represented by formula (I), which process is summarized in Scheme 1 below.

[0009] Scheme 1

[0010] The present invention also provides synthetic intermediates which are useful for the synthesis of 2-(3,5-dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl- ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I).

[0011] In one embodiment the present invention provides (4R)-4-[(2-chlorophenyl)methyl]-3-(1- ethoxyethyl)oxazolidi n-2-one (I I b)

[0012] In another embodiment, the present invention provides (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a- tetrahydrooxazolo[3,4-b]isoquinolin-3-one (lid)

[0013] In yet another embodiment, the present invention provides intermediate (5S,10aR)-9-(1-hydroxy- 1-methyl-ethyl)-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He)

[0014] Detailed description of the invention

[0015] The improved process of synthesis of compound of formula (I) according to the present invention, as set out in Scheme 1 above, is further detailed here below.

[0016] Step (i) is performed by reacting (4R)-[(2-chlorophenyl)methyl]-2-oxazolidinone (Ila) with acetaldehyde diethyl acetal, in the presence of an acid. Ideally, the acid is used in catalytic amount and is methanesulfonic acid. The acetaldehyde diethyl acetal is preferably used in large excess, as the reaction solvent, and the reaction is performed at room temperature.

[0017] Compound (Ila) can be prepared from commercially available (2R)-2-amino-3-(2- chlorophenyl)propan-1-ol (CAS n° 103616-90-6).

[0018] Acetaldehyde diethyl acetal is commercially available (CAS n°105-57-7).

[0019] (4R)-4-[(2-chlorophenyl)methyl]-3-(1-ethoxyethyl)oxazolidin-2-one (lib) obtained as a result of this step is used without further purification in the following step 2.

[0020] Step (ii) is a diastereoselective Pictet-Spengler cyclization of compound of formula (lib). The Pictet-Spengler reaction requires the addition of a Lewis acid. Several conditions have been described in the Prior Art, including in international patent application WO 2020 / 257043. Preferred Lewis acid according to the present invention are either titanium (IV) chloride or zirconium (IV) chloride. In particular, titanium (IV) chloride allows to obtain (5S,10aR)-9-chloro-5-methyl- 1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He) with a diastereoisomeric excess of at least 94%. Once the cyclization is performed, the leaving group eliminated from the reaction media is ethanol which has low environmental impact.

[0021] Compound (He) can be isolated by crystallization or alternatively be used, without further isolation or purification, directly in step (iii).

[0022] Step (iii) is performed by applying a Heck transformation to compound of formula (lie) obtained as a result of step 2, followed by hydrolysis in the presence of a strong acid like hydrogen chloride.

[0023] The Heck reaction according to the present invention is performed by reacting compound of formula (lie) with an excess of ethylene glycol monovinyl ether in the presence of a Palladium catalyst, a ligand and a non-nucleophilic base, at high temperature, to afford (5S,10aR)-9-[1-(2- hyrdoxyethoxy)vinyl]-5-methyl-1 , 5, 10, 10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (Hc-a), which is not isolated,

[0024] (llc-a)

[0025] Examples of Palladium catalyst are Palladium acetate (II) or bis(acetonitrile) chloropalladium (II). Examples of ligands are 1 ,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate), 1 ,3- Bis(diphenylphosphino)propane, and 1 ,3-Bis(di-i-propylphosphino)propane. Examples of base are potassium carbonate, sodium carbonate and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0026] Reaction is typically performed in ethylene glycol monovinyl ether or a mixture thereof with ethylene glycol, at a temperature greater than 100°C.

[0027] Step (iv) & (v) involve an hydrolysis step performed after completion of the Heck reaction by adding an excess of aqueous hydrogen chloride to the reaction mixture to afford (5S,10aR)-9- acetyl-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (lid), which crystallises and is then isolated by filtration. Alternatively, the reaction mixture can be poured into an aqueous solution of hydrogen chloride.

[0028] Compound of formula (lid) has a level of purity of at least 97%.

[0029] This Heck transformation followed by the hydrolysis is quite particular to the extent that it allows a one-pot transformation of an aryl chloride into an aryl ketone.

[0030] The total yield of Steps (i)-(v) is of about 78%.

[0031] Step (vi) involves a Grignard reaction of compound of formula (lid) obtained as a result of step (v). The reaction is typically performed with methyl magnesium chloride, in dichloromethane to afford (5S,10aR)-9-(1 -hydroxy-1 -methyl-ethyl)-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4- b]isoquinolin-3-one (He). Reaction temperature is typically comprised between about -5°C° and about 10°C, preferably between about 0°C and about 5°C.

[0032] Step (vii) involves hydrolysis of the oxazolidinone ring of compound of formula (He) which is performed in a solvent, in the presence of a strong base, to afford (1 S,3R)-1 ,2,3,4-Tetrahydro- a5,a5,1-trimethyl-3,5-isoquinolinedimethanol (Ilf). The strong base is typically an alkali hydroxide like potassium hydroxide, and the solvent is preferably a mixture of ethanol and water. Preferred reaction temperature is about 70°C to about 80°C.

[0033] Compound (Ilf) is crystallized and isolated by filtration. Purity of compound (Ilf) is at least 97%.

[0034] The total yield of Steps (vi) and (vii) is about 77%. The total yield of Steps (i)-(vii) is about 55% to about 65%, preferably about 60%. A process of synthesis of the hydrochloride salt of compound (Ilf) is described in Example 2 of international patent application WO 2021 / 001288. It involves 9 main steps starting from the bromo analog of compound of formula (Ila) and includes successive protection and deprotection steps. The total yield of said process is about 5%. Therefore, the process of synthesis of (Ilf) according to the present invention is considerably more efficient and consequently more cost-effective.

[0035] Step (viii) is a coupling reaction between compound of formula (Ilf) and 2-(3,5-dichloro-1-methyl- indazol-4-yl)acetic acid (III)

[0036] A coupling reaction between compound (Ilf) and compound (III) has been disclosed in Example 2.8 of international patent application WO 2021 / 001288.

[0037] Step (viii) of the present process uses different conditions, namely a different base, i.e. triethylamine, and a different coupling agent, A / ,A / ,A / ',A / '-tetramethylchloroformamidinium hexafluorophosphate. Reaction is performed in the presence of water.

[0038] 2-(3,5-dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl- ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) is obtained as a result of the coupling reaction. In step (ix), it is crystallized by further addition of water and isolated, with a yield of at least about 90%.

[0039] In step (x), compound of formula (I) obtained as a result of step (ix) is recrystallized to enhance purity. The crystallization is typically performed by dissolving compound of formula (I) in dimethyl sulfoxide. The solution is optionally filtered on active charcoal before being heated at a temperature comprised between 85°C and 90°C. Water is progressively added and temperature maintained above about 85°C. After the water is added, the temperature is cooled at about 85°C and the mixture seeded with compound of formula (I) to initiate the crystallization. The mixture is maintained at about 85°C before being progressively cooled down to room temperature to afford the desired crystalline monohydrate form of compound of formula (I).

[0040] Yield forthe coupling and recrystallization steps disclosed in WO 2021 / 001288 is about 64%. The yield for steps (viii)-(x) for the process according to the present invention is about 80% which represents a significant improvement.

[0041] In one embodiment, the present invention therefore provides a process for the preparation of 2- (3,5-dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)- 1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) comprising: (i) reacting (4R)-[(2-chlorophenyl)methyl]-2-oxazolidinone (Ila) with acetaldehyde diethyl acetal, used as a solvent, in the presence of an acid to afford (4R)-4-[(2-chlorophenyl)methyl]-3-(1-ethoxyethyl)oxazolidin-2-one (lib),

[0042] (ii) Pictet-Spengler cyclisation of (4R)-4-[(2-chlorophenyl)methyl]-3-(1 - ethoxyethyl)oxazolidin-2-one (lib) in the presence of a Lewis acid to afford

[0043] (5S,10aR)-9-chloro-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He),

[0044] (iii) Heck reaction of compound of formula (lie) in the presence of ethylene glycol monovinyl ether, palladium catalyst, a ligand and a non-nucleophilic base to afford (5S,10aR)-9-[1-(2-hydroxyethoxy)vinyl]-5-methyl-1 , 5, 10, 10a- tetrahydrooxazolo[3,4-b]isoquinolin-3-one (llc-a),

[0045] (llc-a)

[0046] (iv) hydrolysing compound (llc-a) by pouring the reaction mixture obtained as a result of step (iii) into an aqueous solution of a strong acid, to afford (5S,10aR)-9-acetyl-5- methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (lid),

[0047] (v) isolating (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4- b]isoquinolin-3-one (lid), (vi) Grignard reaction of compound of formula (lid) in the presence of methyl magnesium chloride to afford (5S,10aR)-9-(1 -hydroxy-1 -methyl-ethyl)-5-methyl- 1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He)

[0048] (vii) Hydrolysing compound of formula (lie) by addition of an aqueous solution of a strong base to afford (1S,3R)-1 ,2,3,4-tetrahydro-a5,a5,1-trimethyl-3,5- isoquinolinedimethanol (Ilf)

[0049] (viii) Coupling compound (Ilf) with 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (III) in the presence of a base and A / ,A / ,A / ',A / '-tetramethylchloroformamidinium hexafluorophosphate, and water, to afford crude 2-(3,5-dichloro-1-methyl-indazol-4-yl)- 1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3,4-dihydro-1 H- isoquinolin-2-yl]ethanone monohydrate (I), (ix) Crystallizing crude 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)- 5-(1 -hydroxy-1 -methyl-ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) by adding more water; and

[0050] (x) Optionally recrystallizing 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 S,3R)-3- (hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3,4-dihydro-1 H-isoquinolin-2- yl]ethanone (I) in a mixture of dimethyl sulfoxide and water.

[0051] A process of preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (III) is disclosed in Example 1 of international patent application WO 2021 / 001288.

[0052] The present invention provides an alternative process for the synthesis of intermediate 2-(3,5- dichloro-1-methyl-indazol-4-yl)acetic acid (III), which comprises the following steps:

[0053] (a) A / -methylation of 5-nitro-1 / 7-indazole (Illa) with dimethyl carbonate in the presence of a catalytic amount of 1 ,4-diazobicyclo[2.2.2]octane to afford a mixture of 1-methyl-5-nitro- indazole (lllb) and 2-methyl-5-nitro-indazole (lllc)

[0054] (b) Precipitation of compound of formula (lllb), by addition of water and filtration to afford compound of formula (lllb),

[0055] (c) Reacting compound of formula (lllb) with t-butyl chloroacetate in the presence of a base, followed by addition of a mild acid, to afford tert-butyl 2-(1-methyl-5-nitro-indazol- 4-y I) acetate (Hid),

[0056] (d) Hydrogenation of the nitro group of Intermediate (Hid), with hydrogen on platinum on carbon (Pt / C) to afford tert-butyl- 2-(5-amino-1-methyl-indazol-4-yl)acetate (Hie)

[0057] (e) Formation of the hydrochloride salt of (llle-a) by treatment of intermediate (Hie) with anhydrous hydrogen chloride to afford, after isolation, 4-(2-tert-butoxy-2-oxo-ethyl)-1- methyl-indazol-5-yl]ammonium chloride (llle-a)

[0058] (f) Concomitant Sandmeyer reaction under continuous flow and ester cleavage with an aqueous solution of hydrochloric of intermediate (llle-a) to afford 2-(5-chloro-1-methyl- indazol-4-yl)acetic acid (II If), and

[0059] (g) Chlorination of intermediate (lllf) with 1 ,3-dichloro-5,5-dimethylhydantoin to afford intermediate of formula (III).

[0060] Step (a) is typically performed in dimethyl sulfoxide at a temperature of about 90°C.

[0061] Step (b) allows to obtain compound of formula (lllb) with a purity greater than about 99%.

[0062] In step (c), the base is preferably sodium fe / Y-butoxide or potassium fe / Y-butoxide. Compound of formula (Hid) is precipitated following addition of an aqueous solution of mild acid to the reaction mixture at a controlled neutral pH, followed by further addition of water and cooling at about 0°C. Examples of mild acids are citric acid or acetic acid as they are milder agent than standard hydrochloric acid used.

[0063] In step (d), the pressure of hydrogen is comprised between about 1 and 3 bar.

[0064] In step (e), the formation of the hydrochloric salt is preferably performed in the presence of a solution of hydrochloric acid in isopropyl alcohol, as a source of anhydrous hydrogen chloride.

[0065] In step (f), preferred continuous flow parameters are those described in Example 1 , step (f). In a particular embodiment the present invention provides a process of preparation of 2-(3,5- dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 - methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) as described in steps (i)-(x) above, wherein intermediate (III) is prepared according to the process described in steps (a)-(g) above.

[0066] In a further particular embodiment, the present invention provides 2-(3,5-dichloro-1 -methyl- indazol-4-yl)-1-[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro- 1 H-isoquinolin-2-yl]ethanone monohydrate (I) directly obtained by the process according to the present invention. Preparation protocols

[0067] The following preparations of intermediates and compound of formula (I) are set forth by way of illustration and should not be construed as limiting the invention. It will also be understood that modifications to these preparations can be made by the person skilled in the art.

[0068] Abbreviations / recurrent reagents

[0069] IUPAC names have been determined using Biovia Draw 24.1 .

[0070] Analytical methods

[0071] Acidic elution conditions method A1

[0072] UPLC analyses are performed using a Waters Acquity H-class QSM system equipped with a Waters Acquity PDA Detector (detection from 195 to 350 nm) and a Waters Acquity QDA Detector (detection from m / z 70 to 1100, positive mode and negative mode). The separation is carried out with an Acquity CSH C18 column (2.1 mm x 50 mm, 1 .7 pm) with a column temperature of 50 °C using 0.1 % TFA in water-acetonitrile 99:1 (Phase A) / 0.1 % TFA in acetonitrile (Phase B), an injection volume of 0.5 pL and a flow of 0.8 mL / min. Acidic elution conditions method A2

[0073] HPLC analyses are performed using a Waters Alliance 2690 / 5 system equipped with a Waters PDA Detector (detection from 190 to 400 nm). The separation is carried out with a Sunfire C18 column (4.6 mm x 50 mm, 3.5 pm) with a column temperature of 45 °C using water (Phase A) / acetonitrile (Phase B)Z 0.1 % H3PO4 in water (Phase C), an injection volume of 0.5-1 .0 pL and Acidic elution conditions method A3

[0074] HPLC analyses are performed using a Waters Acquity H-class system equipped with a UV detector (detector setting: single wavelength at 220 nm). The separation is carried out with a Phenomenex Kinetex® Biphenyl (100x2.1 mm, 1.7 pm) with a column temperature of 50 °C using 0.01% formic acid in water (Phase A) / 0.01 % formic acid in acetonitrile (Phase B), an injection volume of 2.0 pL and a flow of 0.5 mL / min.

[0075] Basic elution conditions method B1

[0076] UPLC analyses are performed using a Waters Acquity H-class QSM system equipped with a Waters Acquity PDA Detector (detection from 195 to 350 nm) and a Waters Acquity QDA Detector (detection from m / z 70 to 1100, positive mode and negative mode). The separation is carried out with an Acquity BEH C18 column (2.1 mm x 50 mm, 1 .7 pm) with a column temperature of 55°C using 0.1 % ammonium formate buffer in water-acetonitrile (99:1) (Phase A) / acetonitrile (Phase B), an injection volume of 0.2-0.5 pL and a flow of 0.4 mL / min.

[0077] Basic elution conditions method B2 HPLC analyses are performed using a Waters Alliance 2690 / 5 system equipped with a Waters 2998 PDA Detector (detection from 190 to 400 nm). The separation is carried out with an XBridge C18 column (3.0 mm x 50 mm, 3.5 pm) with a column temperature of 50 °C using water (Phase A) / acetonitrile (Phase B) / 0.1 % ammonium formate buffer (Phase C), an injection volume of 0.5- 1 .0 pL and a flow of 3 mL / min. All reactions involving air or moisture-sensitive reagents were performed under a nitrogen or argon atmosphere using dried solvents and glassware. Commercial solvents and reagents were generally used without further purification, including anhydrous solvents when appropriate (generally Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). In general reactions were followed by thin layer chromatography, HPLC or mass spectrometry analyses.

[0078] Crude materials could be purified by normal phase chromatography, (acidic or basic) reverse phase chromatography, chiral separation or recrystallization.

[0079] Products were generally dried under vacuum before final analyses and submission to biological testing.

[0080] All NMR spectra were obtained at 250 MHz, 300 MHz, 400 MHz or 500 MHz.

[0081] The compounds were studied in DMSO-cfe, CDCh or MeOH-cfe solution at a probe temperature of 300 K and at a concentration of 10 mg / mL. The instrument is locked on the deuterium signal of DMSO-cfe, CDCh or CD3OD. Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) taken as internal standard.

[0082] I. Preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (III)

[0083] Step (a): N-methylation

[0084] 1 10 l% DABCO

[0085] In a 10 L reactor, charge 885 g of 1 H-5-nitro-indazole (Illa) (1 eq, 5.425 mol) and 3.6 L of dimethyl sulfoxide (DMSO, 4 mL / g). Start stirring. Then add 1.35L dimethyl carbonate (1.439 kg, 1.5ml / g, 15.98 mol, ca 3eq) and 62.0 g of 1 ,4-diazobicyclo[2.2.2]octane (0.553 mol, 10mol%, DABCO). Heat the reaction mixture to 90°C for 15-18hours. Sample the reaction mixture to confirm complete conversion of the starting material.

[0086] Step (b) isolation of 1-methyl-5-nitro-indazole (I II b):

[0087] Cool to 70°C. Once at 70°C, add 900 mL of water (1 mL / g) over 1 h30. Cool down to 20°C over 10 hours. Filter on sintered glass Buchner filter. Wash the filter cake twice with 1.4 L DMSO / water (1 :1 v / v, 1.5 mL / g). Then wash twice with 0.9 L of water (1 mL / g). The solid is then dried in the oven at 50°C under vacuum overnight.

[0088] 525g of 1-methyl-5-nitro-indazole (lllb) as light brown solid are recovered (53.8% corrected yield, 97.8%w / w by qNMR, UPLC purity (method A1) 99.4% area method).

[0089] 1 H NMR (400 MHz, CDCI3): 5(ppm) = 8.82 (d, J = 2.1 Hz, 1 H), 8.38 (s, 1 H), 8.23 (dd, J = 9.3, 2.1 Hz, 1 H), 7.86 (d, J = 9.3 Hz, 1 H), 4.13 (s, 3H). LCMS: m / z = 178 [M+H]+. l-5-nitro-indazol-4-'

[0090] Method 1

[0091] In a 10 L reactor, charge 520 g of (lllb) (1 eq, 2.935 mol) and 3.64 L of dry THF (7 mL / g). The reactor is set under an atmosphere of nitrogen. 547 g of t-butyl chloroacetate (1 .2 eq, 519 mL) is added and the mixture is cooled to Tr=0°C. Add ZBuOK in 15 portions of equal size (15x52 g = 782 g, 97% purity, 6.76 mol, 2.3 eq). The addition was carried out in around 4h30. The reaction was complete after 2 hours but was left to stir overnight. To the suspension, 1.340 L of an aqueous solution of citric acid (1 M, 0.46 eq) was carefully added. At the end of the addition, a fluid suspension is obtained. Towards the end of addition, the addition of citric acid is controlled to reach pH 7. The temperature is then brought to Tr=20°C. Water (3.640 L, 7 mL / g) is then added over one hour. The mixture is then cooled to 0°C over 4hours and stirred overnight. The suspension is then filtered on sintered glass Buchner filter and washed with 2 portions of 1 .040 L (2 mL / g) water. The filter cake is dried in oven under vacuum at 50°C.

[0092] 694 g of tert-butyl 2-(1-methyl-5-nitro-indazol-4-yl)acetate (Hid) as an off-white to beige solid is obtained (UPLC purity (method A1) 99.4% area, 81% yield).

[0093] 1H NMR (400 MHz, DMSO-d6): 6(ppm)= 8.52 (s, 1 H), 8.15 (d, J = 9.2 Hz, 1 H), 7.77 (d, J = 9.2 Hz, 1 H), 4.33 (s, 2H), 4.11 (s, 3H), 1 .38 (s, 9H). LC-MS: m / z = 236 [M-C4H7]+.

[0094] Method 2

[0095] In a 15 L reactor, 1072 g of (lllb) (6.051 mol, 1eq) and 7.5 L of dry MeTHF (7 vol) are charged under an atmosphere of nitrogen. The mixture was cooled to Tr=0°C and 1127 g of t-butyl chloroacetate (1 .2 eq, 7.26 mol) were added. The addition of sodium tert-butoxide (1380 g, 13.93 mol, 2.3 eq) was carried out in 15 portions of solid over several hours in order to control the reaction temperature around 0°C. The reaction was left to stir overnight. The resulting suspension was then warmed to 65°C and then water (2.68 L, 2.5 vol) was added. The pH was then adjusted to pH 6.5 by adding 1 .93 L of an aqueous citric acid solution (16% by weight, 1.8 vol). The aqueous layer of the biphasic mixture was removed through decantation. The organic layer was washed by adding 5.36L of water (5 vol.), stirring at 60°C and separating the layers. A solvent switch of the MeTHF towards isopropanol was then carried out on the organic layer by distilling portions of solvent and replacing those portions by equal portions of pure isopropanol until only 5% MeTHF remained as measured by GC. If necessary, the volume of the organic layer is adjusted to 8 volumes by adding isopropanol or continuing the distillation. Water (1 .4 L, 1 .3 vol.) was then added, and the temperature was set to 81 °C. The cristallization is initiated by adding a small portion of solid compound (llld). The mixture is then cooled to 10°C over 17 hours. The solid in suspension was then filtered on sintered glass Buchner filter (porosity 3) and washed successively with 5.36 L (5 vol) of a mixture of isopropanol and water (1 / 1) and with 5.36 L (5 vol) of water. The filter cake was dried in oven under vacuum at 50°C. 1453 g of tert-butyl 2-(1-methyl-5-nitro-indazol-4- yl)acetate (llld) as an off-white to beige solid is obtained (UPLC purity (method A1) 100 % area, 82% yield).

[0096] 1 H NMR (400 MHz, DMSO-d6): 5(ppm) = 8.61 (d, J = 0.9 Hz, 1 H), 8.14 (d, J = 9.2 Hz, 1 H), 7.76 (dd, J = 9.2, 1 .0 Hz, 1 H), 4.32 (s, 2H), 4.11 (s, 3H), 1 .38 (s, 9H). LC-MS: m / z = 236 [M- C4H7]+.

[0097] Step (d): preparation of [tert-butvl- 2-(5-ami no-1 -methy l-i ndazol-4-vl)acetate (I He) by reduction of intermediate (llld)

[0098] To a 20 L pressure reactorwere charged intermediate (llld) (673 g, 2310 mmol, 1 .00 equiv.), Pt / C (type 163 Paste Johnson Matthey, 4.87% w / w Pt assay, 56% w / w moisture; 20.2 g, 5% w / w) and ethyl acetate (6.73 L, 10 vol.). The reactor was pressure-purged three times with nitrogen, then three times with hydrogen to 2.5 bar(g) and the mixture was allowed to stir at 30 °C. A weak, continuous exothermic wave was observed. After 6 to 8 h of stirring, no more hydrogen intake was detected. Upon UPLC analysis, a 99.7% conversion was estimated. The residual catalyst was filtered over Celite®, and the reactor and the pad of Celite® were rinsed with ethyl acetate (2 x 673 mL, 2 x 1 vol.). A yellow and clear solution was obtained which is directly used in step (e).

[0099] Step (e): preparation of [4-(2-tert-butoxy-2-oxo-ethyl)-1-methyl-indazol-5-yl1ammonium chloride (llle-a) At ambient pressure, the solution resulting from step (d) was evaporated to 5.5 L (8 vol.) and dried by azeotropic distillation for 4 h (KF: 0.19 % w / w). The mixture was then cooled down to 20 °C and seeds of the hydrochloride salt (6.73 g, 23.1 mmol, 0.01 eq.) were added to the mixture. A solution of HCI in IPA (titrated 4.8 M; 505 mL, 1 .05 equiv.) was then added over 135 min. The suspension obtained was stirred for 1 h at 20 °C and filtered under a nitrogen atmosphere. The solid was collected and dried under vacuum at 50 °C for 72 h. The title compound (llle-a) was obtained as an off-white crystalline powder (651 g, 95% yield, UPLC purity (method A1) > 99.5 area%, qNMR assay > 98% w / w).

[0100] 1H NMR (400 MHz, DMSO-d6): 6(ppm)= 10.35 (br, 3H), 8.06 (s, 1 H), 7.67 (d, J = 8.9 Hz, 1 H), 7.51 (d, J = 8.9 Hz, 1 H), 4.10 (s, 2H), 4.06 (s, 3H), 1.41 (s, 9H). LCMS: m / z =206 [M-C4CIH8]+.

[0101] Step (f): preparation of 2-(5-chloro-1-methyl-indazol-4-yl)acetic acid (lllf) by saponification and

[0102] Sandmeyer reaction

[0103] A solution of intermediate (llle-a) (160 g, 537 mmol, 1.00 equiv.) in water (480 mL, 3 vol.), precooled at 5 °C, was flowed at 3.00 mL / min and mixed using a T-piece with a solution of 6 M hydrochloric acid (800 mL, 5 vol.), flowed at 3.89 mL / min and also precooled at 5 °C. The combined solution was then passed through a 2 mL flow reactor at 5 °C with a residence time of 17 s. After this first reactor, a solution of sodium nitrite (98% purity; 38.9 g, 564 mmol, 1 .05 equiv.) in water (400 mL, 2.5 vol.), pre-cooled at 5 °C, was introduced at 2.02 mL / min using a standard T-piece. The resulting yellow solution was passed through a 5 mL flow reactor with a residence time of 34 s. The output solution of the reactor was poured into a 40 °C solution of copper (I) chloride (63.8 g, 645 mmol, 1 .20 equiv.) in acetic acid (640 mL, 4 vol.) and 37% w / w hydrochloric acid (480 mL, 3 vol). Gas generation was observed throughout the addition.

[0104] When 100% of the addition was complete, the suspension was allowed to stir for 1 additional hour to complete the t-butyl ester cleavage (control by UPLC), cooled down to 20 °C and filtered. The green solid was resuspended in the filter with 37% w / w hydrochloric acid (320 mL, 2 vol.), refiltered, and then, using the plug-flow method, washed with 37% w / w hydrochloric acid (640 mL, 5 vol.) followed by water (960 mL, 6 vol.). The solid was collected and dried under vacuum at 50 °C for 24 h. The title compound (lllf) was obtained as an off-white powder (92.2 g, 76% yield, UPLC purity (method A1) > 99.5 area%, qNMR assay > 98% w / w)

[0105] 1 H NMR (400 MHz, DMSO-d6): 6(ppm)= 12.51 (br, 1 H), 8.17 (s, 1 H), 7.59 (d, J = 8.9 Hz, 1 H), 7.41 (d, J = 8.9 Hz, 1 H), 4.04 (s, 3H) 4.02 (s, 2H). LCMS: m / z = 225 [M+H]+.

[0106] Step (q): Preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (III)

[0107] To a 3 L reactor were charged intermediate (lllf) (200 g, 890 mmol, 1.00 equiv.), acetonitrile (300 mL, 1.5 vol.), and tetrahydrofuran (300 mL, 1.5 vol.). The white suspension was stirred for 30 min at 20 °C and then 1 ,3-dichloro-5,5-dimethylhydantoin (DCDMH, 95% purity; 25.4 g, 129 mmol, 0.138 eq.) was added portion wise over 10 min. An exothermic wave was observed after 20 minutes of stirring. When this wave has stabilized, an additional amount of DCDMH (95% purity; 76.2 g, 387 mmol, 0.413 eq.) was added portion wise over 40 min. The yellow suspension was stirred for 1 h at 20 °C, and then heated to 60 °C and stirred for 10 min. Water (300 mL, 1 .5 vol.) was added to the hazy yellow solution, and the mixture temperature was stabilized at 60 °C. Then, the solution was cooled down to 44 °C and seeds of undried (III) (577 mg, 0.02% mol) were added to the mixture. The suspension was stirred for 1 h at 44 °C, and then an additional amount of water (300 mL, 1 .5 vol.) was added dropwise over 3 h. When the addition was complete, the mixture was then linearly cooled down to 10 °C over 7 h. The solid was filtered, washed with acetonitrile / water 1 :1 (400 mL, 2 vol.) and dried under vacuum at 50 °C for 24 h. The title compound (III) was obtained as a white crystalline powder (194 g, 84% yield, UPLC purity (method A1) 99.5 area%, qNMR assay > 98% w / w).

[0108] 1H NMR (400 MHz, DMSO-d6): 6(ppm)= 12.66 (s, 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 4.19 (s, 2H), 4.01 (s, 3H). LCMS: m / z = 259 [M+H]+. II. Preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hvdroxymethyl)-5-

[0109] (1 -hydroxy-1 -methyl-ethyl)-1-methyl-3,4-dihvdro-1H-isoquinolin-2-yl]ethanone monohvdrate (I)

[0110] Step (00)- Preparation of (4 / ?)-4-[(2-chlorophenyl)methyl1-3-oxazolidin-2-one (Ila)

[0111] CAS n°103616-90-6 4) Concentration

[0112] A one liter reactor equipped with a mechanical stirrer is charged under nitrogen at 20°C with (2 / ?)- 2-amino-3-(2-chlorophenyl)propano-1-ol (CAS n°103616-90-6; 69.2 g; 0.37 mol; 1 eq.) and dichloromethane (484 mL). The mixture is cooled down to °C before addition of tri phosgene (CAS n°32315-10-9; 39.5 g; 0.13 mol; 0.35 eq.) and N,N-diisopropylethylamine (CAS n°7087-68-5; 146 mL; 0.84 mol; 2.25 eq.). Stirring is pursued at 0°C for one hour then water (150 mL) is added and the mixture is warmed to room temperature. The organic phase is separated and washed with aq. HCI 2N (150 mL) and with water (150 mL). The final organic phase is dried over MgSO4 and concentrated under vacuum at 50°C, 65.0 g of Ila are obtained as an orange solid (82% crude yield; 87.6% HPLC purity (method B1) at 210 nm).

[0113] 1H NMR (400 MHz, DMSO-d6) 5 (ppm) = 7.84 (s, 1 H), 7.49 - 7.35 (m, 2H), 7.35 - 7.24 (m, 2H), 4.29 (t, J = 8.1 Hz, 1 H), 4.15 - 3.98 (m, 2H), 3.01 (dd, J = 13.7, 5.7 Hz, 1 H), 2.87 (dd, J = 13.7, 7.3 Hz, 1 H). UPLC-MS: m / z = 212 [M+H]+.

[0114] Step (D- Preparation of (4R)-4-[(2-chlorophenyl)methyl1-3-(1-ethoxyethyl)oxazolidin-2-one (lib)

[0115] (||a) (Hb)

[0116] Method 1

[0117] In a 30-L reactor, at 25°C under nitrogen, are successively introduced (4R)-4-[(2- chlorophenyl)methyl]oxazolidin-2-one ((Ila); 1.50 kg; 7.10 mol; 1.0 eq.) and acetaldehyde diethyl acetal (CAS n°105-57-7; 15 L; 105.0 mol; 14.8 eq.). Methanesulfonic acid (46.5 mL; 0.71 mol; 0.1 eq.) is added at once then the suspension is stirred at 25°C for 20 hours (at that time HPLC analysis at 210 nm shows less than 2% of Ila). The solution is transferred over 1 / 2h into a decanter previously charged with aqueous Na2COs (3.0 L of 10% w / w). Phases are separated then the organic phase is washed with water (3.0 L). The organic phase is progressively transferred into a 10-L reactor and distilled under vacuum at 50°C down to 1.0 - 1.5 volumes. Heptane (5.0 L) is added to the residual oil and the distillation is pursued at 50°C under vacuum down to 1 .0-1 .5 volumes. The oil is cooled down to room temperature before the addition of dichloromethane (0.5 L). The resulting solution of intermediate (lib) in dichloromethane is analyzed (97.9% HPLC purity (method B2) at 210 nm (two peaks; 84 / 16 ratio);1H NMR in DMSO- d6 shows clean intermediate (lib) as a -85 / 15 mixture of diastereomers with some heptane, dichloromethane and traces of acetaldehyde diethyl acetal. The solution is further diluted with dichloromethane (4.5 L) and stored at room temperature until being engaged in the next step.

[0118] Step (ii) - Preparation of (5S,10aR)-9-chloro-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4- blisoquinolin-3-one (He)

[0119] Method 1

[0120] In a 3 liters reactor, at 20°C under N2 atmosphere, are successively introduced ZrCI4 (149 g; 0.63 mol; 1 .2 eq.) and dichloromethane (600 mL). The suspension is cooled down to -3°C before the addition of a solution of crude intermediate (lib) (150 g theoretical; 0.53 mol; 1.0 eq.) in dichloromethane (roughly 23% w / w) from the previous step over 45 min. The suspension is stirred at 0°C for one hour and at 20°C for one hour (at that time HPLC analysis at 210 nm indicates less than 1 % of intermediate (lib). The suspension is cooled down to 10°C before the addition of ethanol (37 mL; 0.63 mol; 1.2 eq.). The resulting solution is warmed to 20°C and stirred at this temperature for one hour before being transferred into a 3 liters reactor charged with water (750 mL) previously cooled to 5°C at such a rate that the mass temperature remains below 10°C. Afterwards the mixture is warmed to 20°C and the phases are separated. The organic phase is washed with water (750 mL) and aqueous Na2COs (750 ml of 10% w / w). The final solution of (5S,10aR)-9-chloro-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He) in dichloromethane (94.8% HPLC purity (method B2) at 210 nm with typically 2.0-2.5% of the unwanted diastereoisomer) is stored at room temperature until being engaged in the next step.

[0121] 1H NMR (500 MHz, DMSO-d6) 6 (ppm) = 7.37 (dd, J = 7.7, 1.4 Hz, 1 H), 7.33 (d, J = 7.4 Hz, 1 H), 121 (t, J = 7.7 Hz, 1 H), 4.87 (q, J = 6.8 Hz, 1 H), 4.55 (t, J = 8.0 Hz, 1 H), 4.21 (dd, J = 8.3, 5.2 Hz, 1 H), 4.16 (ddt, J = 10.1 , 7.8, 4.7 Hz, 1 H), 3.17 (dd, J = 16.7, 4.6 Hz, 1 H), 2.61 (dd, J = 16.7, 10.4 Hz, 1 H), 1 .43 (d, J = 6.8 Hz, 3H) - LC-MS (m / z) : 238 / 240 (MH+) Method 2

[0122] In a 30-L reactor, at 20°C under N2 atmosphere, are successively introduced dichloromethane (7.6 L) and titanium (IV) chloride (1.56 L; 14.2 mol; 2.0 eq.). The suspension is cooled down to 0°C before the addition of a solution of crude intermediate (lib) (2011 g theoretical; 7.09 mol; 1 .0 eq.) in dichloromethane (roughly 25% w / w) from the previous step over 4.5 hours. The suspension is stirred at 0°C over the night (at that time HPLC analysis at 210 nm (method A2) indicates less than 0.5% of intermediate (lib)). Ethanol (826 mL; 14.2 mol; 2.0 eq.) is added over 20 minutes then water (10 L) is added over 20 minutes at 5°C. Afterwards the mixture is warmed to 20°C and the phases are separated. The organic phase is washed with water (10 L) and the phases are separated. The organic phase is introduced back in the 30-L reactor. Aqueous NaOH 50% w / w (2.5 L; 47.4 mol; 6.7 eq.) is added and the mixture is gently stirred at 20°C for 3 hours (some thin solid appears at the interface). The aqueous phase is separated then the organic phase with some solid in suspension is filtered over a small bed of Celite. The cake is rinsed with a little dichloromethane. As a result, 16.4 kg of solution of (5S,10aR)-9-chloro-5-methyl- 1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He) in dichloromethane (roughly 10% w / w) are obtained (98.2% HPLC purity at 210 nm (method A2) with typically 1 .3-1 .8% of the unwanted diastereomer). The solution is stored at room temperature until being engaged in the next step.

[0123] 1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 7.37 (dd, J = 7.7, 1.4 Hz, 1 H), 7.33 (d, J = 7 A Hz, 1 H), 7.27 (t, J = 7.7 Hz, 1 H), 4.87 (q, J = 6.8 Hz, 1 H), 4.55 (t, J = 8.0 Hz, 1 H), 4.21 (dd, J = 8.3, 5.2 Hz, 1 H), 4.16 (ddt, J = 10.1 , 7.8, 4.7 Hz, 1 H), 3.17 (dd, J = 16.7, 4.6 Hz, 1 H), 2.61 (dd, J = 16.7, 10.4 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3H). LC-MS (m / z) : 238 / 240 (MH+)

[0124] Steps (iii)-(v) - Preparation of (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4- blisoguinolin-3-one did')

[0125] Method 1

[0126] In a one-liter double jacket reactor equipped with a mechanical stirrer, a solution of crude intermediate (He) (157.3 g theoretical; 0.66 mol; 1 eq.) in dichloromethane (roughly 10% w / w) from the previous step is distilled under atmospheric pressure at 55°C (jacket temperature) down to minimum stirrable volume in the reactor. Ethylene glycol monovinyl ether (CAS n°764-48-7; 119 mL; 1.33 mol; 2 eq.) is added to the residue and the distillation is pursued at 70°C under vacuum (not less than 400 mbar) until the level of residual dichloromethane is below 0.03 eq. relative to intermediate (lie) as monitored by 1 H NMR in dmso-d6. Then the reactor is placed under nitrogen and charged with fresh ethylene glycol monovinyl ether (475 mL; 5.30 mol; 8 eq.), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (CAS n°6674-22-2; 119.5 ml; 0.80 mol; 1.2 eq.), 1 ,3- bis(dicyclohexylphosphino) propane bis(tetrafluoroborate) (CAS n°1002345-50-7; 4.56 g; 7.45 mmol; 0.01125 eq.) and palladium acetate (CAS n°3375-31-1 ; 1.14 g; 5.08 mmol; 0.0075 eq.). The reaction mixture is heated to 110°C over two hours and stirred at this temperature for 30 hours (at that time HPLC analysis at 210 nm (with aq. HCI quench) indicates less than 1 .0% of intermediate (He)). The solution is cooled down to room temperature and added over 1.5 hours to aqueous HCI 1 N (0.63 I; 0.63 mol; 0.95 eq.) at 20°C in a 1-L reactor under mechanical stirring; crystallization is observed in the course of the addition. Stirring is pursued at 20°C for 6 hours and then at 5°C for 16 hours before filtration. The cake is rinsed with water (2 x 190 mL) and dried under vacuum at 50°C until constant weight, 128.8 g of (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a- tetrahydrooxazolo[3,4-b]isoquinolin-3-one (lid) are obtained as a yellowish solid (79% yield over three steps; 99.2% HPLC purity (method B2) at 210 nm; qNMR: 95.8% w / w).

[0127] 1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 7.70 (dd, J = 7.8, 1.4 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 4.87 (q, J = 6.7 Hz, 1 H), 4.52 (t, J = 8.2 Hz, 1 H), 4.14 (dd, J = 8.6, 5.2 Hz, 1 H), 4.08 - 3.99 (m, 1 H), 3.22 (dd, J = 17.1 , 4.3 Hz, 1 H), 2.77 (dd, J = 17.1 , 10.9 Hz, 1 H), 2.55 (s, 3H), 1 .44 (d, J = 6.8 Hz, 3H) - LC-MS (m / z) : 246 (MH+)

[0128] Method 2

[0129] In a 10-L double jacket reactor equipped with a mechanical stirrer, a solution of crude intermediate (He) (1684 g theoretical; 7.10 mol; 1 eq.) in dichloromethane (roughly 10% w / w) from the previous step is distilled under atmospheric pressure at 50°C (jacket temperature) down to minimum stirrable volume in the reactor. Then 1 ,8-diazabicyclo[5.4.0]undec-7-ene (CAS n°6674- 22-2; 1.28 L; 8.52 mol; 1.2 eq.) is added to the residue and the distillation is pursued at 50°C under vacuum (down to 20 mbar) until the level of residual dichloromethane is below 0.03 eq. relative to intermediate (lie) as monitored by1H NMR in DMSO-de. Then the reactor is placed under nitrogen and charged with ethylene glycol monovinyl ether (CAS n°764-48-7; 5.09 L; 56.7 mol; 8.0 eq.), 1 ,3-bis(dicyclohexylphosphino) propane bis(tetrafluoroborate) (CAS n°1002345-50- 7; 48.8 g; 79.8 mmol; 0.01125 eq.) and palladium acetate (CAS n°3375-31-1 ; 12.0 g; 53.3 mmol; 0.0075 eq.). The reaction mixture is heated to 110°C over two hours and stirred at this temperature for 20 hours (at that time HPLC analysis at 210 nm (method A2 with aq. HCI quench of the sample) shows less than 1.0% of intermediate (He)). The solution is cooled down to room temperature and diluted with water (3.35 L). Norit® CN1 (375 g) is added and the suspension is gently stirred at room temperature overnight before filtration over a bed of Celite. The cake is rinsed with aqueous ethylene glycol monovinyl ether (60% v / v; 1 .7 L). The mother liquors are added over 2 hours to aqueous HCI 1 N (6.74 L; 6.74 mol; 0.95 eq.) pre-heated at 50°C in a 30-L reactor under mechanical stirring in the presence of 15 g of seeds of (lid); crystallization is observed in the course of the addition. Stirring is pursued at 50°C for one hour then a cooling ramp down to 1 °C over two hours is applied. After stirring over the night at 1 °C, the suspension is filtered. The cake is rinsed with water (2 x 3.4 L) and dried under vacuum at 50°C until constant weight, 1.29 kg of (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin- 3-one (lid) are obtained as a greyish solid (78% yield over three steps; 99.3% HPLC purity (method A2) at 210 nm; qNMR: 96.8% w / w).

[0130] 1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 7.70 (dd, J = 7.8, 1.4 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 4.87 (q, J = 6.7 Hz, 1 H), 4.52 (t, J = 8.2 Hz, 1 H), 4.14 (dd, J = 8.6, 5.2 Hz, 1 H), 4.08 - 3.99 (m, 1 H), 3.22 (dd, J = 17.1 , 4.3 Hz, 1 H), 2.77 (dd, J = 17.1 , 10.9 Hz, 1 H), 2.55 (s, 3H), 1 .44 (d, J = 6.8 Hz, 3H). LC-MS (m / z) : 246 (MH+)

[0131] Step (vi) - Preparation of (5S,10aR)-9-(1-hvdroxy-1-methyl-ethyl)-5-methyl-1 .S.I O.I Oa-

[0132] A 30-L reactor is charged under nitrogen with anhydrous dichloromethane (6.0 L). Mass temperature is decreased to 0°C then methyl magnesium chloride (1.51 L of 3.0 M solution in tetrahydrofuran; 4.54 mol; 1.3 eq.) is added over 15 min (so that mass temperature doesn’t exceed 3°C). Then a solution of intermediate (lid) (857 g; 3.49 mol; 1.0 eq.) in anhydrous dichloromethane (1.7 L) is added over 50 min (so that mass temperature doesn’t exceed 1 °C). Stirring is pursued at 0°C for one hour (at that time HPLC analysis at 210 nm (method B2) shows 2.1 % of intermediate (lid) and 95.2% of intermediate (He)), then the mixture is quenched by addition of a mixture of 2-propanol (0.53 L; 6.9 mol; 2 eq.) and DCM (0.43 L) over 15 min (strong gas evolution and exothermicity are observed at the beginning of the addition). Stirring is pursued at 0°C for 15 min before addition of aqueous citric acid (4.3 L of 1 M; 4.3 mol; 1.2 eq.), then the mixture is warmed to 20°C. Phases are separated then the organic phase is washed with aqueous NaHCOs (4.3 L of 5% w / w). Charcoal (428 g of Cabot CGP Super) is added to the organic phase and the suspension is gently stirred at 20°C over the night. The suspension is then filtered over a bed of celite and the wet cake is rinsed with dichloromethane (2 L). The final solution of (5S,10aR)-9-(1 -hydroxy-1 -methyl-ethyl)-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4- b]isoquinolin-3-one (lie) in dichloromethane / THF is stored at room temperature until being engaged in the next step. Step (vii) - Preparation of (1 S,3R)-1 ,2,3,4-Tetrahvdro-a5,a5,1-trimethyl-3,5- isoquinolinedimethanol (Ilf)

[0133] (He) (Ilf)

[0134] A solution of crude intermediate (lie) (867 g; 3.32 mol; 1 eq.) in dichloromethane / THF (roughly 6.4% w / w) from the previous step is distilled under atmospheric pressure in a 10-Lreactor down to minimum stirrable volume (about 1 .5 L). Ethanol (2.6 L) is added and the distillation is pursued at 80°C under atmospheric pressure until the level of residual THF is below 30% mol relative to intermediate (lie) as detected by1H NMR in dmso-d6. The reactor is placed under nitrogen flow and the mixture is cooled down to 50°C. Ethanol is introduced to reach 3 volumes relative to intermediate (lie) in the reactor: 1.7 L are added. Water (0.52 L) and potassium hydroxide (657 g of 85% w / w; 9.95 mol; 3.0 eq.) are also added and the mixture is heated at 70°C for 20 hours (at that time HPLC analysis at 210 nm (method B2) shows less than 1% of intermediate (He)). Water (5.2 L) is gently added to the mixture at 70°C then the solution is cooled down to 37°C and seeds of intermediate (Ilf) (0.5 g) are introduced. The mixture is cooled down to 2°C over 4 hours. After overnight stirring at 2°C, the mixture is filtered, the cake is rinsed with cold (3°C) water (2 x 1 .75 L) and dried under vacuum at 80°C until constant weight. As a result, 603 g of (1 S,3R)-1 ,2,3,4- Tetrahydro-a5,a5,1-trimethyl-3,5-isoquinolinedimethanol (Ilf) are obtained as a greyish solid (77% yield over two steps; 99.3% HPLC purity (method A2) at 210 nm; qNMR: 99.7% w / w; KF: 0.55% w / w).

[0135] 1H NMR (500 MHz, DMSO-d6) 6 (ppm)= 7.25 (d, J = 7.9 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 4.86 (s, 1 H), 4.62 (t, J = 5.4 Hz, 1 H), 4.07 (q, J = 6.7 Hz, 1 H), 3.48 - 3.32 (m, 3H), 3.00 - 2.91 (m, 1 H), 2.39 (dd, J = 16.3, 10.6 Hz, 1 H), 1 .99 (s, 1 H), 1 .50 (s, 3H), 1 .48 (s, 3H), 1 .34 (d, J = 6.7 Hz, 3H) - LC-MS (m / z) : 236 (MH+)

[0136] Steps (viii) & (lx) - Preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 S,3R)-3-

[0137] (hvdroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2- yllethanone monohvdrate (I)

[0138] Triethylamine (2.5 eq) is added to a suspension of intermediate (III) in acetonitrile (12 vol); Intermediate (Ilf) (1.05 eq) and water (3 eq) are added to the resulting mixture. The resulting suspension is cooled to 0°C before the portion wise addition of N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (1.1 eq in 4-5 portions added every 15-20 mn); seed crystals of (I) (0.002 eq) are added after 0.9 equivalents of TCFH has been added. The reaction mixture is sampled for the reaction completion at least 30 mn after the addition of the last portion of TCFH and the reaction mixture is warmed to 20°C in 30 mn. Upon reaction completion, water (3.8 vol) is added to pursue the crystallization over 90 mn. The suspension is stirred at 20°C for 2 h, then is cooled to 10°C in 2 h and kept under stirred at 10°C for min 6 h. 2- (3,5-dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)- 1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) is isolated by filtration of the cooled suspension, washed twice with a (1 :1) acetonitrile-water mixture (4 vol), then twice with water (4vol) and finally twice with ethyl acetate (4 vol). The filter cake is dried under vacuum (typical drying time on the plant: 15-24 h) to yield crude 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1- [(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro-1 H-isoquinolin-2- yl]ethanone monohydrate (I) as a white to off-white solid in a 90-95% yield.

[0139] (99.5% HPLC purity (method A3) at 220 nm; HPLC assay (on anhydrous substance): 99.5% w / w; KF: 3.8% w / w).

[0140] Step (x) - Recrystallisation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 S,3R)-3- (hvdroxymethyl)-5-(1-hvdroxy-1-methyl-ethyl)-1-methyl-3,4-dihvdro-1 H-isoquinolin-2- yllethanone monohvdrate (I)

[0141] Crude compound (I) is dissolved in dimethyl sulfoxide (DMSO) (7.1 vol) at 20°C. The solution is treated with active charcoal then polish filtered to remove potential foreign particles. The resulting filtrate is transferred to a reactor and heated to 85-90°C. Water (3.8 vol) is added over 30-45 mn, keeping the solution mass at T > 85°C. The mixture is cooled to the seeding temperature (85°C) and seed crystals of (I) (1 %w / w) are added to initiate the crystallization. The suspension is stirred at the seeding temperature for 2 h and is then cooled down to 20°C in 12 h. The suspension is kept under stirring at 20°C for min 1 h. The solid is isolated by filtration of the cooled suspension; the filter cake is washed successively with several portions of water (4 vol) until the residual DMSO content of compound (I) is found lower than 5000 ppm, then twice with ethyl acetate (4 vol). The filter cake is dried under vacuum (typical drying time: 12-15 h. 2-(3,5- dichloro-1 -methyl-indazol-4-yl)-1 -[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1 - methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) is obtained as a white to off- white powder in a 85-95% yield (99.85% HPLC purity (method A3) at 220 nm; HPLC assay (“as is"): 97% w / w; KF: 3.5% w / w. Melting point = 124°C (determined by differential scanning calorimetry - thermogram recorded between 25°C and 240°C at 10°C / mn).

[0142] 1H NMR (600 MHz, DMSO-d6) 5 (ppm) = 7.65 (dd, J = 9.0, 3.3 Hz, 1 H), 7.51 (dd, J = 9.0, 3.1 Hz, 1 H), 7.40 (dd, J = 7.6, 1 .7 Hz, 0.3H), 7.35 (dd, J = 8.0, 1 .3 Hz, 0.7H), 7.23 - 7.11 (m, 2.3 H), 7.07 (dd, J = 7.6, 1.3 Hz, 0.7H), 5.30 (q, J = 6.6 Hz, 0.3H), 5.09 - 5.04 (m, 1.7H), 4.92 - 4.88 (m, 0.7H), 4.61 - 4.30 (m, 3.3H), 4.10 - 4.03 (m, 4H), 3.29 (dt, J = 10.6, 5.4 Hz, 1 ,3H), 3.08 - 2.93

[0143] (m, 1 ,7H), 1 .60 - 1 .55 (double s, 6H), 1 .54 (d, J = 6.5 HZ, 0.9H), 1 .25 (d, J = 6.5 Hz, 2.1 H).

Claims

CLAIMS1. A process for the preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 S,3R)-3- (hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2- yl]ethanone monohydrate (I) comprising:(i) reacting (4R)-[(2-chlorophenyl)methyl]-2-oxazolidinone (Ila)with acetaldehyde diethyl acetal, used as a solvent, in the presence of an acid to afford (4R)-4-[(2-chlorophenyl)methyl]-3-(1-ethoxyethyl)oxazolidin-2-one (lib),(ii) Pictet-Spengler cyclisation of (4R)-4-[(2-chlorophenyl)methyl]-3-(1- ethoxyethyl)oxazolidin-2-one (lib) in the presence of a Lewis acid to afford (5S,10aR)-9- chloro-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He),(iii) Heck reaction of compound of formula (He) in the presence of ethylene glycol monovinyl ether, palladium catalyst, a ligand and a non-nucleophilic base to afford (5S,10aR)-9-[1- (2-hydroxyethoxy)vinyl]-5-methyl-1 , 5, 10, 10a-tetrahydrooxazolo[3,4-b]isoquinolin-3- one (Hc-a),(llc-a)(iv) hydrolysing compound (llc-a) by pouring the reaction mixture obtained as a result of step (iii) into an aqueous solution of a strong acid, to afford (5S,10aR)-9-acetyl-5-methyl- 1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one (lid),(v) isolating (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3- one (lid),(vi) Grignard reaction of compound of formula (lid) in the presence of methyl magnesium chloride to afford (5S,10aR)-9-(1-hydroxy-1-methyl-ethyl)-5-methyl-1 ,5,10,10a- tetrahydrooxazolo[3,4-b]isoquinolin-3-one (He)(vii) Hydrolysing compound of formula (He) by addition of an aqueous solution of a strong base to afford (1 S,3R)-1 ,2,3,4-tetrahydro-a5,a5,1-trimethyl-3,5-isoquinolinedimethanol (Ilf)(viii) Coupling compound (Ilf) with 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (III)in the presence of a base and N,A / ,A / ',A / '-tetramethylchloroformamidinium hexafluorophosphate, and water, to afford crude 2-(3,5-dichloro-1-methyl-indazol-4-yl)- 1-[(1 S,3R)-3-(hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1-methyl-3,4-dihydro-1 H- isoquinolin-2-yl]ethanone monohydrate (I),(ix) Crystallizing 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1- hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2-yl]ethanone monohydrate (I) by adding more water; and(x) Optionally recrystallizing 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1 S,3R)-3- (hydroxymethyl)-5-(1 -hydroxy-1 -methyl-ethyl)-1-methyl-3,4-dihydro-1 H-isoquinolin-2- yl]ethanone (I) in a mixture of dimethyl sulfoxide and water.

2. The process according to Claim 1 wherein in step (i) acetaldehyde diethyl acetal is used as the solvent.

3. The process according to Claim 1 wherein in step (i) the acid is methanesulfonic acid.

4. The process according to Claim 1 wherein in step (ii) the Lewis acid is Zirconium (IV) chloride or titanium (IV) chloride.

5. The process according to Claim 1 wherein in step (iii) the palladium catalyst is selected from Palladium acetate (II) and bis(acetonitrile) chloropalladium (II).

6. The process according to Claim 1 wherein in step (iii) the ligand is selected from 1 ,3- Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate), 1 ,3- Bis(diphenylphosphino)propane and 1 ,3-Bis(di-i-propylphosphino)propane.

7. The process according to claim 1 wherein in step (iii) the base is selected from potassium carbonate, sodium carbonate and preferred base is 1 ,8-diazabicyclo[5.4.0]undec-7-ene.

8. The process according to Claim 1 wherein in step (iv) the strong acid is hydrogen chloride.

9. The process according to Claim 1 wherein step (vi) is performed at a temperature comprised between about 0°C and about 5°C.

10. The process according to Claim 1 wherein in step (vii) the strong base is potassium hydroxide.11 . The process according to Claim 1 wherein in step (vii) the solvent is a mixture of ethanol and water.

12. The process according to Claim 1 wherein in step (vii) the temperature is about 70°C to about 80°C.

13. The process according to Claim 1 wherein steps (iii)-(iv) are performed one-pot.

14. The process according to Claim 1 wherein yield of steps (i)-(vii) is comprised between about 55% and about 65%.

15. The process according to Claim 1 wherein compound (Ilf) is obtained with a purity of at least 97% .

16. The process according to Claim 1 wherein yield of steps (viii) and (ix) is at least 90%.

17. The process according to Claim 1 wherein yield of steps (viii) and (x) is at least about 80%.

18. The process according to Claim 1 wherein intermediate 2-(3,5-dichloro-1-methyl-indazol-4- yl)acetic acid (III),is prepared by a process comprising the following steps:(a) N-methylation of 5-nitro-1 H-indazole (Illa) with dimethyl carbonate in the presence of a catalytic amount of 1 ,4-diazobicyclo[2.2.2]octane to afford a mixture of 1-methyl-5-nitro- indazole (lllb) and 2-methyl-5-nitro-indazole (lllc)(b) Precipitation of compound of formula (lllb), by addition of water and filtration to afford compound of formula (lllb),(c) Reacting compound of formula (lllb) with t-butyl chloroacetate in the presence of a base, followed by addition of a mild acid, to afford te / Y-butyl 2-(1-methyl-5-nitro-indazol-4- yl)acetate (Hid),(d) Hydrogenation of the nitro group of Intermediate (Hid), with hydrogen on platinum on carbon (Pt / C) to afford 2-(5-amino-1-methyl-indazol-4-yl)acetate (Hie)(e) Formation of the hydrochloride salt of (II le-a) by treatment of intermediate (Hie) with anhydrous hydrogen chloride to afford, after isolation, 4-(2-tert-butoxy-2-oxo-ethyl)-1- methyl-indazol-5-yl]ammonium chloride (II le-a),(f) Concomitant Sandmeyer reaction under continuous flow and ester cleavage with an aqueous solution of hydrochloric acid of intermediate (llle-a) to afford 2-(5-chloro-1- methyl-indazol-4-yl)acetic acid (lllf), and(g) Chlorination of intermediate (lllf) with 1 ,3-dichloro-5,5-dimethylhydantoin.

19. The process according to Claim 18, wherein step (a) is performed in dimethyl sulfoxide at a temperature of about 90°C.

20. The process according to Claim 18 wherein the base in step (c) is selected from sodium tert-butoxide and potassium tert-butoxide.21 . The process according to Claim 18 wherein the mild acid in step (c) is citric acid.

22. The process according to Claim 18 wherein the step (d) is performed at a pressure comprised between about 1 bar and 3 bar.

23. The process according to Claim 18 wherein the anhydrous hydrogen chloride in step (e) is a solution of hydrogen chloride in isopropyl alcohol.

24. Synthetic intermediate (4R)-4-[(2-chlorophenyl)methyl]-3-(1-ethoxyethyl)oxazolidin-2-one (Hb)25. Synthetic intermediate (5S,10aR)-9-acetyl-5-methyl-1 ,5,10,10a-tetrahydrooxazolo[3,4- b]isoquinolin-3-one (lid)26. Synthetic intermediate (5S 0aR)-9-(1 -hydroxy-1 -methyl-ethyl)-5-methyl-1 , 5, 10, 10a- tetrahydrooxazolo[3,4-b]isoquinolin-3-one (lie)27. Compound of formula (I) directly obtained from the process according to Claim 18.

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