Glovadalen

CAS 2576359-31-2

MF C24H27Cl2N3O3 MW 476.4 g/mol

2-(3,5-dichloro-1-methyl-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethan-1-one,

2-(3,5-dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone
dopamine D1 receptor positive allosteric modulator, Phase 2, Parkinson’s disease, UCB-0022, UCB 0022, H8T5VKH4CZ

• OriginatorUCB Biopharma
• ClassAlcohols; Antiparkinsonians; Benzene derivatives; Chlorinated hydrocarbons; Isoquinolines; Ketones; Neuroprotectants; Propanols; Pyrazoles; Small molecules
• Mechanism of ActionDopamine D1 receptor modulators
• Phase IIParkinson’s disease
• 27 Aug 2025Chemical structure information added.
• 21 May 2025UCB Biopharma SRL initiate a phase I trial in healthy volunteers (PO) (NCT06970301)
• 11 Apr 2025UCB Pharma completes a phase-II ATLANTIS trial in Parkinson’s disease (In adults, In the elderly, Adjunctive treatment) in USA (PO) (NCT06055985)

Glovadalen (developmental code name UCB-0022) is a dopamine D₁ receptor positive allosteric modulator which is under development for the treatment of Parkinson’s disease.^{[1][2][3][4][5][6]} It has been found to potentiate the capacity of dopamine to activate the D₁ receptor by 10-fold in vitro with no actions on other dopamine receptors.^[5][6] As of May 2024, glovadalen is in phase 2 clinical trials for this indication.^[1][2][5] The drug is under development by UCB Biopharma.^[1][4][5] It is described as an orally active, centrally penetrant small molecule.^[1][5][6]

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021001288&_cid=P21-MH738G-96748-1

1. Preparation of intermediate of formula (ID- 2-(3,5-dichloro-1-methyl-indazol-4- vDacetic acid

1.1. Preparation of intermediate (Xlb) -1-methyl-5-nitro-indazole

5-Nitro-1H-indazole (Xla) (3.00 kg, 18.4 mol) and DMF (30.0 L) are charged into a 50 L three-neck round-bottom flask at 15-30°C. KOH (2.06 Kg, 36.7 mol) is added in one portion into the reactor at 0-5°C. The mixture is stirred at 0-50°C for 1h. Methyl iodide (2.87 kg, 20.2 mol) is then added at 0-5°C and the mixture is stirred for 3h at 15-30°C. The reaction mixture is added into water (30 L) at 0-10°C and the mixture is stirred for 10 min then filtered. The filter cake is washed with water (5 L) and dried. This overall procedure is carried out on 4 batches of the same size in parallel. The solids obtained from the four batches are combined to give 1-methyl-5-nitro-indazole (Xlb) as a brown solid (10.0 kg, 42.3 mol, 75% purity (LC/MS), 57.5% yield) which is used in the next step without further purification.

¹H NMR (400 MHz, CDCIs) d 8.65 (s, 1H), 8.21 (d, J = 9.17 Hz, 1 H), 8.13 (s, 1 H), 7.39 (d, J = 9.17 Hz, 1 H), 4.08 (s, 3 H).

1.2. Preparation of intermediate (Xa)- tert-butyl 2-(1-methyl-5-nitro-indazol-4- yl)acetate

t-BuOK (4.43 kg, 39.5 mol) and THF (30 L) are charged into a 50 L three-neck round-bottom flask and the mixture is cooled to -45 / -35°C under nitrogen and stirring. 1-Methyl-5-nitro-indazole (Xlb) (3.50 kg, 19.7 mol) is then added in portions at -45 / -35°C. Tert-butyl 2-chloroacetate (3.57 kg, 23.7 mol) is added dropwise at the same temperature and the mixture is stirred at 1h. The mixture is warmed up to 15-30°C and stirred for 5h. The reaction is quenched by the addition of a saturated ammonium chloride solution (9 L) and water (2 L) is added. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2 x 5 L). The organic phases are combined, washed with brine (2 L), dried over Na2SC>4, filtered and concentrated under vacuum. The crude product is purified by recrystallization with ethyl acetate (5 L). This overall procedure is carried out on 2 batches of the same size in parallel. The solids obtained from the two batches are combined and dried together to give tert-butyl 2-(1-methyl-5-nitro-indazol-4-yl)acetate as a yellow solid (Xa) (5.30 kg, 17.7 mol, 97.6% purity (LC/MS), 44.9% yield).

¹H NMR (400 MHz, CDCIs) d 8.18-8.20 (m, 2H), 7.37 (d, J = 9.21 Hz, 1 H), 4.27 (s, 2 H), 4.14 (s, 3 H), 1.44 (s, 9 H).

1.3. Preparation of intermediate (Xb) – tert-butyl 2-(5-amino-1-methyl-indazol-4- yl)acetate

Tert-butyl 2-(1-methyl-5-nitro-indazol-4-yl)acetate (Xa) (7.30 kg, 25.0 mol) and MeOH (76 L) are charged into a reactor. Argon is purged and Pd/C (50%, 760 g) is added. Hydrogen is added three times and the mixture is stirred at 50°C under hydrogen atmosphere (50 psi) for 3h. The reaction mixture is filtered and the solid is washed with MeOH (5 L). The mixture is concentrated to give tert-butyl 2-(5-amino-1-methyl-indazol-4-yl)acetate (Xb) as a brown oil (6.50 kg, 23.9 mol, 96.2% purity (LC/MS), 95.4% yield) which is used in the next step without further purification.

¹H NMR (400 MHz, CDCI₃) d 7.72 (s, 1H), 7.27 (d, J = 8.80 Hz, 1 H), 6.91 (d, J = 8.80 Hz, 1 H), 4.60 (s, 2 H), 3.93 (s, 3 H), 3.68 (s, 2H), 1.38 (s, 9 H).

1.4. Preparation of intermediate (Xc)- 2-(5-chloro-1-methyl-indazol-4-yl)acetic acid

Tert-butyl 2-(5-amino-1-methyl-indazol-4-yl)acetate (Xb) (2.00 kg, 7.65 mol) and concentrated HCI (10.0 L, 12M) are charged into a 50 L three-neck round bottom flask and the mixture is cooled to -10/-5°C and stirred. A water solution (5 L) of sodium nitrite (686 g, 9.95 mol) is added dropwise at -10/-5°C and stirred for 30 min. CuCI (833 g, 8.42 mol) and concentrated HCI (10.0 L, 12M) are charged into a 20 L three-neck round bottom flask and the mixture is stirred for 30 min. at -10/-5°C, then added into the other reactor. The mixture is stirred at -10/-5°C for 1 h, then at 10-30°C for 16h. The reaction mixture is filtered and the solid washed with water. This overall procedure is carried out on 3 batches of the same size in parallel. The solids obtained from the three batches are combined and dried together to give 2-(5-chloro-1-methyl-indazol-4-yl)acetic acid (Xc) as a yellow solid (4.00 kg, 16.3 mol, 92% purity (LC/MS), 71.3% yield) which is used in the next step without further purification.

1.5. Preparation of 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (II)

2-(5-Chloro-1-methyl-indazol-4-yl)acetic acid (Xc) (1.30 kg, 5.79 mol) and DMF (6.5 L) are charged into a 50 L three-neck round bottom flask at 20°C. N-Chlorosuccinimide (772 g, 5.79 mol) is added portionwise at 20°C and the mixture is stirred at 20°C for 2h. The reaction mixture is poured into water (25 L) and filtered. The crude product is triturated with isopropyl etherethyl acetate (3:1) (7.0 L) at 20°C for 2h then filtered and dried. This overall procedure is carried out on 3 batches of the same size in parallel. The solids obtained from the three batches are combined to give 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (II) (2.1 kg, 7.9 mol, 97.5% purity (LC/MS), 46% yield).

¹H NMR (400 MHz, CDCI₃) d 12.67 (s, 1 H), 7.68 (d, J = 9.05 Hz, 1 H), 7.53 (d, J = 9.05 Hz, 1 H), 4.20 (s, 2 H), 4.02 (s, 3 H).

2. Preparation of compound of formula (I)

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

2.1. Preparation of intermediate (IX).

(2R)-2-amino-3-(2-bromophenyl)propan-1-ol – a6

(2R)-2-amino-3-(2-bromophenyl)propanoic acid a5 (34.0 kg, 139 mol) and THF (238 L) are charged into a reactor. Sodium borohydride (15.6 kg, 413 mol) is added slowly at 20-30°C. A solution of iodine (35.3 kg, 139 mol) in dry THF (20.0 L) is added slowly at 0-10°C and the reaction mixture is stirred at 70°C for 12h. The reaction was quenched with methanol (70.0 L) at 0°C and heated to 80°C for 30 min. The mixture was cooled down, concentrated under vacuum and the residue was suspended in NaOH (30.0 L, 2N), then filtered. The filter cake was dried under vacuum to give (2R)-2-amino-3-(2-bromophenyl)propan-1-ol a6 as a white solid (31.0 kg, 135 mol, 96.7% yield) which is used in the next step without further purification. ¹H NMR (400 MHz, CDCIs) d 7.57 (d, J = 7.7 Hz, 1H), 7.21 – 7.29 (m, 2H), 7.07 – 7.15 (m, 1H), 3.66 (dd, J = 10.5, 3.6 Hz, 1 H), 3.41 (dd, J = 10.5, 7.2 Hz, 1 H), 3.18 – 3.29 (m, 1 H), 2.95 (dd, J = 13.5, 5.5 Hz, 1 H), 2.70 (dd, J = 13.5, 8.2 Hz, 1H), 1.51 – 1.91 (m, 3H).

2.2. Preparation of intermediate of formula (VIII).

(4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one – a7

(2R)-2-amino-3-(2-bromophenyl)propan-1-ol a6 (31.0 kg, 135 mol) and dichloromethane (220 L) are charged into a reactor. Triphosgene (13.9 kg, 47.1 mol) is added at room temperature then N,N-diisopropylethylamine (39.1 kg, 303 mol) is slowly added at 0-10°C. The reaction mixture is stirred at 0-10°C for 1h then washed with water (50.0 L) twice, dried with anhydrous sodium sulfate and filtered to give (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one a7 as a solution in dichloromethane which is used directly in the next step.

2.3. Preparation of intermediate (VII).

(10aR)-9-bromo-1 ,5, 10, 10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8

A solution of (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one a7 (135 mol) in dichloromethane (220 L) is charged into a reactor and cooled down to 0-5°C. Trimethylsilyl triflate (35.9 kg, 162 mol) and paraformaldehyde (13.3 kg, 148 mol) are added at 0-5°C, then stirred for 2h at 15-20°C. Water (170 L) is added into the mixture which is then extracted twice with dichloromethane (50.0 L). the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. A mixture of petroleum etherethyl acetate (1 :1, 45.0 L) is added and the mixture is stirred at room temperature for 6h and filtered. The solid was dried to get (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8 as an off-white solid (29.0 kg, 80.2% yield).

¹H NMR (400 MHz, CDCI₃) d 7.45 – 7.52 (m, 1H), 7.08 – 7.14 (m, 2H), 4.83 (d, J = 17.0 Hz, 1H), 4.62 (t, J = 8.4 Hz, 1H), 4.36 (d, J = 17.0 Hz, 1H), 4.21 (dd, J = 8.6, 4.9 Hz, 1 H), 3.91 -3.99 (m, 1H), 3.25 (dd, J= 16.3, 4.2 Hz, 1 H), 2.67 (dd, J = 16.1 , 11.0 Hz, 1H).

2.4. Preparation of intermediates (VI)

2.4.1. [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9

Ethanol (120 L) and water (60.0 L) are mixed into a reactor. (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8 (29.7 kg, 111 mol) is added then sodium hydroxide (13.3 kg, 332 mol) is slowly added at 15-20°C. The reaction mixture is stirred at 90°C for 2h then cooled down to room temperature. Water (300 L) is added into the mixture which is centrifugated. The centrifugal cake is dried in circulation oven to give [(3R)-5-bromo- 1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9 as a white solid (23.7 kg, 88.3% yield) which is used in the next step without further purification.

¹H NMR (400 MHz, CDCIs) d 7.37 – 7.47 (m, 1H), 6.95 – 7.08 (m, 2H), 4.00 – 4.10 (m, 2H), 3.85 (dd, J = 10.9, 3.7 Hz, 1 H), 3.57 (dd, J = 10.9, 7.9 Hz, 1 H), 3.06 (ddt, J = 11.3, 7.6, 4.1 , 4.1 Hz, 1H), 2.79 (dd, J= 17.1, 4.4 Hz, 1H), 2.40 (dd, J= 17.1, 10.9 Hz, 1H), 1.93 (br s, 2H).

2.4.2. [(3R)-5-bromo-1 ,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl- silane a10

[(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9 (23.7 kg, 97.8 mol) and dichloromethane (240 L) are charged into a reactor. DMAP (120 g, 0.98 mol) and imidazole (13.3 kg, 196 mol) are added. Tert-butyldimethylsilyl chloride (TBSCI) (17.7 kg, 117 mol) is slowly added at 15-20°C and the mixture is stirred for 12h. Ammonium chloride (100 L) is added into the mixture. The organic phase was separated, washed with water (50.0 L), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum to give [(3R)-5-bromo-1 ,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a10 as a yellow oil (37.6 kg, 86% purity, 93% yield) which is used in the next step without further purification.

¹H NMR (400 MHz, CDCI₃) d 7.36 – 7.45 (m, 1H), 7.01 (d, J = 4.6 Hz, 1H), 4.01 – 4.13 (m, 2H), 3.84 (dd, J = 9.9, 3.7 Hz, 1 H), 3.64 (dd, J = 9.8, 7.2 Hz, 1 H), 2.96 – 3.08 (m, 1 H), 2.75 (dd, J = 17.0, 4.2 Hz, 1 H), 2.44 (dd, J = 17.0, 10.8 Hz, 1H), 1.76 – 2.20 (m, 2H), 0.89 – 0.97 (m, 9H), 0.08 – 0.14 (m, 6H).

2.5. Preparation of intermediate (V).

[(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a11

[(3R)-5-bromo-1 ,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a10 (3.42 kg, 8.31 mol) and THF (30.0 L) are charged into a reactor. N-Chlorosuccinimide (NCS) (1.17 kg, 8.73 mol) is slowly added at room temperature and the mixture is stirred at 25°C for 30 min. A solution of KOH (1.52 kg, 27.1 mol) in dry methanol (7.00 L) is slowly added at room temperature and the reaction is stirred at 25°C for 1h. The reaction is quenched with water (10.0 L) and extracted with petroleum etherethyl acetate (1:2, 5.00 L). The organic layer is separated, washed with brine (10.0 L), dried with anhydrous sodium sulfate and filtered. This overall procedure is carried out on 10 batches of the same size in parallel and the 10 reaction filtrates are combined and concentrated under vacuum to give [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a11 as a brown oil (28.0 kg, crude) which is used in the next step without further purification.

¹H NMR (400 MHz, CDC ) d 8.24 (d, J = 2.6 Hz, 1H), 7.58 (dd, J = 7.8, 1.2 Hz, 1 H), 7.12 -7.25 (m, 2H), 4.03 (dd, J = 9.5, 4.0 Hz, 1 H), 3.67 – 3.77 (m, 2H), 3.07 (dd, J = 17.0, 6.2 Hz, 1H), 2.68 (dd, J = 17.1, 10.9 Hz, 1 H), 0.88 – 0.91 (m, 9H), 0.07 (d, J= 1.5 Hz, 6H).

2.6. Preparation of intermediates of formula (IV)

2.6.1. [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl- dimethyl-silane (IVa)

[(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a11 (3.10 kg, 8.75 mol) and THF (20.0 L) are charged into a reactor. The mixture is cooled down to 0°C and methylmagnesium chloride (3M, 11.6 L) is added. The mixture is stirred at 20°C for 12h. The reaction is quenched with a saturated solution of ammonium chloride. The phases are separated and the aqueous layer is extracted twice with petroleum ether: ethyl acetate (3:1, 5.00 L). The combined organic phases are washed with brine (10.0 L), dried over anhydrous sodium sulfate and filtered. This overall procedure is carried out on 9 batches of the same size in parallel and the nine reaction filtrates are combined and concentrated under vacuum. The crude mixture is purified by silica gel chromatography with petroleum ether : ethyl acetate (10:1) to give [(1S,3R)-5-bromo-1 -methyl-1, 2, 3, 4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane (IVa) as a brown oil (4.60 kg, 99.7% purity, 15.7% yield).

¹H NMR (400 MHz, DMSO-de) d 7.41 (dd, J=7.7, 0.9 Hz, 1H), 7.12 – 7.18 (m, 1H), 7.03 – 7.11 (m, 1H), 4.12 (q, J= 6.8 Hz, 1H), 3.62 (d, J= 5.7 Hz, 2H), 3.07 – 3.17 (m, 1H), 2.67 – 2.76 (m, 1H), 2.26 (dd, J=16.9, 10.0 Hz, 1H), 2.12 (br s, 1 H), 1.32 (d, J= 6.8 Hz, 3H), 0.84 – 0.93 (m, 9H), 0.07 (d, J=0.9 Hz, 6H).

2.6.2. tert-butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4- dihydro-1 H-isoquinoline-2-carboxylate (IVb)

[(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane (IVa) (1.85 kg, 4.99 mol) and dichloromethane (13.0 L) are charged in a reactor. N,N-diisopropylethylamine (1.94 kg, 14.9 mol) and di-tert-butyl dicarbonate (1.14 kg, 5.24 mol) are added at room temperature and the mixture is stirred for 12h. The reaction mixture is washed twice with a saturated ammonium chloride solution (10.0 L), the organic layer is dried with anhydrous sodium sulfate and filtered. This overall procedure is carried out on 2 batches of the same size in parallel and the two reaction filtrates are combined and concentrated under vacuum. The crude mixture is purified by silica gel chromatography with petroleum ether ethyl acetate (30:1) to give tert-butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1 -methyl-3, 4-dihydro-1 H-isoquinoline-2-carboxylate (IVb) as a yellow oil (4.00 kg, 99.5% purity, 85.2% yield).

¹H NMR (400 MHz, DMSO-de) d 7.50 (d, J = 7.9 Hz, 1 H), 7.22 (br d, J = 6.7 Hz, 1 H), 7.06 -7.18 (m, 1 H), 4.84 (br s, 1 H), 4.12 (br s, 1H), 3.46 (br d, J = 15.4 Hz, 2H), 2.94 (br dd, J = 15.8, 5.2 Hz, 1H), 2.71 (br t, J = 9.5 Hz, 1 H), 1.45 (s, 9 H), 1.28 (br s, 3H), 0.81 (s, 9H), -0.08 (s, 6H).

2.6.3. tert-butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(1-hydroxy-1 -methyl- ethyl)-1 -methyl-3, 4-dihydro-1H-isoquinoline-2-carboxylate (IVc)

A solution of tert-butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1 H-isoquinoline-2-carboxylate (IVb) (42.5 g, 90.3 mmol) in dry THF (0.5 M solution) and a commercial solution of n-Buthylithium in Hexanes (1.6 M solution) were pumped at respectively 6.0 ml/min (1.0 equiv) and 2.46 mL/min (1.3 equiv.) and were mixed in a glass microchip cooled at -40°C. The mixed flow stream was pumped through the reaction zone 1 of the microchip (0.3 ml_) and was then combined with a solution of dry acetone (13.5 M) pumped at 6.0 mL/min (27 equiv.). The resulting stream was then passed through the reaction zone 2 of the microchip (0.7 ml_) at -40 °C. Finally, the global flow stream exiting the reactor was collected and quenched at room temperature in a saturated solution of aqueous ammonium chloride. When all the feed solutions were consumed, a bilayer reaction mixture was obtained. The aqueous layer was separated from the organic layer, and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. A yellow oil was obtained (46.5 g) and was purified by SFC chromatography on a GreenSep Nitro column (10m, 5×22.3 using CO298 %/EtOH 2% eluent). The solvent was removed under vacuum to yield to a white solid, tert-butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3, 4-dihydro-1H-isoquinoline-2-carboxylate (IVc) (25 g, 56 mmol, 62 % yield).

UPLC_MS basic 1 pic @ 3.83 min (ES+): 350 (M-Boc+H)⁺, 332 (M-Boc-H₂0+H)⁺, 100 % purity.

¹H NMR (400 MHz, DMSO-de) d 7.44 (d, J = 7.9 Hz, 1H), 7.19 (dt, J = 8.1 , 5.2 Hz, 1 H), 7.09 (t, J = 9.0 Hz, 1H), 4.99 (s, 1 H), 4.87 (dq, J = 13.4, 6.4 Hz, 1 H), 4.11 (s, 1H), 3.96 (t, J = 14.9 Hz, 1 H), 3.48 (dd, J = 9.4, 4.1 Hz, 1H), 2.98 (dd, J = 16.5, 5.0 Hz, 1H), 2.89 (t, J = 9.6 Hz, 1H), 1.65 (s, 3H), 1.58 (s, 3H), 1.55 (d, J = 2.5 Hz, 9H), 1.34 (dd, J = 20.5, 6.6 Hz, 3H), 0.90 (s, 9H), 0.08 (d, J = 7.2 Hz, 3H), -0.00 (s, 3H).

2.7. Preparation of intermediate (III) 2-[(1S,3R)-3-(hydroxymethyl)-1-methyl- 1.2.3.4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride

2.7.1. tert-butyl-dimethyl-[[(1S,3R)-1-methyl-5-(1-methyl-1-trimethylsilyloxy-ethyl)- 1.2.3.4-tetrahydroisoquinolin-3-yl]methoxy]silane- a15

Tert-butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3, 4-dihydro-1H-isoquinoline-2-carboxylate (IVc) (148 g, 87% purity, 287 mmol) is dissolved in 1000 ml_ dichloromethane and transferred to a 2 liter double walled reactor. 2,6-Lutidine (100 ml_, 860 mmol) is added and the jacket temperature is set at-2°C. Trimethylsilyl trifluoromethanesulfonate (154 g, 129 ml_, 692 mmol) is added over 40 min via an addition funnel. Two hours after the start of addition, the reaction is quenched by adding 650 ml_ of an aqueous citric acid solution (1M) and the temperature of the mixture is brought back to 20°C. One hour after the start of the quench, the layers are separated. The organic layer is washed twice with 350 ml_ of an aqueous solution of citric acid (1M). The organic layer is stirred with 750 ml_ of aqueous sodium carbonate (10% w/w) for 10 min before separation of the layers. The organic layer is dried over anhydrous sodium sulfate. The organic layer is then filtered and the filtrate is concentrated under vacuum at 40°C providing a yellow oil (128 g) of tert-butyl-dimethyl-[[(1S,3R)-1-methyl-5-(1-methyl-1-trimethylsilyloxy-ethyl)-1 ,2,3,4-tetrahydroisoquinolin-3-yl]methoxy]silane a15 which is used in the next step without further purification.

¹H NMR (400 MHz, CDC ) d 7.19 (d, J = 7.7 Hz, 1 H), 7.07 (t, J = 7.7 Hz, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 4.24 (q, J = 6.8 Hz, 1 H), 3.75 (dd, J = 9.7, 4.4 Hz, 1H), 3.60 (dd, J = 9.7, 7.0 Hz, 1H), 3.54 (dd, J = 16.3, 3.5 Hz, 1H), 3.15 (ddt, J = 10.9, 7.4, 4.0 Hz, 1 H), 2.52 (dd, J = 16.3, 10.9 Hz, 1H), 1.66 (d, J = 14.6 Hz, 6H), 1.52 – 1.43 (m, 3H), 0.92 (q, J = 1.2 Hz, 9H), 0.14 (q, J = 1.2 Hz, 2H), 0.09 (d, J = 1.1 Hz, 6H), 0.00 (q, J = 1.2, 0.8 Hz, 9H).

2.7.2. 2-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-5- yl]propan-2-ol chloride Intermediate (III)

In a three-neck round bottom flask equipped with a mechanical stirrer, tert-butyl-dimethyl-[[(1S,3R)-1-methyl-5-(1-methyl-1-trimethylsilyloxy-ethyl)-1,2,3,4-tetrahydroisoquinolin-3-yljmethoxyjsilane a15 (20.0 g, 47.4 mmol) is dissolved in 220 ml_ of isopropanol. To this solution, 42.3 ml_ of hydrochloric acid in iso-propanol (5-6 M, around 5 eq.) are added. 45 min after addition of hydrochloric acid, a 100 mg of seeds of the desired product are introduced. After 7 hours at room temperature, the reaction mixture is filtered over a sintered glass filter. The filtercake is washed with 40 ml_ isopropanol and dried under vacuum at room temperature overnight. 11.1 g of 2-[(1S,3R)-3-(hydroxymethyl)-1 -methyl-1 , 2,3,4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride (III) are obtained as a pinkish solid. The yield over the two deprotection steps is 91%.

¹H NMR (400 MHz, CD₃OD) d 7.46 (dd, J = 7.8, 1.3 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.3 Hz, 1H), 4.63 (q, J = 6.9 Hz, 1H), 3.97 (dd, J = 11.7, 3.8 Hz, 1 H), 3.88 (dd, J = 17.2, 4.3 Hz, 1H), 3.78 (dd, J = 11.8, 6.1 Hz, 1H), 3.66 – 3.56 (m, 1 H), 3.14 (dd, J = 17.2, 11 .4 Hz, 1 H), 1 .73 (d, J = 6.8 Hz, 3H), 1 .64 (d, J = 4.8 Hz, 6H). OH and NH protons are not observed.

2.8. Preparation of compound of formula (I).

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

In a 100 ml. Easymax reactor equipped with a mechanical stirrer, 2-(3,5-dichloro-1 -methyl-indazol-4-yl)acetic acid (II) (4.00 g, 15.4 mmol), 2-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1 ,2,3,4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride (III) (4.46 g, 16.4 mmol) and 48 mL of DMF are charged. The suspension is stirred at 20°C and then cooled by setting the jacket temperature to -2°C. Once the temperature of the mixture is below 3°C, N,N-diisopropylethylamine (9.5 mL, 54 mmol) is added. (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (6.4 g, 17 mmol) is added in four portions over 1 hour. The mixture is stirred for 1 h 45 before setting the jacket temperature at 15°C. 16 mL of water are then added over the course of a few minutes. 15 min later, 30 mg of solid product are added as seeds to initiate the crystallization. The jacket temperature is set at 20°C. Half an hour later, 16 mL of water are added over 17 min. Stirring of the suspension is pursued for 2 h 15 at 20°C before being filtered on sintered glass. The filtercake is washed with two portions of 20 mL of water and then dried at 50°C overnight under vacuum yielding 6.03 g 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 (I) (crude material).

A recristallization is carried out on 5.00 g of the crude material obtained by first suspending in 50 mL acetonitrile. The jacket temperature is set to 70°C. Once the solid has dissolved and the mass temperature has reached 66°C, 720 mI of water are added. The mass temperature is then cooled to 59°C and 125 mg of solid product is added as seeding material. The mass temperature is then decreased to 55°C over 25 min at which stage crystallization is occurring. The jacket temperature is then decreased over two hours from 58°C down to 20°C. After 50 min, the suspension is filtered and the filtercake is washed with 7.5 mL acetonitrile. The filtercake is then dried under vacuum at 45°C overnight and 2 hours at 50°C providing 4.04 g 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-1 H-isoquinolin-2-yl]ethanone (I) as an off-white powder (hydrate form) Yield = 64%.

¹H NMR (400 MHz, DMSO-cfe) d 7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.52 (dd, J = 9.0, 2.1 Hz, 1 H), 7.37 (ddd, J = 19.6, 7.6, 1 .7 Hz, 1 H), 7.25 – 7.03 (m, 2H), 5.30 (q, J = 6.5 Hz, 0.3H), 5.16 -4.99 (m, 1 .7H), 4.99 – 4.84 (m, 0.7H), 4.63 – 4.30 (m, 3.3H), 4.17 – 3.93 (m, 4H), 3.28 (dt, J = 10.5, 5.1 Hz, 1.3H), 3.10 – 2.85 (m, 1.7H), 1.56 (dd, J = 13.2, 6.9 Hz, 6.7H), 1.24 (d, J = 6.5 Hz, 2.3H).

PAT

• A Substituted Tetrahydroisoquinoiline Derivative as a D1 Positive Allosteric ModulatorPublication Number: US-2022259179-A1Priority Date: 2019-07-01
• Substituted tetrahydroisoquinoline derivatives as D1 positive allosteric modulatorsPublication Number: CN-113993857-BPriority Date: 2019-07-01Grant Date: 2024-01-02
• Substituted tetrahydroisoquinoline derivatives as D1 positive allosteric modulatorsPublication Number: CN-117700395-APriority Date: 2019-07-01
• Substituted tetrahydroisoquinoline derivatives as D1 positive allosteric modulatorsPublication Number: JP-7510444-B2Priority Date: 2019-07-01Grant Date: 2024-07-03
• Substituted Tetrahydroisoquinoline Derivatives as Positive Allosteric Modulators of D1Publication Number: CN-113993857-APriority Date: 2019-07-01
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: EP-3993794-A1Priority Date: 2019-07-01
• D1 Substituted tetrahydroisoquinoline derivatives as positive allosteric modulatorsPublication Number: KR-20220029686-APriority Date: 2019-07-01
• A SUBSTITUTED TETRAHYDROISOQUINOLINE DERIVATIVE AS A POSITIVE ALOSTERIC MODULATOR OF D1Publication Number: PE-20221020-A1Priority Date: 2019-07-01
• Substituted Tetrahydroisoquinoline Derivatives as D1 Positive Allosteric ModulatorsPublication Number: JP-2022539152-APriority Date: 2019-07-01
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: WO-2021001288-A1Priority Date: 2019-07-01
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: TW-202115010-APriority Date: 2019-07-01
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: WO-2021001288-A9Priority Date: 2019-07-01
• A substituted tetrahydroisoquinoline derivative as a D1 positive allosteric modulatorPublication Number: AU-2020299953-A1Priority Date: 2019-07-01
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: CA-3139571-A1Priority Date: 2019-07-01
• A Substituted Tetrahydroisoquinoline Derivative As A D1 Positive Allosteric ModulatorPublication Number: US-2024059665-A1Priority Date: 2020-12-18
• Prodrugs 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]ethanonePublication Number: US-2024083925-A1Priority Date: 2020-12-18
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: AU-2021403603-A9Priority Date: 2020-12-18
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: EP-4263517-B1Priority Date: 2020-12-18Grant Date: 2024-10-02
• Prodrugs 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]ethanonePublication Number: EP-4263519-B1Priority Date: 2020-12-18Grant Date: 2024-10-02
• Prodrugs 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]ethanonePublication Number: EP-4263519-A1Priority Date: 2020-12-18
• amorphous solid dispersionPublication Number: JP-2023553457-APriority Date: 2020-12-18
• Substituted tetrahydroisoquinoline derivatives as D1-positive allosteric modulatorsPublication Number: JP-2023553671-APriority Date: 2020-12-18
• 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)- Prodrug of 1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanonePublication Number: JP-2024500391-APriority Date: 2020-12-18
• Amorphous solid dispersionsPublication Number: US-2024000769-A1Priority Date: 2020-12-18
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: IL-303693-APriority Date: 2020-12-18
• Substituted tetrahydroisoquinoline derivatives as D1 positive allosteric modulatorsPublication Number: KR-20230121849-APriority Date: 2020-12-18
• amorphous solid dispersionPublication Number: KR-20230121867-APriority Date: 2020-12-18
• Amorphous solid dispersionsPublication Number: EP-4262756-A1Priority Date: 2020-12-18
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: EP-4263517-A1Priority Date: 2020-12-18
• Prodrugs 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]ethanonePublication Number: CA-3203281-A1Priority Date: 2020-12-18
• Substituted tetrahydroisoquinoline derivatives useful as D1 positive allosteric modulatorsPublication Number: CN-116583280-APriority Date: 2020-12-18
• 2-(3,5-Dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl Prodrug of -ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanonePublication Number: CN-116601161-APriority Date: 2020-12-18
• Amorphous Solid DispersionPublication Number: CN-116685308-APriority Date: 2020-12-18
• Amorphous solid dispersionsPublication Number: IL-303688-APriority Date: 2020-12-18
• Amorphous solid dispersionsPublication Number: WO-2022129267-A1Priority Date: 2020-12-18
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: WO-2022129268-A1Priority Date: 2020-12-18
• Prodrugs 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]ethanonePublication Number: WO-2022129356-A1Priority Date: 2020-12-18
• Amorphous solid dispersionsPublication Number: AU-2021401128-A1Priority Date: 2020-12-18
• A substituted tetrahydroisoquinoline derivative as a d1 positive allosteric modulatorPublication Number: AU-2021403603-A1Priority Date: 2020-12-18

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References

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2.  “Delving into the Latest Updates on Glovadalen with Synapse”. Synapse. 8 August 2024. Retrieved 10 August 2024.
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4.  “Glovadalen”. IUPHAR/BPS Guide to PHARMACOLOGY. Retrieved 10 August 2024.
5.  “UCB0022”. ALZFORUM. 3 May 2024. Retrieved 10 August 2024.
6.  Vermeiren C, Ates A, Bouzom F, Delaunois A, Gillard M, Kenda B, et al. (7 September 2022). “Preclinical characterization of UCB0022, an oral, brain penetrant, selective, clinical-stage positive allosteric modulator of the dopamine 1 receptor (D1 PAM)”. Movement Disorders. 37 (Suppl 2 [2022 International Congress September 15-18, 2022. Madrid, Spain]). Retrieved 10 August 2024.

////////Glovadalen, dopamine D1 receptor positive allosteric modulator, Phase 2, Parkinson’s disease, UCB-0022, UCB 0022, H8T5VKH4CZ