Novel Process for Preparation of Tetrabenazine and Deutetrabenazine. Purna Chandra Ray*, Yogesh Dadaji Pawar, Dnyaneshwar Tukaram Singare, Tushar

Transcription

1 Supporting Information Novel Process for Preparation of Tetrabenazine and Deutetrabenazine Purna Chandra Ray*, Yogesh Dadaji Pawar, Dnyaneshwar Tukaram Singare, Tushar Nandkumar Deshpande and Girij Pal Singh Lupin Research Park, Lupin Limited, 46 & 47A, Village Nande, Taluka Mulshi, Pune , Maharashtra, India. Table of contents Supporting Data Large scale preparation of dihydroxy isoquinoline compound 9 and spectral data Page No 2-4 Large scale preparation of tetrabenazine 1 and spectral data 5-7 Purification of tetrabenazine 1 and spectral data 7-9 Large scale preparation of deutetrabenazine 2 and spectral data Large scale purification of deutetrabenazine 2 and spectral data Table S1. Solvent screening for synthesis of 9 16 Table S2. Bases screening for synthesis of 9 16 Table S3. Experimental factors for DoE of 9 16 Table S4. DoE design for optimal conversion for compound 9 17 Table S5. Experimental results for DoE of compound Table S6. Lab optimization of deuterated methanol for synthesis of 2 20 Table S7. Experimental factors for DoE of 2 20 Table S8. DoE design to optimize quantity of deuterated methanol (MeOH-D 4 ) 20 Table S9. Experimental results for DoE to optimize quantity of deuterated methanol (MeOH-D 4 ) 21 1

2 Large Scale Preparation of Dihydroxy Isoquinoline compound 9. In stainless steel cylindrical shape reactor, a slurry of 6,7-dihydroxy-3,4-dihydroisoquinoline hydrochloride 6 (4.0 kg.) in methanol (12 lit.), and water (12 lit.) was stirred and (2-acetyl-4-methyl-pentyl)- trimethylammonium iodide (7) (6.6 kg.) was added to it. The reaction mass was stirred at room temperature and potassium carbonate (2.8 kg.) was added in five equal lots. The reaction mass was heated to C and was stirred for 30 hours. The reaction mass was cooled to room temperature and water (12 lit.) was added to it and stirred for 4 hours. The solid was filtered and washed with water, the solid was taken in isopropanol (10 lit.) and the mixture was heated to C for min. The reaction mass was cooled, the solid was filtered and washed with isopropanol and dried under vacuum till constant weight to give product 9 (4.0 kg., 69%). HPLC purity: 98.50%; Melting point: C; FTIR (In KBr): 3442, 2959, 2456, 1714, 1276, 872, cm -1 ; 1 HNMR (500 MHz, DMSO-d 6 ) δ 8.70 (s, 2H), 6.45 (d, 2H, J = 11.2 Hz.), 3.35 (d, 1H, J = 9.6 Hz.), 3.20 (dd, 1H, J = 11.6, 6.0 Hz.) (m, 1H), (m, 1H), (m, 5H), 2.22 (t, 1H, J = 12.0 Hz.), (m, 2H), (m, 7H); ESI-MS (m/z) [M + H] +. 1 HNMR: Dihydroxy isoquinoline compound 9 2

3 1 HNMR: D 2 O exchange of dihydroxy isoquinoline compound 9 FTIR: Dihydroxy isoquinoline compound 9 3

4 Mass: Dihydroxy isoquinoline compound 9 HPLC Purity: Dihydroxy isoquinoline compound 9 4

5 Large Scale Preparation of Tetrabenazine 1. A slurry of tetrahydrofuran (2000 ml), dihydroxy isoquinoline compound 9 (250 g), methanol (276.8 g) and triphenylphosphine (679.9 g) was prepared in a glass line cylindrical shape reactor, in which slowly added a solution of diisopropylazodicarboxylate (DIAD) (524.1 g) in tetrahydrofuran (500 ml) at C over the period of 1 to 2 hrs. The reaction mass was stirred for 3-6 hours at C. The reaction mass was washed with water and organic layer was concentrated under vacuum. A mixture of water (2500 ml) and toluene (7500 ml) was added to the concentrated mass and the mixture was stirred. The aqueous layer was separated and the organic layer was washed with 5% aqueous sodium hydrogen sulphate solution (2500 ml, 3 times).the aqueous layers were collected together and the ph was adjusted between 9-11 using aqueous ammonia solution (750 ml).dichloromethane (2500 ml) was added to it and the organic layer was separated and concentrated under vacuum. Water (1250 ml) was added to the concentrated mass and the mass was stirred for at C for 2 hours. The solid was filtered, washed and dried under vacuum to give 1 (262.3 g, 96%); FTIR (In KBr): 2942, 2919, 1701, 1516, 1465, 1370, 1263, 1159, 1010, 860, 749 cm -1 ; 1 HNMR (500 MHz, CDCl 3 ) δ 6.63 (s, 1H ), 6.57 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.52 (d, 1H, J = 11.2 Hz.), 3.32 (dd, 1H J = 11.6, 6.4 Hz.), (m, 2H), (m, 1H), (m, 2H), (m, 2H), 2.37 (t, 1H, J = 11.6 Hz.), (m, 1H), (m, 1H), (m, 1H), (m, 6H); ESI-MS (m/z) [M + H] +. 5

6 1 HNMR: Tetrabenazine 1 FTIR: Tetrabenazine 1 6

7 Mass: Tetrabenazine 1 Purification of Tetrabenazine 1. In a glass line cylindrical shape reactor, a slurry of tetrabenazine 1 (10 g) and ethyl acetate (30 ml) was heated to C.The mixture was stirred for minutes and filtered through micron filter. The filtrate was cooled to C and n-heptane (100 ml) was added to it. The mixture was stirred for about 4 hours at C.The solid was filtered, washed with n-heptane and dried under vacuum to give 1 (9.6 g, 96%). HPLC purity: 99.75%; FTIR (In KBr): 2942, 2919, 1701, 1516, 1465, 1370, 1263, 1159, 1010, 860, 749 cm -1 ; 1 HNMR (500 MHz, DMSO-d6) δ 6.70(s, 1H ), 6.69 (s, 1H), 3.72 (s, 6H), 3.46 (d, 1H, J = 10.0 Hz.), 3.24 (dd, 1H, J = 11.5, 6.0 Hz.), (m, 1H), (m, 1H),2.85 (dd,1h J = 13.0, 3.0 Hz), (m, 2H), (m, 2H), 2.28 (t, 1H, J = 12.0 Hz.), (m, 2H), (m, 7H); ESI-MS (m/z) [M + H] +. 7

8 1 HNMR: Purified Tetrabenazine 1 FTIR: Purified Tetrabenazine 1 8

9 Mass: Purified Tetrabenazine 1 HPLC Purity: Purified Tetrabenazine 1 9

10 Large Scale Preparation of Deutetrabenazine 2. A slurry of dichloromethane (24 lit.), dihydroxy benzoquinoline compound 9 (3.0 kg.), deuterated methanol-d 4 (3.75 kg.) and triphenylphosphine (8.16 kg.) was prepared in a glass line cylindrical shape reactor, in which slowly added a solution of diisopropylazodicaboxylate (DIAD) (6.30 kg.) in dichloromethane (6 lit.) at C over the period of 1 to 2 hrs. The reaction mass was stirred for 2 hours at C. The reaction mass was washed with water and organic layer was concentrated under vacuum. Toluene was added to the residue and the mixture was stirred. The mixture was filtered and the filtrate was washed with 5% aqueous sodium hydrogen sulphate solution (15 lit., 3 times). The aqueous layer was collected together and the ph was adjusted between 9-11 using aqueous ammonia solution. Dichloromethane (30 lit.) was added to it and the organic layer was separated and concentrated under vacuum. Ethyl acetate (30 lit.) was added to the residue, carbon treatment was given and ethyl acetate was removed under vacuum. Isopropanol (6 lit.) was added to the residue and the mixture was heated to C for minutes. The reaction mass was cooled, the solid was filtered and washed with isopropanol and dried under vacuum to give 2 (3.06 kg, 92%). HPLC purity: 98.82%; FTIR (In KBr): 2942, 2920, 2246, 2067, 1700, 1513, 1269, 1113, 990, 747 cm -1 ; 1 HNMR (500 MHz, CDCl 3 ) δ 6.63 (s, 1H ), 6.56 (s, 1H), 3.53 (d, 1H, J = 10.5 Hz.), (m, 1H), (m, 2H), 2.92 (dd, 1H, J = 13.5,3.0 Hz ), (m, 2H), (m, 2H), 2.37 (t, 1H, J = 11.5 Hz.), (m, 1H), (m, 1H), (m, 1H), (m, 6H); ESI-MS (m/z) [M + H] + 10

11 1 HNMR: Deutetrabenazine 2 FTIR: Deutetrabenazine 2 11

12 Mass: Deutetrabenazine 2 HPLC Purity: Deutetrabenazine 2 12

13 Large Scale Purification of Deutetrabenazine 2. In a glass line cylindrical shape reactor, a slurry of deutetrabenazine 2 (1.70 kg.) and ethyl acetate (13.6 lit.) was heated to C.The mixture was stirred for minutes and filtered through micron filter. The filtrate was concentrated under vacuum and isopropanol (1.7 lit.) was added to the residue. The mixture was heated to C for minutes and was cooled to C.The off-white solid was filtered, washed with isopropanol and dried under vacuum to give 2 (1.53 kg, 90%). HPLC purity: 99.77%; Melting point: C; FTIR (In KBr): 2942, 2920, 2246, 2067, 1700, 1513, 1269, 1113, 990, 747 cm -1 ; 1 HNMR (500 MHz, DMSO-d6) δ 6.69 (s, 2H), 3.46 (d, 1H, J = 10.0 Hz.), 3.25 (dd, 1H, J = 11.5, 6.0 Hz.), (m, 1H), (m, 1H),2.85 (dd,1h J = 13.5, 3.0 Hz), (m, 2H), (m, 2H), 2.28 (t, 1H, J = 11.5 Hz.), (m, 2H), (m, 7H); ESI-MS (m/z) [M + H] + ; [α] D 0.3 [C 0.3, DCM at 25 C]. 1 HNMR: Purified Deutetrabenazine 2 13

14 FTIR: Purified Deutetrabenazine 2 Mass: Purified Deutetrabenazine 2 14

15 HPLC Purity: Purified Deutetrabenazine 2 15

16 Table S1. Solvent screening for synthesis of 9 entry solvent-1 solvent-2 K 2 CO 3 (mol. equiv. w.r.t 6) 9 (% area HPLC) 1 MeOH Water % EtOH IPA n-butanol DMF Diglyme 1, 4-Dioxane -- Water Water Water Water Water Water Water % 4% 18% 59% 56% 60% 62% Table S2. Bases screening for synthesis of 9 entry MeOH (Vol.) Water (Vol.) Base (mol. equiv. w.r.t 6) 9 (% area HPLC) K 2 CO 3 (1.2) 70% Na 2 CO 3 (1.25) TEA (2.5) DIPEA (2.5) NaOH (2.5) KOH (2.5) DBU (2.5) 53% 25% 25% 56% 57% 62% Table S3. Experimental factors for DoE of 9 Factors Initial parameters Low level High level A: 7 DTTSC mol mol. 1.0 mol. 1.5 mol. B: MeOH: Water ratio C: K 2 CO 3 mol. D: Reaction Temp 1:3 ratio 1.0 mol C 1:5 ratio 0.7 mol. 35 C 1:1 ratio 1.5 mol. 70 C 16

17 Table S4. DoE design for optimal conversion for compound 9 factor 1 factor 2 factor 3 factor 4 expt. A: 7 (DTTSC) B:water C:K 2 CO 3 D:Rxn no. mol. equiv. volume mol. equiv. temp

18 Table S5. Experimental results for DoE of compound 9 (DTR-I) Factor 1 Factor 2 Factor 3 Factor 4 Reaction Monitoring expt. no. A:7 (DTTSC) mol. equiv. B: Water MeOH Volume C:K 2 CO 3 mol. equiv. D:Rxn Temp. Sample Hrs. % 6 % 9 DTR-I : Solid : Solid : Solid : Solid :

19 Solid : Solid : Solid : Solid : Solid : Solid

20 Table S6. Lab optimization of deuterated methanol for synthesis of 2 entry TPP (mol.equiv.) DIAD (mol.equiv) deuterated methanol (mol.equiv) 2 (% area HPLC) % % 78% 77% Table S7. Experimental factors for DoE of 2 factors Initial parameters Low level High Level A: MeOH-D 4 mol. 10 mol. 2 mol. 12 mol. B: DIAD & TPP mol. C: Addition temp. & Reaction Temp 3 mol. (each) C 2 mol. (each) 10 C 6 mol. (each) 40 C Table S8. DoE design to optimize quantity of deuterated methanol (MeOH-D 4 ) Factor 1 Factor 2 Factor 3 expt. no. A: MeOH-D 4 (mol. equiv.) B:TPP & DIAD (mol. equiv.) C: Addition temp. & reaction temp

21 Table S9. Experimental results for DoE to optimize quantity of deuterated methanol (MeOH- D 4 ) expt.no. 1 3 Factor 1 Factor 2 Factor 3 Factor 4 B: TPP & C: DIAD A:MeOH-D 4 D:Rxn. DIAD Mole Addition Mole Ratio Temp. Ratio temperature Sample Time Reacttion Monitiring 9% 2% % RRT 0.61 % RRT ND 0.03 ND ND 0.03 ND ND 0.03 ND ND 0.02 ND ND ND ND ND 23.0 ND 0.04 ND ND ND ND 84.4 ND ND ND 83.1 ND ND ND ND 2.0 ND ND ND ND ND ND ND ND ND ND ND ND ND ND