Diastereospecific Enolate Addition and Atom- of L/T Calcium Channel Blocker ACT

Transcription

1 Supporting Information Diastereospecific Enolate Addition and Atom- Efficient Benzimidazole Synthesis for the Production of L/T Calcium Channel Blocker ACT Jacques-Alexis Funel, Stephan Brodbeck, Yves Guggisberg, Remy Litjens, Thomas Seidel, Martin Struijk, and Stefan Abele, * Process Research Chemistry, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland Technical perations, Drug Substance, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH 4123 Allschwil, Switzerland CML Europe BV, Vliesvenweg 1, P.. Box 8, Weert, The Netherlands. Valsynthese SA, Fabrikstrasse 48, CH-3900 Brig, Switzerland Corresponding author. stefan.abele@actelion.com. Telephone:

2 Table of Contents 1. verall scheme Analytical methods Synthesis of N-methylacetamide DSC analyses X-Ray analyses LC MS and NMR spectra

3 1. verall scheme NC Cl CN step 1 step 2 step 3 TMS Cl Me 3 Si CN Cl step 4 H C 2 H steps 8-9 steps 5-7 resolution by HPLC on 200-kg scale Me steps Me Me Me N N H HN step 13 2 C 2 H C 2 H Me H N Me HN N Me steps Me N HN Me N Me ACT (1 bis maleate) Step 1 to step 7: Funel, J.-A.; Schmidt, G.; Abele, S. rg. Process Res. Dev. 2011, 15, Step 8 to 17: this paper. 3

4 2. Analytical methods HPLC method 1: Injection volume: Pump: Column: Column flow: Eluent: 5 L Gradient Pump with mobile phase degasser Halo C18; 100 x 3.0 mm, 2.7 μm 1.0 ml/min Preparation of Eluent A: add approximately 700 ml of Milli Q water to a 1000 ml volumetric flask. Add 1 ml of TFA. Fill up to 1000 ml with Milli Q water. Preparation of Eluent B: add approximately 700 ml of acetonitrile to a 1000 ml volumetric flask. Add 1.2 ml of TFA. Fill up to 1000 ml with acetonitrile. Gradient mode: Time % A 0 min 70% 7 min 5% 8.0 min 5% 8.1 min 70% 10.0 min 70% Temperature: 35 C Detection wavelength: 220 nm 4

5 HPLC method 2: Injection volume: Pump: Column: 5 L Gradient Pump with mobile phase degasser Machery Nagel Nucleodur C18 Pyramid, 125 mm x 4 mm, 3 μm Column flow: Eluent: 0.8 ml/min Eluent A: water, 0.025% TFA Eluent B: acetonitrile, 0.025% TFA Gradient mode: Time % A 0 min 95% 15 min 5% 25 min 5% 26 min 95% Temperature: 50 C Detection wavelength: 210 nm 5

6 HPLC method 3 Injection volume: Pump: Column: 5 L Gradient Pump with mobile phase degasser Ascentis RP-Amide, 150 mm x 4.6 mm, 3 μm Column flow: 0.8 ml/min Eluent: Eluent A: H2, MeH, formic acid (95/5/0.075) Eluent B: H2, MeH, formic acid (5/95/0.075) Gradient mode: Time % A 0 min 60% 10 min 45% 20 min 5% 27 min 5% 27.1 min 60% 32 min 60 Temperature: 15 C Detection wavelength: 255 nm 6

7 3. Synthesis of N-methylacetamide 17 N-(3-(4,7-Dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)-N-methylacetamide (17) 4 2 HCl (32.0 g, 100 mmol) was suspended in DCM (100 ml) and treated with 1 M NaH to reach ph > 12 (Caution: gas evolution). After phase separation, the aqueous layer was extracted with DCM (10 vol, twice). The combined organic phases were concentrated under reduced pressure to afford the corresponding free base 4 as an oil. Yield: 20.0 g (81%). This material was used as such. Isopropenyl acetate (28.9 g, mmol, 3.6 equiv) was added to a solution of crude 4 (20.0 g, 80.2 mmol) in toluene (20 ml). The resulting mixture was heated to reflux for 3 h. It was cooled to 20 C and concentrated to dryness. The crude residue (10 g) was dissolved in EtH (60 ml) and treated with acetyl chloride (17.1 ml, mmol, 3 equiv). The resulting suspension was stirred at 20 C for 1 h, diluted with AcEt, filtered and washed with AcEt to afford 10 2 HCl as a white solid. Yield: 25.2 g (70%). Alternatively, the corresponding oxalate salt was isolated (75 80% yield) upon treatment with oxalic acid (1.4 equiv) in EtH. Purity (HPLC method 2): 99.4% a/a, t R 7.0 min, [M + 1] + = 292; 1 H NMR (D 6 -DMS): δ 15.2 (br s, 1H), 6.95 (s, 2H), 4.75 (br s, 3H), 3.93 (br s, 6H), (m, 2H), (m, 1H), 3.06 (t, J = 7.6 Hz, 1H) (br s, 2H), (m, 1H), (m, 2H), 1.95 (br s, 2H); 13 C NMR (D 6 -DMS): δ 170.6, 153.9, 141.1, 122.7, 106.7, 56.7 (2 C), 49.5, 45.7, 35.9, 33.0, 25.1, 23.6, 22.1,

8 4. DSC analyses DSC of a 9:1 mixture of 11a/11b DSC of a 9:1 mixture of 11a/11b doped with 5% w/w water 8

9 DSC of a purified sample of 12a (flash chromatography over Si 2, light-beige solid) 9

10 5. X-Ray analyses X-ray structure of rac-6: tert-butyl 2-((1R,2R,4R)-2-hydroxy-5-phenylbicyclo[2.2.2]oct-5-en-2-yl)acetate An analytical sample of rac-6 was purified by flash chromatography on silica gel using a gradient of ethylacetate in heptane. Crystals of suitable quality for X-Ray analysis were grown from heptane. rac. 6 H C 2 tbu 10

11 X-ray structure of 2-((1R,2R,4R)-2-hydroxy-5-phenylbicyclo[2.2.2]oct-5-en-2-yl)-N-((R)-1-(naphthalen- 1-yl)ethyl)acetamide To a solution of 2 (500 mg, 1.94 mmol) and (R)-(+)-1-(1-Naphthyl)ethylamine (0.373 ml, 2.32 mmol, 1.2 equiv.) in DCM (4 ml) was added Et 3 N (0.566 ml, 4.06 mmol, 2.1 equiv). A solution of 1- propanephosphonic anhydride (T3P) in DCM (1.65 ml, 2.9 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at 20 C for 1 h. It was quenched with the addition of 1 M HCl. It was extracted twice with DCM, dried over Na 2 S 4, filtered and concentrated. The residue was purified by preparative TLC eluting with heptane / AcEt (1/1) to afford the expected product as a white foam. Yield: 490 mg (62%). An aliquot was recrystallized from toluene to afford needles-like crystals that were suitable for X-Ray analysis. NMR (CDCl 3 ): δ 8.07 (d, J = 8.1Hz, 1H), (m, 1H), 7.82 (d, J = 8.1Hz, 1H), (m, 4H), (m, 4H), (m 1H), 6.47 (dd, J = 6.9, 1.8 Hz, 1H), (m, 2H), 4.92 (s, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 1.72 (d, J = 6.5 Hz, 3H), (m, 2H), (m, 1H). H NH 11

12 12

13 6. LC MS and NMR spectra The following LC MS traces and 1 H NMR spectra of the phenylenediamines 12a and 12b are shown to demonstrate the purging of the regioisomer 11b in the hydrogenation step. LC MS trace of 12a, starting with a 7:1 mixture of 11a and 11b. The peak at t R = 1.8 min is the injection peak. 13

14 LC MS trace of 12b obtained from pure 11b in 19% yield. The peak at t R = 1.46 min is derived from residual toluene in ethanol. 14

15 Me NH 2 Standard CH 3 and 12a CH 3 NH 2 Me 12a Standard arom. C H 12a, arom. C H EtH 1 H NMR assay of a solution of 12a in ethanol (in CDCl 3 ), obtained from a 9:1 mixture of 11a and 11b (18.2% water (Karl-Fischer), 1 H NMR assay 72% w/w with regard to 11a). Internal standard 1,4-dimethoxybenzene. Concentration of this solution: 30% w/w. 15

16 Me NH 2 Standard CH 3 and 12a CH 3 Standard arom. C H NH 2 Me 12a 12a, arom. C H 12a, NH 2 1 H NMR assay of crude 12a (in D 6 -DMS) obtained from a 9:1 mixture of 11a and 11b with 12% water by Karl-Fischer. Assay: 88% w/w. Internal standard 1,4-dimethoxybenzene. The LC MS shows a purity of 93 95% a/a at 210 nm. 16

17 12b 12b, arom. C H 12b, NH 2 1 H NMR spectra of crude 12b (in D 6 -DMS) obtained from 11b in 19% yield. 17

18 Standard arom. C H Standard CH HCl (mono-hydrate) 1 H NMR assay of 4. 2 HCl (in MeD). Assay: 72% w/w with respect to free base. Theoretical maximum assay for the free base is 73% w/w considering the mono-hydrate bis-hcl salt. Internal standard 1,4-dimethoxybenzene. 18

19 1 H NMR spectra of 1 2 C 4 H 4 4 (in MeD) 19

20 1 H NMR assay of 1 2 C 4 H 4 4 (in MeD). Assay: 99.0% w/w with respect to free base Mass of sample: 8.3 mg, mass of reference standard: 10.4 mg. 20