SUPPORTING INFORMATION SECTION: The manufacture of a homochiral 4-silyloxy-cyclopentenone intermediate for. the synthesis of prostaglandin analogues

Transcription

1 SUPPORTING INFORMATION SECTION: The manufacture of a homochiral 4-silyloxy-cyclopentenone intermediate for the synthesis of prostaglandin analogues Julian P. Henschke,* a Yuanlian Liu, b Xiaohong Huang, b Yungfa Chen, a Dechao Meng, b Lizhen Xia, b Xiuqiong Wei, b Aiping Xie, b Danhong Li, b Qiang Huang, b Xinyan Huang, b Ting Sun, b Juan Wang, b Xuebin Gu, b Longhu Wang, a Jun Xiao b and Shenhai Qiu. b a ScinoPharm Taiwan, Ltd, 1 Nan-Ke 8 th Rd, Tainan Science Industrial Park, Shan-Hua, Tainan, Taiwan 74144; b ScinoPharm (Changshu) Pharmaceutical, Ltd, 16 Dong Zhou Rd., Economic Development Zone, Changshu, Jiangsu province, China *Corresponding Author: julian.henschke@scinopharm.com.tw. 1

2 1) Synthesis of aldehyde 3 from furfural. Allyl furylcarbinol A, prepared in high yield by 1,2-addition of an allyl Grignard reagent to furfural under standard conditions, was converted in one pot by a Piancatelli rearrangement and further isomerisation, via the less thermodynamically stable isomer 5-allyl-4-hydroxy-2-cyclopentenone (B), to cyclopentenone C using a ph 4.8 buffer solution at 100 ºC in 45% yield (see the scheme below). About 50% of the mass balance was an insoluble, probably polymeric (broad peaks in its 1H NMR spectrum) material; see Clissold, et al. (U.S. Patent 7,109,371) for closely a related approach that gave C in 40% isolated yield from A. TBS protection furnished silyl ether D in 91% yield, which was directly converted into aldehyde 3 using a one-pot regioselective olefin dihydroxylation and oxidative cleavage with NaIO 4 in the presence of 4.5 mol% K 2 OsO 2 (OH) 4. The two step oxidative cleavage via diol 7 proceeded in less than half the yield. 2

3 2) Synthesis of 4-(tert-butyldimethylsilyloxy)-4-(furan-2-yl)-butene (5). NMR spectra: Figure 1 H NMR spectrum of 5 3

4 Figure 13 C NMR spectrum of 5 4

5 3) Synthesis of 4-(tert-butyldimethylsilyloxy)-4-(furan-2-yl)-butane-1,2-diol (6). NMR spectra: Figure 1 H NMR spectrum of 6 5

6 Figure 13 C NMR spectrum of 6 6

7 4) Synthesis of 3-(tert-butyldimethylsilyloxy)-3-(furan-2-yl)-propanal (4). NMR spectra: Figure 1 H NMR spectrum of 4 7

8 Figure 13 C NMR spectrum of 4 8

9 5) Synthesis of isopropyl (Z)-8-(tert-butyldimethylsilyloxy)-8-(furan-2-yl)-oct-5-enoate (8). i) NMR spectra: Figure 1 H NMR spectrum of 8 (small peaks are trans-isomer) 9

10 Figure 13 C NMR spectrum of 8 (small peaks are trans-isomer) 10

11 ii) Synthesis of isopropyl (Z)-8-(tert-butyldimethylsilyloxy)-8-(furan-2-yl)-oct-5-enoate (8) using low temperature Wittig reaction. To a suspension of (4-carboxybutyl)triphenylphosphonium bromide (40.4 Kg, 91.0 mol) in THF (190 Kg) in a 1000 L reactor under an atmosphere of argon at 0-10 ºC was added a solution of NaHMDS (2 M solution in THF, Kg, 175 mol) over 45 min at 0-10 ºC. The resulting mixture was stirred for 0.5 h and then cooled to between -60 to -70 ºC. A pre-chilled (-50 to -60 ºC) solution of aldehyde 4 (17.8 Kg, 70 mol) in THF (50 Kg) in a 80 L reactor was then added over 1 h at-60 to -70 ºC and was stirred until the aldehyde 4 was consumed (GC analysis; 2 h) and then acetone (5.6 Kg) was added and then stirred for 30 min. EtOAc (150.6 Kg) was added, followed by a solution of saturated aqueous NH 4 Cl (298.2 Kg) at -45 ºC. The reaction temperature was warmed to -5 ºC and the aqueous phase was separated. Water (55.2 Kg) was added to the aqueous phase to dissolve the precipitate and was extracted with EtOAc (49.66 Kg) which was then combined with the former organic phase and was washed twice with saturated aqueous NaCl (73.3 Kg each) and was concentrated at <55 ºC under reduced pressure to provide crude 9. To an acetone ( Kg) solution of the crude carboxylic acid 9 in a 500 L reactor was added K 2 CO 3 (28.12 Kg, mol) and 2-iodopropane (34.53 Kg, mol) and then heated under reflux for 4 h. Another portion of K 2 CO 3 (14.06 Kg, mol) and 2-iodopropane (17.77 Kg, mol) was added and the reaction was heated under reflux until complete (TLC analysis). Water (112.1 Kg) and MTBE (83.1 Kg) were added and the mixture was stirred for 20 min. The aqueous layer was separated and extracted with MTBE (26.3 Kg) and the MTBE portions were combined and washed twice with saturated aqueous NaCl (47.3 Kg each) and then was concentrated at <55 ºC under reduced pressure to provide a brown oil. The oil was dissolved in EtOAc (20.1 Kg) and n-heptane (45.9 Kg) was added to cause the formation of a precipitate that was removed by filtration and washed with a 1:3 mixture of EtOAc and n-heptane (34.17 Kg). The combined filtrates were evaporated under reduced pressure and the resulting oil was purified by column chromatography (eluting with a 1:10 mixture of EtOAc and n-heptane) and the fractions containing the title product were combined and concentrated (<60 ºC) under reduced pressure to provide 8 (17.02 Kg, 42 mol, 60% over three steps from diol 6) with 94% GC 11

12 purity. 12

13 iii) Influence of solvent and temperature on the Wittig reaction in graphical form. 8 (yield) 8 (HPLC area%) 15 (HPLC area%) trans-14 (HPLC area%) 13

14 6) Synthesis of isopropyl (Z)-7-(3-hydroxy-5-oxo-cyclopent-1-en-1-yl)-hept-5-enoate (rac-16). NMR spectra: Figure 1 H NMR spectrum of rac-16 (small peaks are trans-isomer) 14

15 Figure 13 C NMR spectrum of rac-16 7) Synthesis of isopropyl (3R,Z)-7-(3-hydroxy-5-oxo-cyclopent-1-en-1-yl)-hept-5-enoate ((R)-16) 15

16 i) NMR spectra of isopropyl (3R,Z)-7-(3-acetoxy-5-oxo-cyclopent-1-en-1-yl)-hept-5-enoate ((R)-17): Figure 1 H NMR spectrum of (R)-17 16

17 Figure 13 C NMR spectrum of (R)-17 (small peaks are trans-isomer) 17

18 ii) Chiral HPLC analysis of acetate ((R)-17) derivatives of (R)-16: Agilent 1100 HPLC monitoring at 216 nm; Chiral column: Chiralcel OJ-H 250 mm x 4.6 mm, 5 µm, run at 25 o C. Sample solvent: 1:1 n-hexane/isopropanol; Flow rate: 1.2 ml/min run isocratically with 100:2 n-hexane/isopropanol as the mobile phase. Figure - chiral HPLC trace of acetate derivatives ((R)-17) of (R)-16 following the second enzymatic resolution and column chromatographic purification iii) Research on the resolution of rac-16: As compared to the original protocol reported by Babiak and Wong for the resolution of structurally similar alcohols (see J. Org. Chem. 1990, 55, 3377 and US patent 5,106,750), an improved ee of the desired (R)-acetate (R)-17 could be achieved in the first resolution step at about 40 ºC by reducing the amount of vinyl acetate and diluting it with large volumes of n-hexane (50 v/w n-hexane and 3 v/w vinyl acetate (w.r.t. rac-16); n- heptane can be used instead of n-hexane to avoid toxicities associated with n-hexane). Under these conditions a 45% conversion (90% theoretical conversion) of racemic rac-16 to (R)-acetate (R)-17 with 92.4% ee was obtained after 72 h, which compared to only a 67% ee of (R)-acetate (R)-17 at a 44% conversion (68 h) of racemic rac-16 when using the originally report conditions (25 volumes of vinyl acetate at r.t.). The resolution reaction was extremely sensitive to water: in n-hexane (100 v/w; 3 v/w of vinyl acetate) with ca ppm of water added, the reaction was greatly retarded (about 20% conversion in 3 days at r.t.) and the ee was 29.2%. When 50,000 ppm of water was added, essentially no resolution occurred. 18

19 iv) NMR spectra of (R)-16: 1 H and 13 C NMR spectra are identical to the racemic material (i.e., rac-16) v) Chiral HPLC analysis of (R)-16: Agilent 1100 HPLC monitoring at 216 nm. Chiral column: Chiralcel OJ-H 5 µm, 250 x 4.6 mm, run at 25 o C. Sample solvent: 1:1 n-hexane/isopropanol Flow rate: 1.2 ml/min run isocratically with 100:2 n-hexane/isopropanol as the mobile phase. Figure - chiral HPLC trace of (R)-16 following guanidinolysis of (R)-18 19

20 8) Synthesis of isopropyl (3R,Z)-7-(3-(tert-butyldimethylsilyloxy)-5-oxo-cyclopent-1-en-1-yl)-hept-5-enoate ((R)-1). i) NMR spectra of (R)-1: Figure 1 H NMR spectrum of (R)-1 (small peaks are trans-isomer) 20

21 Figure 13 C NMR spectrum of (R)-1 (small peaks are trans-isomer) 21

22 ii) Chiral HPLC analysis of (R)-1: Agilent 1100 HPLC monitoring at 220 nm. Chiral column: Chiralcel OD mm x 4.6 mm, 3 µm, run at 25 o C. Flow rate: 0.2 ml/min run isocratically with 99:1 n-hexane/isopropanol as the mobile phase. Figure - chiral HPLC trace of (R)-1 following column chromatographic purification 22

23 iii) High resolution mass spectrometery: HRMS Electrospray ionization mass spectrometry was performed using Bruker MicrOTOF instrument with a TOF analyzer: Capillary Voltage: 4.5 kv (Positive mode); End Plate Offset: -500 V; Collision Cell RF: 600 Vpp; Dry Heater: 180 o C; Scan range: 50 amu amu Intens. x MS, min #( ), Background Subtracted m/z Figure - HRMS mass spectrum of (R)-1 23

24 iv) GC analysis of (R)-1: Column: DM-1701, 30 m x 0.25 mm. Injection temperature 280 o C; detector temperature 300 o C. Gradient: 40 o C, hold for 3 min, then ramp at 30 o C/min to 210 o C, hold for 13 min at 210 o C, then ramp at 30 o C/min to 260 o C and hold for 10 min. Figure - GC trace of (R)-1 following column chromatography 24

25 Figure 1 H NMR spectrum of (R)-1 containing 0.62 mol% trans-isomer (prepared from purified salt 2) 25

26 v) Chiral HPLC analysis of (R)-1: Agilent 1100 HPLC monitoring at 220 nm. Chiral column: Chiralcel OD mm x 4.6 mm, 3 µm, run at 25 o C. Flow rate: 0.2 ml/min run isocratically with 99:1 n-hexane/isopropanol as the mobile phase. Figure - chiral HPLC trace of (R)-1 containing 0.62 mol% trans-isomer (prepared from purified salt 2) 26

27 9) Synthesis of (Z)- 8-(furan-2-yl)-8-hydroxy-oct-5-enoic acid (19). Figure 1 H NMR spectrum of 19 27

28 HO 2 C O OH 19 Figure 13 C NMR spectrum of 19 28

29 10) Synthesis and recrystallization of (4-methoxyphenyl)-methanaminium (Z)-8-(furan-2-yl)-8-hydroxy-oct-5-enoate (2). i) NMR spectra of 2: Figure 1 H NMR spectrum of 2 29

30 Figure 13 C NMR spectrum of 2 30

31 ii) HPLC analysis of 2: Agilent 1200 HPLC monitoring at 215 nm; Column: Zorbax SB-C18, 150 mm x 4.6 mm, 5 µm, maintained at 30 o C Flow rate: 1.5 ml/min run with 90:10 10 mm K 2 HPO 4 /MeCN for 0-11 min (isocratic), then 90 to 50: 10 to mm K 2 HPO 4 /MeCN (as a linear gradient) from min, then 50 to 20:50 to mm K 2 HPO 4 /MeCN (as a linear gradient) for min, then 20:80 10 mm K 2 HPO 4 /MeCN (isocratic) for min as the mobile phase. Figure - HPLC trace of recrystallised 2 which appears as 19 showing the cis- and trans- isomers 31

32 11) Synthesis of isopropyl (Z)-8-(furan-2-yl)-8-hydroxy-oct-5-enoate (14). i) NMR spectra of 14: Figure 1 H NMR spectrum of cis-14 32

33 Figure 13 C NMR spectrum of cis-14 33

34 ii) HPLC analysis of 14: Agilent 1200 HPLC monitoring at 215 nm; Column: Zorbax SB-C18 column (150 mm x 4.6 mm, 5 µm) maintained at 30 o C. Flow rate: 1.5 ml/min run with 80 to 60:20 to mm KH2PO4/MeCN for 0-15 min (linear gradient), then 60:40 10 mm KH2PO4/MeCN (isocratic) from 5-18 min, then 60 to 20:40 to mm KH2PO4/MeCN (linear gradient) for min, then 20:80 10 mm KH2PO4/MeCN (isocratic) for min as the mobile phase. Figure - HPLC trace of cis-14 after purification 34