Research ArticleProceedings of the 4th International Symposium on Vitamin D and Analogs in Cancer Prevention and Therapy, May 20-21, 2011, Homburg/Saar, Germany

Process Development for the Practical Production of Eldecalcitol by Linear, Convergent and Biomimetic Syntheses

NOBORU KUBODERA and SUSUMI HATAKEYAMA
Anticancer Research January 2012, 32 (1) 303-309;

Abstract

Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3], an analog of calcitriol (1α,25-dihydroxyvitamin D3), possesses a hydroxypropoxy substituent at the 2β-position of calcitriol. Eldecalcitol has potent biological effects on bone disease such as osteoporosis. The marketing of eldecalcitol has very recently started in Japan. In consideration of this, we have been investigating practical synthesis of eldecalcitol for industrial-scale production. Eldecalcitol was initially synthesized in a linear manner. The 27-step linear sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%). Next, we developed a convergent approach based on the Trost coupling reaction, in which the A-ring fragment (ene-yne part obtained in 10.4% overall yield) and the C/D-ring fragment (bromomethylene part obtained in 27.1% overall yield) are coupled to produce the triene system of eldecalcitol (15.6%). Although the overall yield of the convergent synthesis was better than that of the linear synthesis, significant improvements were still necessary. Therefore, additional biomimetic studies were investigated. Process development for the practical production of eldecalcitol is described herein.

It is well-established that cholecalciferol (vitamin D3, Figure 1, 1), ingested in foods or synthesized in the skin, is metabolized to calcifediol (25-hydroxyvitamin D3, 2) in the liver, which is further hydroxylated at the 1α-position in the kidney to produce active vitamin D3, calcitriol (1α,25-dihydroxyvitamin D3, 3) (1). Calcitriol (3) is well recognized as a potent regulator of calcium and phosphorous metabolism while also possessing regulatory effects on cell proliferation and differentiation (2). In Japan, calcitriol and its synthetic prodrug, alfacalcidol (1α-hydroxyvitamin D3, 4), which is also activated to 3 in the body (liver and bone), have been widely used for the treatment of osteoporosis for more than a quarter of a century (3). Calcitriol and alfacalcidol (4) have been recognized as very safe medicines that show mild or moderate increase in bone mineral density (BMD) in osteoporotic patients. There exists intense interest in obtaining active vitamin D3 analogs more potent than 3 and 4 towards increasing BMD and preventing bone fracture with less calcemic activity for treating osteoporosis. Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (5), developing code: ED-71], which possesses a hydroxypropoxy substituent at the 2β-position of calcitriol, is such an analog that shows potent effects on bone therapy (4-9). The recent completion of a phase III clinical trial of eldecalcitol in comparison with alfacalcidol for bone fracture prevention produced excellent results (10, 11). The marketing of eldecalcitol with the sales name of Edirol as an excellent medicine for the treatment of osteoporosis has very recently started in Japan.

Considering the marketing of eldecalcitol, we have been investigating its practical synthesis for industrial-scale production. Eldecalcitol was initially synthesized in a linear manner in which 1,2α-epoxide 28, prepared from lithocholic acid (6) via 25-hydroxycholesterol (17), served as a key intermediate for the introduction of the hydroxypropoxy substituent at the 2β-position (4, 12). The 27-step linear sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%). Next, we developed a convergent approach based on the Trost coupling reaction, in which A-ring fragment 37 (ene-yne part prepared from C2 symmetrical epoxide 30 in 10.4% overall yield) and C/D-ring fragment 40 (bromomethylene part obtained from calcifediol (2) in 27.1% overall yield) are coupled to produce the triene system of eldecalcitol (15.6%) (13, 14). Although the overall yield of the convergent synthesis was better than that of the linear synthesis, significant improvements were still necessary. Therefore, additional biomimetic studies on the microbial 25-hydroxylation of the steroidal side chain using cholesterol (42) as a starting material were investigated (15). In this paper, process development for the practical production of eldecalcitol, the linear synthesis, convergent synthesis, and biomimetic synthesis are described.

Figure 1.
Figure 1.

Activation of cholecalciferol (1), calcifediol (2), and alfacalcidol (4) to calcitriol (3) and the structure of eldecalcitol (5).

Materials and Methods

Eldecalcitol (5) by linear synthesis. Detailed experimental procedures for the linear synthesis have been described elsewhere (4, 12).

Eldecalcitol (5) by convergent synthesis. Detailed experimental procedures for the convergent synthesis have also been described elsewhere (13).

Eldecalcitol (5) by biomimetic synthesis. Conversion of cholesterol (42) to 1,2α-epoxide 53 has been previously described (16) and detailed experimental procedures for microbial 25-hydroxylation of 55 have been described in a patent (17).

Results and Discussion

Synthesis of eldecalcitol by the linear method. Eldecalcitol (5) was originally synthesized by the linear method using lithocholic acid (6) as a starting material during the exploratory research for 5 (4). Thus, oxidative bromination of 6 with N-bromosuccinimide (NBS) in aqueous dioxane afforded ketobromide 7, quantitatively, which was then dehydrobrominated to enone 8, quantitatively, by treatment with lithium carbonate. The carboxylic acid moiety in 8 was converted to the methyl ester 9, which was treated with acetic anhydride (Ac2O) in the presence of p-toluenesulfonic acid (TsOH) to give dienolacetate 10 in 87% yield from 6. Stereoselective reduction of the enolacetate group in 10 was achieved with excess sodium borohydride (NaBH4) in methanol (MeOH) and tetrahydrofuran (THF), affording 11 in 54% yield. Bromide 14, prepared from 11 in 74% overall yield by a known procedure (18, 19), was treated with lithio-2-methyl-1,3-dithiane in THF to give dithiane 15 in 88% yield. The conversion of 15 into 25-hydroxycholesterol (17) was effected in 62% yield by a two-step sequence: hydrolysis of the dithiane and THP groups in 15 with methyl iodide in aqueous acetone, followed by the reaction with methylmagnesium bromide (MeMgBr) (12). An important intermediate, 1,2α-epoxide 28, was obtained from 17 by a 13-step sequence, which is basically the same procedure as the conversion of cholesterol (42) to epoxide 53 described in Figure 4. Treatment of 28 with 1,3-propanediol in the presence of potassium tert-butoxide (t-BuOK) resulted in stereo- and regioselective introduction of the characteristic 3-hydroxypropoxy group into the 2β-position to give proeldecalcitol (29) in 36% yield. Finally 29 was converted to eldecalcitol (5) in 23% yield by irradiation at 0°C using a high pressure mercury lamp (400 W, Vycor filter), followed by thermal isomerization in boiling THF (Figure 2) (4). In the linear synthesis from lithocholic acid (6) to eldecalcitol (5), the 27-step sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%).

Figure 2.
Figure 2.

Linear synthesis of eldecalcitol (5) from lithocholic acid (6) via 25-hydroxycholesterol (17). Reagents and conditions: a: NBS/dioxane, 40°C to 55°C. b: LiCO3/DMF, 90°C. c: HCl/MeOH, rt. d: TsOH/Ac2O, 85°C. e: NaBH4/MeOH/THF, 0°C. f: DHP/Amberlyst 15/CH2Cl2, rt. g: Red-Al/benzene, reflux. h: NBS/Ph3P/NaHCO3/DMF, 0°C. i: 2-methyl-1,3-dithiane/n-BuLi/THF/n-hexane, −78°C to 4°C. j: MeI/acetone/H2O, reflux. k: MeMgBr/THF, −5°C to 0°C. l: (Oi-Pr)3Al/cyclohexanone. m: DDQ/AcOEt. n: NaOEt/EtOH. o: NaBH4/MeOH/THF. p: Ac2O/DMPA/pyridine, rt. q: NBS/AIBN/n-hexane, reflux. r: γ-collidine/toluene, reflux. s: KOH/MeOH, rt. t: PTAD/CH2Cl2, rt. u: TBSCl/imidazole. v: MCPBA/CH2Cl2. w: DMI, 140°C. x: TBAF/THF. y: HO(CH2)3OH/t-BuOK, 110°C. z: 400 W high pressure mercury lamp/THF, 0°C then reflux without mercury lamp.

Synthesis of eldecalcitol by the convergent method. Next, we developed a convergent approach based on the Trost coupling reaction (20, 21), in which A-ring fragment 37 and C/D-ring fragment 40 are coupled to produce the triene system of eldecalcitol (5) (13, 14). Thus, cleavage of the C2 symmetrical epoxide 30 (22) with 1,3-propanediol in the presence of potassium t-BuOK gave diol 31 in 86% yield. After protection of the primary hydroxyl group to give pivalate 32 in 88% yield, cleavage of the benzyl ether moiety in 32 and subsequent protection of the resulting 1,2-diol as the acetonide gave alcohol 33 in 87% overall yield. Swern oxidation of 33 and subsequent Grignard reaction of the resulting aldehyde with vinylmagnesium bromide (CH2=CHMgBr) followed by pivaloylation of the resulting alcohol afforded pivalate 34 as an epimeric mixture (R/S=3/2). Without separation of the epimeric mixture, the acetonide moiety in 34 was cleaved quantitatively to give the diol 35. Exposure of 35 to Mitsunobu conditions (23) afforded the epimeric epoxide 36 in 77% yield. The acetylene unit was successfully installed by regioselective epoxide-opening of 36 with lithium trimethylsilylacetylide (LiC ≡ CTMS) to provide ene-yne 37 as the A-ring fragment for eldecalcitol in 36% yield after protecting group exchange from the pivalate to the tert-butyldimethylsilyl (TBS) ether. The accompanying (S)-epimer 37 was separated in 24% yield by simple column chromatography (24). The synthesis of the C/D-ring fragment 40 from readily and commercially available calcifediol (2) was performed (13). Calcifediol (2) was protected as the bis-triethylsilyl (TES) ether using triethylsilyl trifluoromethanesulfonate (TESOTf), and was then converted to the alcohol 38 by ozonolysis and treatment with NaBH4 in 72% yield. The hydroxyl moiety in 38 was oxidized to ketone 39 with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO) in 99% yield. Wittig reaction of 39 with (bromomethylene)triphenylphosphonium bromide (Ph3P+CH2Br/Br−) and sodium hexamethyldisilazide (NaHMDS) gave rise to bromomethylene 40 as the C/D-ring fragment in 38% yield. Thus, upon treatment of 37 and 40 with triethylamine (Et3N), triphenyphosphine (PPh3) and tris(dibenzylideneacetone)dipalladium-chloroform [(dba)3Pd2-CHCl3] in boiling toluene, the coupled product 41 was obtained in 26% yield together with recovered 37 (45%) and 40 (56%). Deprotection of the silyl moiety in 41 with tetrabutylammonium fluoride (TBAF) afforded eldecalcitol (5) in 60% yield (Figure 3). Although the overall yield of the convergent synthesis (A-ring fragment 37 from 30: 10.4%, C/D-ring fragment 40 from 2: 27.1% and coupling 37 with 40: 15.6%) was better than the linear synthesis (ca. 0.03%), significant improvements were still required for large-scale production. The convergent methodology of production of eldecalcitol, however, proved quite useful for the synthesis of related compounds, such as putative metabolites (25).

Figure 3.
Figure 3.

Convergent synthesis of eldecalcitol (5) by coupling A-ring fragment 37 with C/D-ring fragment 40. Reagents and conditions: a: HO(CH2)3OH/t-BuOK, 120°C. b: t-BuCOCl/pyridine/CH2Cl2, rt. c: H2/Pd(OH)2/MeOH, rt. d: Me2C(OMe)2/TsOH/acetone, rt. e: DMSO/(COCl)2/CH2Cl2, −60°C. f: CH2=CHMgBr/THF, −60°C. g: t-BuCOCl/Et3N/DMAP/CH2Cl2, rt. h: 1 M HCl/MeOH, rt. i: Ph3P/DEAD/benzene, reflux. j: LiC ≡ CTMS/BF3-OEt2, −78°C. k: 10 N NaOH/MeOH, rt. l: TBSOTf/Et3N/CH2Cl2, 0°C. m: TESOTf/Et3N/CH2Cl2, 0°C. n: O3/CH2Cl2/MeOH, −78°C then NaBH4/MeOH, −78°C. o: NMO/TPAP/4Ams/CH2Cl2, rt. p: Ph3P+CH2BrBr−/NaHMDS/ THF, −60°C to rt. q: (dba)3Pd2-CHCl3/PPh3/Et3N/toluene, reflux. r: TBAF/THF/toluene, reflux.

Figure 4.
Figure 4.

Industrial synthesis of alfacalcidol (4) and biomimetic synthesis of eldecalcitol (5) from cholesterol (42). Reagents and conditions: a: [Al(Oi-Pr)3]/cyclohexanone. b: DDQ/AcOEt. c: NaOEt/EtOH. d: NaBH4/MeOH/THF. e: Ac2O/DMPA/pyridine, rt. f: NBS/AIBN/n-hexane, reflux. g: γ-collidine/toluene, reflux. h: KOH/MeOH, rt. i: PTAD/CH2Cl2, rt. j: TBSCl/imidazole. k: MCPBA/CH2Cl2. l: DMI, 140°C. m: TBAF/THF. n: NaBH4/EtOH. o: 400 W high pressure mercury lamp/THF, 0°C then reflux without mercury lamp. p: HO(CH2)3OH/t-BuOK, 110°C. q: Microbial 25-hydroxylation.

Synthesis of eldecalcitol by the biomimetic method. Figure 4 shows the practical synthesis of alfacalcidol (4), which has been completely established during the manufacturing production (16). Thus, cholesterol (42) was oxidized with aluminum isopropoxide [Al(Oi-Pr)3] in 80% yield to 4-en-3-one 43, which was further oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to 1,4-dien-3-one 44 in 75% yield. Treatment of 44 with sodium ethoxide (NaOEt) gave 1,5-diene-3-one 45 in 53% yield, which was reduced with NaBH4 yielding 3β-hydroxy-1,5-diene 46 in 78% yield. After protection of hydroxyl moiety in 46 as acetate 47, the 5,7-diene system in 48 was fashioned through bromination with NBS/2,2-azobisisobutyronitrile (AIBN) in hexane and dehydrobromination with γ-collidine in toluene follwed by deacetylation. The 5,7-diene moiety in 48 was protected via adduct formation with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) to give the PTAD adduct 49, in 80% yield from 47. The hydroxyl group in 49 was protected as its TBS ether 50 in 95% yield, which was then regio- and stereoselectively epoxidized with m-chloroperbenzoic acid (MCPBA) to give 1,2α-epoxide 51 in 78% yield. Retro-cycloaddition of PTAD adduct 51 to regenerate the 5,7-diene system in 52 was carried out by simply heating (140°C) 51 in 1,3-dimethyl-2-imidazolidinone (DMI) in 75% yield (26). The 3β-hydroxyl moiety in 53, obtained by deprotection of TBS group in 52 with TBAF, contributed to the regio- and stereoselective cleavage of epoxide ring with NaBH4 to give proalfacalcidol (54), quantitatively. Finally, 54 was subjected to photolysis and thermal isomerization to afford alfacalcidol (4) (Figure 4) (16). Since microbial 25-hydroxylation of steroidal and secosteroidal side chain was known (27, 28), we applied this methodology to the preparation of proeldecalcitol (29). Thus, 1,2α-epoxide 53 was cleaved by 1,3-propanediol in the presence of t-BuOK to introduce the 3-hydroxypropoxy group at the 2β-position giving 55 in 29% yield (4). By culturing Amycolata autotrophica ATCC 33796, hydroxylation of 55 at the 25-position was successfully carried out to afford proeldecalcitol (29) in moderate yield (17), which was converted to eldecalcitol (5) by irradiation and thermal isomerization as described above (Figure 4). The yields for converting steroidal framework in 29 to secosteroidal structure in 5 by photolysis and thermal isomerization are usually moderate to low, since several structural variants such as lumisterol, tachisterol, etc. are also formed.

Conclusion

The summary of process development for eldecalcitol (Figure 1, 5) between the linear synthesis, convergent synthesis, and biomimetic synthesis is shown in Table I. The biomimetic synthesis was adopted for the practical production of 5 and has been used in industrial-scale preparations. The detailed methodology of the biomimetic synthesis including microbial hydroxylation of 55 will be reported in due course.

View this table:
Table I.

Summary of process development for eldecalcitol (5).

Acknowledgements

We are grateful to Professor David Horne of the Division of Molecular Medicine, City of Hope for helpful suggestions and reading of the manuscript.

  • Received September 7, 2011.
  • Revision received October 20, 2011.
  • Accepted October 21, 2011.

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Process Development for the Practical Production of Eldecalcitol by Linear, Convergent and Biomimetic Syntheses
NOBORU KUBODERA, SUSUMI HATAKEYAMA
Anticancer Research Jan 2012, 32 (1) 303-309;
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