A modified synthesis of the antiosteoporosis drug alfacalcidol via a key photochemical transformation of 1α-5,6-Trans-Vitamin D3

Article abstract of DOI:10.1055/s-0033-1339867

Alfacalcidol (1α-hydroxyvitamin D₃) is an important clinical drug for the treatment of osteoporosis. Its practical synthesis has been intensively pursued across academia. The difficulties of separating 5,6-cis and 5,6-trans isomers in the current process was avoided by photochemical transformation of the 5,6-trans isomer into the 5,6-cis isomer. Employing vitamin D₃ as a starting material, alfacalcidol was obtained by a five-step reaction sequence of esterification, cyclization, oxidation, solvolysis ring-opening, and subsequent photochemical reaction. The overall yield has been greatly improved from 17% to 31%. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339867

2606▌
LETTER
lAetteMr odified Synthesis of the Antiosteoporosis Drug Alfacalcidol via a Key
Photochemical Transformation of 1α-5,6-trans-Vitamin D3
Modified Synthesis of Alfacalcidol
Junyuan Ding, Xianghai Guo,* Zhouliangzi Zeng, Ningzhi Liu
Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical
Engineering and Technology, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27403487; E-mail: guoxh@tju.edu.cn
Received: 28.07.2013; Accepted after revision; 28.08.2013
of cyclovitamin D. The isomers are hard to separate by
Abstract: Alfacalcidol (1α-hydroxyvitamin D3) is an important
column chromatography, even including preparative
clinical drug for the treatment of osteoporosis. Its practical synthe-
high-performance liquid chromatography (prep. HPLC).7
sis has been intensively pursued across academia. The difficulties of
separating 5,6-cis and 5,6-trans isomers in the current process was
At present, a Diels–Alder reaction was adopted to selec-
avoided by photochemical transformation of the 5,6-trans isomer tively remove the trans isomer.8 With this method, a lot of
into the 5,6-cis isomer. Employing vitamin D3 as a starting material,
alfacalcidol was obtained by a five-step reaction sequence of ester-
ification, cyclization, oxidation, solvolysis ring-opening, and subse-
intermediates become unusable, thus the overall yield is
usually around 15%.
Our work has been concerned with the Mazur’s solvolysis
method, trying to overcome the separation issue of iso-
mers. A photochemical reaction can be used to convert the
5,6-trans isomer into the targeted 5,6-cis isomer selective-
ly; this replaces the previous Diels–Alder reaction
(Scheme 1). Also, we have studied some important pa-
rameters in the 1α-hydroxy-vitamin D3 synthetic process,
such as solvent, temperature, and molar ratio of raw mate-
rials of esterification and cyclization reactions. In summa-
ry, an efficient procedure was reported here to produce the
corresponding 1α-hydroxyvitamin D3 from vitamin D3 in
30% overall yield.
quent photochemical reaction. The overall yield has been greatly
improved from 17% to 31%.
Key words: antiosteoporosis drug, vitamin D3, photochemical
transformation
Alfacalcidol (1α-hydroxyvitamin D3) is a drug for the
treatment of parathyroid dysfunction, renal osteodystro-
phy, and osteoporosis caused by menopause.1 It has been
shown recently that 1α-hydroxyvitamin D3 exhibits nota-
ble activities against some cancers.2,3 Therefore an effi-
cient synthesis of 1α-hydroxyvitamin D3 is important in
pharmaceutical industry with both clinical and industrial
significance.
First, vitamin D3 (1) was treated with p-toluenesulfonyl
chloride in quantitative yield to the vitamin D3 tosylate
(2). Pyridine was reported to be used as solvent,9 which is
miscible with water and conjugated with the triene struc-
ture of the product to form π–π bond interaction. Thus te-
dious extraction and washing procedures were necessary
for separation to avoid product loss with pyridine. In order
to simplify the operating conditions and the posttreatment
process, as well as to avoid product waste, dichlorometh-
ane was used as solvent to replace pyridine.10 As a result,
it significantly reduced pyridine hydrochloride waste and
improved process economy. On the other hand, we select-
ed 4-dimethylaminopyridine as catalyst, and the reaction
temperature was changed from 4 °C to room temperature;
and the reaction time was shortened from 48 hours to 6.5
hours. Compound 2 was obtained in ca. 100% yield.11
Currently, two approaches have been used for the indus-
trial synthesis of 1α-hydroxyvitamin D3, both using vita-
min D3 as a starting material.4 Route one treated vitamin
D3 with sulfur dioxide to produce two cyclic adducts
which are protected via a silyl group. These protected ad-
ducts undergo base-catalyzed sulfur dioxide removal and
rearrangement to a single silyl 5,6-trans-vitamin D3. Al-
lylic oxidation then affords the corresponding 1α-hydroxy
derivative, which is then deprotected to yield crystalline
1α-hydroxy-5,6-trans-vitamin D3, photochemical isomer-
ization of the 1α-hydroxy-5, 6-trans-vitamin D3 may yield
1α-hydroxyvitamin D3.3,5 However, the use of sulfur diox-
ide as a solvent and the instability of the silyl compound
have made syntheses by this process inefficient.
In the cyclization reaction, a large amount of sodium bi-
carbonate was used as catalyst.12 This, however, made
stirring difficult and subsequent filtration inconvenient,
since it can hardly dissolve in the reaction system. In order
to simplify operations and improve yield, we attempted to
find out the optimal temperature and molar ratio of raw
materials. Molar ratio of sodium bicarbonate and 2 was re-
duced from 18.3:1 to 3.6:1, which saved both sodium bi-
carbonate and filtration. At this molar ratio, the best
reaction temperature is 63 °C, and the reaction time was
shortened from 5.3 hours to 2.3 hours. Under optimized
The second route, based on Mazur’s observation on the
vitamin–cyclovitamin conversion, devised by DeLuca
and their collaborators, entails three main chemical oper-
ations: formation of cyclovitamin D, C-1 hydroxylation of
the cyclovitamin D, and solvolysis of cyclovitamin D.6
This method suffers from 5,6-cis and 5,6-trans isomers
which are obtained with a molar ratio of 4:1 by solvolysis
SYNLETT 2013, 24, 2606–2608
Advanced online publication: 14.10.2013
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DOI: 10.1055/s-0033-1339867; Art ID: ST-2013-W0709-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Modified Synthesis of Alfacalcidol
2607
NaHCO3
SeO2, CH2Cl2
TsCl, py
MeO
MeOH
(78%)
t-BuOOH
(61%)
DMAP
(quant.)
TsO
HO
2
3
1
AcOH
+
MeO
DMSO
(87%)
HO
OH
OH
HO
OH
4
5a
5b
anthracene
MeOH, hν
(50%)
Scheme 1 The synthetic route of alfacalcidol
conditions, the yield of 3,5-cyclovitamin D3 (3) was im-
Supporting Information for this article is available online at
proved from 73% to 78%.13
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Selective oxidation of 3 was effected under tert-butyl al-
cohol peroxide and SeO2, giving 4 as a yellowish oil in a
yield of 61%, which was further solvolyzed under acetic
acid and DMSO to give a mixture of 5a and 5b. The un-
desired byproduct of the solvolysis ring-opening reaction,
5,6-trans-isomer (5b),14 which was formerly consumed
and separated from 5,6-cis-1α-hydroxyvitamin D3 (5a) by
a selective Diels–Alder reaction with maleic anhydride as
dienophile and further separation by column chromatog-
raphy, was converted into 5a by photochemical reaction
employing anthracene as a photosensitizer.15 5,6-trans-
1α-Hydroxyvitamin D3 (5b) could be completely convert-
ed into 5,6-cis-1α-hydroxyvitamin D3 (5a), and the total
yield of the ring-opening and subsequent photochemical
reaction [from 1α-hydroxy-3,5-cyclovitamin D3 (4) to 5a]
came up to 66%. By this way, tedious procedure was sim-
plified and loss of 5b was reasonably avoided. To our sat-
isfaction, the overall yield of the whole synthesis process
is greatly improved from 17% to 31%.16
References and Notes
(1) (a) Kubodera, N.; Muromachi, N.; Chuo, K. Molecules
2009, 14, 3869. (b) Higuchi, Y.; Sato, K.; Nanjo, M.; Isogai,
T.; Takeda, S.; Kumaki, K.; Nishii, Y. Vitamins 1994, 68,
87. (c) Nishii, Y. J. Bone Miner. Metab. 2002, 20, 57.
(d) Shiraishi, A.; Higashi, S.; Ohkawa, H.; Kubodera, N.;
Hirasawa, T.; Ezawa, I.; Ilera, K.; Ogata, E. Calcif. Tissue
Int. 1999, 10, 339.
(2) (a) Plum, L. A.; Deluca, H. F. Nat. Rev. 2010, 9, 941.
(b) Holick, M. F. J. Cell. Biochem. 2003, 88, 296.
(3) Kubodera, N.; Muromachi, N.; Chou, K. Heterocycles 2010,
80, 83.
(4) (a) Nemoto, H.; Kimura, T.; Kurobe, H.; Fukumoto, K.;
Kametani, T. Chem. Lett. 1985, 1131. (b) Hirsch, A. L. In
Vitamin D; Vol. 1; Feldman, D.; Pike, J. W.; Adams, J. S.,
Eds.; Elsevier: Oxford, 2011, 73–93. (c) Zhu, G. D.;
Okamura, W. H. Chem. Rev. 1995, 95, 1877.
(5) (a) Yamada, S.; Suzuki, T.; Takayama, H.; Miyamoto, K.;
Matsunaga, I.; Nawata, Y. J. Org. Chem. 1983, 48, 3483.
(b) Paaren, H. E.; Deluca, H. F.; Schnoes, H. K. J. Org.
Chem. 1980, 45, 3253. (c) Marshall, J. A.; Grote, J.; Sheater,
B. J. Org. Chem. 1986, 51, 1635. (d) Singleton, D. A.; Hang,
C. J. Org. Chem. 2000, 65, 7554.
(6) (a) Chen, Y. S.; Ren, L.; Zhai, C. Y. Chin. J. New Drugs
2005, 14, 1441. (b) Sheves, M.; Mazur, Y. J. Chem. Soc.,
Chem. Commun. 1977, 21.
(7) (a) Calverley, M. J. Tetrahedron 1987, 43, 4609. (b) Chen,
Y. S.; Zhai, C. Y.; Ren, L. Chin. J. New Drugs 2005, 14, 69.
(8) DeLuca, H. F.; Schnoes, H. K.; Lee, S. H.; Phelps, M. E. US
4,554,106, 1985; Chem. Abstr. 1986, 105, 60827
(9) Wang, M. G.; Ren, L.; Sun, G. Y.; Chen, Y. S.; Liu, X. X.
CN 101,607,931, 2009; Chem. Abstr. 2009, 152, 144887
In conclusion, we have simplified the synthetic method of
1α-hydroxyvitamin D3 with a higher yield. The tedious
workup of the esterification reaction was simplified, and
the reaction time was greatly reduced. The cyclization re-
action was also improved with optimal temperature and
molar ratio of raw materials and shorter reaction time. It
is noteworthy that the previous Diels–Alder reaction used
for separating the cis/trans mixtures was replaced by pho-
tochemical reaction. In this way, the loss of product was
prevented and higher product yield was then achieved.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2606–2608

2608
J. Ding et al.
LETTER
(10) Ng, C. S.; Wei, C. P. US 20,090,318,722, 2009; Chem.
Abstr. 2009, 152, 75277
(11) Synthesis of Vitamin D3 Tosylate (2)
dissolved in DMSO (28.1 mL) and glacial acetic acid (22.4
mL). The mixture was heated to 50 °C under argon
protection for 1 h and was then quenched by pouring the
mixture over ice. The aqueous suspension was extracted
with EtOAc (3 × 50 mL). The combined organic extracts
were then washed with sat. NaHCO3 (3 × 100 mL) and sat.
NaCl (3 × 100 mL), dried over MgSO4, and concentrated in
vacuo. Silica gel column chromatography in PE–EtOAc
(4:6) afforded 2.20 g (87% yield) of a yellowish crystalline
solid, which contained 5,6-cis-1α-hydroxyvitamin D3 (5a)
and 5,6-trans-1α-hydroxyvitamin D3 (5b).
Vitamin D3 (1, 1.00 g, 2.6 mmol), 4-dimethylaminopyridine
(1.00 g, 8.2 mmol), and dry pyridine (1.55 mL), contained in
a 25 mL round-bottom flask, was kept cool in an ice bath. A
solution of freshly recrystallized p-toluenesulfonyl chloride
(0.87 g, 4.6 mmol) in CH2Cl2 (8.5 mL) was added to it
several times. The solution system was stirred and reacted
until its color deepened to glassy yellow. It was kept airtight
under argon protection and being stirred at r.t. away from
light. After 6.5 h, the solution turned light red and colorless
transparent needle crystals were formed at the bottom of the
flask. The mixture was transferred into a 100 mL beaker and
sat. NaHCO3 (20 mL) was added in several times with
stirring. Then the organic layer was washed with 3% HCl
(3 × 30 mL), sat. NaHCO3 (1 × 20 mL), and sat. NaCl
(1 × 20 mL), dried over MgSO4, and concentrated to 1.40 g
of a white crystalline solid 2 in vacuo.
(15) Mawhand, P. S.; Yiannikouros, G. P.; Belica, P. S.; Madan,
P. J. Org. Chem. 1995, 60, 6574.
(16) Phototransformation of 5,6-trans-1α-Hydroxyvitamin D3
(5b) to 5,6-cis-1α-Hydroxyvitamin D3 (5a)
A solution of of the crystalline solid (0.5 g, 1.2 mmol) from
the last step in anhydrous MeOH (80 mL) containing
anthracene (18.0 mg, 0.1 mmol) was thoroughly degassed. A
medium-pressure 500 W ultraviolet lamp was placed such
that the outside of the water-cooled jacket was 15 cm from
the reaction vessel. Ice water was passed in the jacket of the
quartz tube to keep the reaction cool. The mixture was
irradiated for 4.0 h under argon protection at r.t., until all of
5a was converted into 5b and then concentrated in vacuo.
The residue was eluted by PE–EtOAc (4:6) to separate 5a,
and further recrystallization from EtOAc and cyclohexane
afforded 0.37 g (75% yield) of a white crystalline solid (5a)
Analytcal Data
(12) (a) Edwards, H. M. III.; Majetich, G. WO 2,011,002,756,
2011; Chem. Abstr. 2011, 154, 109857 (b) Ruan, Y. M.; Hu,
W. X.; Lu, J. Q. Chin. J. Synth. Chem. 2002, 10, 56.
(13) Synthesis of 3,5-Cyclovitamin D3 (3)
To a stirring solution of anhydrous MeOH (150 mL) was
added finely divided NaHCO3 (2.00 g, 23.8 mmol) and
vitamin D3 tosylate (2, 3.50 g, 6.50 mmol). The mixture was
heated to 63 °C under Argon protection for 2.3 h, cooled to
r.t. and concentrated in vacuo. The residue was diluted with
distilled H2O (70 mL) and was extracted with EtOAc (3 × 50
mL). The combined organic extracts were washed with sat.
brine (1 × 150 mL), dried over MgSO4, and concentrated to
a transparent yellowish oil in vacuo. Silica gel column
chromatography in PE–EtOAc (19:1) yielded 2.01 g of
colorless 3,5-cyclo-vitamin D3 (3), which could be used for
the next reaction without further purification.
IR (KBr): 3406, 1643, 1629, 1059, 909 cm–1. 1H NMR
(500MHz, CDCl3): δ = 0.55 (3 H, s, 18-CH3), 0.87 (6 H, dd,
J1 = 2.3 Hz, J2 = 6.6 Hz, 26-CH3, 27-CH3), 0.92 (3 H, d,
J = 6.5 Hz, 21-CH3), 2.32 (1 H, dd, J1 = 6.6 Hz, J2 = 13.4
Hz, H-4β), 2.60 (1 H, dd, J1 = 3.3 Hz, J2 = 13.4 Hz, H-4α),
2.83 (1 H, dd, J1 = 3.8 Hz, J2 = 11.8 Hz, H-14), 4.24 (1 H, m,
H-3α), 4.44 (1 H, dd, J1 = 4.3 Hz, J2 = 7.8 Hz, H-1β), 5.01 (1
H, s, H-19E), 5.33 (1 H, t, J = 1.5 Hz, H-19Z), 6.02 (1 H, d,
J = 11.3 Hz, H-7), 6.39 (1 H, d, J = 11.3 Hz, H-6).
(14) General Procedure for 1α-Hydroxyvitamin D3 5a and 5b
lα-hydroxy-3,5-cyclo-vitamin D3 (4, 2.62 g, 6.3 mmol) was
Synlett 2013, 24, 2606–2608
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