Industrial synthesis of maxacalcitol, the antihyperparathyroidism and antipsoriatic vitamin D3 analogue exhibiting low calcemic activity

Article abstract of DOI:10.1021/op049822x

Maxacalcitol, the 22-oxa-derivative of 1α,25-dihydroxyvitamin D ₃ and used currently as an antihyperparathyroidism and antipsoriatic drug, has been synthesized in seven chemical steps from 1α- hydroxydehydroepiandrosterone on the basis of our previously developed route. The present synthesis allows the production of the protected form of the penultimate intermediate in 26% overall yield in a kilogram scale reaction employing neither difficult reaction conditions nor chromatographic purification, having overcome all the difficulties involved in the previous route.

Full text of DOI:10.1021/op049822x

Organic Process Research & Development 2005, 9, 278−287
Industrial Synthesis of Maxacalcitol, the Antihyperparathyroidism and
Antipsoriatic Vitamin D3 Analogue Exhibiting Low Calcemic Activity
Hitoshi Shimizu,*,† Kazuki Shimizu,‡ Noboru Kubodera,‡ Tetsuhiro Mikami,† Kaname Tsuzaki,† Hiroyuki Suwa,†
Koji Harada,† Akira Hiraide,† Motoki Shimizu,† Kaichiro Koyama,† Yoshihide Ichikawa,† Daisuke Hirasawa,†
Yasushi Kito,† Mio Kobayashi,† Masaharu Kigawa,† Masahiro Kato,† Toshiro Kozono,† Hideki Tanaka,§ Makoto Tanabe,§
Masanori Iguchi,§ and Mitsutaka Yoshida§
Synthetic Technology Research Department, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-Ku,
Tokyo 115-8543, Japan, Chemistry Research Department I, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado,
Gotemba, Shizuoka 412-8513, Japan, and Fujieda Plant, Chugai Pharmaceutical Co., Ltd., 2500 Takayanagi,
Fujieda, Shizuoka 426-0041, Japan
Abstract:
Maxacalcitol, the 22-oxa-derivative of 1r,25-dihydroxyvitamin
D3 and used currently as an antihyperparathyroidism and
antipsoriatic drug, has been synthesized in seven chemical steps
from 1r-hydroxydehydroepiandrosterone on the basis of our
previously developed route. The present synthesis allows the
production of the protected form of the penultimate intermedi-
ate in 26% overall yield in a kilogram scale reaction employing
neither difficult reaction conditions nor chromatographic
purification, having overcome all the difficulties involved in the
previous route.
Figure 1
of the secondary alcohol 8 by diastereoselective hydrobo-
Introduction
ration-oxidation reaction, (iv) the Williamson etherification
forming the 22-ether 9, (v) the Wacker oxidation forming
the methyl ketone 11, (vi) the Grignard reaction forming the
tertiary alcohol 12, and (vii) the sequential photolysis and
thermolysis forming the triene 14 via the isomeric triene 13.
In carrying out the synthesis, we have encountered four
difficulties to reach the target molecule, namely (a) instability
of the conjugated diene system in the intermediates during
the synthesis, (b) sluggish etherification of the secondary
alcohol 8, giving rise to a 1:1 mixture of the target ether 9
and the useless endo-olefin byproduct 10, (c) facile enoliza-
tion of 11 preventing the nucleophilic addition, and (d)
indispensability of chromatographical purification throughout
the synthesis (Scheme 1).
Maxacalcitol1,2 (1) is the 22-oxa-analogue of 1R,25-
2
dihydroxyvitamin D3 (2) (calcitriol) and used currently as
the antihyperparathyroidism and antipsoriatic drug with low
calcemic activity (Figure 1). The first synthesis of maxacal-
citol (1) was carried out in a sequence of nine chemical steps
of reactions1a starting from 1R-hydroxydehydroepiandros-
terone (3) which is accessible from dehydroepiandrosterone
by microbial oxidation.3 The nine-step synthesis involved
the following critical seven steps besides the protection-
deprotection steps, namely (i) introduction of 7,8-double
bond by sequential treatment with NBS and γ-collidine to
give the diene 6 via the bromide 5, (ii) two-carbon elongation
by the Wittig reaction to give the Z-olefin 7, (iii) formation
Of these difficulties, we have so far circumvented the
etherification step by replacing the Williamson etherification
by the Michael addition using N,N-dimethylacrylamide as
the electrophile in our second synthesis.4 Thus, on treatment
of the secondary alcohol 8 with a large excess of the
acrylamide in the presence of sodium hydride in THF
afforded a good yield of the ether 15. However, the Michael
reaction was found to be very capricious, owing to secondary
reactions such as the retro-Michael reaction and polymeri-
zation under these basic conditions necessitating chromato-
graphical purification to separate the target molecule 15 from
undesired byproducts. Moreover, the obtained new ether 15
* To whom correspondence should be addressed. E-mail: shimizuhts@
chugai-pharm.co.jp.
† Synthetic Technology Research Department.
‡ Chemistry Research Department I.
§ Fujieda Plant.
(1) (a) Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, I.
Chem. Pharm. Bull. 1986, 34, 4410. (b) Kubodera, N.; Watanabe, H.;
Kawanishi, T.; Matsumoto, M. Chem. Pharm. Bull. 1992, 40, 1494. (c)
Kubodera, N. J. Synth. Org. Chem. Jpn. 1996, 54, 139.
(2) (a) Lythgoe, B. Chem. Soc. ReV. 1980, 9, 449. (b) Ikekawa, N.; Fujimoto,
Y. J. Synth. Org. Chem. Jpn. 1988, 46, 455. (c) Dai, H.; Posner, G. H.
Synthesis 1994, 1383. (d) Bouillon, R.; Okamura, W. H.; Norman, A. W.
Endocr. ReV. 1995, 16, 200. (e) Zhu, G.-D.; Okamura, W. H. Chem. ReV.
1995, 95, 1877. (f) Feldman, D., Glorieux, F. H., Pike, J. W., Eds. Vitamin
D; Academic Press: New York, 1997. (g) Jankowski, P.; Marczak, S.;
Wicha, J. Tetrahedron 1998, 54, 12071. (h) Nishii, Y.; Okano, T. Steroids
2001, 66, 137. (i) Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2003,
3889. (j) Yamada, S.; Shimizu, M.; Yamamoto, K. Med. Res. ReV. 2003,
23, 89.
(4) (a) Mikami, T.; Iwaoka, T.; Kato, M.; Watanabe, H.; Kubodera, N. Synth.
Commun. 1997, 27, 2363. (b) Mikami, T.; Kato, M.; Kubodera, N.; Ochi,
K. Abstract Paper, 112th Annual Meeting of the Pharmaceutical Society of
Japan, 1992, Vol. 2, 62.
(3) Dodson, R. M.; Goldkamp, A. H.; Muir, R. D. J. Am. Chem. Soc. 1960, 82,
4026.
278
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Vol. 9, No. 3, 2005 / Organic Process Research & Development
10.1021/op049822x CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/29/2005

Scheme 1
Scheme 2
brought about a new problem as it was found to be so
enolizable in the reaction with methylmagnesium halides or
methyllithium that the desired nucleophilic reaction was
prevented. Although the desired reaction proceeded by using
cerium(III) chloride as an additive,4a,5 it required more than
a stoichiometric amount of the cerium reagent to transform
the amide 15 into the methyl ketone 11 which must be
isolated as the reaction terminated at this stage. The ketone
11 obtained was more enolizable, and it again required the
cerium additive to transform it into the tertiary alcohol 12
(Scheme 2). We therefore explored a more practical proce-
dure and have developed an alternative procedure without
employing the Michael addition procedure in the etherifi-
cation step, allowing truly industrial production of the key
intermediate 12 of maxacalcitol (1) in seven chemical steps
in a kilogram scale with no chromatographical purification.
Results and Discussion
In the present synthesis, we first examined the etherifi-
cation of the secondary alcohol 17 prior to the introduction
of the 7,8-double bond to alleviate instability caused by the
presence of the conjugated diene system in the molecule
under the basic conditions involved in the synthesis. The
1R-hydroxydehydroepiandrosterone (3) was thus transformed
directly into the secondary alcohol 17 in 61% overall yield
via the endo-olefin 16 in a 20-kg-scale reaction without
chromatographical purification by sequential stereoselective
Wittig olefination and stereo- and regio-selective hydrobo-
ration-oxidation reaction under the same conditions as for
the diene counterparts 6 and 7. In this large-scale transforma-
(5) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J.
Am. Chem. Soc. 1989, 111, 4392.
Vol. 9, No. 3, 2005 / Organic Process Research & Development
•
279

Scheme 3
Table 1. Hydroboration-oxidation of Z-olefin 16
tion of the Z-olefin 16 as a substantial amount of the
undesirable E-olefin isomer (∼8.6%) was generated when
the reaction temperature exceeded 65 °C. Transformation of
the Z-olefin 16 into the secondary alcohol 17 could be carried
out in a regio- and stereoselective manner as reported, but it
was dependent on the conditions (Scheme 3). As shown in
Table 1, 9-BBN gave the desired secondary alcohol 17 in
satisfactory yield without affecting the internal olefin func-
tionality in THF at 45 °C. Although the stereoselectivity was
91% de, the secondary alcohol 17 was obtained in 90% yield
as crystals with spontaneous removal of the undesired
diastereomer in the crystallization stage in a large-scale
production.
Etherification the secondary alcohol 17 was first carried
out by application of the method employed for the diene
counterpart 8 in our previous industrial production of
maxacalcitol (1). In the same way as the diene 8, 17 afforded
the Michael adduct 18 only with N,N-dimethylacrylamide
under basic conditions (Scheme 4). Again a complex mixture
was generated with either methyl vinyl ketone or methyl
acrylate under basic conditions. During the preliminary
experiment, we have confirmed the monoene 17 to be much
more stable than the diene counterpart 8 under the same basic
conditions employed in the previous synthesis. As shown in
Table 2, the reaction using the acrylamide was highly
dependent on the conditions. Among the bases examined,
production ratiob of 17
(20S:20R)
entry reagenta temp. (°C) time (h)
1
2
BH3-THF
9-BBN
rt
rt
4
4
81.3:18.7
reaction was incomplete
(conversion 78%b)
95.8:4.2
3
9-BBN
45
4
a 2 equiv of borane reagent was used. b Determined by HPLC.
tion, we had to find an appropriate solvent to enable complete
bis-silylation of 3, owing to its low solubility in cyanoal-
kanes, such as acetonitrile, propionitrile, and butyronitrile,
which are used as good solvents for O-silylation with tert-
butyldimethylsily chloride (TBS-Cl). The silylation did not
complete in each of these solvents, each containing 0.1 equiv
of 4-N,N-(dimethylamino)pyridine (DMAP) as an additive,
with more than 3 equiv of TBS-Cl in the presence of more
than 6 equiv of imidazole even at 90-130 °C. However,
the desired reaction was found to proceed completely without
any additive when 3 was treated with 3 equiv of TBS-Cl in
DMF in high concentration (ca. 20%w/v) in the presence of
6 equiv of imidazole at 125 °C for 6 h to give the crystalline
bis-silyl ether 4 in 74% yield without chromatographical
purification. In the Wittig reaction, it was found that
temperature control is critical for the stereoselective forma-
Scheme 4
Table 2. Reaction between 17 and N, N-Dimethyacrylamidea
concentration
temp.
production ratioc
yield of 18
entry
baseb
KH
MeONa
t-BuOK
NaH
NaH
NaH
NaH
NaH
additive (mol %)
[17(g):THF(mL)]
(°C)
(17:18)
(%)d
1
2
3
4
5
6
7
8
9
-
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:4
1:3
0
0
0
0
>99.9:0.1
29.0:71.0
>99.9:0.1
7.3:92.7
19.8:80.2
>99.9:0.1
6.2:93.8
3.0:97.0
1.2:98.8
1.1:98.9
1.2:98.8
-
-
-
-
-
-
70.2
31.0
-
-
45
reflux
0
0
0
0
0
-
18-crown-6 (10)
15-crown-5 (10)
15-crown-5 (30)
15-crown-5 (30)
15-crown-5 (30)
81.0
86.7
81.9
85.6
83.1
NaH
NaH
NaH
10
11
a 3 equiv of N, N-dimethylacrylamide was used. b 1.5 equiv of base was used. c Determined by HPLC. d Isolated yield.
280
•
Vol. 9, No. 3, 2005 / Organic Process Research & Development

Scheme 5
sodium hydride only afforded the desired ether 18 in high
yield with some recovery of the starting material, indicating
the reaction to be in an equilibrium state. We found that the
reaction reached up to 98.9:1.1 on the product side by
addition of a catalytic amount of crown ether, particularly,
15-crown-5, although the reaction was never completed.
After an extensive examination, the construction of the 22-
ether linkage was finally optimized to a practical level to
carry out the Michael addition using more than a 10 kg of
17 in a minimum amount of THF (ca. 20% w/v) as solvent
in the presence of sodium hydride and a catalytic amount of
15-crown-5. Thus, 11.1 kg of 17 was introduced in THF
containing 1.5 equiv of sodium hydride and 10 mol % of
15-crown-5 at 0 °C to generate the alkoxide which then was
treated with 3 equiv of N,N-dimethylacrylamide at the same
temperature to produce the desired ether 18 in 87% yield as
crystals without chromatographical purification. It should be
noted that sodium hydride may be used as dispersion form
in mineral oil, which is more safe than sodium hydride itself
and easier to handle in this large-scale production as the oil
included could be readily removed during the separation
stage of the ether 18 as crystals.
In contrast, both potassium hydride and potassium tert-
butoxide, even with a crown ether, did not promote the
addition reaction but induced the retrograde reaction which
was confirmed by the separate experiment. Thus, on exposure
to 1.5 equiv of either potassium hydride or potassium tert-
butoxide at room temperature, the ether 18 collapsed
completely into the secondary alcohol 17 very facilely.
Although the transformation of the ether 18 into the
tertiary alcohol 20 through the methyl ketone 19 had to use
the cerium reagent,6a owing to facile enolization of the ether
18 as well as the methyl ketone 19 thereof the target molecule
20 was obtained in 71% yield in a two-step sequence using
the same conditions employed for the diene counterparts 15
and 11. The transformation, however, could be carried out
more easily than that for the diene counterparts due to higher
stability of the monoene intermediates 18 and 19 as well as
the monoene product 20. All the monoenes were ac-
companied by a much smaller amount of byproducts than
that for their diene counterparts and gave rise to the
crystalline tertiary alcohol 20 without requiring chromato-
graphical purification.
Transformation of the monoene alcohol 20 into the diene
alcohol 12 was carried out by employing the same conditions
those employed in the transformation of the monoene 4 into
the diene 66a using hepatane in place of hexane in the
bromination step and toluene in place of xylene in the
dehydrobromination step. When hexane was used as the
solvent in the bromination of 20 as for the monoene 4, the
reaction took place violently in foams, while the use of
heptane allowed the reaction to proceed in a controllable
manner. The use of toluene, in place of xylene used for 5,
in the dehydrobromination step allowed facile crystallization
to make purification of the product 12 easier. The yield of
the diene 12 in a large-scale production was a little less than
satisfactory, but the product could be obtained as crystals
without chromatographical purification. Thus, treatment of
19.6 kg of 20 with 1.2 equiv of NBS in heptane at 78 °C in
the presence of 12 mol % of AIBN afforded the allyl bromide
21 which, on immediate heating with 2 equiv of γ-collidine
at 110 °C in toluene, furnished the diene 12 in 43% overall
yield after crystallization (Scheme 5).
Seemingly, all the difficulties mentioned above, namely
(a) instability owing to the diene functionality, (b) sluggish-
ness in etherification, (c) facile enolization, and (d) indis-
pensability of chromatography, have been solved at this point.
(6) (a) Shimizu, H.; Shimizu, K.; Kubodera, N.; Yakushijin, K.; Horne, D. A.
Tetrahedron Lett. 2004, 45, 1347. (b) Shimizu, H.; Shimizu, K.; Kubodera,
N.; Yakushijin, K.; Horne, D. A. Heterocycles 2004, 63, 1335.
Vol. 9, No. 3, 2005 / Organic Process Research & Development
•
281

Scheme 6
Table 3. Reaction between 17 and the epoxy bromide 24
epoxy
base
(equiv)
bromide
temp. time product
entry
24 (equiv) solvent (°C) (h) (%)a of 25
1
2
3
t-BuOK (6.0)
NaH (3.0)
NaH (3.0)
6.8
12.0
2.0
THF
DMF
THF
50
80
50
2
5
4
42
45
88
Scheme 7
a Determined by HPLC.
synthesis. The generation of the pivalate 30 may be due to
the generation of the allene oxide 26 generated from the
epoxy bromide 24 by competing dehydrobromination under
the basic conditions employed. As has been well estab-
lished,11 the allene oxide 26 could rearrange to the cyclo-
propanone 27 which would then react with the steroid
alkoxide 28 to undergo the Favorskii rearrangement to give
rise to the pivalate 30 by regioselective cleavage12 (Scheme
8).
Although our expected sodium bis(methoxyethoxy)alu-
minohydride (Red-Al), which was known to reduce 2,3-
epoxy alcohols into the corresponding 1,3-diols in a regio-
selective manner,13 failed to give rise to the tertiary alcohol
20, we have found good conditions applicable to a large-
scale production after extensive examination using boron and
aluminum hydride reagents. Among the reagents exam-
ined,6,14 the cleavage of the epoxide 25 proceeded regiose-
lectively in the desired way with the boron reagents to give
rise to tertiary alcohol 20 as the major product, in particular,
with lithium triethylborohydride (Super Hydride) or lithium
sec-butylborohydride (L-Selectride) in THF. Very interest-
ingly, the reaction did not proceed with potassium sec-
butylborohydride (K-Selectride) or other lithium borohy-
drides even under more forcing conditions (Scheme 9 and
Table 4).
In these alkylation and reduction reactions to transform
17 into 20 involving the diastereomeric intermediates 24 and
25, no diastereomeric discrimination could be observed.
Since these two reactions were carried out in the anhydrous
THF solution, we attempted to perform these two steps in
the same reaction vessel without isolation of the epoxide
intermediate 25 to facilitate industrial preparation. The
reaction did really proceed in an expected way to give rise
to the crystalline tertiary alcohol 20 when the secondary
alcohol 17 in THF was treated with the epoxy bromide 24
in the presence of sodium hydride, followed by L-Selectride.
This one-pot reaction could be carried out in 17.2 kg in
THF in high concentration (50% w/w) in the presence of 2
equiv of sodium hydride with 1.3 equiv of the epoxy bromide
24 at refluxing temperature for 1 h, followed by 1.8 equiv
of 1 M THF solution of L-Selectride at the same temperature
for 1 h to furnish the crystalline alcohol 20 in 99% yield.
Two points should be noted in this one-pot reaction. The
first is the use of sodium hydride in a dispersion form without
However, it is still less than satisfactory from the industrial
viewpoint, in particular the two steps to transform the amide
18 into the tertiary alcohol 20 via the ketone 19 in which
more than a stoichiometric amount of cerium (III) chloride
was required to alleviate enolization and left a large amount
of useless waste. Since this cannot be overcome as long as
the present etherification method is employed, we sought
an alternative route to eliminate the cerium reagent and have
established an efficient alternative route without requiring
the cerium reagent.
As mentioned above, we have thus far found in the
previous syntheses that the secondary alcohol 8 reacted very
sluggishly with alkyl halides under Williamson etherification
conditions which brought about rearrangement of the olefin
functionality of the desired product 9 to give rise to a
substantial amount of the undesired isomer 10. On the other
hand, we have found that the secondary alcohol 17 reacted
smoothly with prenyl bromide 22 to give the prenyl ether
23 which gave regioselectively the desired tertiary alcohol
20 in good yield by application of the oxymercuration-
reduction method6a,7 in which use of the mercury salt was
unavoidable (Scheme 6). During the investigation, we knew
the report described that the epoxide8 24 exhibited high
reactivity toward primary and secondary alcohols as its allylic
precursor 22 under Williamson conditions to give the
corresponding ethers.8,9,10 We, thus, examined the preparation
of the tertiary alcohol 20 via the epoxy ether 25 by
application of this etherification followed by reductive
cleavage of the epoxy functionality. The Williamson etheri-
fication of 17 with the racemic epoxy bromide 24 afforded
the expected epoxy ether 25 in excellent yield in THF in
the presence of sodium hydride. However, either when
potassium tert-butoxide in place of sodium hydride or when
DMF in place of THF was used, the yield of the ether 25
was diminished considerably (Scheme 7 and Table 3).
In this transformation, a byproduct was formed consis-
tently (though in 0.5% yield and readily removable during
the crystallization of the major product 25 in the optimized
conditions). It was isolated and determined as the pivalate
30 spectroscopically and unambiguously by the separate
(7) Brown, H. C.; Geoghegan, P., Jr. J. Am. Chem. Soc. 1967, 89, 1522.
(8) Winstein, S.; Goodman, L. J. Am. Chem. Soc. 1954, 76, 4373.
(9) Waters, R. C.; VanderWerf, C. A. J. Am. Chem. Soc. 1954, 76, 709.
(10) Gevorkyan, A. A.; Kazaryan, P. I.; Avakyan, S. V.; Panosyan, G. A. Khim.
Get. Soed. 1981, 7, 878.
(11) Chan, T. H.; Ong, B. S. Tetrahedron 1980, 36, 2269.
(12) Wharton, P. S.; Fritzberg, A. R. J. Org. Chem. 1972, 37, 1899.
(13) (a) Viti, S. M. Tetrahedron Lett. 1982, 23, 4541. (b) Ma, P.; Martin, V. S.;
Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem. 1982, 47, 1378.
(14) Majetich, G.; Zhang, Y.; Wheless, K. Tetrahedron Lett. 1994, 35, 8727.
282
•
Vol. 9, No. 3, 2005 / Organic Process Research & Development

Scheme 8
Scheme 9
Table 4. Reaction of the epoxide ether 25 with hydrides
was examined on the basis of the report by Strauss and
Ku¨hnel15 in 1933 who found one-sep generation of the
bromoepoxide from 1,1-dimethylallyl alcohol 32 with aque-
ous hypobromite solution. Although later in 1954, Winstein
and Goodman8 proposed the involvement of the conjugate
base 33 of the alcohol 32 and hypobromous acid in this
reaction, no study intending the practical utilization of this
reaction has been reported to date. We therefore examined
the synthesis of the epoxy bromide 24 by employing the
aqueous conditions and have established a large-scale
production. Thus, the reaction of 1 kg of the tertiary alcohol
32 upon exposure to 1.5 equiv of potassium hypobromite,
prepared in situ in 10 L of water, furnished the desired epoxy
bromide 24 directly in 82% yield after distillation (Scheme
11).
temp. time conv. production
entry
hydride (equiv)
(°C)
(h) (%)a ratioa (20:31)
1
2
3
4
5
6
7
8
9
Red-Alb(5.0)
LiAlH4 (3.0)
reflux 6.5
0
94
72
5
100
-
rt
rt
reflux
rt
4
2
5
3
92.6:7.4
15.4:84.6
n.d.c
i-Bu2AlH (5.0)
NaBH4 (10.0)
LiEt3BHd(5.0)
Li-s-Bu3BHe (5.0)
K-s-Bu3BHf (10.0)
98.2:1.8
99.7:0.3
n.d.
n.d.
-
n.d.
rt
reflux
2.5 100
8
24
18
7
4
50
0
Li-s-Am3BHg (10.0) rt
K-s-Am3BHh (10.0) rt
10 LiPh3BH (10.0)
reflux
7
a Determined by HPLC. b Sodium bis(2-methoxyethoxy)aluminum hydride.
c Not determined. d Super Hydride. e L-Selectride. f K-Selectride. g LS-Selectride.
h KS-Selectride.
We have now truly overcome all the difficulties encoun-
tered in our previous synthesis leading to the protected form
12 of the penultimate intermediate 34 of maxacalcitol (1).
We have now been able to carry out the final photochemical
reaction utilizing the tetracyclic diene 34 in a 100-g scale
after deprotection of the disilyl ether 12 thus obtained. Thus,
the photolysis of the triol 34 in THF by irradiation with a
high-pressure mercury lamp at 10 °C generated the pre-22-
oxa-D3 product 35 as crystals, after purification by HPLC,
which on stirring in THF at 25 °C, furnished maxacalcitol
(1). Overall yield of Maxacalcitol (1) from the diene 34 was
16% after HPLC purification (Scheme 12).
We can now summarize our present synthesis leading to
maxacalcitol (1) in a sequence of seven chemical steps
starting from 1R-hydroxydehydroepiandrosterone (3) in
Scheme 13. The present method allowed the production of
the key intermediate 12 in 26% overall yield in a kilogram-
scale conversion without formation of any undesired byprod-
ucts employing neither difficult reaction conditions nor
chromatographic purification during the conversions in-
volved.
Scheme 10
removal of the mineral oil. As described in the preparation
of the ether 18, utilization of sodium hydride in a dispersion
form undoubtedly facilitates a large-scale production. The
oil contained could be readily removed in the following stage.
The second point is the use of alkaline hydrogen peroxide
in the termination of the reaction. The one-pot reaction may
proceed accompanied by an intractable byproduct mixture
derived from the reducing agent disturbing the crystallization
of 20 unless treated with the alkaline peroxide in the workup
(Scheme 10).
The epoxy bromide 24 was prepared from prenyl bromide
22 on oxidation with m-chloroperbenzoic acid in dicloro-
methane. To avoid the use of undesirable solvent, an
alternative route capable of carrying out in aqueous media
(15) Strauss, F.; Ku¨hnel, R. Ber. 1933, 66B, 1834.
Vol. 9, No. 3, 2005 / Organic Process Research & Development
•
283

Scheme 11
Scheme 12
Scheme 13
Conclusions
The retention times of 35 and 1 were 280 and 160 min,
respectively.
A practical seven-step synthesis of maxacalcitol (1) from
1R-hydroxydehydroepiandrosterone (3) has been developed
on the basis of our original synthesis by exclusion of all the
difficulties encountered in the original method. The present
synthesis allowed a multikilogram-scale production, except
the final photoreaction stage, employing neither difficult
conditions nor chromatographic separation.
(1S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)androst-5-
en-17-one (4). To a stirred solution of 1R-hydroxydehy-
droepiandrosterone 3 (7.13 kg, 23.42 mol) and imidazole
(9.57 kg, 140.57 mol) in DMF (35.7 L) was added tert-
butyldimethylsilyl chloride (10.50 kg, 69.66 mol) at 20 °C.
The mixture was heated at 125 °C, and the stirring was
continued for 6 h at the same temperature. After cooling to
30 °C, the mixture was diluted with MeOH (21.4 L) with
stirring to separate crystalline precipitate, and the stirring
was continued at same temperature for 4 h. The product
separated was collected centrifugally and dried at 50 °C to
give 4 as light-yellow crystals (9.2 kg, 74.0%): mp 153 °C;
[R]20D +53.0° (c 1.02, CHCl3); FT-IR (KBr, cm-1): ν 2954,
2927, 2856, 1740, 1471, 1462, 1255, 1103, 1084, 837, 775,
669; 1H NMR (CDCl3): δ 5.48 (1H, d, J ) 5.6), 3.99-4.05
(1H, m), 3.78 (1H, br s), 2.38-2.52 (1H, m), 2.00-2.17 (1H,
m), 1.95-2.12 (1H, m), 1.90-2.05 (1H, m), 1.80-1.95 (1H,
m), 1.75-1.87 (1H, m), 1.70-1.90 (1H, m), 1.60-1.75 (1H,
m), 1.50-1.70 (2H, m), 1.45-1.65 (1H, m), 1.25-1.35 (1H,
m), 1.15-1.32 (1H, m), 0.95 (3H, s), 0.88 (18H, s), 0.64
(3H, s), 0.08 (3H, s), 0.06 (3H, s), 0.05 (3H, s), 0.03 (3H,
s). Anal. Calcd for C31H56O3Si2: C, 69.86; H, 10.59.
Found: C, 68.87; H, 10.64.
Experimental Section
General Methods. All reagents and solvents were
obtained from commercial sources and used without further
purification. NMR spectra were measured on a JEOL EX-
270 spectrometer at 270 MHz for 1H and 67.8 MHz for 13C.
Chemical shifts (δ) are reported in parts per million (ppm)
referenced to CHCl3 at 7.26 for 1H, and CDCl3 at 77.00 for
13C. Coupling constants (J) are reported in hertz. IR spectra
were recorded on a JEOL JIR-6000 spectrophotometer as
KBr pellets with a scan range of 4000-400 cm-1. The
melting points were determined on a hot-stage and are
uncorrected. Optical rotations were determined on a JASCO
model DIP-1000 polarimeter. Both 35 and 1 were isolated
by HPLC (SiO2 column: Merck art. no. 9385, Φ 20 cm ×
100 cm, UV: 254 nm) at room temperature using a mixture
of hexane/AcOEt as the mobile phase (flow rate: 1.0 L/min).
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(17Z)-(1S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)pregna-
5, 17-dien (16). To a stirred solution of the ylide, prepared
in situ by treating EtPPh3Br (28.0 kg, 75.42 mol) with
potassium tert-butoxide (8.50 kg, 75.74 mol) in THF (101
L) at 20 °C, was added 4 (20.1 kg, 37.71 mol) at 25 °C, and
the temperature was raised to 30 °C. After stirring for 4 h at
the same temperature, the mixture was cooled to 25 °C, and
to this mixture was added THF (60 L), heptane (161 L), and
water (85 L) sequentially. After stirring for 0.5 h at the same
temperature, the organic layer was separated and was washed
with brine (114 L × 2) and concentrated under reduced
pressure to leave a solid residue. The residue was dissolved
in heptane (175 L) with stirring at 15 °C for 1 h, and the
insoluble material was removed by filtration. The filtrate was
evaporated under reduced pressure to leave a colorless solid.
This was dissolved in acetone (500 L) at 35 °C, and to this
solution was added H2O (60 L) at the same temperature; the
mixture was then cooled to -5 °C to separate out a
crystalline material.
1.70 (1H, m), 1.40-1.65 (1H, m), 1.25-1.53 (3H, m), 1.20-
1.40 (1H, m), 1.05-1.20 (1H, m), 1.00-1.25 (2H, m), 0.90-
1.20 (1H, m), 1.22 (3H, s), 0.96 (3H, s), 0.88 (18H, s), 0.68
(3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.04 (3H, s), 0.02 (3H,
s); 13C NMR: δ 138.4, 123.2, 73.5, 70.3, 67.5, 58.5, 56.8,
42.3, 42.2, 41.6, 41.0, 38.9, 38.7, 31.7, 31.6, 26.0, 25.9, 25.6,
24.3, 23.5, 20.2, 19.3, 18.1, 18.1, 12.6, -3.7, -4.4, -4.5,
-5.2. Anal. Calcd for C33H62O3Si2: C, 70.40; H, 11.10.
Found: C, 70.01; H, 11.16.
(1S,3R,20S)-1,3-Bis(tert-butyldimethylsilyloxy)-20-{(2-
dimethylaminocarbonyl)ethyloxy}preg-na-5-ene (18). To
a stirred suspension of the alkoxide generated in situ from
the secondary alcohol 17 (11.1 kg, 19.72 mol) and NaH (60%
dispersion in mineral oil, 1.18 kg, 29.50 mol) in the presence
of 15-crown-5 (0.44 kg, 2.00 mol) in THF (44.4 L) was
added N,N-dimethylacrylamide (5.86 kg, 59.11 mol) at 0 °C,
and the stirring was continued for 6 h at the same temper-
ature. The reaction was quenched by addition of aqueous
NH4Cl (22.2 L), and the mixture was extracted with AcOEt
(36.6 L). The extract was washed with aqueous brine (55.7
L × 2) and concentrated under reduced pressure to leave a
solid residue. The residue was suspended in hexane (33.3
L) at room temperature and cooled to -20 °C with stirring.
After stirring for 1 h at the same temperature, the crystalline
precipitate was collected centrifugally and dried at 50 °C to
give 18 as colorless crystals (11.4 kg, 87.3%): mp 153 °C;
[R]D20 +25.4° (c 1.02, CHCl3); FT-IR (KBr, cm-1): ν 2954,
2854, 1653, 1473, 1252, 1090, 1066, 837, 771, 677; 1H NMR
(CDCl3): δ 5.46 (1H, d, J ) 5.6), 3.90 (1H, m), 3.86 (1H,
m), 3.76 (1H, br s), 3.57 (1H, m), 3.27 (1H, m), 3.02 (3H,
s), 2.93 (3H, s), 2.56 (1H, m), 2.15-2.35 (2H, m), 1.15 (3H,
d, J ) 5.9), 0.95 (3H, s), 0.88 (18H, s), 0.64 (3H, s), 0.08
(3H, s), 0.06 (3H, s), 0.05 (3H, s), 0.03 (3H, s); 13C NMR
(CDCl3): δ 171.5, 138.3, 123.2, 78.3, 73.5, 67.5, 64.7, 56.9,
56.8, 42.3, 42.2, 41.3, 41.0, 38.9, 38.7, 37.5, 35.3, 34.1 31.7,
31.6, 25.9, 25.9, 25.9, 24.2, 20.2, 19.3, 19.2, 18.1, 18.1, 12.5,
-3.8, -4.4, -4.5, -5.3. Anal. Calcd for C38H71NO4Si2: C,
68.93; H, 10.81; N, 2.12; Si, 8.48. Found: C, 68.83; H,
10.84; N, 2.16; Si, 8.5.
(1S,3R,20S)-1,3-Bis(tert-butyldimethylsilyloxy)-20-(3-
hydroxy-3-methylbuthyloxy)pregn-5-ene (20). To a stirred
suspension of CeCl3 (5.77 kg, 23.40 mol) in THF (19.0 L)
was added MeMgCl (19.7 L, 1M in THF, 19.70 mol) at -15
°C, and after 0.5 h, to this mixture was added the amide 18
(3.52 kg, 5.32 mol) at the same temperature, and the stirring
was continued for 0.5 h at the same temperature. The mixture
was diluted with hexane (18.7 L) and the reaction was
quenched by addition of aqueous KHSO4 (16.2 kg in H2O
54 L) at -15 °C, and the mixture stirred at the same
temperature for 0.5 h. After removal of the insoluble material
by filtration, the organic layer was separated and washed
sequentially with brine (35.1 L), saturated aqueous NaHCO3
(35.1 L), and brine (35.1 L). Evaporation of the organic layer
under reduced pressure left methyl ketone 19 as a pale-yellow
oil which was used for the next reaction: FT-IR (KBr, cm-1):
ν 2936, 1728, 1464, 1378, 1258, 1096, 886, 872, 838, 774;
1H NMR (CDCl3): δ 5.44 (1H, d, J ) 5.6), 3.98 (1H, m),
3.80 (1H, m), 3.77 (1H, br s), 3.52 (1H, m), 3.23 (1H, m),
The product was collected centrifugally and dried at 60
°C to give the diene 16 as colorless crystals (18.5 kg,
90.0%): mp 123 °C; [R]D20 +21.1° (c 1.00, CHCl3); FT-IR
(KBr, cm-1): ν 2954, 2856, 1471, 1373, 1255, 1082, 837,
1
771, 671; H NMR (CDCl3): δ 5.46 (1H, d, J ) 5.6), 5.13
(1H, m), 3.99 (1H, m), 3.78 (1H, m), 2.20-2.40 (1H, m),
2.15-2.40 (2H, m), 2.10-2.50 (2H, m), 1.90-2.05 (1H, m),
1.66 (3H, m), 1.60-1.95 (2H, m), 1.60-1.85 (1H, m), 1.55-
1.75 (1H, m), 1.50-1.70 (1H, m), 1.40-1.50 (1H, m), 1.40-
1.60 (1H, m), 1.35-1.60 (2H, m), 1.10-1.35 (1H, m), 1.05-
1.30 (1H, m), 0.98 (3H, s), 0.89 (3H, s), 0.88 (18H, s), 0.07
(3H, s), 0.05 (3H, s), 0.04 (3H, s), 0.03 (3H, s); 13C NMR
(CDCl3): δ 150.5, 138.3, 123,1, 113.4, 73.5, 67.6, 56.7, 44.1,
42.3, 42.3, 41.0, 38.9, 36.8, 31.6, 31.5, 31.5, 26.0, 25.9, 24.6,
20.7, 19.3, 18.1, 18.1, 16.8, 13.2, -3.8, -4.4, -4.5, -5.2.
Anal. Calcd for C33H60O2Si2: C, 72.73; H, 11.10. Found:
C, 72.09; H: 11.09.
(1S,3R,20S)-1,3-Bis(tert-butyldimethylsilyloxy)-20-hy-
droxypregn-5-ene (17). To a stirred solution of 9-BBN (0.5
mol/L in THF, 133 kg, 74.38 mol) was added 16 (18.5 kg,
33.94 mol) at room temperature, and the mixture was stirred
at 45 °C for 4 h. After cooling to -5 °C, the mixture was
treated sequentially with 10% NaOH (99.0 kg, 247.50 mmol)
and 35% H2O2 (42.0 kg, 407.99 mmol) with stirring; the
stirring was continued at 25 °C for 1 h. Then the mixture
was extracted with AcOEt (222 L), and the extract was
washed sequentially with aqueous Na2S2O3 (53.0 kg, 213.55
mmol in H2O, 161 L) and brine (294 L × 2) and evaporated
under reduced pressure to leave a colorless solid. The solid
was dissolved in MeOH (149 L) at 35 °C and then cooled
to 8 °C for 1.5 h to separate a crystalline material. The
product separated was collected centrifugally and dried at
60 °C to give the secondary alcohol 17 as colorless crystals
(17.2 kg, 90.0%): mp 183 °C; [R]20D +12.0° (c 1.05, CHCl3);
FT-IR (KBr, cm-1): ν 3408, 2954, 2856, 1471, 1380, 1257,
1
1101, 1084, 835, 773, 675; H NMR: δ 5.45 (1H, d, J )
5.6), 3.75-3.77 (1H, m), 3.99 (1H, m), 3.78 (1H, m), 2.15-
2.37 (2H, m), 1.80-2.05 (1H, m), 1.80-2.00 (2H, m), 1.60-
2.00 (2H, m), 1.55-1.85 (1H, m), 1.50-1.80 (1H, m), 1.50-
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285

2.61 (2H, m), 2.15-2.28 (5H, m), 1.14 (3H, d, J ) 5.6),
0.99 (3H, s), 0.87 (18H, s), 0.80 (3H, s), 0.08 (3H, s), 0.06
(3H, s), 0.04 (3H, s), 0.03 (3H, s). Anal. Calcd for C37H68O4-
Si2: C, 70.19; H, 10.83; Si, 8.87. Found: C, 70.05; H, 10.81;
Si, 8.9.
ature. Then the suspension was centrifuged, and a colorless
crystalline solid collected was dried at 50 °C to leave the
tertiary alcohol 20 (19.6 kg, 99.0%) as colorless granules:
20
mp 131 °C; [R]D +23.3° (c 1.00, CHCl3); FT-IR (KBr,
cm-1): ν 3518, 2956, 2856, 1473, 1381, 1255, 1088, 837,
1
To the cerium reagent, prepared in situ from CeCl3 (5.77
kg, 23.40 mol) in THF (19.0 L) and MeMgCl (19.7 L 1M
in THF, 19.70 mol) at -15 °C as above, was added the
ketone 19 in THF (3.6 L) at -15 °C, and the stirring was
continued for 0.5 h at the same temperature. The mixture
was diluted with hexane (18.7 L), and the reaction was
quenched by addition of aqueous KHSO4 (10.4 kg in H2O,
35 L) at -15 °C. After stirring at the same temperature for
0.5 h, the organic layer was separated and washed sequen-
tially with brine (35.1 L), saturated aqueous NaHCO3 (35.1
L), and brine (35.1 L) and evaporated under reduced pressure
to leave a pale-yellow solid. The solid was dissolved in
refluxing MeOH (17.6 L) and cooled to 0 °C with stirring
to separate out a crystalline product. After stirring for 1 h at
the same temperature, the product was collected centrifugally
and dried at 50 °C to give the tertiary alcohol 20 (2.45 kg,
773, 675; H NMR (CDCl3): δ 5.45 (1H, d, J ) 5.6), 4.85
(1H, m), 3.81 (1H, m), 3.76 (1H, br s), 3.47 (1H, m), 3.25
(1H, m), 2.20-2.28 (2H, m), 1.18 (3H, s), 0.95 (3H, s), 0.88
(18H, s), 0.66 (3H, s), 0.08 (3H, s), 0.06 (3H, s), 0.05 (3H,
s), 0.03 (3H, s); 13C NMR (CDCl3): δ 138.3, 123.2, 78.8,
73.5, 70.4, 67.5, 65.4, 56.8, 56.6, 42.3, 42.2, 41.5, 41.4, 40.9,
38.9, 38.7, 31.8, 31.5, 29.3, 29.1, 26.5, 25.9, 25.9, 24.3, 20.2,
19.3, 18.7, 18.1, 18.1, 12.6, -3.8, -4.4, -4.5, -5.2. Anal.
Calcd for C38H72O4Si2: C, 70.31; H, 11.18; Si, 8.65.
Found: C, 70.41; H, 11.10; Si, 8.7.
(1S,3R,20S)-1,3-Bis(tert-butyldimethylsilyloxy)-20-(3-
hydroxy-3-methylbuthyloxy)pregna-5,7-dien (12). A solu-
tion of the tertiary alcohol 20 (19.6 kg, 30.2 mol) in heptane
(119 L) was stirred with NBS (6.6 kg, 37.1 mol) and AIBN
(0.70 kg, 4.26 mol) at 78 °C for 15 min. The mixture after
cooling was filtrated, and the filtrate was concentrated under
reduced pressure. The residual oil was dissolved in toluene
(204 L) and was stirred with γ-collidine (9.60 kg, 79.2 mol)
at 110 °C for 2.5 h. The mixture after cooling to 20 °C was
filtrated, and the filtrate was evaporated under reduced
pressure to leave a light-yellow solid. The solid was dissolved
in AcOEt (73 L) at 35 °C, and to this solution was added
acetonitrile (235 L) at 40 °C, and the mixture was cooled to
-5 °C to separate the crystals. After stirring for 1 h at the
same temperature, the crude 12 separated as a light-yellow
crystalline solid and was collected centrifugally. The solid
was again dissolved in AcOEt (73 L) at 35 °C, and to the
solution was added acetonitrile (234 L) at 40 °C; the solution
was then cooled at 5 °C for 1 h. The separating crystalline
material was collected centrifugally and dried at 45 °C to
give the diene 12 as colorless crystals (8.4 kg, 43.0%): mp
146 °C; [R]D20 +14.7° (c 1.01, CHCl3); FT-IR (KBr, cm-1):
20
71.0%) as colorless crystals: mp 134 °C; [R]D +25.2° (c
1.00, CHCl3); FT-IR (KBr, cm-1): ν 3518, 2956, 2856, 1473,
1381, 1255, 1088, 837, 773, 675; 1H NMR (CDCl3): δ 5.45
(1H, d, J ) 5.6), 4.85 (1H, m), 3.81 (1H, m), 3.76 (1H, br
s), 3.47 (1H, m), 3.25 (1H, m), 2.20-2.28 (2H, m), 1.18
(3H, s), 0.95 (3H, s), 0.88 (18H, s), 0.66 (3H, s), 0.08 (3H,
s), 0.06 (3H, s), 0.05 (3H, s), 0.03 (3H, s); 13C NMR
(CDCl3): δ 138.3, 123.2, 78.8, 73.5, 70.4, 67.5, 65.4, 56.8,
56.6, 42.3, 42.2, 41.5, 41.4, 40.9, 38.9, 38.7, 31.8, 31.5, 29.3,
29.1, 26.5, 25.9, 25.9, 24.3, 20.2, 19.3, 18.7, 18.1, 18.1, 12.6,
-3.8, -4.4, -4.5, -5.2.
(1S,3R,20S)-1,3-Bis(tert-butyldimethylsilyloxy)-20-(3-
hydroxy-3-methylbuthyloxy)pregn-5-ene (20). To a solu-
tion of the secondary alcohol 17 (17.2 kg, 30.55 mol) in
THF (61.0 kg) was added NaH (60% dispersion in mineral
oil, 2.4 kg, 60.0 mol) portionwise with stirring at room
temperature so as to control evolution of hydrogen at an
appropriate rate. Afte the evolution of hydrogen ceased, to
the resulting suspension was added the bromide 24 (7.1 kg,
43.02 mol) dropwise at the same temperature with stirring,
and the mixture was refluxed for 1 h. After cooling to room
temperature, to this mixture containing the epoxy-ether 25
was added L-Selectride (1 M in THF, 49.0 kg, 55.06 mmol)
dropwise, and the mixture was refluxed for 1 h. The mixture
was then cooled to -10 °C and treated sequentially with
10% NaOH (91.0 kg, 227.5 mol) and 35% H2O2 (43.0 kg,
417.7 mol); the stirring was continued for 1 h at room
temperature. To this mixture was then added aqueous
Na2S2O3 (35.0 kg in H2O 101 L, 141.0 mol) at the same
temperature, and after stirring for 1 h, the mixture was
extracted with AcOEt (106 L) and separated. The organic
layer was washed sequentially with brine (2 × 110 L) and
evaporated under reduced pressure to leave a colorless solid.
The solid was dissolved in refluxing methanol (124 L), and
to this solution, after cooling to 25 °C, was added water (52
L) with stirring to form a suspension which was cooled to 5
°C; the stirring was continued for 1 h at the same temper-
1
ν 3516, 2960, 2856, 1473, 1380, 1255, 1099, 837, 683; H
NMR (CDCl3): δ 5.58 (1H, m), 5.32 (1H, d, J ) 5.6), 4.04
(1H, m), 3.84 (1H, m), 3.69 (1H, br s), 3.49 (1H, m), 3.26
(1H, m), 2.78 (1H, m), 2.30-2.36 (2H, m), 1.23 (3H, s),
1.22 (3H, s), 1.20 (3H, d, J ) 3.2), 0.89 (3H, s), 0.87 (18H,
s), 0.60 (3H, s), 0.10 (3H, s), 0.06 (6H, s), 0.05 (3H, s); 13
C
NMR (CDCl3): δ 139.7, 137.6, 120.1, 115.3, 79.0, 73.9,
70.4, 66.3, 65.6, 56.4, 54.6, 42.7, 42.0, 41.5, 40.8, 39.0, 38.4,
37.5, 29.3, 29.1, 26.4, 26.0, 25.9, 22.9, 20.5, 18.9, 18.2, 18.0,
16.7, 12.6, -3.8, -4.4, -4.5, -4.9. Anal. Calcd for
C38H70O4Si2: C: 70.53; H: 10.90. Found: C: 70.16; H:
10.83.
(1S,3R,20S)-20-(3-Hydroxy-3-methylbuthyloxy)pregna-
5,7-dien-1,3-diol (34). To a stirred solution of TBAF in THF
(1.0 M solution, 66.0 kg, 73.08 mmol) was added 12 (8.4
kg, 12.98 mol) at 20 °C, and the mixture was heated at 66
°C for 9 h. After cooling to 25 °C, the mixture was diluted
with H2O (378 L) at 20 °C with stirring. After stirring for
1.5 h at the same temperature, crude 34 was separated as a
light-yellow crystalline solid and was again dissolved in
acetone (45 L) at 30 °C and cooled at -18 °C for 1 h to
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leave a crystalline material. Centrifugal collection gave the
triol 34 as colorless crystals (4.1 kg, 75.5%) after drying at
35 °C: mp 185 °C; [R]D20 -38.0° (c 1.00, EtOH); IR (KBr,
cm-1): ν 3458, 3371, 2972, 2875, 1464, 1369, 1146, 1049,
941, 825, 771; 1H NMR (CDCl3): δ 5.71 (1H, dd, J ) 1.6,
5.3), 5.38 (1H, dd, J ) 2.6, 5.5), 4.05 (1H, m), 3.85 (1H,
m), 3.76 (1H, br s), 3.49 (1H, m), 3.27 (1H, m), 2.73 (1H,
m), 2.54 (1H, m), 2.34 (1H, m), 2.13 (1H, m), 1.26 (3H, s),
1.23 (3H, s), 1.20 (3H, d, J ) 6.3), 0.91 (3H, s), 0.61 (3H,
s); 13C NMR (CDCl3+ 5% DMSO-d6): δ 140.2, 136.9, 120.9,
115.2, 78.6, 71.9, 70.1, 65.2, 64.4, 56.2, 54.1, 41.9, 41.7,
41.3, 39.8, 38.3, 38.0, 37.3, 29.0, 28.8, 26.0, 22.6, 20.0, 18.6,
15.9, 12.2; Anal. Calcd for C26H42O4: C, 74.60; H, 10.11.
Found: C, 74.36; H, 9.93.
>95%) 1-bromo-3-methyl-2-butene 22 (100 g, 0.671 mol)
in CH2Cl2 (2 L) was slowly added mCPBA (80-85%, 200
g, 0.93-0.99 mol) at room temperature. The reaction mixture
was stirred for 2 h, and the resulting solid was removed by
filtration. An aqueous 5% Na2S2O4 solution (1 L) was added
to the filtrate and stirred for 1 h. The CH2Cl2 layer was then
separated, washed with saturated aqueous NaHCO3 (2 L ×
2) and brine (2 L), and dried over MgSO4. After evaporation
of the solvent, the remaining liquid was distilled to afford
epoxy bromide 24 (88.6 g, 80.0%) as a colorless oil.
Industrial Synthesis of 1-Bromomethyl-2,2-dimethyl-
oxirane (24). To a stirred solution of aqueous KOH (2.9 kg
in H2O 10 L) was slowly added bromine (2.8 kg, 17.42 mol)
at 5 °C. The mixture was stirred for 15 min at the same
temperature, and then to this solution was added 2-methyl
3-buten-2-ol 32 (1.0 kg, 11.61 mol) at 10 °C and stirred for
20 h. The mixture was diluted with hexane (5 L) at the same
temperature; the organic layer was separated and evaporated
under reduced pressure and distilled to afford epoxy bromide
24 (1.6 kg, 82.0%) as a colorless oil: bp 52 °C/25 mmHg;
FT-IR (KBr, cm-1): ν 2966, 2929, 1456, 1435, 1412, 1381,
1319, 1252, 1221, 1130, 1022, 922, 885, 843, 742, 685, 652,
496, 436, 432, 409; 1H NMR (CDCl3): δ 3.48 (1H, dd, J )
10.4, 6.0), 3.23 (1H, dd, J ) 10.4, 7.0), 3.05 (1H, dd, J )
7.5, 6.0), 1.33 (3H, s), 1.29 (3H, s); 13C NMR (CDCl3): δ
62.1, 60.5, 29.8, 24.3, 18.1.
(+)-(5Z,7E)-(1S,3R,20S)-20-(3-Hydroxy-3-methylbutyl-
oxy)-9,10-secopregna-5,7,10(19)triene-1,3-diol (1). A stirred
solution of the triol 34 (100 g, 0.239 mmol) in THF (2.5 L)
was irradiated at 10 °C for 420 min in a quartz apparatus
equipped with a high-pressure mercury lamp (1 kW). After
evaporation of the solvent under reduced pressure, the residue
was triturated in acetone (0.25 L) to separate out the
unreacted triol 34 (43.0 g, 0.103 mmol) as crystals, which
were recovered by filtration. The filtrate containing the
photoproduct was evaporated under reduced pressure, and
the residue was purified by preparative HPLC (AcOEt:
hexane ) 85:15) to give the pre-triene 35. The pre-triene
35 was dissolved in THF (0.4 L), and the solution was stirred
at 25 °C for 85 h. After evaporation of the solvent under
reduced pressure, the residue was purified by HPLC (AcOEt:
hexane ) 85:15) to leave a colorless oil 1 which was
crystallized from hexane and AcOEt to give maxacalcitol
Acknowledgment
We thank Dr. Kunio Ogasawara, Professor Emeritus,
Tohoku University, for his helpful suggestions. We also
thank Dr. Eigoro Murayama, Executive officer of Pharma-
ceutical Technology Division, Mr. Tomoyuki Nakayama,
Executive officer of Pharmaceutical Production Division, Mr.
Kazuo Sasahara, Director of Production & Logistics Coor-
dination Department, and Dr. Kazumi Morikawa, Director
of Chemistry Research Department I, Chugai Pharmaceutical
Co., Ltd., for their encouragement. We also wish to thank
Dr. Paul Langman, Regulatory Affairs Department, Chugai
Pharmaceutical Co., Ltd., for his assistance with English
usage.
20
(1) as colorless crystals (16.0 g, 16.0%): mp 122 °C; [R]D
+49.4° (c 1.00, EtOH); FT-IR (KBr, cm-1): ν 3350, 3344,
3332, 2966, 2926, 2872, 2846, 1635, 1471, 1433, 1431, 1377,
1367, 1329, 1221, 1146, 1092, 1057, 1012, 957, 908, 899,
879, 800, 752; 1H NMR (CDCl3): δ 6.35 (1H, d, J ) 11.2),
6.02 (1H, d, J ) 11.2), 5.32 (1H, s), 4.98 (1H, s), 4.42 (1H,
m), 4.22 (1H, m), 3.85 (1H, m), 3.47 (1H, m), 3.26 (1H,
m), 2.82 (1H, dd, J ) 0.3, 12.9), 2.58 (1H, dd, J ) 3.6,
7.0), 2.30 (1H, dd, J )7.3, 13.2), 1.82-2.20 (8H, m), 1.63-
1.75 (4H, m), 1.46-1.52 (4H, m), 1.18-1.32 (10H, m), 0.53
(3H, s); 13C NMR (CDCl3): δ 147.6, 142.1, 133.4, 124.6,
117.5, 111.8, 78.7, 70.7, 70.6, 66.7, 65.5, 57.0, 56.0, 45.2,
44.7, 42.8, 41.4, 39.5, 29.2, 29.1, 28.9, 25.5, 23.2, 22.2, 18.8,
12.6; UV (EtOH): λmax 263 nm.
Received for review October 1, 2004. Accepted February 25,
2005.
Original Synthesis of 1-Bromomethyl-2,2-dimethylox-
irane (24). To a stirred solution of commercial (purity
OP049822X
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