Economical Process for Preparation of the 19-nor A Ring of Paricalcitol from (-)-Shikimic Acid

Article abstract of DOI:10.1021/acs.oprd.9b00209

An economical and efficient means of preparing the 19-nor A ring, a key precursor of the vitamin D receptor (VDR) activator Paricalcitol, is here described. This process begins with commercially available (-)-shikimic acid and was easily scaled up to kilo

Full text of DOI:10.1021/acs.oprd.9b00209

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Full Paper
An economical process for the preparation of 19-
nor A ring of Paricalcitol from (-)-shikimic acid
Shengfeng Zhou, Runyu Zhu, Jingwen Hu, Lixiong Zhang, Qian Lu, and Xinhong Yu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00209 • Publication Date (Web): 24 Jul 2019
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An Economical Process for the Preparation of 19-
nor A Ring of Paricalcitol from (-)-Shikimic Acid
Shengfeng Zhou, Runyu Zhu, Jingwen Hu, Lixiong Zhang, Qian Lu, Xinhong Yu*
Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of
Education; Shanghai Key Laboratory of New Drug Design; State Key Laboratory of
Bioengineering Reactors; School of Pharmacy, East China University of Science &
Technology, Shanghai 200237, China
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ABSTRACT
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An economical and efficient means of preparing 19-nor A ring, a key precursor of vitamin
D receptor (VDR) activator Paricalcitol, is here described. This process begins with
commercially available (-)-shikimic acid and was easily scaled up to kilograms in a total yield
over 17.8%. Davis oxidation was applied for the synthesis of the key precursor of α-hydroxyl
carboxylic ester.
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KEYWORDS: Paricalcitol, 19-Nor A ring, (-)-Shikimic acid, Davis reagent.
INTRODUCTION
Paricalcitol, namely 19-nor-1, 25-(OH)2-vitamin D2, is a synthetic, biologically active
vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring.
It is marketed by Abbott Laboratories under the trade name of Zemplar and used for the
prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.
It has been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and
secretion[1]. As of now, many synthetic methods have been developed for the preparation of
paricalcitol [2–11]. Most of them have used convergent synthesis by assembling A-rings and C/D-
rings through the WittigHorner reaction[3,4,6,8,10], SuzukiMiyaura coupling [9], or
alkynylation[5,12] (Fig. 1).
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Ph
P
R
O
Ph
R
Wittig–Horner
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9
O
OTBS
O
TBSO
OTBS
C
D
OH
alkynylation
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R
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Suzuki–Miyaura coupling
O
X
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A
HO
OH
O
TBSO
OTBS
OMe
B
TBSO
OTBS
O
1
7
8
5
4
Figure 1. Retro synthetic approach of Paricalcitol
Some methods for the efficient synthesis of 19-nor A rings have been reported [36,810,1215]
.
Phosphine oxide 2 used in WittigHorner reaction is the most popular intermediate. One of the
standard procedures for its synthesis was developed by the DeLuca group[3]. (-)-Quinic acid (18)
was used for the chiral synthon of the A ring through a 11-step synthesis in an overall yield of
13%.
Herein, we describe a new, economical, scalable route for synthesis of this structure from
another biochemical metabolite, (-)-shikimic acid (11) (Scheme 1). Since (-)-shikimic acid is the
raw material of a major anti-viral drug, oseltamivir phosphate (Tamiflu), its manufacturing
process has been improved, rendering it far more affordable. Now the price of (-)-shikimic acid
is about one-tenth that of (-)-quinic acid. [36]
RESULTS AND DISCUSSION
The key intermediates in the synthesis of phosphine oxide 2 are the two precursors of
ketone 9 and α-hydroxyl carboxylic ester 10 (Fig. 2). (-)-Shikimic acid 11 was chosen as the
starting material, since it has the same (3R, 5R) hydroxy configurations as those in the precursors
(Scheme 1).
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HOOC OH
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Ph
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OH
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N
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w
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h
o
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OTBS
TBSO
OTBS
COOH
TBSO
OTBS
9
2
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HO
OH
OH
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Figure 2. Retro synthetic scheme for phosphine oxide 2
Literature review revealed that HCl/MeOH[16], SOCl2//MeOH[17,18], CSA/MeOH[19]
,
CH2N2/MeOH[20], and acidic cation resin/MeOH[21-23] have been applied for producing methyl
(-)-shikimate 12. The workup was easier using resin because it can be simply filtered from the
reaction mixture after completion of the reaction and it is convenient to recycle. Hydrogenation
of 12 took place readily in the presence of palladium carbon under atmospheric pressure.
Selective protection of dihydro methyl (-)-shikimate with tert-butyldimethylchlorosilane
produced di-TBS 14. Those three steps can be optimized in 76% yield. Hermann O.L.
Fischer[24,25] reported the absolute configurations of dihydro methyl (-)-shikimate 13 to be (1S,
3R, 4S, 5R), since 1,4-lactone was produced easily from dihydromethyl (-)-shikimate 13 or
dihydro (-)-shikimic acid. NOESY spectra of dihydro methyl (-)-shikimate 13, di-TBS 14 and
thiocarbaimidazolide 15 were confirmed to have the correct stereochemistry.
Barton and McCarnbiea free radical deoxygenation[26,27] was used for the removal of 4-OH.
Reaction of 14 with 1, 1-thiocarbonyldiimidazole in the presence of DMAP in dichloromethane
gave thiocarbaimidazolide 15, which underwent further radical deoxygenation with sodium
hypophosphite in the presence of azobisisobutyronitrile (AIBN) under argon to produce 4-
desoxy-ester 16 at a yield of 65% in two steps.
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COOH
COOMe
COOMe
COOMe
COOMe
a
e
d
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OH
HO
OH
OH
HO
OH
OH
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OTBS
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OTBS
OH
OH
OCSIM
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O
Ph
COOMe
O
MeOOC OH
g,h
f
i,j
k,l,m
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
16
10
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2
Scheme 1. Reagents and conditions: (a) Amberlyst 15 ion-exchange resin, MeOH, reflux, 10 h; (b) 5%Pd-C, H2, MeOH, rt, 2 h;
(c) TBSCl (3 equiv), Imidazole (4 equiv), DMF, rt, 18 h; (d) 1,1-thiocarbonyldiimidazole (1.2 equiv), imidazole (1 equiv),
DMAP (cat), DCM, rt, 18 h; (e) sodium hypophosphite (5 equiv), AIBN (cat), 2-methoxyethanol, reflux, 2 h; (f) KHMDS (2.5
equiv), 3-phenyl-2-(phenylsulfonyl)oxaziridine (2 equiv), THF, -70°C, 2 h; (g) NaBH4 (2 equiv), EtOH, 10–15°C, 12 h; (h)
NaIO4 (1.5 equiv), THF/H2O, rt, 4 h; (i) (TMS)CH CO2Et (2 equiv), LDA (2 equiv), THF, -78°C; (j) DIBAL-H (3 equiv);
toluene, -30°C, 1 h; (k) n-BuLi (1.1 equiv), THF, then TsCl (1.05 equiv), -10°C, 2 h; (l) HPPh 2 (1.1 equiv), n-BuLi (1.1 equiv),
THF, 0°C, 1 h; (m) H 2 O 2 (7.7 equiv), THF/H2O, 0°C, 4 h.
2
For the preparation of the ester 10, Davis reagent[2833] was used to add the α-hydroxy group.
Potassium enolate was produced easily by deprotonation using KHMDS in THF at -70°C,
followed by oxidation with Davis reagent to produce the α-hydroxyl carboxylic ester 10 in 78%
yield. Results showed that Davis reagent is not stable at room temperature. It is better to be
freshly prepared and stored below 5°C under nitrogen.
Reduction of 10 with NaBH4 in EtOH and subsequent oxidative cleavage of the resulting
vicinal diol using NaIO4 afforded the key ketone 9 in 79% yield for two steps. Peterson
olefination[34] of the ketone 9 with methyl (trimethyl-sily1)acetate gave the allylic ester, which
was reduced by diisobutylaluminum hydride (DIBALH) to the primary alcohol 17 in 83% total
yield. Several methods have been reported to prepare phosphine oxide 2 via halide[3,8], tosylate or
mesylate[6] derived from alcohol 17. An in-situ formation of the allyl tosylate with n-butyllithium
and p-toluenesulfonyl chloride[35] was applied. After treatment with diphenylphosphine lithium
salt and subsequent oxidation using hydrogen peroxide, the desired phosphine oxide 2 was
successfully produced at a total yield of 70.6% in three steps.
CONCLUSION
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An efficient and scalable synthesis of 19-nor A ring phosphine oxide 2 was developed here.
Starting from readily available (-)-shikimic acid 11, phosphine oxide 2 was obtained in 17.8%
overall yield. This 13-step sequence has been carried out starting with 1305 g of (-)-shikimic acid
to provide 678 g of 2 in one batch.
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The key intermediate for this novel preparation was α-hydroxyl carboxylic ester 10, which
was synthesized via Davis oxidation.
EXPERIMENTAL SECTION
General. All reagents were commercially available and used without further purification.
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1H and C NMR spectra were obtained using a Bruker 400 MHz spectrometer. Monitoring of
reaction progress and purity analysis of scale-up samples were accomplished by reverse-phase
HPLC (Agilent 1260) according to the following conditions: column Agilent ZORBAX SB-C18
(4.6×250 mm, 3.5 μm); eluent A: 0.1% TFA in HPLC grade water; eluent B: acetonitrile; flow
rate, 1.0 mL/min.; wavelength, 210 nm; column temperature, 30°C; injection volume, 10 μL; at t
=0 min, 20% eluent B; at t = 15 min, 95% eluent B; at t = 18 min, 95% eluent B; hold for 3 min;
post-run: 20% eluent B for 3 min. The remaining reactions must be monitored by TLC on silica
gel (China) with n-hexane/AcOEt and DCM/methanol of various ratios. The TLC plates were
sprayed with a solution of molybdophosphoric acid (20 g) in ethanol (200 mL) followed by
heating.
(1S,3R,4S,5R)-3,5-bis[(tert-butyl)dimethylsilyloxy]-4-hydroxycyclohex-1-carboxylic
acid methyl Ester (14). Shikimic acid (1305 g, 7.5 mol) and Amberlyst 15 ion-exchange resin
(1305 g) was added to methanol (10,440 g) at 20–25°C. The reaction was refluxed for 10 h. After
in-process control (HPLC) showed >98% conversion of the starting material, the mixture was
filtered and the resin was washed with methanol (1044 g). To the filtrate was added 5% Pd-C
(125 g, 53% wet) under nitrogen. Nitrogen was then exchanged with hydrogen 3 times. The
reaction was hydrogenated at atmospheric pressure and 20–25°C for 3 h. After in-process control
(TLC DCM/ methanol 10:1) showed no starting material, the reaction mixture was filtered and
concentrated to give the crude dihydro methyl shikimic acid 13. DMF (6525 g) was then added
to dissolve the crude 13. Imidazole (1272 g, 18.7 mol) and TBSCl (2475 g, 16.5 mol) were then
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added, keeping the reaction temperature within 0–5°C. The mixture was stirred for 5 h at 5–10°C.
After in-process control (TLC DCM/methanol 10:1) showed reaction completion, the mixture
was then quenched by addition of water (1.2 kg) and extracted with MTBE (0.5 kg ×2). The
MTBE extracts were then washed with water (0.2 kg) and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/AcOEt, 100:1) to afford 14 (2527 g,
6.1 mol) as an oily solid (76%, (over 3 steps)). Spectral data of 13: 1H NMR (400 MHz, D2O) δ:
3.92 (m, 1H), 3.87 (m, 1H), 3.57 (S, 3H), 3.56 (m, 1H), 2.67 (m, 1H), 1.75–1.95 (m, 3H), 1.58
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(m, 1H); C NMR (100 MHz, D2O): δ177.9, 72.2, 68.4, 67.8, 52.2, 36.0, 30.2, 29.6; ESIMS:
191 (M+H) . [a]D -11.3 (c 0.75, MeOH). Spectral data of 14:1H NMR (400 MHz, CDCl3) δ:
+
20
4.04 (m, 1H), 3.93 (m, 1H), 3.61 (S, 3H), 3.53 (m, 1H), 2.66 (m, 1H), 1.58-1.83 (m, 4H), 0.82 (m,
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18H), 0.01 (m, 12H); C NMR (100 MHz, CDCl3): δ175.6, 72.5, 69.5, 68.7, 51.7, 35.7, 30.9,
29.9, 25.8, 25.7, 18.0, 17.9, -4.7, -4.9, -5.1; ESIMS: 419 (M+H)+. [a]D20 -9.4 (c 0.48, MeOH).
(3S,5S)-3,5-Bis[(tert-butyl)dimethylsilyloxy]-1-hydroxycyclohex-1-carboxylic
acid
methyl Ester (10). To a solution of 16 (1.45 kg, 3.6 mol) in THF (2.9 kg) was added dropwise
potassium bis(trimethylsilyl)amide (18 L of 0.5 M toluene solution, 9 mol) at -70 - -65°C under
nitrogen. The mixture was stirred for one hour at -70 - -65°C, and then a solution of 3-phenyl-2-
(phenylsulfonyl)oxaziridine (1.88 kg, 7.2 mol) in THF (2.9 kg) was added dropwise over 1h.
After 2 h at -70 - -65°C and in-process control (TLC n-hexane/AcOEt 10:1) showed no starting
material, the reaction was quenched with saturated aqueous ammonium chloride solution (10 kg).
The reaction mixture was then warmed to room temperature and separated. The aqueous layer
was extracted with EtOAc (6 kg). The combined extracts were washed with brine (2 kg), dried
over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column
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chromatography (heptane /AcOEt, 100:1 to 100:5) to afford 10 (1174 g, 2.8 mol) (78% yield).
H NMR[3] (400 MHz, CDCl3 ):δ: 4.74 (S, 1H), 4.41 (m, 1H), 4.32 (m, 1H), 3.77 (S, 3H), 2.22
(m, 1H), 2.06 (m, 1H), 1.95 (m, 2H), 1.73 (m, 1H), 1.50 (m, 1H), 0.89-0.91 (m, 18H), 0.03-0.12
(m, 12H). [a]D20 4.2 (c 1.01, MeOH).
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(3S,5S)-3,5-Bis[(tert-butyl)dimethylsilyloxy]-1-cyclohexanone (9). To a solution of 10
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(1150 g, 2.75 mol) in EtOH (10 kg) was added NaBH4 (209 g, 5.5 mol) at 0~5°C, and the
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mixture was stirred at 10~15°C for 12 h. After in-process control (TLC n-hexane/AcOEt 5:1)
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showed no starting material, the reaction mixture was poured into saturated aqueous NH4Cl (5
kg), concentrated to remove ethanol and extracted with EtOAc (9 kg × 2). The combined extracts
was concentrated in vacuo. THF (9 kg) was added to dissolve the crude diol. NaIO4 (883 g, 4.1
mol) in water (5 kg) was added dropwise to the solution at 0~5°C, and the mixture was stirred at
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20~25°C for 4 h. After in-process control (TLC n-hexane/AcOEt 5:1) showed no starting
material, the reaction mixture was diluted with MTBE (5 kg). Water (6 kg) was added to the
mixture, the organic layer was separated, and the aqueous layer was extracted with MTBE (5 kg).
The organic layer and extracts were combined and washed with brine, dried over sodium sulfate,
and concentrated in vacuo. Purification by silica gel column chromatography (heptane/AcOEt)
100:1 to 100:3) gave 9 (779 g, 2.17 mol) as a white solid in 79% yield (over 2 steps). Mp 34.5-
35.5 oC; 1 H NMR[3] (400 MHz, CDCl3 ):δ: 4.35 (m, 2H), 4.32 (m, 1H), 2.55 (m, 2H), 2.35 (m,
20
2H), 1.94 (m, 2H), 1.73 (m, 1H), 1.50 (m, 1H), 0.87 (s, 18H), 0.06 (m, 12H). [a]D 19.4 (c
1.01, MeOH).
(3R,5R)-3,5-[Bis-(tert-butyldimethylsilanyloxy)]-cyclohexylidene-ethanol (17). n-BuLi (2.5
M in hexanes, 1.68 L, 4.2 mol) was added to a solution of diisopropylamine (424 g, 4.2 mmol) in
anhydrous THF (7 kg) under argon at -10- 0°C. The mixture was stirred for 1h at 0-5°C and then
cooled to -78 - -70 °C. Methyl (trimethylsily1)acetate (672 g, 4.2 mmol) was added dropwise.
After 30 min, the compound 9 (750 g, 2.1 mmol) in anhydrous THF (2 kg) was added. The
solution was stirred for 1 h at -78- -70°C. After in-process control (TLC n-hexane/AcOEt 10:1)
showed no starting material, the reaction was quenched with saturated ammonium chloride
solution (10 kg) and the mixture extracted with MTBE (10 kg × 2). The combined MTBE
extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give
the crude ester. Toluene (5 kg) was added to dissolve the ester. Diisobutylaluminum hydride
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(1.5 M in toluene, 4 L, 6.0 mol) was added dropwise to the solution under argon at -30- -25°C
After the addition, stirring was continued for 1 h at -30- -25°C. After in-process control
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(HPLC) showed >98% conversion of the starting material, the reaction was then quenched by
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the addition of 2 N potassium sodium tartrate (10 kg), the organic phase was separated, and the
aqueous phase was extracted with ethyl acetate (10 kg). The combined organic phases were
washed with brine (2 kg), dried over sodium sulfate, filtered and evaporated. The residue was
purified by silica gel column chromatography (heptane /AcOEt, 100:5 to 100:10) to afford 17
(674 g, 1.74 mol) as a white solid in 83% yield (over 2 steps). Mp 62.5-66 °C; 1 H NMR[3] (400
MHz, CDCl 3 ): 5.60 (t, J=7.3 Hz, 1H), 4.13 (m, 2H), 4.03 (m, 2H), 2.35 (m, 2H), 2.18 (dd, 1H),
2.06 (dd, 1H), 1.82 (m, 1H), 1.64 (m, 1H), 1.30 (m, 1H), 0.89 (s, 18H), 0.06 (s , 6H), 0.05 (s, 3H),
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0.04 (s, 3H). [a]D20 16.0 (c 1.02, MeOH).
(3R,5R)-3,5-[Bis-(tert-butyldimethylsilanyloxy)]-cyclohexylidene-ethyl-diphenyl-
phosphine oxide (2). n-BuLi (2.5 M in hexane, 740 ml, 1.85 mol) was added dropwise to a
solution of the allyl alcohol 17 (650 g, 1.68 mol) in THF (4 kg) at -20- -10 °C. After addition the
reaction was stirred for 15min at -20- -10 °C. A solution of toluene-4-sulfonyl chloride (336 g,
1.76 mol) in THF (600 g) was then added dropwise and the mixture was stirred at -20- -10°C for
2 h. After in-process control (HPLC) showed >98% conversion of the starting material, this
solution was then added dropwise at -20- -10°C to a solution of lithium diphenylphosphide,
prepared by addition of n-BuLi (2.5 M in hexane, 740 mL, 1.85 mol) to a solution of
diphenylphosphine (344 g, 1.85 mol) in THF (3kg) at -20- -10°C . The reaction mixture was
stirred at 0-5°C for 2 h. After in-process control (HPLC) showed >98% conversion of the
starting material, the mixture was slowly diluted with water (3 kg) and hydrogen peroxide (28%,
1.6 kg, 13 mol) was added dropwise at 0- 5°C. The mixture was stirred for 4 h. After in-process
control (HPLC) showed >98% conversion of the starting material, the organic layer was
separated and the aqueous layer was extracted with MTBE (5 kg). The combined organic phases
were washed with 10%NaHSO3 (5 kg), brine (2 kg), dried over sodium sulfate, filtered and
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evaporated. The residue was purified by silica gel column chromatography (heptane/AcOEt,
100:10 to 100:30) to afford 2 (678 g, 1.74 mol, 98.1% HPLC purity) as a white solid in 70.6 %
yield (over 3 steps) Mp 72-75 °C; 1 H NMR[3] (400 MHz, CDCl3) δ: 7.72 (m , 4H ), 7.47 (m,
6H), 5.28 (q, J=7.2 Hz, 1H), 3.98 (m, 2H) , 3.11 (m, 2H), 2.21 (m, 1H), 2.00 (m, 2H), 1.90 (m,
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1H), 1.65 (m, 2H), 0.85 (s, 9H ), 0.83 (s, 9H ), 0.00 and -0.01 (s, 12H). [a]D 14.1 (c 1.0,
MeOH).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
Copies of 1H NMR, 13C NMR and NOESY spectra analyses (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: xhyu@ecust.edu.cn
ORCID:
Xinhong Yu: 0000-0003-0193-3702
Shengfeng Zhou: 0000-0003-3955-3772
Notes:
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully acknowledge financial support from National Natural Science Foundation of
China (21476078) and Science and Technology Commission of Shanghai Municipality (No.
12431900902).
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