A new way to tert-Butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate, a key intermediate of atorvastatin synthesis

Article abstract of DOI:10.1081/SCC-120021507

A new synthesis of tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate, a key intermediate of the synthesis of an effective HMG-CoA reductase inhibitor atorvastatin, is described. The synthesis is based on the Henry reaction of nitromethane and tert-butyl [(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate. The formed nitroaldol was then O-acetylated and the sodium borohydride reduction of the intermediate provided tert-butyl [(4R,6R)-2,2-dimethyl-6-nitroethyl-1,3-dioxan-4-yl] acetate. Catalytic hydrogenation of the nitro group led to the title compound.

Full text of DOI:10.1081/SCC-120021507

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A New Way to tert-Butyl [(4R,6R)-6-Aminoethyl-2,2-
dimethyl-1,3-dioxan-4-yl]acetate, a Key Intermediate
of Atorvastatin Synthesis
Stanislav Rádl a
a Research Institute of Pharmacy and Biochemistry, Dolni, Mecholupy Prague, Czech Republic
Published online: 17 Aug 2006.
To cite this article: Stanislav Rádl (2003): A New Way to tert-Butyl [(4R,6R)-6-Aminoethyl-2,2-dimethyl-1,3-dioxan-4-
yl]acetate, a Key Intermediate of Atorvastatin Synthesis, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:13, 2275-2283
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2275–2283, 2003
A New Way to tert-Butyl [(4R,6R)-6-Aminoethyl-
2,2-dimethyl-1,3-dioxan-4-yl]acetate, a Key
Intermediate of Atorvastatin Synthesis
*
Stanislav Radl
Research Institute of Pharmacy and Biochemistry,
Dolni, Mecholupy Prague, Czech Republic
ABSTRACT
A new synthesis of tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-
1,3-dioxan-4-yl]acetate, a key intermediate of the synthesis of an
effective HMG-CoA reductase inhibitor atorvastatin, is described.
The synthesis is based on the Henry reaction of nitromethane and
tert-butyl [(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate.
The formed nitroaldol was then O-acetylated and the sodium boro-
hydride reduction of the intermediate provided tert-butyl [(4R,6R)-
2,2-dimethyl-6-nitroethyl-1,3-dioxan-4-yl] acetate. Catalytic hydro-
genation of the nitro group led to the title compound.
*Correspondence: Stanislav Radl, Research Institute of Pharmacy and
Biochemistry, Dolni Mecholupy 130, 102 37 Prague, Czech Republic; E-mail:
radl@vufb.cz.
2275
DOI: 10.1081/SCC-120021507
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2276
Radl
Key Words: Atorvastatin; Synthesis; Swern oxidation; Henry
reaction.
Atorvastatin (1, LipitorÕ, SortisÕ) is a leading HMG-CoA reductase
inhibitoron the market. [1] There are several efficient methods of synthesis
of this drug, mostly based on the convergent synthesis using tert-butyl
[(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (2) as a key
intermediate. All the described methods of preparation of this intermedi-
ate are based on a catalytic reduction of tert-butyl [(4R,6R)-6-cyano-
methyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (3).[2,3] The reduction should
be done under elevated pressure and to prevent secondary amine
formation, ethanolic ammonia is used as a solvent.
Several methods of preparation of the starting tert-butyl [(4R,6R)-6-
cyanomethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate have been published
[3–6]
and/orpatented.
Ourattention was given to tert-butyl [(4R,6S )-6-
hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (4) having all the
necessary steric features of atorvastatin. The compound has been pre-
pared by several methods[7,8] and is also commercially available from
Kaneka.[9] Brower et al.[2] used this compound forthe synthesis of nitrile
3 by a method shown in Sch. 1. The methodology is based on the well-
known carbon chain extension starting from the corresponding hydroxy
derivative 4. This compound was transferred to the corresponding ben-
zenesulfonyl derivatives 5. However, common benzenesulfonyl deriva-
tives 5a or 5b were not enough reactive in the next step, i.e., in the
reaction with sodium cyanide, under various conditions. Therefore
more reactive 4-chlorobenzensulfonyl or 4-nitrobenzensulfonyl

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tert-Butyl [(4R,6R)-6-Aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate
2277
Scheme 1.
Scheme 2.
derivatives 5c or 5d were used and the reaction times were still impracti-
cally long. No substantial improvement was achieved if the correspond-
ing iodo derivative was used and the product was obtained in lower
yields.[2]
Though the article[2] stated that the corresponding methanesulfonyl
derivative was not reactive enough for the reaction with alkaline
cyanides, we tried to use it for the reaction with tetrabutylammonium
cyanide. However, the reactivity of the methanesulfonyl compound
was found insufficient also underthese conditions. Then we tired to
use more reactive trifluoromethanesulfonyl derivative generated in situ
and then treated with tetrabutylammonium cyanide, as it had been
[10,11]
successfully used forsimilarsystems.
Underthe used conditions,
we obtained a complex mixture containing less then 10% of the
required nitrile (GC).
At the outset of our project we also decided to explore the possibility
of using the hydroxy derivative as it is shown in Sch. 2.
The Swern oxidation of 4 leading to tert-butyl [(4R,6S )-6-formyl-2,2-
dimethyl-1,3-dioxan-4-yl]acetate (6) has been reported without any

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2278
Radl
details.[7] This compound can be also prepared from 2-propyl tartarate in
several steps.[12] First we examined several modifications of the Swern
reaction,[13,14] the classical setup using dimethyl sulfoxide activated
by oxalyl chloride was found optimal giving repeatedly the required
aldehyde 6 in about 70–80% yields. Though Wess et al. stated that the
oxidation could not be done using chromium(VI)-based oxidants,[7] we
succeeded in preparing the compound using pyridinium chlorochromate
on alumina,[15] but the yields in a range of 45–55% were substantially
lowerthan with the Swern method. Reaction of some aldehydes similar
to 6, e.g., 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, with nitromethane
to give the corresponding nitroaldol (the Henry reaction) are well docu-
mented.[16,17] We found, that condensation of nitrometane with 6 using
potassium fluoride in 2-propanol at room temperature, the conditions
described by Wollenberg and Miller,[18] proceeded sufficiently well
giving complete conversion after 5 h. The mixture, containing the corre-
sponding nitroaldol as the only detectable product (TLC), after simple
work-up provided 7 as a colorless, slowly solidifying oil. Though we were
not particularly interested in studying the stereoselectivity of this reac-
tion, it seems to be higher than for the similar Henry reaction of (R)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde, where only moderate (80:20)
stereoselectivity was reported.[17] In ourcase, the stereoselectivity seems
to be highersince the sample obtained in high yield afterone cyrstal-
lization was shown to be pure one isomer of 7 (GC, 1H NMR). Acylation
of nitroaldols and the following reductive elimination is a well-known
procedure using the Henry reaction products to the synthesis of simple
nitroalkanes.[18,19] We acetylated crude nitroaldol 7 with acetic anhydride
using DMAP as a catalyst. The reaction was sufficiently fast (r.t., 1 h) and
simple elaboration provided high yield of pure 8 (GC purity higher than
99%). Reductive elimination of acetoxy group from 8 was done by
sodium borohydride in ethanol at room temperature[18] to give from 85
to 92% yield of 9 as a colorless oil (98% GC purity). For patent protec-
tion reasons, also similar O-propionyl and O-butyryl analogs of 8 were
prepared. Though their reductive elimination proceeded analogously to
the acetyl derivative 8, their use is not practical since the compounds were
obtained as colorless oils and our attempts to get crystalline compounds
failed. Methanolic solution of 9 was surprisingly smoothly catalytically
hydrogenated at atmospheric pressure and room temperature using
Raney nickel or Pd/C. Simple filtering and evaporation provided 2 as a
colorless oily product in nearly quantitative yields (98% GC purity).
Though the amine was reported[2] to be unstable, in ourhands the com-
pound was found stable enough to be stored at ꢀ30ꢁC underargon for
several weeks without appreciable decomposition (GC).

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tert-Butyl [(4R,6R)-6-Aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate
2279
In conclusion, we have developed a new way of preparation
of tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate
(2) from tert-butyl [(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-
4-yl]acetate (4). All the reaction steps are simple, fast, and can be done
at room temperature. The method provided the title compound in about
50–60% overall yield.
EXPERIMENTAL
Melting points were measured on a Kofler block and are uncor-
rected. 1H NMR spectra were recorded on a Bruker instrument
(250 MHz); chemical shifts are given in ppm (ꢀ-scale). Infrared spectra
(KBr) were recorded on a Perkin-Elmer FT-IR System Spectrum BX
spectrometer, wavenumbers are given in cmꢀ1. Ultraviolet spectra were
measured on a Shimadzu UV-260 spectrometer in ethanol, wavelengths
are given in nm. Mass spectra were measured on a GC-MS instrument
Finnigan MAT. The purity of the substances prepared was evaluated by
TLC on silica gel (FP KG F 254, Merck). Flash chromatography was
performed on silica gel Merck, particle size 0.04–0.063 mm.
tert-Butyl [(4R,6S )-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (6).
A solution of dimethyl sulfoxide (1.9 g, 22 mmol) in dichloromethane
(5 mL) was added to a solution of oxalyl chloride (1.4 g, 11 mmol) in
dichloromethane (20 mL) stirred at ꢀ50 to ꢀ60ꢁC. Five minutes after
the addition, a solution of 1 (2.6 g, 10 mmol) in dichloromethane
(20 mL) was added during 10 min and the solution was stirred at
ꢀ50ꢁC foradditional 30 min. Then triethylamine (8 mL) was added, the
mixture was allowed to warm to room temperature during 2 h. Water
(50 mL) was added and the mixture was extracted with dichloromethane;
the combined extracts were washed with brine, dried with magnesium
sulfate and evaporated. The residue was purified by flash chromatogra-
phy (hexane–ethyl acetate, 9:1) to give 2.1 g of 6 (77%) as a colorless oil.
1H NMR spectrum (CDCl3): ꢀ 1.24 (m, 1H), 1.40 (bs, 3H), 1.45 (bs, 3H),
1.52 (s, 9H), 1.84 (dt, J¼3.2, 12.7 Hz, 1H), 2.40 (m, 2H), 4.35 (m, 2H),
9.58 (d, J ¼ 0.5 Hz, 1H).
tert-Butyl [(4R,6S )-6-(1-hydroxy-2-nitroethyl)-2,2-dimethyl-1,3-dioxan-
4-yl]acetate (7). Nitromethane (5 mL) was added dropwise to a stirred
mixture of tert-butyl [(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]ace-
tate (6) (9.7 g, 37.6 mmol) and dry potassium fluoride (0.25 g) in 2-propanol
(50 mL) and the mixture was stirred at room temperature for 5 h. Then the
mixture was evaporated to dryness, the residue was dissolved in ether
(250 mL), the insoluble portion was filtered through a Celite pad and the

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Radl
filtrate was evaporated to give 11.4 g of white crystals (95%) of GC purity
of 98.8%. Analytical sample was crystallized from a heptane-ether mixture
giving white crystals, m.p. 129–137ꢁC. Anal. calcd. for: C, 52.65; H, 7.89;
N, 4.39. Found: C, 52.37; H, 7.77; N, 4.41. [a]D ¼ þ3.08ꢁ. 1H-NMR
20
spectrum (CDCl3): ꢀ1.28 (dt, ¼ 11.6, 12.7 Hz, 1H), 1.36 (bs, 3H), 1.43
(bs, 3H), 1.45 (s, 9H), 1.82 (dt, J ¼ 2.6, 12.7 Hz, 1H), 2.33 (dd, J ¼ 6.0,
15.2 Hz, 1H), 2.45 (dd, J ¼ 7.2, 15.2 Hz, 1H), 2.81 (bs, 1H), 3.90 (ddd,
J ¼ 2.6, 6.6, 11.6 Hz, 1H), 4.13–4.33 (m, 2H), 4.45 (dd, J ¼ 8.5, 13.5 Hz,
1H), 4.63 (dd, J ¼ 2.9, 13.5 Hz, 1H). UV spectrum, ꢁmax (log "): 207.2 (3.6).
IR spectrum (KBr): 1556 (NO2), 1722 [C-C(¼ O)-O], 3566 (OH).
tert-Butyl [(4R,6S )-6-(1-Acetoxy-2-nitroethyl)-2,2-dimethyl-1,3-dio-
xan-4-yl]-acetate (8). Method A. Acetic anhydride (1.2 g) was added drop-
wise to a solution of 7 (3.2 g, 10 mmol) and 4-dimethylaminopyridine
(0.05 g) in ether (50 mL) and the mixture was stirred at room temperature
for 1 h. Then the solution was washed with brine and dried with magne-
sium sulfate. Evaporation of the filtrate provided 3.5 g of crude 7 of GC
purity of 93%. Analytical sample was obtained by repeated crystalliza-
tion from hexane giving white crystals, m.p. 92–95ꢁC (GC purity
of at least 99%). Anal. calcd. for: C, 53.18; H, 7.53; N, 3.88. Found:
C, 52.96; H, 7.43; N, 3.72. 1H NMR spectrum (CDCl3): ꢀ 1.32 (dt,
J ¼ 11.4, 12.8 Hz, 1H), 1.38 (bs, 3H), 1.41 (bs, 3H), 1.43 (s, 9H), 1.66
(dt, J ¼ 2.9, 12.8 Hz, 1H), 2.02 (s, 3H), 2.30 (dd, J ¼ 6.0, 15.2 Hz,
1H), 2.42 (dd, J ¼ 7.2, 15.2 Hz, 1H), 4.03 (m, 1H), 4.18 (m, 1H), 4.68
(m, 2H), 5.28 (m, 1H). UV spectrum, ꢁmax (log "): 206.0 (3.7). IR
spectrum (KBr): 1228 [C-C(O)-C], 1560 (NO2), 1724 [C-C(¼O)-O],
1750 [C-C(¼ O)-O]. GC-MS, m/e (%): 290 (16), 248 (25), 230 (79),
188 (25), 170 (26), 139 (29), 81 (13), 59 (38), 57 (83), 43 (100), 41 (60),
39 (37).
Method B. Nitromethane (5 mL) was added dropwise to a stirred
mixture of 6 (9.7 g, 37.6 mmol) and dry potassium fluoride (0.25 g) in
2-propanol (50 mL) and the mixture was stirred for 5 h at room tem-
perature. Then the mixture was evaporated to dryness and the residue
was dissolved in ether(250 mL). 4-Dimethylaminopyidrine (0.1 g)
and acetic anhydride (1.2 g) were added to the cloudy solution and
the mixture was stirred at room temperature for 1 h. Work-up
described in Method A then provided 12.1 g of crude 8 (GC purity
of 93%).
tert-Butyl [(4R,6R)-2,2-dimethyl-6-(2-nitroethyl)-1,3-dioxan-4-yl]ace-
tate (9). A solution of 8 (12,1 g, 33.5 mmol) in ethanol (100 mL) was
added dropwise to a stirred suspension of sodium borohydride (5 g) in
ethanol (50 mL) with cooling in an ice bath and the mixture was stirred at
room temperature for 1 h. Then the solution was poured into 10% solu-

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tert-Butyl [(4R,6R)-6-Aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate
2281
tion of acetic acid (100 mL), the formed solution was extracted with ether,
the extract was washed with brine and dried with magnesium sulfate.
Evaporation of the filtrate provided 9.3 g of 9 (92%) as colorless oil of
GC purity of 98%. [a]D þ 18.17ꢁ. H NMR spectrum (CDCl3): ꢀ 1.22
(dt, J¼11.4, 12.7 Hz, 1H), 1.34 (d, J¼0.7 Hz, 3H), 1.42 (d, J¼0.7 Hz, 3H),
1.44 (s, 9H), 1.61 (dt, J¼2.5, 12.7 Hz, 1H), 2.02 (dddd, J¼5.7, 8.1,
9.1, 14.6 Hz, 1H), 2.22 (dddd, J¼3.3, 6.5, 7.1, 14.6 Hz, 1H), 2.30 (dd,
J¼6.1, 15.2 Hz, 1H), 2.42 (dd, J¼7.0, 15.2 Hz, 1H), 3.96 (dddd, J¼2.5,
3.3, 9.1, 11.4 Hz, 1H), 4.25 (dddd, J¼2.5, 6.1, 7.0, 11.4 Hz, 2H), 4.45
(ddd, J¼5.7, 7.0, 13.4 Hz, 1H), 4.54 (ddd, J¼6.5, 8.1, 13.4 Hz, 1H). UV
spectrum, ꢁmax (log "): 205.8 (3.7). IR spectrum (KBr): 1554 (NO2), 1721
[C-C(¼ O)-O].
20
1
tert-Butyl [(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]a-
cetate (2). Method A. 10% Palladium on carbon (0.5 g) was added to a
solution of 9 (3 g, 10 mmol) in methanol (50 mL) and the mixture was
hydrogenated with stirring at room temperature without pressure till a
hydrogen consumption was registered (about 2 h). The catalyst was fil-
tered through a Celite pad, the filtrate was evaporated giving 0.3 g of 2 as
a colorless oily product of GC purity of 98%. [a]D ¼ þ13.12ꢁ. 1H NMR
20
spectrum (CDCl3): ꢀ 1.23 (m, 1H), 1.37 (s, 3H), 1.47 (s, 3H), 1.47 (s, 9H),
1.56 (m, 1H), 1.60 (m, 2H), 2.24 (bs, 2H), 2.30 (dd, J ¼6.0, 15.1 Hz, 1H),
2.43 (dd, J¼7.0, 15.1 Hz, 1H), 2.85 (m, 2H), 3.99 (m, 1H), 4.26 (m, 1H).
UV spectrum, ꢁmax (log "): 204.2 (2.6). IR spectrum (KBr): 1721
[C-C(¼O)-O], 3382 (NH2). GC-MS: 274 (M þ 1), 202 (M-CH3–C4H8),
200 (M-OC4H9), 30 (CH2NH2).
Method B. The same setup using Raney nickel catalyst was used.
ACKNOWLEDGMENT
Financial support provided by Leciva Praha is greatly appreciated.
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2282
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Received in the UK October1, 2002

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