Synthesis of some impurities and/or degradation products of atorvastatin

Article abstract of DOI:10.1135/cccc20080229

Synthesis of some impurities and/or degradation products of atorvastatin, calcium (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl) pyrrol-1-yl]-3,5-dihydroxyheptanoate, is described. These include its desfluoro analog, the corresponding (3S,5S)-and (3S,5R)-epimers, atorvastatin lactone, and some other potential impurities. The synthesized compounds as well as the corresponding intermediates were characterized by ¹H NMR, ¹³C NMR and MS.

Full text of DOI:10.1135/cccc20080229

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
229
SYNTHESIS OF SOME IMPURITIES AND/ OR DEGRADATION
PRODUCTS OF ATORVASTATIN
1,
2
3
4
Jan STACH *, Jaroslav HAVLÍČEK , Lukáš PLAČEK and Stanislav RÁDL
1
Zentiva, U Kabelovny 130, 102 37 Prague 10, Czech Republic; e-mail: jan.stach@zentiva.cz,
jaroslav.havlicek@zentiva.cz, lukas.placek@zentiva.cz, stanislav.radl@zentiva.cz
2
3
4
Received Novem ber 22, 2007
Accepted February 24, 2008
Publish ed on lin e March 7, 2008
Syn th esis of som e im purities an d/or degradation products of atorvastatin , calcium (3R,5R)-7-
[2-(4-fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)pyrrol-1-yl]-3,5-dih ydroxy-
h eptan oate, is described. Th ese in clude its desfluoro an alog, th e correspon din g (3S,5S)-
an d (3S,5R)-epim ers, atorvastatin lacton e, an d som e oth er poten tial im purities. Th e syn th e-
sized com poun ds as well as th e correspon din g in term ediates were ch aracterized by 1H NMR,
13C NMR an d MS.
Keyw ord s: Atorvastatin ; Im purities; Degradation products; Lacton es; Esters; Lipitor; Pyrroles.
Atorvastatin (1; Lipitor , Sortis ) is a leadin g HMG-CoA reductase in h ibi-
tor on th e m arket1–3, with th e poten tial becom in g on e of th e m ost success-
ful gen eric drugs of th is decade. Probably all producers of th is drug use
com poun d 2 as th e key in term ediate.
Th ere are several efficien t m eth ods of syn th esis of th is in term ediate,
m ostly based on th e con vergen t syn th esis usin g tert-butyl [(4R,6R)-6-
(2-am in oeth yl)-2,2-dim eth yl-1,3-dioxan -4-yl]acetate (3). Th is com poun d is
usually prepared by catalytic reduction of tert-butyl [(4R,6R)-6-(cyan o-
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246
© 2008 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20080229

230
Stach, Havlíček, Plaček, Rádl:
m eth yl)-2,2-dim eth yl-1,3-dioxan -4-yl]acetate (4)3–5. We h ave recen tly
publish ed a n ew m eth od of preparation of 3 from tert-butyl [(4R,6S)-6-
(h ydroxym eth yl)-2,2-dim eth yl-1,3-dioxan -4-yl]acetate (5) based on th e
Hen ry reaction 6.
We h ave also developed our own m eth od of preparation of am orph ous
atorvastatin 7 an d a gen eric atorvastatin version usin g th is substan ce h as
been laun ch ed. Beside im purities th at can n ot be com pletely elim in ated
durin g th e substan ce preparation an d purification , degradation products
form ed at various stages of h an dlin g an d storin g m ay im pose a problem .
Th e specification for a gen eric drug substan ce sh ould in clude a list of im pu-
rities, with th e specified im purities bein g eith er iden tified or un iden tified.
Th e iden tified im purities sh ould be in cluded in th e specification wh en th ey
are presen t at a level greater th an th e iden tification th resh old wh ich is usu-
ally 0.10%. Th us, iden tification an d settin g specification s for th e evaluation
of th e quality of a drug substan ce are im portan t aspects of an y gen eric pro-
ject, wh ich m ust also in clude iden tification an d syn th esis of all key im puri-
ties an d degradation products.
As far as we kn ow, n o paper on im purities of atorvastatin h as been pub-
lish ed, an d th e on ly publish ed report8 on degradation products deals with
atorvastatin ph otodegradation products, wh ich are n ot presen t in well-
h an dled substan ce. In th is paper, we would like to report th e syn th esis of
som e im purities used as HPLC stan dards for th e API evaluation .
Sin ce atorvastatin h as two stereogen ic carbon atom s, four possible dia-
stereom ers are possible. For ch iral HPLC an alysis, we prepared atorvastatin
in th e form of its cis-racem ate via the (cis)-tert-butyl 6-(cyanom ethyl)-2,2-di-
m ethyl-1,3-dioxane-4-acetate9. On th e oth er h an d, trans-atorvastatin , wh ich
is a com m on atorvastatin im purity, is usually determ in ed by HPLC as th e
sum of both isom ers 6 an d 7. We prepared com poun d 6 as a stan dard for
th is determ in ation .
Durin g th e developm en t of gen eric atorvastatin , we iden tified several im -
purities form ed durin g th e m ultistep syn th esis of th is substan ce. Som e of
th em usually accom pan y th e substan ce in depen den tly of th e procedure,
oth ers are specific to th e procedure used. Th e m ost frequen tly en coun tered
im purity as well as degradation product is atorvastatin lacton e (8). Th is
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
231
substan ce is form ed both durin g atorvastatin syn th esis an d from ator-
vastatin un der acidic con dition s. An oth er com m on ly presen t im purity is
th e desfluoro derivative of atorvastatin 9.
Im pure am in e 3 probably causes th e presen ce of “diam in o atorvastatin ”
10 in th e atorvastatin API. Th is im purity could also be form ed durin g th e
form ation of th e pyrrole rin g. Several atorvastatin esters can be presen t in
th e atorvastatin substan ce, depen din g on th e procedure used. Meth yl ester
11a can be foun d in th e product prepared by th e origin al Parke–Davis pro-
cedure10 sin ce m eth an ol is used as a cosolven t. On th e oth er h an d, sm all
am oun ts of tert-butyl ester 11b are som etim es presen t due to an in com plete
h ydrolysis of th e tert-butyl group of 2.
Elim in ation of th e 3-h ydroxy group of atorvastatin can lead to th e corre-
spon din g un saturated atorvastatin derivative, wh ich can be presen t eith er
as th e E- or Z-form (12). In terestin gly, on ly th e trans isom er 12 was de-
tected in th e real sam ples.
Stan dard of (S,S)-atorvastatin (13) for ch iral HPLC m eth od was also
n eeded.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

232
Stach, Havlíček, Plaček, Rádl:
In th e subsequen t part of th e paper, syn th esis of th e discussed im purities
an d/or degradation products will be described.
Preparation of “trans-atorvastatin ” (6) started from com m ercially available
eth yl (R)-4-cyan o-3-h ydroxybutan oate (14). Th is com poun d (Sch em e 1)
treated with tert-butyl lith ioacetate in tetrah ydrofuran usin g th e m eth odol-
ogy described in a U.S. paten t11 provided 15 in good yield. Reduction with
sodium boroh ydride in acetic acid yielded dih ydroxy in term ediate 16 with
m oderate diastereoselectivity (82:18); subsequen t crystallization from eth yl
acetate/h exan e gave th e product with satisfactory diastereoselectivity (95:5).
Reduction with tetram eth ylam m on ium triacetoxyboroh ydride in acetic acid/
aceton itrile provided 16 with a sligh tly better diastereoselectivity (88:12).
The protection with acetone and subsequent catalytic hydrogenation afforded
unstable crude am ine 18. Reaction with the com m ercially available diketone
19 provided 20 in good yield. Deprotection and alkaline hydrolysis using the
m ethod described in a patent7 then furnished “trans-atorvastatin” (6).
Atorvastatin lacton e (8) is easily form ed from th e correspon din g ator-
vastatin acid un der acidic con dition s. Atorvastatin acid can be obtain ed
both from in term ediate 2 by th e procedure used for th e syn th esis of
atorvastatin an d directly from atorvastatin itself.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
233
SCHEME 1
Reagen ts an d con dition s: (i) LDA, tert-butyl acetate, THF, –78 °C; (ii) NaBH4, acetic acid, r.t.;
(iii) 2,2-dim eth oxypropan e, aceton e, para-TsOH, r.t.; (iv) H2, Ra–Ni, 40 °C; (v) pivalic acid,
h eptan e; (vi) h eptan e/toluen e 9:1, reflux; (vii) HCl, THF; (viii) NaOH; (ix) calcium acetate
Preparation of desfluoroatorvastatin (9) used th e procedure startin g from
an ilide 21, paten ted for th e preparation of atorvastatin itself, in wh ich
4-fluoroben zaldeh yde was replaced by ben zaldeh yde (Sch em e 2). Th e start-
in g com poun d 21 treated with ben zaldeh yde in th e presen ce of am in o-
acetic acid an d acetic acid with azeotropic rem oval of water provided 22 in
59% yield10b. Com poun d 22 treated with ben zaldeh yde in eth an ol un der
th e catalysis with 3-eth yl-5-(2-h ydroxyeth yl)-4-m eth ylth iazolium brom ide
yielded diketon e 23 in good yield. Th is is, in fact, a m odification of th e
Stetter reaction 12. Th e n ext step, i.e. reaction of 23 with am in e 3 was cata-
lyzed by pivalic acid an d th e in term ediate 24 was obtain ed in 60% yield.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

234
Stach, Havlíček, Plaček, Rádl:
Subsequen t acid an d alkalin e treatm en t of com poun d 24 provided th e cor-
respon din g acid, wh ich was tran sform ed in to desfluoroatorvastatin 9 by a
procedure used in th e atorvastatin syn th esis.
SCHEME 2
Reagen ts an d con dition s: (i) toluen e, acetic acid, ben zaldeh yde; (ii) acetic acid, h exan e, ben z-
aldeh yde; (iii) 3, pivalic acid, h eptan e/toluen e 9:1, reflux; (iv) HCl, NaOH, calcium acetate
Syn th esis of diam in o atorvastatin (10) (Sch em e 3) started from lacton e 8
wh ich , wh en treated with am in o derivative 3, provided th e correspon din g
am ide 25. Th is com poun d was deprotected in usual way with out isolation
an d th e obtain ed sodium salt was tran sform ed in to th e correspon din g cal-
cium salt 10.
Ester 11a was easily prepared by esterification of atorvastatin free acid
with m eth an ol or by treatm en t of atorvastatin lacton e with m eth an ol. Th e
correspon din g tert-butyl ester 11b was obtain ed by m ild acidic h ydrolysis of
th e pen ultim ate atorvastatin in term ediate 2.
All attem pts to syn th esize th e E-isom er 12 or its free acid 12b failed, th e
im purity stan dard was even tually obtain ed as th e acid from a com plex reac-
tion m ixture con tain in g 9% of 12b usin g flash ch rom atograph y. Th e m ix-
ture was obtain ed by a n on selective deh ydration of atorvastatin m eth yl
ester 11a with acetic an h ydride followed by alkalin e h ydrolysis.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
235
SCHEME 3
Reagen ts an d con dition s: (i) 3, toluen e, reflux; (ii) HCl, THF, NaOH, calcium acetate
Syn th esis of (S,S)-atorvastatin (Sch em e 4) started with th e com m ercially
available eth yl (S)-4-cyan o-3-h ydroxybutan oate (26). Th is com poun d,
treated with tert-butyl lith ioacetate in tetrah ydrofuran usin g th e m eth odol-
ogy described in th e U.S. paten t11, provided 27 in good yield. Reduction
with sodium boroh ydride in th e presen ce of dieth yl(m eth oxy)boran e pro-
vided diol 28 wh ich was protected as an acetal to give a h igh ly crystallin e
ester 29. Catalytic h ydrogen ation of ester 29 afforded crude am in e 30,
wh ich was subjected to pyrrole cyclization with th e com m ercially available
diketon e 19 to give th e protected com poun d 31. Deprotection an d alkalin e
h ydrolysis usin g th e m eth od described in th e paten t for th e syn th esis of
atorvastatin th en provided (S,S)-atorvastatin (13).
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

236
Stach, Havlíček, Plaček, Rádl:
SCHEME 4
Reagen ts an d con dition s: (i) LDA, tert-butyl acetate, THF, –78 °C; (ii) Et2BOMe, NaBH4, THF,
–78 °C; (iii) 2,2-dim eth oxypropan e, aceton e, para-TsOH, r.t.; (iv) H2, Ra–Ni, 40 °C; (v) pivalic
acid, heptane; (vi) heptane/toluene 9:1, reflux; (vii) HCl, THF; (viii) NaOH; (ix) calcium acetate
In sum m ary, we h ave prepared several im purities an d degradation prod-
ucts of atorvastatin n eeded for an alytical support of our com m ercially pro-
duced atorvastatin .
EXPERIMENTAL
Meltin g poin ts were m easured on a Kofler block an d are un corrected. Th e IR spectra were
m easured on a Perkin Elm er Spectrum BX FT-IR m ach in e in KBr pellets, waven um bers are
.
given in cm –1 1H and 13C NMR spectra were recorded on Bruker instruments (250 and 500 MHz).
Chemical shifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. Th e purity of th e sub-
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
237
stan ces prepared was evaluated by TLC on silica gel (FP KG F 254, Merck). Flash ch rom atog-
raph y was perform ed on silica gel Merck, particle size 0.04–0.063 m m . Mass spectra were
m easured usin g a Sciex API 3000 m ass spectrom eter with positive atm osph eric pressure ion -
ization (TurboIon spray) or usin g LTQ Orbitrap h ybrid m ass spectrom eter with direct in jec-
tion in to APCI (Atm osph eric Pressure Ch em ical Ion isation ) source in positive m ode.
Th e followin g in term ediates were prepared accordin g to th e literature: 2-isobutyryl-N,3-di-
ph en ylacrylam ide (22)10b; tert-butyl (5R)-6-cyan o-5-h ydroxy-3-oxoh exan oate (15) an d tert-
butyl (5S)-6-cyan o-5-h ydroxy-3-oxoh exan oate (27)12
.
(3S,5R)-tert-Butyl 6-Cyan o-3,5-dih ydroxyh exan oate (16)
Sodium boroh ydride (2.1 g, 55.5 m m ol) was added with stirrin g to cold acetic acid (30 m l)
at a rate sufficien t to m ain tain th e tem perature of th e reaction m ixture at 20–25 °C. A solu-
tion of com poun d 15 (3.5 g, 15.4 m m ol) in acetic acid (5 m l) was added dropwise over
10 m in . After stirrin g at 25 °C for addition al 30 m in , th e m ixture was diluted with eth yl ace-
tate (200 m l), th e resultan t solution was wash ed with saturated sodium carbon ate (3 ×
20 m l) an d dried with an h ydrous m agn esium sulfate. Th e desiccan t was filtered off an d th e
filtrate was evaporated to give com poun d 16 as an oil (3.1 g). Th e crude product was crystal-
lized from eth yl acetate/h exan e to give 16 (1.41 g, 40%), m .p. 58–63 °C. Cis:trans ratio
(5:95) was determ in ed by GC on th e correspon din g aceton ide. 1H NMR (250 MHz, CDCl3,
25 °C): 4.28 m , 1 H (CHOH); 4.28 m , 1 H (CHOH); 2.59 dd, 2 H, J =5.6, 1.8 (CH2CN);
2.44 d, 2 H, J = 6.4 (CH2CO); 1.72 m , 2 H [CH(OH)CH2CH(OH)]; 1.47 s, 9 H [C(CH3)].
13C NMR (125 MHz, CDCl3, 25 °C): 172.1 (CO); 117.7 (CN); 81.7 [C(CH3)]; 65.0 (3-CHOH);
64.6 (5-CHOH); 42.0 (CH2CO); 41.3 [CH(OH)CH2CH(OH)]; 28.0 [C(CH3)]; 26.0 (CH2CN).
IR: 2246 (CN), 1710 (ester C=O). HR-MS: for C11H20NO4 [M + H]+ calculated 230.1387 m/z,
foun d 230.1383.
tert-Butyl (4S,6R)-6-(Cyan om eth yl)-2,2-dim eth yl-1,3-dioxan e-4-acetate (17)
2,2-Dim eth oxypropan e (6 m l) an d 4-m eth ylben zen e-1-sulfon ic acid m on oh ydrate (30 m g)
were added to a stirred solution of 16 (1.28 g, 5.58 m m ol) in dry aceton e (4 m l). After stir-
rin g at 25 °C for addition al 60 m in , trieth ylam in e (0.1 m l) was added an d th e reaction m ix-
ture was evaporated. Th e residual oil was purified by colum n ch rom atograph y usin g h exan e/
aceton e (7:3, v/v) to provide 17 (1.07 g, 71%) as a colorless oil. 1H NMR (250 MHz, CDCl3,
25 °C): 4.28 m , 1 H [(CH(O)]; 4.18 m , 1 H [(CH(O)]; 2.51 dd, 2 H, J = 1.6, 5.6 (CH2CN);
2.47 d, 1 H, J = 6.4 (CH2CO); 1.72 m , 2 H [CH(OH)CH2CH(OH)]; 1.47 s, 9 H [C(CH3)];
1.45 q, 3 H, J = 0.6 (CH3); 1.38 q, 3 H, J = 0.6 (CH3). 13C NMR (125 MHz, CDCl3, 25 °C):
169.7 (CO); 117.0 (CN); 101.2 (OCO); 80.8 [C(CH3)3]; 63.5 [CH(O)]; 62.6 [CH(O)]; 41.8
(CH2CO); 36.7 [CH(O)CH2CH(O)]; 28.0 [C(CH3)3]; 24.6 (CH2CN); 24.3 (CH3); 24.3 (CH3). IR:
2246 (CN), 1725 (ester C=O). MS, m/z (%): 270 [M + H]+ (10), 231 (25), 214 (30), 156 (100),
149 (50), 138 (45).
tert-Butyl (4S,6R)-6-(2-Am in oeth yl)-2,2-dim eth yl-1,3-dioxan e-4-acetate (18)
A solution of com poun d 17 (2.54 g, 9.4 m m ol) in MeOH (50 m l) saturated with am m on ia
gas was h ydrogen ated at 40 °C (810 kPa). After 5 h , th e m ixture was filtered an d th e filtrate
evaporated to give crude am in e 18 (2.7 g, 100%) wh ich was used with out furth er purification .
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

238
Stach, Havlíček, Plaček, Rádl:
tert-Butyl (4S,6R)-6-{2-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]eth yl}-2,2-dim eth yl-1,3-dioxan e-4-acetate (20)
A m ixture of am in e 18 (2.3 g, 8.4 m m ol), diketon e 19 (3 g, 7.2 m m ol) an d pivalic acid (0.61 g,
6.1 m m ol) was refluxed in a m ixture of h eptan e (40 m l) an d toluen e (5 m l) for 19 h . Th e
m ixture was th en evaporated an d crystallized from propan -2-ol to give 20 (4 g, 73%) as a
wh ite solid, m .p. 165–167 °C. 1H NMR (500 MHz, CDCl3, 25 °C): 7.20 m , 2 H (an ilide H-3);
7.19 m , 2 H (Ph H-2); 7.19 m , 1 H (Ph H-4); 7.19 m , 2 H (4-FC6H4 H-2); 7.16 m , 2 H (Ph
H-3); 7.07 d, 2 H, J = 8.8 (an ilide H-2); 6.99 m , 2 H (FC6H4H-3); 6.99 m , 1 H (an ilide H-4);
6.87 s, 1 H (NH); 4.14 m , 1 H (dioxan e H-4); 4.06 m , 1 H (NCH2CH2); 3.80 m , 1 H
(NCH2CH2); 3.63 m , 1 H (dioxan e H-6); 3.59 sept, 1 H, J = 7.1 [CH(CH3)2]; 2.37 dd, 1 H, J =
15.4, 6.9 (CH2COO); 2.29 dd, 1 H, J = 15.4, 6.2 (CH2COO); 1.70 m , 2 H (NCH2CH2); 1.54 d,
3 H, J = 7.5 [CH(CH3)2]; 1.54 d, 3 H, J = 7.5 [CH(CH3)2]; 1.48 m , 2 H (dioxan e H-5); 1.44 s,
9 H [C(CH3)3]; 1.29 s, 3 H [C(CH3)2]; 1.24 s, 3 H [C(CH3)2]. 13C NMR (125 MHz, CDCl3, 25 °C):
170.0 (COO); 164.8 (CONH); 162.3, JC,F = 248.5 (4-FC6H4 C-4); 141.6 (pyrrole C-5); 138.5
(an ilide C-1); 134.7 (C-1 of Ph ); 133.2, JC,F = 8.2 (4-FC6H4 C-2); 130.5 (2 C-3 Ph ); 128.8 (pyr-
role C-2); 128.6 (Ph C-2); 128.3 (C-3 of an ilide); 128.2, JC,F = 2.8 (4-FC6H4 C-1); 126.6 (Ph
C-4); 123.5 (an ilide C-4); 121.8 (pyrrole C-3); 119.6 (an ilide C-2); 115.3 (pyrrole C-4); 115.3,
JC,F = 21.4 (4-FC6H4 C-3); 100.4 (dioxan e C-2); 80.6 [C(CH3)3]; 64.3 (dioxan e C-6); 63.6
(dioxan e C-4); 42.1 (CH2COO); 41.4 (NCH2); 37.6 (NCH2CH2); 37.3 (dioxan e C-5); 28.1
[C(CH3)3]; 26.1 [CH(CH3)2]; 24.6 [C(CH3)2]; 24.6 [C(CH3)2]; 21.7 [CH(CH3)2]; 21.6
[CH(CH3)2]. IR: 1660 (C=O), 1718 (ester C=O). HR-MS: for C40H48FN2O5 [M + H]+ calculated
655.3541 m/z, foun d 655.3543.
Calcium (3S,5R)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]-3,5-dih ydroxyh eptan oate (6)
Dilute h ydroch loric acid (10%; 3 m l) was added to a solution of 20 (1 g, 1.5 m m ol) in
tetrah ydrofuran (15 m l). Th e m ixture was stirred at 25 °C for 6 h an d th en a con cen trated
solution of sodium h ydroxide (40%; 2 m l) was added over 5 m in , m ain tain in g th e tem pera-
ture below 35 °C. Th e resultan t h eterogen eous m ixture was vigorously stirred for 15 h , an d
th en poured in to a separatin g fun n el con tain in g water (30 m l) an d h exan e (10 m l). Th e or-
gan ic layer was rem oved an d th e aqueous layer was extracted with a m ixture of h exan e (8 m l)
an d tetrah ydrofuran (2 m l). After com plete separation , th e aqueous layer was extracted with
eth yl acetate (3 × 8 m l) an d th e com bin ed extracts sh aken with a solution of calcium acetate
(20%; 3 × 1 m l). Th e resultin g eth yl acetate solution was wash ed with water (2 × 1 m l) an d,
after dryin g with an h ydrous calcium sulfate, con cen trated in vacuo to 4 m l. After filtration ,
th e clear solution was added dropwise over 5 m in to h exan e (40 m l) un der vigorous stirrin g,
an d th e m ixture was stirred for addition al 20 m in . Th e precipitate was filtered off, wash ed
with h exan e (20 m l) an d dried to give 0.72 g (82%) of 6, m .p. 160 °C (dec.). 1H NMR
(500 MHz, CD3OD, 25 °C): 7.3–6.9 (NH); 7.29 m , 2 H, J = 8.1 (an ilide H-2); 7.23 m , 2 H
(4-FC6H4 H-2); 7.22 m , 2 H (Ph H-2); 7.13 m , 2 H (Ph H-3); 7.09 m , 2 H (an ilide H-3);
7.06 m , 2 H (4-FC6H4 H-3); 7.04 m , 1 H (Ph H-4); 7.02 m , 1 H (an ilide H-4); 4.09 m , 1 H
(CH2CH2CHOH); 4.09 m , 1 H [CH(OH)CH2CHOH]; 3.92 m , 1 H (CH2CH2CHOH); 3.61 m ,
1 H [CH(OH)CH2CHOH]; 3.37 sept, 1 H, J = 7.5 [CH(CH3)2]; 2.25 m , 2 H (CH2CO); 1.67 m ,
2 H (CH2CH2CHOH); 1.48 d, 6 H, J = 7.5 [CH(CH3)2]; 1.37 m , 2 H [CH(OH)CH2CHOH].
13C NMR (125 MHz, CDCl3, 25 °C): 182.2 (COO); 169.5 (CONH); 163.8 JC,F = 247.2 (C-4 of
4-FC6H4); 139.8 (an ilide C-1); 139.0 (pyrrole C-2); 136.3 (Ph C-1); 134.7, JC,F = 7.8 (2 C-2
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
239
4-FC6H4); 130.9 (2 C-3 Ph ); 130.2, JC,F = 2.9 (4-FC6H4 C-1); 129.6 (pyrrole C-5); 129.6 (2 C-2
Ph ); 128.9 (2 C-3 of an ilide); 126.9 (Ph C-4); 125.2 (an ilide C-4); 123.3 (pyrrole C-4); 121.5
(2 C-2 of an ilide); 118.1 (pyrrole C-3); 116.3, JC,F = 21.5 (2 C-3 of 4-FC6H4); 67.0 (5-CHOH);
66.9 (3-CHOH); 45.5 (CH2CO); 44.7 [CH(OH)CH2CHOH]; 42.5 (CH2CH2CHOH); 41.0
(CH2CH2CHOH); 27.7 [CH(CH3)2]; 22.8 [CH(CH3)2]; 22.8 [CH(CH3)2]. IR: 1559 (C=O), 1700
(acid C=O). HR-MS: for C33H36FN2O5 [M + H]+ calculated 559.2603 m/z, foun d 559.2608.
(3R,5R)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]-3,5-dih ydroxyh eptan o-5-lacton e (8)
Aqueous h ydroch loric acid (10%; 22 m l, 0.06 m ol) was slowly added to a solution of 2 (6.5 g,
10 m m ol) in tetrah ydrofuran (300 m l) an d th e m ixture was stirred at room tem perature for
24 h . Powdered sodium h ydroxide (5.4 g, 0.135 m ol) was added an d th e m ixture was stirred
for an oth er 5 h . Water (200 m l) was th en added an d th e m ixture was extracted with h exan e
(150 m l) an d dieth yl eth er (2 × 50 m l). Th e aqueous layer was acidified with con cen trated
h ydroch loric acid an d extracted with eth yl acetate (200 m l). Th e solution was wash ed with
brin e (2 × 50 m l) an d dried with an h ydrous m agn esium sulfate; th e residue after evapora-
tion was dissolved in toluen e (100 m l) an d th e solution refluxed for 6 h . Toluen e was evapo-
rated an d th e residue (5.4 g) was crystallized from eth yl acetate (ch arcoal) to give 3.9 g
(72%) of wh ite crystals, m .p. 160–162 °C. 1H NMR (500 MHz, CDCl3, 25 °C): 7.18 m , 2 H
(an ilide H-3); 7.18 m , 2 H (Ph H-2); 7.17 m , 2 H (Ph H-4); 7.17 m , 1 H (4-FC6H4 H-2);
7.14 d, 2 H, J = 7.6 (Ph H-3 ); 7.05 d, 2 H, J = 8.8 (an ilide H-2); 7.02 m , 2 H (4-FC6H4 H-3);
6.99 m , 1 H (an ilide H-4 ); 6.87 s, 1 H (NH); 4.52 m , 1 H (lacton e H-5); 4.20 m , 1 H
(NCH2CH2); 4.09 m , 1 H (lacton e H-3); 4.02 m , 1 H (NCH2CH2); 3.52 sept, 1 H, J = 7.2
[CH(CH3)]; 2.65 dd, 1 H, J = 15.4, 3.8 (H-2 of lacton e); 2.55 dd, 1 H, J = 15.5, 8.7 (lacton e
H-2); 2.25 s, 1 H (OH); 1.85 m , 1 H (NCH2CH2); 1.73 m , 1 H (NCH2CH2); 1.70 m , 1 H
(lacton e H-4); 1.60 m , 1 H (lacton e H-4); 1.54 d, 3 H, J = 7.5 [CH(CH3)]; 1.52 d, 3 H, J = 7.5
[CH(CH3)]. 13C NMR (125 MHz, CDCl3, 25 °C): 169.4 (COO); 164.8 (CONH); 162.3, JC,F
248.4 (4-FC6H4 C-4); 141.3 (pyrrole C-2); 138.2 (an ilide C-1); 134.4 (Ph C-1); 133.5, JC,F
=
=
8.4 (2 C-2 of 4-FC6H4); 130.4 (2 C-3 Ph ); 128.7 (pyrrole C-5); 128.7 (2 C-2 Ph ); 128.4 (2 C-3
of an ilide); 128.0, JC,F = 3.6 (4-FC6H4 C-1); 126.7 (Ph C-4); 123.7 (an ilide C-4); 122.1 (pyrrole
C-4); 119.7 (2 C-2 of an ilide); 115.6, JC,F = 21.2 (2 C-3 of 4-FC6H4); 115.6 (pyrrole C-3); 73.0
(lacton e C-5); 62.4 (lacton e C-3); 40.7 (NCH2CH2); 38.4 (lacton e C-2); 37.1 (NCH2CH2); 35.6
(lacton e C-4), 26.1 [CH(CH3)]; 22.0 [CH(CH3)]; 21.7 [CH(CH3)]. IR: 1700 (lacton e C=O),
1660 (C=O). HR-MS: for C33H34FN2O4 [M + H]+ calculated 541.2497 m/z, foun d 541.2489.
4-Meth yl-3-oxo-2-(2-oxo-1,2-diph en yleth yl)-N-ph en ylpen tan am ide (23)
Solven t (8 m l) was distilled off from a solution of 3-eth yl-5-(2-h ydroxyeth yl)-4-m eth ylth ia-
zolium brom ide (0.6 g, 2.4 m m ol) in dry eth an ol (10 m l). Th en 2-isobutyryl-N,3-diph en yl-
acrylam ide (22; 3.3 g, 11 m m ol), trieth ylam in e (1.2 g, 12 m m ol) an d ben zaldeh yde (1.4 g,
13 m m ol) were added an d th e m ixture was stirred at 80 °C un der argon for 24 h . Crystalliza-
tion from propan -2-ol provided 2.6 g (59%) of wh ite crystals as a m ixture of isom ers, m .p.
193–198 °C. IR: 1670 (C=O), 1718 (C=O), 1650 (C=O am ide). HR-MS: for C26H26NO3 [M +
H]+ calculated 400.1907 m/z, foun d 400.1906.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

240
Stach, Havlíček, Plaček, Rádl:
tert-Butyl (4R,6R)-6-{2-[2-Isopropyl-4,5-diph en yl-3-(ph en ylcarbam oyl)-
pyrrol-1-yl]eth yl}-2,2-dim eth yl-1,3-dioxan e-4-acetate (24)
A m ixture of diketon e 23 (2.33 g, 5.83 m m ol), am in e 3 (1.9 g, 7.1 m m ol) an d pivalic acid
(0.72 g, 7.1 m m ol) was refluxed in a m ixture of h eptan e (40 m l) an d toluen e (5 m l) for 30 h .
Th e m ixture was th en evaporated an d th e residue crystallized from propan -2-ol to give 23
(2.23 g, 60%) as a wh ite solid, m .p. 127–132 °C. 1H NMR (500 MHz, CDCl3, 25 °C): 7.28 m ,
2 H (4-Ph H-2); 7.26 m , 1 H (4-Ph H-4); 7.20 m , 2 H (5-Ph H-2); 7.19 m , 2 H (4-Ph H-3);
7.17 m , 2 H (an ilide H-3); 7.16 m , 2 H (5-Ph H-3); 7.14 m , 1 H (5-Ph H-4); 7.07 d, 2 H, J =
8.8 (an ilide H-2); 6.97 m , 1 H (an ilide H-4); 4.13 m , 1 H (dioxan e H-4); 4.07 m , 1 H
(NCH2CH2); 3.87 m , 1 H (NCH2CH2); 3.65 m , 1 H (dioxan e H-6); 3.62 sept, 1 H, J = 7.4
[CH(CH3)2]; 2.37 dd, 1 H, J = 15.2, 6.9 (CH2COO); 2.21 dd, 1 H, J = 15.2, 6.2 (CH2COO);
1.67 m , 2 H (NCH2CH2); 1.54 d, 3 H, J = 7.5 [CH(CH3)2]; 1.53 d, 3 H, J = 7.5 [CH(CH3)2];
1.48 m , 2 H (dioxan e H-5); 1.44 s, 9 H [C(CH3)3]; 1.34 s, 3 H [C(CH3)2]; 1.28 s, 3 H
[C(CH3)2]. 13C NMR (125 MHz, CDCl3, 25 °C): 170.2 (COO); 164.9 (CONH); 141.5 (pyrrole
C-2); 138.5 (an ilide C-1); 134.9 (4-Ph C-1); 132.3 (5-Ph C-1); 131.5 (2 C-2 of 5-Ph ); 130.6
(2 C-3 of 4-Ph ); 130.0 (pyrrole C-5); 128.6 (2 C-2 of 4-Ph ); 128.6 (2 C-3 of an ilide); 128.2
(2 C-3 of 5-Ph ); 126.7 (4-Ph C-4); 126.4 (5-Ph C-4); 123.4 (an ilide C-4); 121.5 (pyrrole C-4);
119.6 (2 C-2 of an ilide); 115.3 (pyrrole C-3); 98.6 (dioxan e C-2); 80.6 [C(CH3)3]; 66.5
(dioxan e C-6); 65.9 (dioxan e C-4); 40.9 (NCH2); 42.5 (CH2COO); 38.0 (NCH2CH2); 35.9
(dioxan e C-5); 28.1 [C(CH3)3]; 26.1[CH(CH3)2]; 21.7 [CH(CH3)2]; 21.6 [CH(CH3)2]; 19.7
[2 C(CH3)2]. IR: 1635 (C=O), 1710 (ester C=O). HR-MS: for C40H49N2O5 [M + H]+ calculated
637.3636 m/z, foun d 637.3641.
Calcium (3R,5R)-3,5-Dih ydroxy-7-[2-isopropyl-4,5-diph en yl-3-(ph en ylcarbam oyl)-
pyrrol-1-yl]h eptan oate (9)
A solution of h ydroch loric acid (10%; 3 m l) was added to a solution of com poun d 24 (1 g,
1.57 m m ol) in tetrah ydrofuran (15 m l), an d th e m ixture was stirred at 25 °C for 6 h . A solu-
tion of con cen trated sodium h ydroxide (40%; 2 m l) was th en added over 5 m in , m ain tain -
in g th e tem perature below 35 °C. Th e h eterogen eous m ixture form ed was vigorously stirred
for 15 h , an d th en poured in to a separatory fun n el con tain in g water (30 m l) an d h exan e
(10 m l). Th e organ ic layer was rem oved, an d th e aqueous layer extracted with a m ixture of
h exan e (8 m l) an d tetrah ydrofuran (2 m l). After com plete separation , th e aqueous layer was
extracted with eth yl acetate (3 × 8 m l), an d th e com bin ed eth yl acetate extracts were sh aken
with a solution of calcium acetate (20%; 3 × 1 m l). Th e resultin g eth yl acetate solution was
wash ed with water (2 × 1 m l), dried with an h ydrous calcium sulfate an d con cen trated in
vacuo to 4 m l. After filtration , th e clear solution was added dropwise durin g 5 m in to h ex-
an e (40 m l) un der vigorous stirrin g, an d th e m ixture was stirred for addition al 20 m in . Th e
precipitate was filtered off, wash ed with h exan e (20 m l) an d dried to give 0.54 g (62%) of 9
as a wh ite solid, m .p. 150 °C (dec.). 1H NMR (500 MHz, CD3OD, 25 °C): 7.33 m , 2 H (5-Ph
H-3); 7.3–6.9, 1 H (NH); 7.30 m , 1 H (an ilide H-4); 7.29 d, 2 H, J = 8.1 (an ilide H-2); 7.29 m ,
1 H (5-Ph H-4); 7.21 m , 2 H (4-Ph H-2); 7.21 m , 2 H (5-Ph H-2); 7.13 m , 2 H (4-Ph H-3);
7.06 m , 2 H (an ilide H-3); 7.02 m , 1 H (4-Ph H-4); 4.05 m , 1 H (CH2CH2CHOH); 3.95 m ,
1 H [CH(OH)CH2CHOH]; 3.93 m , 1 H (CH2CH2CHOH); 3.63 m , 1 H [CH(OH)CH2CHOH];
3.37 sept, 1 H, J = 7.1 [CH(CH3)2]; 2.29 dd, 1 H, J = 15.4, 3.8 (CH2CO); 2.19 dd, 1 H, J =
15.5, 8.7 (CH2CO); 1.67 m , 2 H (CH2CH2CHOH); 1.49 d, 3 H, J = 6.9 [CH(CH3)2]; 1.48 d,
3 H, J = 6.9 [CH(CH3)2]; 1.48 m , 1 H [CH(OH)CH2CHOH]; 1.33 m , 1 H [CH(OH)CH2CHOH].
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
241
13C NMR (125 MHz, CD3OD, 25 °C): 181.9 (CO); 169.6 (CONH); 139.9 (an ilide C-1); 138.9
(pyrrole C-2); 136.5 (4-Ph C-1); 134.1 (5-Ph C-1); 132.8 (2 C-2 of 5-Ph ); 130.9 (2 C-3 of
4-Ph ); 130.8 (pyrrole C-5); 129.6 (2 C-2 of 4-Ph ); 129.5 (2 C-3 of 5-Ph ); 128.9 (5-Ph C-4);
128.8 (2 C-3 of an ilide); 126.8 (4-Ph C-4); 125.1 (an ilide C-4); 123.0 (pyrrole C-4); 121.5
(2 C-2 of an ilide); 118.1 (pyrrole C-2); 69.1 (CHOH); 69.1 (CHOH); 44.9 (CH2CO); 43.8
[CH(OH)CH2CHOH]; 42.1(CH2CH2CHOH); 40.5 (CH2CH2CHOH); 27.6 [CH(CH3)2]; 22.9
[CH(CH3)2]; 22.9 [CH(CH3)2]. IR: 1657 (acid C=O), 1591 (C=O). HR-MS: for C33H37N2O5
[M + H]+ calculated 541.2697 m/z, foun d 541.2696.
Calcium (3R,5R)-7-{(3R,5R)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en yl-
carbam oyl)pyrrol-1-yl]-3,5-dih ydroxyh eptan am ido}-3,5-dih ydroxyh eptan oate (10)
A m ixture of lacton e 8 (0.25 g, 0.46 m m ol) an d am in e 3 (0.18 g, 0.48 m m ol) was refluxed in
toluen e in th e presen ce of trieth ylam in e (0.2 m l) for 2 h . Th e reaction m ixture was evapo-
rated, dissolved in tetrah ydrofuran (4 m l) an d a solution of h ydroch loric acid (10%; 1 m l)
was added. After stirrin g at 25 °C for 6 h , a solution of con cen trated sodium h ydroxide
(40%; 0.5 m l) was added over 5 m in , m ain tain in g th e tem perature below 35 °C. Th e m ixture
was vigorously stirred for 15 h , an d th en poured in to a separatory fun n el con tain in g water
(5 m l) an d h exan e (5 m l). Th e organ ic layer was rem oved an d th e aqueous layer extracted
with a m ixture of h exan e (8 m l) an d tetrah ydrofuran (2 m l). After com plete separation , th e
aqueous layer was extracted with eth yl acetate (3 × 5 m l) an d th e com bin ed eth yl acetate ex-
tracts were sh aken with a solution of calcium acetate (5%; 3 × 1 m l). Th e resultin g eth yl ace-
tate solution was wash ed with water (2 × 1 m l) an d, after dryin g with an h ydrous calcium
sulfate, evaporated in vacuo to give 0.16 g (69%) of 10 as a wh ite solid. 1H NMR (500 MHz,
CD3OD, 25 °C): 7.3–6.9, 1 H (NHCO); 7.29 d, 2 H, J = 8.1 (an ilide H-2); 7.24 m , 2 H
(4-FC6H4 H-2); 7.22 m , 2 H (Ph H-2); 7.13 m , 2 H (Ph H-3); 7.10 m , 2 H (an ilide H-3);
7.06 m , 2 H (4-FC6H4 H-3); 7.05 m , 1 H (Ph H-4); 7.03 m , 2 H (an ilide H-4); 4.14 m , 1 H
[CH(OH)CH2COO]; 4.07 m , 1 H (NCH2); 3.95 m , 1 H (NCH2); 3.95 m , 1 H [CH(OH)CH2CO];
3.82 m , 1 H [NHCH2CH2CH(OH)]; 3.65 m , 1 H [NCH2CH2CH(OH)]; 3.37 sept, 1 H, J = 7.3
[CH(CH3)2]; 3.27 m , 2 H (NHCH2); 2.38 m , 2 H (CH2COO); 2.30 m , 2 H (CH2CO); 1.73 m ,
2 H (NCH2CH2); 1.70 m , 1 H (NCH2CH2); 1.65 m , 2 H [CH2CH(OH)CH2COO]; 1.60 m , 1 H
(NHCH2CH2); 1.55 m , 1 H (CH2CH(OH)CH2CO]; 1.48 d, 6 H, J = 7.0 [CH(CH3)2]; 1.45 m ,
1 H [CH2CH(OH)CH2CO]. 13C NMR (125 MHz, CD3OD, 25 °C): 180.5 (COO); 174.0 (CO);
169.6 (CONH); 163.8, JC,F = 246.8 (4-FC6H4 C-4); 139.8 (an ilide C-1); 139.0 (pyrrole C-2);
134.7 (Ph C-1); 134.7, JC,F = 8.1 (2 C-2 of 4-FC6H4); 130.9 (2 C-3 of Ph ); 130.2, JC,F = 3.8
(4-FC6H4 C-1); 129.6 (2 C-2 of Ph ); 128.7 (2 C-3 of an ilide); 127.3 (pyrrole C-5); 126.7 (Ph
C-4); 125.1 (an ilide C-4); 123.3 (pyrrole C-4); 121.5 (2 C-2 of an ilide); 118.1 (pyrrole C-3);
116.3, JC,F = 21.9 (2 C-3 of 4-C6H4); 69.1 [CH(OH)CH2COO]; 68.8 [NHCH2CH2CH(OH)]; 68.5
[NCH2CH2CH(OH)]; 68.2 [CH(OH)CH2CO]; 45.0 [CH(OH)CH2COO]; 44.5 [CH(OH)CH2CO];
44.4 (NCH2CH2); 44.4 [CH2CH(OH)CH2CO]; 42.2 (NCH2CH2); 40.2 [CH2CH(OH)CH2COO];
37.9 (NHCH2CH2); 37.1 (NHCH2CH2); 27.6 [CH(CH3)2]; 22.8 [CH(CH3)2]. IR: 1645 (acid
C=O), 1600 (C=O). MS, m/z (%): 718 [M + H]+ (10), 607 (100), 558 (55), 477 (30).
Meth yl (3R,5R)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]-3,5-dih ydroxyh eptan oate (11a)
Atorvastatin (2 g, 1.73 m m ol) was dissolved in tetrah ydrofuran (10 m l) an d con cen trated
h ydroch loric acid (0.5 m l) was added. Th e resultin g solution was diluted with eth yl acetate
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

242
Stach, Havlíček, Plaček, Rádl:
(40 m l), th e solution was wash ed with brin e (2 × 5 m l) an d dried with an h ydrous m agn e-
sium sulfate. After evaporation , th e residue was redissolved in a m ixture of m eth an ol (20 m l)
an d con cen trated h ydroch loric acid (0.2 m l), an d th e m ixture was refluxed for 5 h . Th e so-
lution was evaporated an d th e residue was crystallized from h exan e/eth yl acetate to give
wh ite crystals of 11a (1.2 g, 61%), m .p. 110–112 °C. 1H NMR (500 MHz, CDCl3, 25 °C):
7.18 m , 2 H (an ilide H-3); 7.18 m , 2 H (Ph H-2); 7.18 m , 2 H (4-FC6H4 H-2); 7.16 m , 1 H (Ph
H-4); 7.16 m , 2 H, J = 7.4 (Ph H-3); 7.05 d, 2 H, J = 8.7 (an ilide H-2); 6.99 m , 2 H (4-FC6H4
H-3); 6.96 m , 1 H (an ilide H-4); 6.85 s, 1 H (NH); 4.15 m , 1 H [CH(OH)CH2CHOH]; 4.10 m ,
1 H (CH2CH2CHOH); 3.94 m , 1 H (CH2CH2CHOH); 3.73 m , 1 H [CH(OH)CH2CHOH];
3.71 s, 3 H; 3.58 sept, 1 H, J = 7.1 [CH(CH3)2]; 2.41 m , 1 H (CH2CO); 1.64 m , 2 H
(CH2CH2CHOH); 1.54 d, 3 H, J = 7.1 [CH(CH3)2]; 1.54 d, 3 H, J = 7.1 [CH(CH3)2]; 1.36 m ,
2 H [(CH2CH(OH)]. 13C NMR (125 MHz, CDCl3, 25 °C): 172.9 (CO); 164.8 (CONH); 162.2,
JC,F = 247.6 (4-FC6H4 C-4); 141.3 (pyrrole C-2); 137.4 (an ilide C-1); 134.4 (Ph C-1); 133.1,
JC,F = 8.2 (2 C-2 of 4-FC6H4); 130.4 (2 C-3 of Ph ); 128.7 (pyrrole C-5); 128.7 (2 C-2 of Ph );
128.4, JC,F =3.6 (4-FC6H4 C-1); 128.2 (2 C-3 of an ilide); 126.4 (Ph C-4); 123.2 (an ilide C-4);
121.8 (pyrrole C-4); 119.5 (2 C-2 of an ilide); 115.3, JC,F = 21.6 (2 C-3 of 4-FC6H4); 115.3
(pyrrole C-3); 69.7 [CH(OH)CH2CHOH]; 68.8 [CH(OH)CH2CHOH]; 51.8 (OCH3); 41.7
[CH(OH)CH2CHOH]; 42.1 (CH2CO); 41.2 (NCH2); 38.0 (NCH2CH2); 26.0 [CH(CH3)2]; 21.8
[CH(CH3)2]; 21.7 [CH(CH3)2]. IR: 1690 (C=O), 17159 (ester C=O). HR-MS: for C34H38N2O5F
[M + H]+ calculated 573.2759 m/z, foun d 573.2759.
tert-Butyl (3R,5R)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]-3,5-dih ydroxyh eptan oate (11b)
A solution of h ydroch loric acid (10%; 15 m l) was slowly added to a solution of com poun d 2
(4 g, 6.1 m m ol) in tetrah ydrofuran (60 m l) an d th e m ixture was stirred at am bien t tem pera-
ture for 6 h . A solution of sodium h ydroxide (5.4 g, 0.135 m ol) in water (100 m l) was th en
added an d th e m ixture was extracted with h eptan e (80 m l). Th e organ ic layer was wash ed
with water (10 m l) an d dried with an h ydrous m agn esium sulfate. Th e extract was filtered
and evaporated to give 11b as a white solid (2.7 g, 64%), m .p. 155 °C (dec.). 1H NMR (500 MHz,
CDCl3, 25 °C): 7.18 m , 2 H (an ilide H-3); 7.18 m , 2 H (Ph H-2); 7.18 m , 2 H (4-FC6H4 H-2);
7.17 m , 1 H (Ph H-4); 7.16 m , 2 H, J = 7.6 (Ph H-3); 7.07 d, 2 H, J = 8.8 (an ilide H-2);
6.99 m , 2 H (4-FC6H4 H-3); 6.98 m , 1 H (an ilide H-4); 6.87 s, 1 H (NH); 4.13 m , 1 H
[CH(OH)CH2CHOH]; 4.13 m , 1 H (CH2CH2CHOH); 3.95 m , 1 H (CH2CH2CHOH); 3.74 m ,
1 H [CH(OH)CH2CHOH]; 3.57 sept, 1 H, J = 7.4 [CH(CH3)2]; 2.65 m , 1 H (CH2CO); 1.70 m ,
1 H (CH2CH2CHOH); 1.65 m , 1 H (CH2CH2CHOH); 1.54 d, 3 H, J = 7.5 [CH(CH3)2]; 1.54 d,
3 H, J = 7.5 [CH(CH3)2]; 1.45 m , 1 H (CH2CH2CHOH); 1.43 s, 9 H [C(CH3)3]; 1.25 m , 1 H
(CH2CH2CHOH). 13C NMR (125 MHz, CDCl3, 25 °C): 172.2 (CO); 164.8 (CONH); 162.2,
JC,F = 247.6 (4-FC6H4 C-4); 141.6 (pyrrole C-2); 138.4 (an ilide C-1); 134.6 (Ph C-1); 133.2,
JC,F = 8.2 (2 C-2 of 4-FC6H4); 130.5 (2 C-3 of Ph ); 128.7 (pyrrole C-5); 128.7 (2 C-2 of Ph );
128.4, JC,F = 3.6 (4-FC6H4 C-1); 128.3 (2 C-3 of an ilide); 126.5 (Ph C-4); 123.5 (an ilide C-4);
121.8 (pyrrole C-4); 119.5 (2 C-2 of an ilide); 115.3, JC,F = 21.6 (2 C-3 of 4-FC6H4); 115.3
(pyrrole C-3); 81.9 [C(CH3)3]; 69.7 [CH(OH)CH2CHOH]; 69.2 [CH(OH)CH2CHOH]; 41.7
[CH(OH)CH2CHOH]; 42.1 (CH2CO); 41.3 (NCH2); 38.0 (NCH2CH2); 28.1 [C(CH3)3]; 26.1
[CH(CH3)2]; 21.8 [CH(CH3)2]; 21.7 [CH(CH3)2]. IR: 1698 (C=O), 1725 (C=O ester). HR-MS: for
C
37H44N2O5F [M + H]+ calculated 615.3229 m/z, foun d 615.3223.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
243
(2E,5S)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]-5-h ydroxyh ept-2-en oic Acid (12b)
Acetic anhydride (1.5 g, 14.7 mmol) was slowly added to a solution of ester 11a (10 g, 17.5 mmol),
trieth ylam in e (5.2 g, 51.5 m m ol) an d 4-(dim eth ylam in o)pyridin e (0.1 g) in toluen e (100 m l)
an d th e m ixture was stirred at 60 °C for 2 h . Th e reaction m ixture was th en con cen trated,
tetrah ydrofuran (50 m l) an d a solution of sodium h ydroxide (0.54 g, 13.5 m ol) in water (10 m l)
were added, an d th e m ixture was stirred at am bien t tem perature for 16 h . Heptan e (50 m l)
was th en added, th e organ ic layer was rem oved an d th e aqueous layer was acidified an d ex-
tracted with eth yl acetate (100 m l). Th e organ ic extract was evaporated to give a foam con -
tain in g 30% of atorvastatin , 9% of “E alken e” 12 an d 30% of th e correspon din g “Z alken e”
(HPLC). Th e residue was purified by colum n ch rom atograph y usin g toluen e/propan -2-ol/
acetic acid (70:25:5, v/v) to afford com poun d 12b (0.45 g, 5%) as a wh ite solid, m .p.
125–130 °C. 1H NMR (500 MHz, CD3OD, 25 °C): 8.54 s, 1 H (NH); 7.29 d, 2 H, J = 8.1
(an ilide H-2); 7.23 d, 2 H (4-FC6H4 H-2); 7.22 m , 2 H (Ph H-2); 7.13 m , 2 H (Ph H-3);
7.09 m , 2 H (an ilide H-3); 7.06 m , 2 H (4-FC6H4 H-3); 7.04 m , 1 H (Ph H-4); 7.02 m , 1 H
(an ilide H-4); 6.55 ddd, 1 H, J = 15.2, 7.3 (CHCHCO); 5.81 d, 1 H, J = 15.5 (CHCHCO);
4.05 m , 1 H (CH2CH2CHOH); 3.85 m , 1 H (CH2CH2CHOH); 3.47 q, 1 H, J = 7.0 (CHOH);
3.35 sept, 1 H, J = 6.9 [CH(CH3)2]; 2.16 m , 2 H [CH(OH)CH2]; 1.64 m , 2 H (CH2CH2CHOH);
1.48 d, 3 H, J = 7.0 [CH(CH3)2]; 1.47 d, 3 H, J = 7.0 [CH(CH3)2]. 13C NMR (125 MHz,
CD3OD, 25 °C): 175.9 (COOH); 169.6 (CONH); 163.8, JC,F = 246.4 (4-FC6H4 C-4); 140.2
(CHCHCO); 139.8 (an ilide C-1); 138.9 (pyrrole C-5); 136.4 (Ph C-1); 134.7, JC,F = 8.1 (2 C-2
of 4-FC6H4); 131.2 (CHCHCO); 130.9 (2 C-3 of Ph ); 130.2, JC,F = 3.2 (4-FC6H4 C-1); 129.6
(2 C-2 of Ph ); 128.9 (pyrrole C-2); 128.8 (an ilide 2 C-3); 126.8 (Ph C-4); 125.1 (an ilide C-4);
123.3 (pyrrole C-3); 121.5 (an ilide 2 C-2); 118.0 (pyrrole C-4); 116.3, JC,F = 22.0 (2 C-3 of
4-FC6H4); 69.5 (CHOH); 42.4 (CH2CH2CHOH); 41.1 [CH(OH)CH2]; 39.8 (CH2CH2CHOH);
27.6 [CH(CH3)2]; 22.8 [CH(CH3)2]; 22.8 [CH(CH3)2]. IR: 1566 (C=O), 1668 (acid C=O).
HR-MS: for C33H34 FN2O4 [M + H]+ calculated 541.2497 m/z, foun d 541.2496.
tert-Butyl (3S,5S)-6-Cyan o-3,5-dih ydroxyh exan oate (28)
(5S)-tert-Butyl 6-cyan o-5-h ydroxy-3-oxoh exan oate (27; 2.22 g, 9.8 m m ol) was dissolved in a
m ixture of tetrah ydrofuran (20 m l) an d m eth an ol (3 m l), th e solution was cooled to –78 °C
an d a 1 M solution of dieth yl(m eth oxy)boran e in THF (9.7 m l, 9.7 m m ol) was added. So-
dium boroh ydride (0.33 g, 8.7 m m ol) was subsequen tly added in two portion s, an d th e m ix-
ture was m ain tain ed at –78 °C for 4 h . Th e reaction was quen ch ed by th e addition of acetic
acid (10 m l) an d water (10 m l), an d th e resultan t m ixture was extracted with eth yl acetate
(40 m l). Th e organ ic layer was wash ed with water (10 m l), dried with an h ydrous m agn esium
sulfate an d evaporated to provide th e crude product wh ich was used for th e followin g step
with out furth er purification .
tert-Butyl (4S,6S)-6-(Cyan om eth yl)-2,2-dim eth yl-1,3-dioxan e-4-acetate (29)
Crude tert-butyl (3S,5S)-6-cyan o-3,5-dih ydroxyh exan oate (28; 2.2 g, 9.6 m m ol) was dissolved
in a m ixture of aceton e (5 m l) an d 2,2-dim eth oxypropan e (10 m l). 4-Meth ylben zen e-
1-sulfon ic acid was added (200 m g), an d th e solution was stirred for an oth er 5 h . Th e reac-
tion was quen ch ed by th e addition of trieth ylam in e (0.2 m l), th e resultan t m ixture was
evaporated an d subjected to colum n ch rom atograph y usin g h exan e/aceton e (7:3, v/v) to
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

244
Stach, Havlíček, Plaček, Rádl:
provide com poun d 29 as an oil. Crystallization from h exan es gave 29 as a wh ite solid (2.1 g,
81%), m .p. 65–67 °C. 1H NMR (250 MHz, CDCl3, 25 °C): 4.28 dddd, 1 H, J = 2.5, 4.5, 7.6,
8.2 [(CH(O)]; 4.14 ddt, 1 H, J = 1.6, 7.6 [(CH(O)]; 2.51 dd, 2 H, J = 1.6, 7.6 (CH2CN);
2.47 dd, 1 H, J = 8.2, 14.2 (CH2CO); 1.72 m , 2 H [CH(OH)CH2CH(OH)]; 1.46 s, 9 H
[C(CH3)]; 1.45 q, 1 H, J = 0.6 (CH3); 1.38 q, 3 H, J = 0.6 (CH3). 13C NMR (125 MHz, CDCl3,
25 °C): 172.9 (CO); 117.5 (CN); 104.4 (OCO); 80.3 [C(CH3)3]; 68.1 [CH(O)]; 66.7 [CH(O)];
41.3 (CH2CO); 41.0 [CH(O)CH2CH(O)]; 27.7 [C(CH3)3]; 24.9 (CH2CN); 20.0 (CH3). IR: 225
(CN), 1724 (C=O ester). HR-MS: for C14H24NO4 [M + H]+ calculated 270.1700 m/z, foun d
270.1701.
tert-Butyl (4S,6S)-6-(2-Am in oeth yl)-2,2-dim eth yl-1,3-dioxan e-4-acetate (30)
A solution of com poun d 29 (2 g, 7.4 m m ol) in MeOH (50 m l) saturated with am m on ia gas
was h ydrogen ated at 40 °C (810 kPa). After 5 h , th e catalyst was filtered off an d th e filtrate
evaporated to give crude am in e 30 (2.2 g), wh ich was used in th e n ext step with out furth er
purification .
tert-Butyl (4S,6S)-6-{2-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]eth yl}-2,2-dim eth yl-1,3-dioxan e-4-acetate (31)
A m ixture of am in e 30 (2.2 g, 6 m m ol), diketon e 19 (2 g, 4.8 m m ol) an d pivalic acid (0.60 g,
6 m m ol) was refluxed in a m ixture of h eptan e (40 m l) an d toluen e (5 m l) for 19 h . Th e m ix-
ture was th en evaporated an d th e residue was crystallized from propan -2-ol to give 31 (4.05 g,
77%) as a wh ite solid, m .p. 175–177 °C. 1H NMR (500 MHz, CDCl3, 25 °C): 7.18 m , 2 H
(an ilide H-2); 7.18 m , 2 H (Ph H-2); 7.17 m , 1 H (Ph H-4); 7.17 m , 2 H (4-FC6H4 H-2);
7.16 m , 2 H (Ph H-3); 7.07 d, 2 H, J = 8.8 (an ilide H-3); 6.99 m , 2 H (4-FC6H4 H-3); 6.99 m ,
1 H (an ilide H-4); 6.87 s, 1 H (NH); 4.15 m , 1 H (dioxan e H-4); 4.10 m , 1 H (NCH2CH2);
3.83 m , 1 H (NCH2CH2); 3.67 m , 1 H (dioxan e H-6); 3.58 sept, 1 H, J = 7.4 [CH(CH3)2];
2.39 dd, 1 H, J = 15.4, 6.9 (CH2COO); 2.24 dd, 1 H, J = 15.4, 6.2 (CH2COO); 1.67 m , 2 H
(NCH2CH2); 1.54 d, 3 H, J = 7.5 [CH(CH3)2]; 1.54 d, 3 H, J = 7.5 [CH(CH3)2]; 1.43 s, 9 H
[C(CH3)3]; 1.36 s, 3 H [C(CH3)2]; 1.35 m , 1 H (dioxan e H-5); 1.30 s, 3 H [C(CH3)2]; 1.05 m ,
1 H (dioxan e H-5). 13C NMR (125 MHz, CDCl3, 25 °C): 170.1 (COO); 164.8 (CONH); 163.2,
JC,F = 248.5 (4-FC6H4 C-4); 141.5 (pyrrole C-5); 138.4 (an ilide C-1); 134.6 (Ph C-1); 133.1,
JC,F = 8.2 (4-FC6H4 C-2); 130.5 (2 C-3 of Ph ); 128.7 (pyrrole C-2); 128.6 (Ph C-2); 128.3
(an ilide C-3); 128.2, JC,F = 2.8 (4-FC6H4 C-1); 126.5 (Ph C-4); 123.5 (an ilide C-4); 122.7 (pyr-
role C-3); 119.5 (an ilide C-2); 115.3 (pyrrole C-4); 115.3, JC,F = 21.4 (4-FC6H4 C-3); 98.6
(dioxan e C-2); 80.7 [C(CH3)3]; 66.4 (dioxan e C-6); 65.1 (dioxan e C-4); 42.4 (NCH2); 40.8
(CH2COO); 38.0 (NCH2CH2); 35.9 (dioxan e C-5); 29.9 [C(CH3)2]; 28.1 [C(CH3)3]; 26.1
[C(CH3)2]; 21.7 [CH(CH3)2]; 21.5 [CH(CH3)2]; 19.6 [C(CH3)2]. IR: 1615 (C=O), 1715 (ester
C=O). HR-MS: for C40H48FN2O5 [M + H]+ calculated 655.3542 m/z, foun d 655.3543.
Calcium (3S,5S)-7-[2-(4-Fluoroph en yl)-5-isopropyl-3-ph en yl-4-(ph en ylcarbam oyl)-
pyrrol-1-yl]-3,5-dih ydroxyh eptan oate (13)
Dilute h ydroch loric acid (10%; 3 m l) was added to a solution of 31 (1 g, 1.5 m m ol) in
tetrah ydrofuran (15 m l). Th e m ixture was stirred at 25 °C for 6 h , an d th en a con cen trated
solution of sodium h ydroxide (40%; 2 m l) was added over 5 m in wh ile m ain tain in g th e
tem perature below 35 °C. Th e form ed h eterogen eous m ixture was vigorously stirred for 15 h ,
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

Synthesis of Some Impurities and/or Degradation Products of Atorvastatin
245
an d th en poured in to a separatory fun n el con tain in g water (30 m l) an d h exan e (10 m l). Th e
organ ic layer was rem oved an d th e aqueous layer was extracted with a m ixture of h exan e
(8 m l) an d tetrah ydrofuran (2 m l). After separation , th e aqueous layer was extracted with
eth yl acetate (3 × 8 m l), an d th e com bin ed extracts were sh aken with a solution of calcium
acetate (20%; 3 × 1 m l). Th e resultin g eth yl acetate solution was wash ed with water (2 ×
1 m l), dried with an h ydrous calcium sulfate an d con cen trated in vacuo to 4 m l. After filtra-
tion , th e clear solution was added dropwise over 5 m in to h exan e (40 m l) un der vigorous
stirrin g, an d th e m ixture was stirred for an oth er 20 m in . Th e precipitate was filtered off,
wash ed with h exan e (20 m l) an d dried to give 0.82 g (93%) of 13, m .p. 170 °C (dec.). Ch iral
purity (HPLC) > 99.5% ee. 1H NMR (500 MHz, CD3OD, 25 °C): 7.3–6.9, 1 H (NH); 7.28 m ,
2 H, J = 8.1 (an ilide H-2); 7.22 m , 2 H (4-FC6H4 H-2); 7.20 m , 2 H (Ph H-2); 7.13 m , 2 H (Ph
H-3); 7.08 m , 2 H (an ilide H-3); 7.04 m , 2 H (4-FC6H4 H-3); 7.03 m , 1 H (Ph H-4); 7.02 m ,
1 H (anilide H-4); 4.05 m , 1 H (CH2CH2CHOH); 4.01 m , 1 H [CH(OH)CH2CHOH]; 3.91 m , 1 H
(CH2CH2CHOH); 3.66 m , 1 H [CH(OH)CH2CHOH]; 3.36 sept, 1 H, J = 7.1 [CH(CH3)2];
2.33 dd, 1 H, J = 15.4, 3.5 (CH2CO); 2.22 dd, 1 H, J = 15.6, 8.7 (CH2CO); 1.68 m , 2 H
(CH2CH2CHOH); 1.53 m , 1 H [CH(OH)CH2CHOH]; 1.49 d, 3 H, J = 7.2 [CH(CH3)2]; 1.48 d,
3 H, J = 7.2 [CH(CH3)2]; 1.36 m , 1 H [CH(OH)CH2CHOH]. 13C NMR (125 MHz, CD3OD,
25 °C): 182.0 (COO); 169.3 (CONH); 163.8, JC,F = 247.2 (4-FC6H4 C-4); 139.8 (an ilide C-1);
139.2 (pyrrole C-2); 136.3 (Ph C-1); 134.7, JC,F = 7.8 (2 C-2 of 4-FC6H4); 131.0 (2 C-3 of Ph );
130.2, JC,F = 2.9 (4-FC6H4 C-1); 129.6 (pyrrole C-5); 129.6 (2 C-2 of Ph ); 128.9 (2 C-3 of
an ilide); 126.9 (Ph C-4); 125.1 (an ilide C-4); 123.3 (pyrrole C-4); 121.5 (2 C-2 of an ilide);
118.1 (C-3 of pyrrole); 116.3, JC,F = 21.5 (2 C-3 of 4-FC6H4); 67.0 (5-CHOH); 66.9 (3-CHOH);
45.3 (CH2CO); 44.5 [CH(OH)CH2CHOH]; 42.4 (CH2CH2CHOH); 41.0 (CH2CH2CHOH); 27.6
[CH(CH3)2]; 22.8 [CH(CH3)2]; 22.8 [CH(CH3)2]. IR: 1569 (C=O), 1710 (C=O acid). HR-MS: for
C
33H36 FN2O5 [M + H]+ calculated 559.2603 m/z, foun d 559.2608.
Financial support provided by Zentiva Praha Co. is greatly appreciated.
REFERENCES
1. Graul A., Castaner J.: Drugs Fut. 1997, 22, 956.
2. The Merck Index, 13th ed., p. 148. Merck & Co., Whitehouse Station, U.S.A. 2001.
3. Hájková M., Kratochvíl B., Rádl S.: Chem. Listy 2008, 102, 3.
4. Brower P. L., Butler D. E., Deering C. F., Le Tung V., Millar A., Nanninga T. N., Roth
B. D.: Tetrahedron Lett. 1992, 33, 2279.
5. Baumann K. L., Butler D. E., Deering C. F., Mennen K. E., Millar A., Nanninga T. N.,
Palmer C. W., Roth B. D.: Tetrahedron Lett. 1992, 33, 2283.
6. Rádl S.: Synth. Commun. 2003, 33, 2275.
7. Rádl S., Stach J. (Léčiva Praha): WO 03/068739 A1; Chem. Abstr. 2003, 139, 185711.
8. Hurley T. R., Colson C. E., Clippert S. A., Uhlendorf S. E., Reily M. D.: Tetrahedron 1993,
49, 1979.
9. Rádl S., Stach J., Hájíček J.: Tetrahedron Lett. 2002, 43, 2087.
10. a) Butler D. E., Deering C. F., Millar A., Nanninga T. N., Roth B. D. (Warner–Lambert Co.):
U.S. 4 681 893; Chem. Abstr. 1987, 107, 198087; b) Briggs C. A., Jennings R. A., Wade R.,
Harasawa K., Ichikawa S., Minohara K., Nakagawa S. (Warner–Lambert Co.): U.S. 5 969 156;
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246

246
Stach, Havlíček, Plaček, Rádl:
Chem. Abstr. 1997, 126, 212037; c) McKenzie A. T. (Warner–Lambert Co.): U.S. 6 121 461;
Chem. Abstr. 1997, 126, 204216.
11. Nanninga T. N., Le Tung V., Millar A., Butler D. (Warner–Lambert Co.): U.S. 5 155 251;
Chem. Abstr. 1993, 118, 41188.
12. Stetter H.: Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229–246