A new synthesis of rizatriptan based on radical cyclization

Article abstract of DOI:10.1135/cccc20080116

A new methodology useful for preparation of indole derivatives bearing a 2-(dialkylamino)-ethyl substituent at the 3-position has been developed. Application of this methodology to the synthesis of N,N-dimethyl-2-{5-[(1H-1,2, 4-triazol-1-yl)methyl]-1H-indol-3-yl}ethan-1-amine (rizatriptan; 3) is described. The key reaction step is based on the radical cyclization of N-[4-(dimethylamino)but-2-yn-1-yl]-N-(2-iodo-4-[(1H-1,2,4-triazol-1-yl)methyl] phenyl}-acetamide (21), easily available by the Mannich reaction, and subsequent isomerization of the primarily formed methylidene derivative 22.

Full text of DOI:10.1135/cccc20080116

116
Rádl, Klecán, Klvaňa, Havlíček:
A NEW SYNTHESIS OF RIZATRIPTAN BASED ON
RADICAL CYCLIZATION
1,
2
3
4
Stanislav RÁDL *, Ondřej KLECÁN , Robert KLVAŇA and Jaroslav HAVLÍČEK
Zentiva, U kabelovny 130, 102 37 Prague 10, Czech Republic;
1
2
3
e-mail: stanislav.radl@zentiva.cz, ondrej.klecan@zentiva.cz, robert.klvana@zentiva.cz,
4
jaroslav.havlicek@zentiva.cz
Received Decem ber 6, 2007
Accepted Jan uary 23, 2008
A n ew m eth odology useful for preparation of in dole derivatives bearin g a 2-(dialkylam in o)-
eth yl substituen t at th e 3-position h as been developed. Application of th is m eth odology
to th e syn th esis of N,N-dim eth yl-2-{5-[(1H-1,2,4-triazol-1-yl)m eth yl]-1H-in dol-3-yl}eth an -
1-am in e (rizatriptan ; 3) is described. Th e key reaction step is based on th e radical cyclization
of N-[4-(dim eth ylam in o)but-2-yn -1-yl]-N-{2-iodo-4-[(1H-1,2,4-triazol-1-yl)m eth yl]ph en yl}-
acetam ide (21), easily available by th e Man n ich reaction , an d subsequen t isom erization of
th e prim arily form ed m eth yliden e derivative 22.
Keyw ord s: Rizatriptan ; Triptan s; Migrain e treatm en t drugs; Seroton in agon ists; Radical
cyclization s; In doles; Man n ich reaction .
A class of poten t seroton in 5-HT1B/1D receptor agon ists collectively term ed
triptan s brough t a substan tial im provem en t in th e m igrain e treatm en t.
Sum atriptan 1 (1; Im itrex , Im igran ) was th e first of th ese com poun ds on
th e m arket. Th is drug was quickly followed by a n um ber of secon d gen era-
tion triptan s, e.g. zolm itriptan 2 (2; Zom ig ), an d rizatriptan 3 (3; Maxalt ),
ch aracterized by im proved ph arm acokin etic properties an d/or tolerability
profiles.
Th ere are several m eth ods of syn th esis of th ese drugs, m ostly based on
th e Fisch er in dole syn th esis4. However, m an y side-reaction s h ave been
observed durin g th e syn th esis, very often providin g 2-substituted an alogs
or dim ers lin ked at th e 2-position 5. Th e Japp–Klin gem an n reaction was
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 1, pp. 116–126
© 2008 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20080116

Synthesis of Rizatriptan
117
used to overcom e th e dim er form ation 6, but h igh tem peratures in suitable
for in dustrial production are n ecessary for th e decarboxylation step. Vari-
ous m odification s of th e Fisch er in dolization were foun d useful in th e syn -
th esis of som e triptan s7 but all of th em , with th e exception of th e Japp–
Klin gem an n reaction 8, were foun d in effective in th e syn th esis of riza-
triptan . A differen t approach to th e syn th esis of rizatriptan based on th e
Larock9 palladium -catalyzed rin g closure h as been also described10. Applica-
tion of th is m eth odology in th e syn th esis of rizatriptan usin g disilylated
com poun d 5 led to th e form ation of in term ediate 6, wh ich was th en tran s-
form ed in to rizatriptan 3 in th ree steps (Sch em e 1).
SCHEME 1
Th e sam e approach was useful also in th e preparation of avitriptan 7b an d
zolm itriptan 7c, an d also in th e syn th esis of com poun d 9, wh ich was th en
tran sferred in to h allucin ogen ic m ush room alkaloid psilocin 11 (Sch em e 2).
SCHEME 2
Grigg an d co-workers described palladium -catalyzed cascade reaction s12
startin g from 2′-iodo-N-propargylacetan ilides 10, wh ere th e in term ediate
form ation of 11 can be expected (Sch em e 3).
SCHEME 3
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118
Rádl, Klecán, Klvaňa, Havlíček:
Form ally sim ilar radical cyclization of several 2′-brom o-N-propargylacet-
an ilides with term in al acetylen ic bon d h as also been described13. Th e use of
Bu3Sn H an d AIBN provided h igh yields of a m ixture of exo- an d en docyclic
products 14 an d 15 (ref.13a) (Sch em e 4) wh ile th e Sm I2-prom oted cycliz-
ation 13b of com poun d 13 yielded on ly th e deacetylated 3-m eth yl derivative
correspon din g to com poun d 15. An efficien t syn th esis of pin eal h orm on e
m elaton in based on radical cyclization of th e correspon din g N-(2-iodo-
ph en yl)m eth an esulfon am ide in itiated by 1-eth ylpiperidin e h ypoph osph ite
(EPHP) or tris(trim eth ylsilyl)silan e (TTMSS) h as been reported14
.
SCHEME 4
A differen t approach based on th e carban ion addition leadin g to in doles
h as been recen tly reported15. Allen e 17, obtain ed from th e correspon din g
acetylen ic com poun d 16 by treatm en t with potassium tert-butoxide, wh en
treated with 2.4 equivalen ts of tert-butyllith ium gave a good yield of 18 as a
m ixture of th e E an d Z isom ers (Sch em e 5). On th e oth er h an d, th e sam e
treatm en t of 16 provided on ly a com plex m ixture.
SCHEME 5
Th e expected easy availability of N-[4-(dim eth ylam in o)but-2-yn -1-yl]-
N-(2-iodoph en yl)acetam ides via th e Man n ich reaction of th e correspon d-
in g propargylic in term ediates in spired us to develop a n ew way useful for
preparation of in dole derivatives bearin g th e 2-(dim eth ylam in o)eth yl
substituen t at position 3. We h ave con sidered all th e above m en tion ed vari-
ation s, i.e. palladium -catalyzed cyclization , carban ion cyclization , an d radi-
cal cyclization . In th is paper we report application of th is approach to th e
syn th esis of rizatriptan .
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Synthesis of Rizatriptan
119
Th e startin g iodo derivative 4 was prepared by iodin ation of th e corre-
spon din g an ilin e with iodin e m on och loride in th e presen ce of calcium
carbon ate accordin g to th e literature8a,10. Acetylation of 4 with acetic an -
h ydride in acetic acid provided an ilide 19. Its sodium salt gen erated in situ
with sodium h ydride in DMF was th en alkylated with propargyl brom ide to
give 20 as an oil. In itially we tried to isolate th e com poun d by ch rom atog-
raph y an d iden tified it by NMR spectroscopy but th e com poun d was foun d
rath er un stable. Th erefore, it was used with out purification an d its treat-
m en t with paraform aldeh yde in a dioxan e solution of dim eth ylam in e gave
21. Th is com poun d obtain ed as yellow oil was ch aracterized as h ydroch lo-
ride. In th e reaction s, h owever, it was used as th e oily base.
For th e cyclization we tried first th e palladium -catalyzed cyclization un -
der differen t con dition s. Th e reaction usin g palladium acetate–sodium
carbon ate as well as com bin ation s of palladium acetate an d triph en yl-
ph osph in e with both sodium carbon ate an d silver carbon ate gave com plex
m ixtures with on ly traces of com poun d 23 (TLC).
Better results were obtain ed wh en th e cyclization was don e un der con di-
tion s of radical cyclization . Our in itial experim en ts usin g tributyltin h y-
dride led to a m ixture of two com poun ds with very sim ilar RF in several
used solven t m ixtures. Relatively good resolution with RF ca. 0.4 an d 0.45
was obtain ed usin g th e system toluen e–eth an ol–dioxan e–con cen trated
aqueous am m on ia 5:2:4:1. After workup an d ch rom atograph ic separation ,
low yields of both com poun ds, wh ich were iden tified as th e correspon din g
exocyclic derivative 22 (RF = 0.40) an d en docyclic derivative 23 (RF = 0.45),
were obtain ed. In attem pts to alleviate problem s associated with toxic tin
residues an d to im prove th e yields, we applied con dition s described by
Th om pson et al.14, usin g EPHP or TTMSS. Again , m ixtures of exocyclic an d
SCHEME 6
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120
Rádl, Klecán, Klvaňa, Havlíček:
en docyclic derivatives 22 an d 23, respectively, were form ed. Th e overall
yields obtain ed in repeated run s with 1-eth ylpiperidin e h ypoph osph ite or
tris(trim eth ylsilyl)silan e reaction s were com parable or h igh er th an with
tributyltin h ydride, but th e ratio of com poun d 22 an d 23 varied, probably
due to th e easy isom erization of 22 to 23 (Sch em e 6). Th e exocyclic com -
poun d 22 is n ot quite stable an d its partial isom erization occurs even dur-
in g attem pts of crystallization of th e correspon din g crude ch rom atograph ic
fraction from eth yl acetate. Th erefore, n o elem en tal an alysis results are re-
ported an d th e com poun d was ch aracterized on ly by MS an d NMR of th e
correspon din g ch rom atograph ic fraction after evaporation .
In dolin e derivatives sim ilar to 22 are kn own to isom erize un der acid con -
dition s to th e correspon din g in dole derivatives14,16. In our case, treatm en t
of 22 or m ixture of 22 an d 23 with 4-m eth ylben zen e-1-sulfon ic acid was
used to get pure in dole 23 in a h igh yield. Its alkalin e h ydrolysis with so-
dium h ydroxide in aqueous m eth an ol at room tem perature provided th e
target product – rizatriptan base (Sch em e 7).
SCHEME 7
Sin ce th e yields in our in itial experim en ts of deacetylation of 23 were low
an d our supply of 23 was lim ited, we decided to prepare 23 by acetylation
of rizatriptan (3) prepared by th e Fisch er in dole syn th esis. Fin ally, th e
acetylation with acetic an h ydride in aceton itrile was successful. However,
our first attem pt don e in dich lorom eth an e provided surprisin gly a m ixture
of th e required acetyl derivative 23 an d its quatern ary salt 24 (Sch em e 8).
Form ation of 24 un der such m ild con dition s is, in our opin ion , in terestin g
an d quotable.
SCHEME 8
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Synthesis of Rizatriptan
121
All th e prepared com poun ds were duly ch aracterized by elem en tal an aly-
1
sis, IR, UV an d MS/MS spectra as well as by th e H an d 13C NMR spectra. For
th e assign m en t of sign als in proton an d carbon NMR spectra, 2D NMR
1
1
tech n iques (COSY, H-13C HSQC, H-13C HMBC) were used.
In con clusion , a n ovel m eth od of preparation of rizatriptan based on
a radical cyclization of easily available in term ediates was developed. Th is
m eth odology could be also used in th e syn th esis of sim ilar 3-(2-am in o-
eth yl)in dole derivatives. Un like th e Fisch er in dole syn th esis, wh ich pro-
vides on ly low yields of rizatriptan , our approach does n ot use poten tially
carcin ogen ic aryl h ydrazin e in term ediates. Com pared to sim ilar approach
based on th e Pd-catalyzed Larock m eth odology, our approach is sim pler
an d m ore straigh tforward.
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 by th e diffuse reflectan ce m eth od
(KBr); waven um bers are given in cm –1. Th e UV spectra were recorded on a Hewlett–Packard
8452A spectroph otom eter (eth an ol) in th e ran ge 190–400 n m . 1H an d 13C NMR spectra were
recorded on a Bruker Avan ce 500 in strum en t (Bruker Biospin Gm bH) at 500.13 MHz (1H),
125.77 MHz (13C). At 500 MHz, stan dard 5 m m TXO (triple-n ucleus X-observe) an d TBI
(triple-broadban d in verse) probeh eads equipped with z-gradien t coils were em ployed for all
m easurem en ts. Ch em ical sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. Th e
m ass spectra (MS/MS; ion ization m ode APCI(+)) were m easured on an API 3000 PE device
(Sciex In strum en ts, Applied Biosystem s). Th e purity of th e substan ces prepared was evalu-
ated by TLC on silica gel (FP KG F 254, Merck). Flash ch rom atograph y was perform ed on
silica gel Merck, particle size 0.04–0.063 m m .
2-Iodo-4-[(1H-1,2,4-triazol-1-yl)m eth yl]an ilin e (4) was prepared accordin g to th e pub-
lish ed procedure8a,10 1H NMR (CDCl3): 4.22 bs, 2 H (NH2); 5.16 s, 2 H (CH2); 6.70 d, 2 H,
.
J = 10.0 (H-6); 7.06 dd, 2 H, J = 10.0, 2.5 (H-5); 7.58 d, 2 H, J = 2.5 (H-3); 7.95 s, 1 H (H-5 of
triazole); 8.01 s, 1 H (H-3 of triazole). 13C NMR (CDCl3): 52.3 (CH2), 83.6 (C-2), 114.6 (C-6),
125.4 (C-4), 129.5 (C-5), 138.8 (C-3), 142.7 (C-1), 147.2 (C-5 of triazole), 152.1 (C-3 of tri-
azole). UV, λm ax (log ε): 216 (4.54), 248 (4.11), 302 (3.52).
N-{2-Iodo-4-[(1H-1,2,4-triazol-1-yl)m eth yl]ph en yl}acetam ide (19)
Acetic an h ydride (51 g, 0.5 m ol) was added dropwise to a solution of 4 (30 g, 0.1 m ol) in
acetic acid (100 m l) an d th e m ixture was stirred at am bien t tem perature for 2 h . Th e m ix-
ture was poured on to ice an d th e m ixture was n eutralized with con cen trated sodium h y-
droxide. Th e form ed solid was filtered off, wash ed with water an d dried. Crystallization
from eth an ol provided 27.6 g (81%) of off-wh ite solid, m .p. 170–171 °C. For C11H11IN4O
(342.1) calculated: 38.62% C, 3.24% H, 37.09% I, 16.38% N; foun d: 38.33% C, 3.27% H,
37.41% I, 16.07% N. 1H NMR (DMSO-d6): 2.04 s, 3 H (CH3CO); 5.38 s, 2 H (CH2); 7.27dd,
2 H, J = 6.6, 1.5 (H-5); 7.37 d, 2 H, J = 7.1 (H-6); 7.80 d, 2 H, J = 1.3 (H-3); 7.98 s, 1 H (H-5
of triazole); 8.66 s, 1 H (H-3 of triazole); 9.38 bs, 1 H (NH). 13C NMR (DMSO-d6): 23.1 (CH3),
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Rádl, Klecán, Klvaňa, Havlíček:
50.6 (CH2), 96.3 (C-2), 127.2 (C-6), 128.1 (C-5), 135.4 (C-4), 138.1 (C-3), 139.4 (C-1), 144.2
(C-5 of triazole), 151.8 (C-3 of triazole), 168.3 (C=O). IR: 1516, 1573 (arom .), 1685 (CO),
3326 (NH). UV, λm ax (log ε): 208 (4.36), 222 (4.40), λin fl = 245 n m .
N-[4-(Dim eth ylam in o)but-2-yn -1-yl]-N-{4-[(1H-1,2,4-triazol-1-yl)m eth yl]-2-iodoph en yl}-
acetam ide (21)
Sodium h ydride (50% dispersion in m in eral oil, 4.8 g, 0.1 m ol) was added to a solution of
19 (27 g, 80 m m ol) in dry DMF (200 m l) an d th e m ixture was stirred at am bien t tem pera-
ture un der n itrogen for 1 h . A solution of propargyl brom ide (80% in toluen e, 15 g, 0.1 m ol)
was added an d th e m ixture was stirred at 50 °C un der n itrogen for 2 h . Th e m ixture was
cooled an d poured in to water (750 m l), th e form ed precipitate was filtered off on Celite. Th e
pH of th e filtrate was adjusted to 8–9 with acetic acid, th e m ixture was extracted with eth yl
acetate an d th e com bin ed extracts were dried with an h ydrous m agn esium sulfate. Th e solu-
tion con tain in g on ly on e m ajor product (TLC, toluen e–eth an ol–dioxan e–con cen trated aque-
ous am m on ia 5:2:4:1) was evaporated to give 35 g of a brown oily residue. Th e residue was
dissolved in dry dioxan e (250 m l), an d paraform aldeh yde (9 g, 0.3 m ol), copper(I) ch loride
(3 g, 30 m m ol) an d a 20% solution of dim eth ylam in e in dioxan e (50 m l) were added. Th e
m ixture was th en stirred at 50 °C for 2 h an d filtered th rough a Celite pad wh ile h ot. Th e
filtrate was evaporated, th e residue was dissolved in 5% aqueous h ydroch loric acid (500 m l),
th e turbid solution was wash ed with eth er (2 × 25 m l). Th e aqueous solution was th en alka-
lin ized with saturated aqueous sodium carbon ate an d th e form ed greasy precipitate was fil-
tered off with Celite. Th e Celite pad was wash ed with water (500 m l) an d dich lorom eth an e
(1000 m l). Th e com bin ed aqueous fraction s were extracted with dich lorom eth an e wash in gs
(5 × 200 m l) an d th e organ ic solution was dried with an h ydrous m agn esium sulfate. Th e
desiccan t was filtered th rough a pad of silica an d th e residue after evaporation (24.4 g,
69.7%) was used with out isolation in th e followin g step. A sm all sam ple (1 g) was tran s-
form ed in to h ydroch loride, m .p. 135–142 °C (dec.) an d repeatedly recrystallized from eth yl
acetate–eth an ol 2:1. For C17H21ClIN5O (473.7) calculated: 43.10% C, 4.47% H, 7.48% Cl,
26.79% I, 14.78% N; foun d: 42.79% C, 4.21% H, 7.48% Cl, 26.93% I, 14.55% N. 1H NMR
(DMSO-d6): 1.69 s, 3 H (CH3); 2.69 s, 6 H (CH3N); 4.00 s, 2 H (Me2NCH2); 4.04 d, 1 H, J =
12.6 (AcNCH2); 4.84 d, 1 H, J = 12.4 (AcNCH2); 5.49 s, 2 H (CH2); 7.42 dd, 2 H, J = 7.6, 1.3
(H-5); 7.60 _, 1 H, J = 8.0 (H-6); 7.96 d, 2 H, J = 1.3 (H-3); 8.20 s, 1 H (H-5 of triazole);
8.98 s, 1 H (H-3 of triazole); 11.40 bs, 1 H (HCl). 13C NMR (DMSO-d6): 22.2 (CH3CO), 36.7
(AcNCH2), 41.1 (CH3N), 45.4 (Me2NCH2), 50.6 (CH2), 73.6 (Me2NCH2C), 84.9 (AcNCH2C),
101.3 (C-2), 129.3 (C-6), 130.6 (C-5), 138.5 (C-4), 138.8 (C-3), 143.1 (C-1), 144.7 (C-5 of tri-
azole), 150.8 (C-3 of triazole), 168.5 (C=O). IR: 1487, 1653 (CO). UV, λm ax (log ε): 206 (4.42),
λin fl = 227 n m . MS/MS (m/z, %): 438 (100, M + 1), 393 (87), 351 (8), 325 (10), 282 (38).
1-{(Z)-3-[2-(Dim eth ylam in o)eth yliden e]-5-[(1H-1,2,4-triazol-1-yl)m eth yl]-
2,3-dih ydro-1H- in dol-1-yl}eth an -1-on e (22) an d
1-{3-[2-(Dim eth ylam in o)eth yl]-5-[(1H-1,2,4-triazol-1-yl)m eth yl]-
1H-in dol-1-yl}eth an -1-on e (23)
A) EPHP (17.9 g, 0.1 m ol) an d AIBN (0.25 g, 1.5 m m ol) were added to a solution of 21
(4.4 g, 10 m m ol) in toluen e (500 m l) an d th e solution was refluxed un der n itrogen for 2 h .
Th e m ixture was evaporated, th e residue was dissolved in dich lorom eth an e (150 m l) an d th e
solution was successively wash ed with saturated sodium carbon ate (25 m l) an d brin e, an d
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Synthesis of Rizatriptan
123
dried with an h ydrous m agn esium sulfate. Th e residue after evaporation was purified by flash
ch rom atograph y (dich lorom eth an e–m eth an ol–trieth ylam in e 40:1:1) to give 2.1 g of 22
(67%) as wh ite crystals, m .p. 150–159 °C (dec.) an d 0.16 g of 23 (5%) as wh ite crystals, m .p.
135–137 °C.
Compound 22: 1H NMR (CDCl3): 2.33 s, 3 H (CH3CO); 2.68 s, 6 H (CH3N); 3.51 m , 2 H
(Me2NCH2); 4.92 s, 2 H (H-2); 5.35 s (CH2); 6.04 m , 1 H (Me2NCH2CH); 7.27 dd, 1 H, J =
8.2, 1.5 (H-6); 7.41 d, 1 H, J = 8.2, 1.5 (H-4); 8.00 s, 1 H (H-3 of triazole); 8.10 s, 1 H (H-5 of
triazole); 8.34 d, 1 H, J = 8.5 (H-7). MS/MS (m/z, %): 312 (48, M + 1), 267 (100), 243 (14),
225 (33), 198 (39), 158 (11), 156 (90).
Compound 23: For C17H21N5O (311.4) calculated: 65.57% C, 6.80% H, 22.49% N; foun d:
65.43% C, 6.41% H, 22.72% N. 1H NMR (DMSO-d6): 2.32 s, 6 H (CH3N); 2.60 s, 3 H
(CH3CO); 2.62 t, 2 H, J = 7.5 (Me2NCH2CH2); 2.84 t, 2 H, J = 7.5 (Me2NCH2); 5.44 s (CH2);
7.26 d, 1 H, J = 10.0 (H-6); 7.30 s, 1 H (H-2); 7.45 s, 1 H (H-4); 7.97 s, 1 H (H-3 of triazole);
8.05 s, 1 H (H-5 of triazole); 8.40 d, 1 H, J = 10.0 (H-7). 13C NMR (DMSO-d6): 22.3
(Me2NCH2CH2), 23.8 (CH3CO), 45.4 (Me2N), 53.8 (CH2), 59.0 (Me2NCH2), 117.2 (C-7), 118.6
(C-6), 120.8 (C-3), 123.0 (C-4), 125.2 (C-2), 129.5 (C-3a), 131.2 (C-5), 135.7 (C-7a), 142.9
(C-5 of triazole), 152.0 (C-3 of triazole), 168.2 (C=O). IR: 1 386, 1 693 (CO). UV, λm ax (log ε):
206 (4.42), 242 (4.44), 294 (3.87), 304 (3,88). MS/MS (m/z, %): 312 (100, M + 1), 243 (82),
201 (18), 200 (11), 158 (48), 58 (32).
B) Tributyltin h ydride (1.5 g, 5 m m ol) an d AIBN (0.05 g, 0.3 m m ol) were added to a solu-
tion of 21 (0.87 g, 2 m m ol) in toluen e (150 m l) an d th e solution was refluxed un der n itro-
gen for 2 h . Th e solution was evaporated un der reduced pressure, th e residue was dissolved
in dich lorom eth an e (50 m l) an d th e solution was successively wash ed with saturated sodium
carbon ate (10 m l) an d brin e, an d dried with an h ydrous m agn esium sulfate. Th e residue after
evaporation was purified by flash ch rom atograph y (dich lorom eth an e–m eth an ol–trieth yl-
am in e 40:1:1) to give 0.27 g of 22 (43%) as wh ite crystals, m .p. 152–160 °C (dec.) an d 0.05 g
of 23 (8%) as wh ite crystals, m .p. 135–137 °C.
C) A solution of AIBN (0.2 g) an d TTMSS (2 m l, 1.5 g, 6 m m ol) in toluen e (20 m l) was
added via a syrin ge pum p durin g 5 h to a refluxin g solution of 21 (3 g, 6.8 m m ol) in tolu-
en e (400 m l) un der argon an d th e solution was refluxed for addition al 1 h . Th e cold solu-
tion was wash ed with saturated sodium carbon ate an d brin e, dried with an h ydrous
m agn esium sulfate an d th e residue after evaporation was purified by flash ch rom atograph y
(dich lorom eth an e–m eth an ol–trieth ylam in e 40:1:1) to give 1.1 g of 22 (52%) as wh ite crys-
tals, m .p. 152–159 °C (dec.) an d 0.25 g of 23 (12%) as wh ite crystals, m .p. 135–137 °C.
D) A solution of 1,1′-azodi(cycloh exan e-1-carbon itrile) (0.05 g) an d TTMSS (0.5 m l, 0.75 g,
3 m m ol) in toluen e (8 m l) was added via a syrin ge pum p durin g 5 h to a refluxin g solution
of 21 (0.75 g, 1.7 m m ol) in toluen e (100 m l) un der argon . Th e solution was wash ed with
saturated sodium carbon ate an d brin e, dried with an h ydrous m agn esium sulfate an d th e res-
idue after evaporation was purified by flash ch rom atograph y (dich lorom eth an e–m eth an ol–
trieth ylam in e 40:1:1) to give 0.21 g of 22 (40%) as wh ite crystals, m .p. 152–159 °C (dec.)
an d 0.17 g of 23 (32%) as wh ite crystals, m .p. 135–137 °C.
1-{3-[2-(Dim eth ylam in o)eth yl]-5-[(1H-1,2,4-triazol-1-yl)m eth yl]-1H-in dol-1-yl}-
eth an -1-on e (23)
A) EPHP (12.5 g, 70 m m ol) an d AIBN (0.2 g, 1.2 m m ol) were added to a solution of 21
(3 g, 67 m m ol) in toluen e (400 m l) an d th e solution was refluxed un der n itrogen for 2 h .
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124
Rádl, Klecán, Klvaňa, Havlíček:
Th e m ixture was evaporated, th e residue was dissolved in dich lorom eth an e (100 m l) an d th e
solution was succesively wash ed with saturated sodium carbon ate an d brin e. Solid
4-m eth ylben zen esulfon ic acid m on oh ydrate (1.9 g, 100 m m ol) was added an d th e m ixture
was refluxed for 24 h . Th en an oth er portion of th e acid (1.9 g, 100 m m ol) was added an d
th e reflux con tin ued for addition al 24 h . Th e cold m ixture was wash ed with saturated so-
dium carbon ate an d brin e, th e residue after evaporation was purified by flash ch rom atogra-
ph y (dich lorom eth an e–m eth an ol–trieth ylam in e 40:1:1) followed by crystallization from
eth yl acetate–eth an ol 1:1 to give 1.1 g (53%) of wh ite crystals, m .p. 135–137 °C.
B) A m ixture of 22 (0.3 g, 1 m m ol), dich lorom eth an e (25 m l) an d 4-m eth ylben zen e-
sulfon ic acid m on oh ydrate (0.2 g) was refluxed for 24 h . After coolin g, it was wash ed with
saturated sodium carbon ate an d brin e, th e residue after evaporation was purified by flash
ch rom atograph y (dich lorom eth an e–m eth an ol–trieth ylam in e 40:1:1) followed by crystalliza-
tion from eth yl acetate–eth an ol 1:1 to give 0.25 g (83%) of wh ite crystals, m .p. 135–137 °C.
3-[2-(Dim eth ylam in o)eth yl]-5-[(1H-1,2,4-triazol-1-yl)m eth yl]in dole (3)
Aqueous sodium h ydroxide (10%, 25 m l) was added to a solution of com poun d 23 (1.55 g,
5 m m ol) in m eth an ol (25 m l) an d th e solution was stirred at room tem perature for l h .
Th en it was evaporated, diluted with water (25 m l), extracted with eth yl acetate an d th e
extract was dried with an h ydrous m agn esium sulfate. Th e residue after evaporation was dis-
solved in boilin g isopropyl acetate, th en h eptan e was added un til th e solution becam e tur-
bid. Th e solution was seeded an d left stan din g overn igh t at –20 °C. Th e form ed crystallin e
solid was filtered off to give 1.15 g (85%) of rizatriptan base; m .p. 119–122 °C. 1H NMR
(CDCl3): 2.34 s, 6
H (CH3N); 2.65 t, 2 H, J = 7.5 (Me2NCH2); 2.92 t, 2 H, J = 7.5
(Me2NCH2CH2); 5.39 s (CH2); 7.03 m , 2 H (H-4, H-6); 7.24 d, J = 7.5, 1 H (H-7); 7.53 s, 1 H
(H-2); 7.97 s, 1 H (H-3 of triazole); 7.98 s, 1 H (H-5 of triazole); 9.20 bs (NH). 13C NMR
(CDCl3): 23.4 (Me2NCH2CH2), 45.2 (Me2N), 54.5 (CH2), 60.1 (Me2NCH2), 111.8 (C-7), 114.1
(C-3), 119.0 (C-2), 122.0 (C-6), 122.8 (C-4), 124.6 (C-5), 127.6 (C-3a), 136.2 (C-7a), 142.7
(C-5 of triazole), 151.7 (C-3 of triazole). IR: 1364, 1440, 1505, 3181. UV, λm ax (log ε): 204
(4.31), 228 (4.62), 284 (3.74). MS/MS (m/z, %): 270 (65, M + 1), 201 (100), 158 (58), 58 (17).
1-{3-[2-(Dim eth ylam in o)eth yl]-5-[(1H-1,2,4-triazol-1-yl)m eth yl]-
1H-in dol-1-yl}eth an -1-on e (23) an d
2-{1-Acetyl-5-[(1H-1,2,4-triazol-1-yl)m eth yl]-1H-in dol-3-yl}eth yl-
(ch lorom eth yl)dim eth ylam m in ium Ch loride (24)
DMAP (68 m g, 0.56 m m ol), trieth ylam in e (0.93 m l, 6.7 m m ol) an d acetic an h ydride (0.63 m l,
6.7 m m ol) were added to rizatriptan (1.5 g, 5.6 m m ol) in dich lorom eth an e (15 m l). Th e re-
action m ixture was stirred at room tem perature for 65 h . Th e form ed solid was filtered off to
give 0.3 g (14%) of quatern ary am m on ium salt 24, m .p. 168–170 °C. 1H NMR (DMSO-d6):
2.63 s, 3 H (CH3CO); 3.23 m , 2 H (Me2NCH2CH2); 3.33 s, 6 H (CH3N); 3.85 m , 2 H
(Me2NCH2); 5.52 s (CH2); 5.66 s, 2 H (CH2Cl); 7.32 dd, 1 H, J = 7.5, 1.2 (H-6); 7.75 d, 1 H,
J = 1.2 (H-4); 7.93 s, 1 H (H-2); 7.97 s, 1 H (H-3 of triazole); 8.28 d, 1 H, J = 7.5 (H-7); 8.75 s,
1 H (H-5 of triazole). 13C NMR (DMSO-d6): 18.1 (Me2NCH2CH2), 24.0 (CH3CO), 49.1
(Me2N), 52.5 (CH2), 60.1 (Me2NCH2), 68.4 (CH2Cl), 116.7 (C-3), 116.2 (C-7), 119.1 (C-4),
125.3 (C-6), 125.9 (C-2), 129.9 (C-3a), 131.4 (C-5), 134.8 (C-7a), 144.3 (C-5 of triazole),
151.7 (C-3 of triazole), 169.3 (C=O). IR: 1700 (CO). UV, λm ax (log ε): 204 (4.39), 240 (4.37),
264 (3.94), 292 (3.77), 302 (3.80). MS/MS (m/z, %): 362 (32), 360 (100), 267 (37), 225 (10).
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 1, pp. 116–126

Synthesis of Rizatriptan
125
Th e filtrate was wash ed with water an d th e organ ic layer was dried with an h ydrous so-
dium sulfate. Th e residue after evaporation was crystallized from eth yl acetate to give 585 m g
(34%) of 23, m .p. 138–139 °C.
1-{3-[2-(Dim eth ylam in o)eth yl]-5-[(1H-1,2,4-triazol-1-yl)m eth yl]-1H-in dol-1-yl}-
eth an -1-on e (23)
DMAP (136 m g, 1.2 m m ol), trieth ylam in e (1.9 m l, 13.4 m m ol) an d acetic an h ydride (1.3 m l,
13.4 m m ol) were added to rizatriptan (3 g, 11.1 m m ol) in aceton itrile (15 m l). Th e reaction
m ixture was stirred at room tem perature for 24 h . Th e precipitated product was filtered off
an d wash ed with cold aceton itrile to give 2.7 g (78%) of 23 as wh ite crystals; m .p. 138–139 °C.
Spectral ch aracteristics of th is com poun d were iden tical with th e com poun d prepared by iso-
m erization of com poun d 22.
Financial support provided by Zentiva Praha is greatly appreciated. The authors’ thanks are due to
Ms. L. Tisovská for measuring the IR and UV spectra and Mr. L. Plaček for MS spectra.
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