An improved synthesis of the antiulcer drug ranitidine from N-[2-[[[5- (hydroxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N'-methyl-2-nitro-1,1- ethenediamine

Article abstract of DOI:10.1002/(SICI)1521-4184(199806)331:6<228::AID-ARDP228>3.0.CO;2-U

An improved synthesis of the antiulcer drug ranitidine from N-[2-[[[5- (hydroxymethyl)-2-furanyl]-methyl]-thiol]-ethyl]-N'methyl-2-nitro-1,1- ethenediamine is reported.

Full text of DOI:10.1002/(SICI)1521-4184(199806)331:6<228::AID-ARDP228>3.0.CO;2-U

228
Aasen and Skramstad
An Improved Synthesis of the Antiulcer Drug Ranitidine from
N-[2-[[[5-(hydroxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N′-methyl-
2-nitro-1,1-ethenediamine
a)
b)
Arne Jørgen Aasen * and Jan Skramstad
a) Department of Pharmacy, University of Oslo, P. O. Box 1155 Blindern, N-0317 Oslo, Norway
b) Department of Chemistry, University of Oslo, P. O. Box 1033 Blindern, N-0315 Oslo, Norway
Key Words: Ranitidine; antiulcer drug; reductive amination
Summary
Results and Discussion
The intermediate alcohol 1 is polyfunctional and prone to
decomposition or unwanted side-reactions . A number of
An improved synthesis of the antiulcer drug ranitidine from
N-[2-[[[5-(hydroxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N′-
methyl-2-nitro-1,1-ethenediamine is reported.
[5]
methods were attempted to convert the hydroxymethyl group
to the corresponding dimethylaminomethyl group. Reactions
such as chlorination with thionyl chloride, or tosylation fur-
nished complex, tarry mixtures only. However, oxidation of
the alcohol 1 to the corresponding aldehyde followed by
reductive amination furnished ranitidine in excellent overall
yield.
Introduction
[1]
The antiulcer remedy ranitidine has for a number of years
[2]
been the most widely sold drug in the world . Its importance,
however, is declining due to the introduction of alternative
treatments such as combinations of antibacterial drugs and
either a proton pump inhibitor (e. g. omeprazole or lansopra-
zole) or H -receptor antagonists (e. g. cimetidine or ranitid-
2
[3]
ine)
.
Two main syntheses are presently being used for the pro-
duction of ranitidine. Both of them employ 5-(dimethylami-
nomethyl)furfuryl alcohol as starting material. In the original
[1]
TM
synthesis, ranitidine (Zantac ) was constructed through
a series of nucleophilic substitution reactions using the hy-
droxyl group as a leaving group (as water on protonation) and
retaining the dimethylaminomethyl group intact throughout
the synthesis.
[4]
TM
In a subsequent synthesis ranitidine (Noctone ) was
assembled in a series of similar reactions which included
removal of the dimethylamino group (as trimethylamine on
quaternization with methyl bromide) which, consequently,
had to be reintroduced in the final step. Thus, the intermediate
alcohol 1, N-[2-[[[5-(hydroxymethyl)-2-furanyl]-methyl]-
thio]-ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, prepared
in an overall yield of 59% from 5-(dimethylaminomethyl)fur-
furyl alcohol, was converted to ranitidine in a one-pot syn-
thesis by its reaction with tetramethylformamidinium
chloride and dimethylamine for 16 h in an autoclave at 90 °C.
Ranitidine hydrochloride was obtained after extensive puri-
fication by chromatography on silica gel and acidification
with hydrochloric acid. The yield for this step was reported
as 56%. In our hands, however, this last process consistently
furnished impure ranitidine hydrochloride in yields not ex-
ceeding 20%. Thus, an improved method for the conversion
of the intermediate alcohol 1 to ranitidine constitutes the
subject of the present communication.
Scheme 1. Alternative synthesis of ranitidine
Manganese dioxide is considered to be particularly suited
for selective oxidation of benzylic alcohols to corresponding
[6]
aldehydes or ketones. Furthermore, benzaldehyde and sub-
stituted benzaldehydeshave previouslybeenreductively ami-
nated with primary or secondary amines employing sodium
cyanoborohydride as reducing agent; e. g. the conversion of
3,4-dimethoxybenzaldehyde to N,N-dimethyl-3,4-di-
methoxybenzylamine using dimethylamine and sodium cy-
[7,8]
anoborohydride.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
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Antiulcer Drug
229
nitro-1,1-ethenediamine (2, 93 mg, 0.33 mmol) in methanol (10 ml). Sodium
cyanoborohydride (66 mg, 1.05 mmol) was added to the mixture which was
kept at –70 °C for 3 h and at –18 °C over the weekend. TLC revealed, in
addition to ranitidine, a minor, less polar component which was interpreted
as remaining aldehyde 2. Additional sodium cyanoborohydride (59 mg, 0.94
mmol) was added and the mixture left for another 24 h at –18 °C. A capillary
drop of the reaction mixture on moist pH-paper indicated pH ca. 6.5. Most
of the solvent was removed in vacuo and the residue redissolved in water
(10 ml) and transferred to a separatory funnel. The solution was acidified
with 6N HCl to pH ca. 1.5 and extracted with dichloromethane (2 × 20 ml).
The two extracts were combined, dried over Na2SO4, and concentrated to
dryness. The residue (6 mg) consisted (TLC) of at least six, non-basic
compounds of which twomight havebeenthe alcohol 1 (co-chromatography)
and the aldehyde 2.
Ammonium hydroxide (3 ml, concd.) and brine (8 ml, satd.) were added
to the remaining aqueous solution in the separatory funnel. The solution
whose pH was approximately 9.5, was extracted with dichloromethane (6 ×
35 ml). The combined extracts were dried over Na2SO4 and the solvent
removed in vacuo leaving a slightly orange-coloured oil (75 mg). TLC
revealed minor impurities. An estimated purity of >90% indicated an overall
yield of 62% of ranitidine from the alcohol 1 (NMR). The major constituent,
Rf 0.44 (TLC; silica gel; CHCl3:CH3OH = 1:1; UV- and I2-detection), did
not separate from authentic ranitidine when co-chromatographed (TLC). MS
[CI/methane], 1H- and 13C NMR spectra were nearly identical to those of
authentic ranitidine. Ref.[12] presents a detailed study on the spectroscopic
properties of ranitidine.
Thus, ranitidine was readily obtained in a two-step synthe-
sis from the benzylic-type alcohol1 by (a) manganese dioxide
oxidation to the corresponding aldehyde 2 (N-[2-[[[5-(for-
myl)-2-furanyl]-methyl]-thio]-ethyl]-N′-methyl-2-nitro-1,1-
ethenediamine; purity > 90%; yield 94%) which was sub-
jected, without purification, to (b) reductive amination to
ranitidine with dimethylamine and sodium cyanoborohy-
dride in an overall yield of 62%. The yield was not optimized.
The purity of ranitidine was estimated to be better than
90%.
Ranitidine has previously been prepared in a multistep
process starting from 2-[(aminoethyl)thio]methylfuran in-
cluding in situ hydrolysis and reductive amination of an acetal
of the aldehyde 2. However, the overall yield ranged from 4%
[9]
to 19% only
.
Experimental
General
1H NMR and 13C NMR spectra were recorded on a Varian XL-200
instrument at 200 MHz and 50 MHz, respectively, using CD3OD as solvent.
The yields given below have not been optimized. The reactions were per-
formed in an inert atmosphere of nitrogen.
References
N-[2-[[[5-(Formyl)-2-furanyl]-methyl]-thio]-ethyl]-N-methyl-2-nitro-
1,1-ethenediamine (2)
[1] B. J. Price, J. W. Clitherow, J. Bradshaw (Allen & Hanburys Ltd.) DE
2,734,070 A1. 1978 [Chem. Abstr. 1978 88:190580b].
Manganese dioxide (506 mg, Fluka no. 63548, ‘Manganese(IV) oxide
precipitated activated’) was added to a suspension of N-[2-[[[5-(hy-
droxymethyl)-2-furanyl]-methyl]-thio]-ethyl]-N-methyl-2-nitro-1,1-ethene-
diamine[10] (1, 100 mg, 0.348 mmol) in dichloromethane (150 ml) [11]. The
mixture was stirred at ambient temp. and the progress of the reaction was
monitored by TLC (silica gel; CHCl3:CH3OH = 9:1; UV- and I2-detection).
Traces only of the alcohol 1 was detected after 4 h and the reaction mixture
was filtered through a Celite pad which was subsequently washed with
dichloromethane (40 ml). The combined solutions were concentrated in
vacuo to a slightly yellow oil (93 mg, 94%). The purity was >90% (NMR).
Rf 0.42 (Rf 0.34 for the alcohol 1; TLC-system: vide supra); 1H NMR
(CD3OD): δ = 2.83 (t, J = 6.8 Hz, S-CH2-CH2-N), 2.89 (s, NHCH3), 3.46 (t,
J = 6.6 Hz, S-CH2-CH2-N), 3.90 (s, CH2-S-CH2-CH2-N), 4.85 (H2O), 5.51
(CH2Cl2), 6.58 (d, J = 3.5 Hz, =CH-), 6.69 (s, =CH-NO2), 7.37 (d, J = 3.6 Hz,
=CH-), 9.50 (s, -CHO); 13C NMR (CD3OD): δ = 28.8 (broad, 2 × 13C), 32.0,
41.9, 98.9, 111.3, 124.6, 152.9, 156.9, 159.8, 178.0. MS (70 eV); m/z (%);
ions ≥ m/z 84 with relative intensity ≥ 15%]: 285 (M+, 4), 176 (41), 142 (29),
140 (16), 131 (15) 130 (53), 111 (27), 110 (40), 109 (100), 97 (16), 96 (27),
85 (18), 84 (32). The aldehyde was used in the next step without further
purification.
[2] Lehman Brothers, PharmaPipelines, 1994, April 12.
[3] F. Lerang, B. Moum, E. Ragnhildstveit, Int. J. Gastroent. 1997, 92, 1–6.
[4] B. Alhede, O. Buchardt, F. P. Clausen, K. K. McCluskey, H. Petersen
(A/S Gea Farmaceutisk Fabrik) DE 4,020,964 A1. 1991. [Chem. Abstr.
1991 115:49378m].
[5] P. A Haywood, M. Martin-Smith, T. J. Cholerton, J. Chem. Soc. Perkin
Trans. 1987, 951–954.
[6] E. Adler, H.-D. Becker, Acta Chem. Scand. 1961, 15, 849–852.
[7] C. F. Lane, Synthesis 1975, 135–146.
[8] R. F. Borch, M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc. 1971, 93,
2897–2904.
[9] D. E. Bays, J. W. Clitherow, D. B. Judd (Glaxo Group Ltd.) EP 55,625.
1982. [Chem. Abstr. 1982 97:215972g].
[10] The alcohol 1 was prepared according to ref. [4].
[11] Adsorption of the substrate 1 and/or the product 2 to the manganese
dioxide might explain inconsistent yields obtained on employing dif-
ferent concentrations.
Ranitidine (= N-[2-[[[5-[(dimethylamino)-methyl)-2-furanyl]-methyl]-
thio]-ethyl]-N-methyl-2-nitro-1,1-ethenediamine)
[12] T. J. Cholerton, J. H. Hunt, G. Klinkert, M. Martin-Smith, J. Chem. Soc.
Perkin Trans. II 1984, 1761–1766.
Sodium acetate (434 mg, 5.29 mmol) and dimethylammonium hydrochlo-
ride (436 mg, 5.35 mmol) were added in succession to a chilled (–70 °C)
solution of N-[2-[[[5-(formyl)-2-furanyl]-methyl]-thio]-ethyl]-N′-methyl-2-
Received: March 12, 1998 [FP285]
Arch. Pharm. Pharm. Med. Chem. 331, 228–229 (1998)