Organic Process Research & Development 2002, 6, 279290

ReViews

Organic Processes to Pharmaceutical Chemicals Based on Fine Chemicals from

Lignosulfonates
Hans-Rene Bjrsvik* and Lucia Liguori
Department of Chemistry, UniVersity of Bergen, Allegaten 41, N-5007 Bergen, Norway

Abstract: alcohol [4-(3-hydroxypropenyl)phenol] 3. The relative quan-

This is a general overview of some first-, second- and third- tities of the original phenylpropene units 1-3 are dependent
generation fine chemicals with origins from the lignin oxidation on the source of the lignin. Typically, hardwood lignin is
process. The synthetic organic processes of these substances are composed mostly of sinapyl alcohol 2, while softwood lignin,
presented as well as several applications for the synthesis of a for example the lignin orginating from Norwegian spruce,
variety of pharmaceutical chemicals. is principally composed of coniferyl alcohol 1, with minor
quantities of both sinapyl alcohol 2 and p-hydroxycoumaryl
alcohol 3 present.
1. Introduction
The side stream from chemical pulping by means of the
sulfite pulping process creates a side stream known as sulfite-
spent liquor. The major component of the sulfite-spent liquor
is water-soluble lignosulfonates. During the past decades,
lignosulfonates, have been shown to be a highly valuable
raw material for fine chemicals. A hydrolytic and oxidative
depolymerization is the crucial step in the process of making
fine chemicals from the lignosulfonates. This process, also The biosynthesis of lignin proceeds through radical
referred to as lignin oxidation, produces the compounds that polymerization processes with the phenylpropenol derivatives
in the following will be referred to as first-generation fine 1-3 as the monomers. The first step of the process is an
chemicals. Due to the composition of the functional groups enzymatic dehydrogenation of one of the phenylpropenol
of these compounds, a range of valuable derivatives that can derivatives, for example in softwood, the coniferyl alcohol
be used as substrates or reagents within a wide field of 1 gives the phenoxy radical 1a, Scheme 1. Several resonance
synthetic processes can be obtained. By performing one or forms (1a-1e) stabilize the phenoxy radical but provide also
some few simple functional group transformations on these, the origin of the complex lignin biopolymer structure due
a great variety of second-generation fine chemicals can be to random coupling of the radicals 1a-1e. These coupling
obtained. Third-generation fine chemicals are obtained when reactions leads to the formation of linkages such as -O-4,
more extensive molecular transformations or changes in the R-O-4, -5, 5-5, 4-O-5, -1, and - between the original
molecular framework are performed. First-, second-, and monomers.
third-generation compounds may all be utilized for the
production of a pharmaceutical chemical that is an active Scheme 1
ingredient of a pharmaceutical product. In the following,
organic processes leading to several of the fine chemicals
that can be obtained from lignosulfonates will be discussed.
Moreover, organic processes yielding a variety of pharma-
ceutical chemicals will be discussed, both phased out
pharmaceuticals as well as substances that at the moment
are in the early-development phase.

2. The Origin of the Raw Material

All kinds of lignins are composed by some few phenyl-
propene derivatives, namely, coniferyl alcohol [4-(3-hydroxy-
propenyl)-2-methoxyphenol] 1, sinapyl alcohol [4-(3- hydroxy-
propenyl)-2,6-dimethoxyphenol] 2, and p-hydroxycoumaryl
* To whom correspondence should be sent. E-mail: [email protected].

10.1021/op010087o CCC: $22.00 2002 American Chemical Society Vol. 6, No. 3, 2002 / Organic Process Research & Development 279
Published on Web 03/22/2002
3. The Lignin Biopolymer Dissolving Process: Sulfite Scheme 4
Pulping
Lignosulfonates (LS), also known as black liquor or
sulfite-spent liquor, is a mixture of lignin fragments that
contain a certain number of sulfonic groups introduced during
the sulfite pulping of wood. The sulfite-pulping process may
be performed under several conditions, depending on the
desired quality of the cellulose to be produced. Such
processes are digestion for 6-7 h within temperature It is obvious that, when materials without exactly defined
intervals such as 126-129 C and 140-145 C. Moreover, molecular structures such as lignosulfonates with various
variation of the amounts of Ca2+/SO2 is also an important molecular weights and a large variety of alkyl-aryl and
process variable, which gives rise to a variation in the number aryl-aryl linkages are subjected to hydrolytic and oxidative
of sulfonic groups found in the lignosulfonates. depolymerization, a range of different products may be
The practical benefits of the sulfonating are that the lignin formed. The conditions used during the pulping process may
fragments are released from the cellulose fibers and that the also influence the product profile obtained during the
lignins becomes water-soluble. oxidation process. Due to these variations one may also
The key chemical reactions that occur in the acidic anticipate a different product profile with respect to the
sulphite pulping process can schematically be described as quantities of the principal products as well as to which
the following; the benzyl ether bond of the lignin fragment products formed during the depolymerization process. De-
L is protonated, giving L2 which is subsequently attacked spite all the possible variations of the raw material, the only
by the nucleophile HSO3- performing a substitution reaction significant variation observed is in the mutual quantities of
resulting in formation of the fragment R2-OH and the the different depolymerization products.
sulfonated lignin LS. An outline of this lignin-dissolving
process is given in Scheme 2. 4. Producing First-Generation Fine Chemicals from
Scheme 2 Lignosulfonate by Means of the Lignin Oxidation Process
Several hydrolysis and oxidation processes yielding low-
molecular weight well-defined molecular entities may be
implemented for depolymerization of lignosulfonate (LS).
Such methods are basic hydrolysis and oxidation, alkaline
nitrobenzene oxidation, and metal salt-catalyzed air oxidation
in alkaline media. Common for all of the processes are that
they are performed under elevated reaction pressure and
temperature. The method that has found the widest applica-
During the chemical-pulping process, some of the various tion in industry involves basic hydrolysis and oxidation using
feasible process conditions may, however, also induce sodium hydroxide and copper(II)-catalyzed air oxidation, a
consecutive reactions where a lignosulfonate fragment first process originally developed by Monsanto Chemical Com-
loses a HSO3- group, giving a carbocation that may undergo pany.1,2
a Friedel-Craft alkylation reaction on an aromatic nucleus Several studies of lignin oxidation have been performed
in another lignin unit or a lignosulfonate fragment yielding with the objective of determining the product profile and
condensation products as outlined in Scheme 3. Moreover, thus giving insight into lignin structure. A variety of products
Scheme 3 are determined after such oxidation experiments. Scheme 5
outlines products determined after oxidation experiments on
Norwegian spruce lignin. Leopold3 determined the following
compounds as reaction products after alkaline nitrobenzene
hydrolysis and oxidation experiments: vanillin 4, vanillic
acid 5, acetovanillone 6, p-hydroxy benzaldehyde 7, sy-
ringealdehyde 8, syringic acid 9, 5-formylvanillin 10,
5-formylvanillic acid 11, 5-carboxyvanillin 12, dehydrodi-
vanillin 13, and dehydrodivanillic acid 14. In experiments
carried out using copper(II)-catalyzed air oxidation in alkaline
media, four additional products were reported by Pearl,4,5
guaiacol 15, bis-(4-hydroxy-3-methoxyphenyl)methanone 16,

(1) Hocking, M. B. J. Chem. Educ. 1997, 74(9), 1055.

(2) Final Report on Vanillin from Sulfite Waste Liquor. Monsanto Chemical
Company, Organic Chemical Division. St. Louis Research Department,
substitution of R-carbonyl groups and sulfonation of aldehyde U.S.A. Research Report No. 1343.
(3) Leopold, B. Acta Chem. Scand. 1952 , 6, 38.
groups yields R-hydroxysulfonic acid. The reaction is (4) Pearl, I. A. J. Am. Chem. Soc. 1942, 64, 1429.
outlined in Scheme 4. (5) Pearl, I. A. J. Am. Chem. Soc. 1950, 72, 2309.

280 Vol. 6, No. 3, 2002 / Organic Process Research & Development

Scheme 5 Scheme 6

pharmaceutical chemicals, namely, cyclovalone7 19, etami-

van8 (ethamivan) 20 and levodopa9 21. These compounds
cover a variety of areas of pharmaceutical applications:
cyclovalone 19 is a digestant or choleretic, etamivan 20 is
an analeptic and a central nervous system and respiratory
system stimulant, and levodopa 21 is an antiparkinson agent.
Reaction of vanillin 4 with cyclohexanone 22 in the presence
of hydrochloric acid yields cyclovalone 19 in one synthetic
step, as shown in Scheme 6.
Etamivan 20 can be obtained via two synthetic routes,
one starting from vanillin 4 and the other from vanillic acid
5. The process involving vanillin 4 as starting material is
carried out by reacting vanillin 4 and diethylamine 23 in the
presence of sulphur and gives thiovandid [N,N-diethyl-4-
hydroxy-3-methoxythiobenzamide] 24 as an intermediate.
Etamivan 20 is obtained when thiovanidid is oxidized with
hydrogen peroxide. The process is outlined in Scheme 7.

Scheme 7

1,2-bis-(4-hydroxy-3-methoxyphenyl)ethane-1,2-dione 17,
and 1,3-bis-(4-hydroxy-3-methoxyphenyl)propenone 18.
Vanillin 4, vanillic acid 5, and acetovanillone 6, are
however the three principal compounds found in the reaction
mixture. In a process that recently was further developed The other process for the synthesis of etamivan 20 starting
and optimized by Bjrsvik and Minisci,6 using lignosul- from vanillic acid 5 is described in the section concerning
fonates from Norwegian spruce as raw material, yields of vanillic acid 5.
2-8% of the three major compounds 4, 5, and 6 were Levodopa 21 can be synthesized following several dif-
obtained. However, substantial amounts of several inorganic ferent synthetic pathways. Two of them are based on vanillin
compounds including sodium sulphate, sodium carbonate, 4 as substrate. Vanillin 4 is reacted with hydantonin 25 to
calcium carbonate, calcium oxalate, and copper oxides (the give the intermediate 5-(4-hydroxy-3-methoxybenzylidene)-
catalyst) are also found in the reaction mixture. Substantial imidazolidine-2,4-dione 26, which is hydrogenated over
quantities of other higher-molecular weight carboxylic and palladium on charcoal and treated with hydrobromic acid to
give DL-dopa 27. Levodopa 21 is separated from the racemic
phenolic compounds as well as volatile organic acids such
mixture by a racemate-resolution process.10-12 The process
as acetic acid are found.
is outlined in Scheme 8.
Dr. William S. Knowles (Nobel laureate, 2001) developed
5. First- and Second-Generation Fine Chemicals From the first asymmetric synthesis for the production of levodopa
Lignosulfonate and Pharmaceutical Chemicals (L-DOPA) 21, today called the Monsanto process.13-19 An
Vanillin 4 is the most important first-generation fine
(7) Rumpel, W. (A. V. Waldheim Chemisch-Pharmazeutische Fabrik). AT 180
chemical directly obtained from the hydrolysis-oxidation of 258, 1954.
lignosulfonates. In addition to being employed as a flavoring (8) Kratzl, K.; Kvasnicka, E. (Osterreichische Stickstoffwerke AG). U.S. Patent
and fragrance ingredient, vanillin 4 may be used as a reagent 2,641,612, 1953.
(9) Britton, E. C.; White, H. C. (Dow Chemical Company). U.S. Patent 2,-
or substrate in the synthesis of several second-generation 605,282, 1952.
fine chemicals, such as veratraldehyde, veratric acid, pro- (10) Kaiser, A.; Scheer, M.; Hausermann, W.; Marti, L. (F. Hoffmann-La Roche
& Co AG). DE 1 964 420, 1970.
tocatechualdehyde, and protocatechuic acid. Moreover, vanil- (11) Berenyi Poldermann, E.; Budai, Z.; Pallos, L.; Benko, P.; Magdanyi, L.
lin 4 can also be used in synthetic processes leading to several (E.GY.T Gyogyszervegyeszeti Gyar). DE 2 052 953. 1971.
(12) Berenyi Poldermann, E.; Budai, Z.; Pallos, L.; Magdanyi, L.; Benko, P.
(E.GY.T Gyogyszervegyeszeti Gyar). DE 2 052 995, 1971.
(6) Bjrsvik, H.-R.; Minisci, F. Org. Process Res. DeV. 1999, 3, 330. (13) Losse, G.; Barth, A.; Jasche, K. J. Prakt. Chem. 1963 21(1-2), 32.

Vol. 6, No. 3, 2002 / Organic Process Research & Development 281

Scheme 8 in water this last gives 2-acetylamino-3-(4-hydroxy-3-meth-
oxyphenyl)acrylic acid 31, the free hydroxy group of which
is acetylated using acetic acid anhydride 29 to afford 32.
Acetovanillon (4-hydroxy-3-methoxyacetophenone) 6 is
also a first-generation fine chemical obtained as a reaction
product from the oxidation-hydrolysis of lignosulfonate LS.
The compound serves as substrate in synthetic processes
leading to several second-generation fine chemicals, such as
acetoveratron, veratric acid, and veratric acid chloride. More-
over, recently, a new compound iloperidone20,21 34 [1-(3-
(4-acetyl-2-methoxyphenoxy)propyl)-4-(6-fluorobenzisoxazol-
3-yl)piperidine] that includes an acetovanillon 6 moiety was
reported to be under development for use as an antipsychotic
Scheme 9 dopamine D2 antagonist and a 5-HT2A antagonist.
The synthesis of iloperidone 34 is performed by means
of an eight-step synthetic process. The acetovanillon 6, which
constitutes an integral part of this substance, is condensed
with 3-chloropropylbromide 43 in DMF in the presence of
potassium carbonate or sodium hydride as base to obtain the
key intermediate 44. In the last step of the process 44 is
reacted with 42 to afford iloperidone 34. The intermediate
42 is synthesised by reacting piperidine-4-carboxylic acid
35 with formic acid and acetic acid anhydride to obtain
1-formylpiperidine-4-carboxylic acid 36 that upon treatment
with thionyl chloride in acetic acid anhydide gives the
corresponding acyl chloride 37 (1-formylpiperidine-4-car-
bonyl chloride). Under Friedel-Craft conditions, the acyl
chloride 37 is condensed with 1,3-difluorobenzene 38 to
afford 4-(2,4-difluorobenzoyl)piperidine-1-carbaldehyde 39.
Treatment of this intermediate with hydroxylamine in re-
Scheme 10

outline of the process is given in Scheme 9. The crucial

reaction of this process is the asymmetric hydrogenation of
3-(4-acetoxy-3-methoxyphenyl)-2-acetylaminoacrylic acid
32. In this step Knowles and co-workers used a stereose-
lective catalyst known as Rh(DiPAMP). The intermediate
N-acetyl-3-(4-acetoxy-3-methoxyphenyl)-L-alanine 33 ob-
tained from this asymmetric hydrogenation reaction, is
deacetylated using hydrobromic acid to give levodopa 21.
The synthetic process to the key intermediate 32 involves
the reaction of vanillin 4, glycine 28, and acetic acid anhydride
29 to give acetic acid 4-(2,5-dioxoimidazolidin-4-ylidene-
methyl)-2-methoxyphenyl ester 30. Upon treatment with acid

(14) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D. (Monsanto Company).

U.S. Patent 4,005,127, 1977.
(15) Knowles, W. S.; Sabaky, M. J. (Monsanto Company). DE 2 123 063, 1971.
(16) Knowles, W. S.; Sabaky, M. J.; Vineyard, B. D. (Monsanto Company).
DE 2 210 938, 1972.
(17) Knowles, W. S.; Sabacky, M. J. (Monsanto Company). U.S. Patent 4,-
124,533, 1978.
(18) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D.; Weinkauff, D. J. J. Am.
Chem. Soc. 1975, 97, 2567.
(19) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946.

282 Vol. 6, No. 3, 2002 / Organic Process Research & Development

fluxing ethanol yields the oxime 40 (4-[(2,4-difluorophenyl)- Scheme 12
hydroxyiminomethyl]piperidine-1-carbaldehyde). When the
oxime 40 is exposed to basic conditions by means of sodium
hydride in hot DMF and THF in the following step, a
cyclisation proceeds to afford benzo[d]isoxazol 41 (4-(6-
fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbaldehyde), which
upon treatment with HCl in refluxing ethanol affords the key
intermediate 42.
Even though vanillic acid (4-hydroxy-3-methoxybenzoic
acid) 5 is found in the reaction mixture after the hydrolysis-
oxidation of LS, vanillic acid 5 is usually obtained from
vanillin 4 by oxidation with, for example, sodium chlorite
NaOCl2.22 Moreover, vanillic acid 5 may also be obtained
via a process reported by Pearl.23 That process involves
treatment of vanillin 4 with fused potassium hydroxide at a
temperature in the range 140-240 C followed by quenching
the reaction mixture with water and acidifying with a mineral
acid such as hydrochloric acid or sulphuric acid to give
vanillic acid 5. Vanillic acid 5 may be used in the synthesis
of etamivan 20 as outlined in Scheme 11. Etamivan 20 can

Scheme 11

by Bjrsvik and Norman.27 Furthermore, veratric acid 46 and

other benzoic acid derivatives may also be obtained by using
a modified nitrobenzene oxidation process lately reported by
Bjrsvik et al.28 This method is based on oxidizing the corres-
also be obtained from vanillin 4 via the process as earlier ponding acetophenone, benzyl alcohol, benzaldehyde, or
described in Scheme 7. mandelic acid derivative using 1,3-dinitrobenzene in alkaline
Veratraldehyde (3,4-dimethoxybenzaldehyde) 45, Scheme aqueous media at a moderate temperature (100 C), Scheme
12, is a second-generation fine chemical, obtained by meth- 13.
ylation of vanillin 4. Veratraldehyde 45 is a versatile reagent
usable as substrate or reagent in several processes leading Scheme 13
to valuable active ingredients for pharmaceuticals. Examples
of such ingredients are verabutine,24 also known as profen-
veramine, and revatrine that is used as a uterus relaxant.
Rimiterol,25 bronchodilator, and moxaverine,26 antispasmodic
agent, are two other active ingredients synthesized from
veratraldehyde 45.
Veratric acid (3,4-dimethoxybenzoic acid) 46, Scheme 12, Protocatechualdehyde (3,4-dihydroxybenzaldehyde) 49
is a second-generation fine chemical that can be obtained and protocatechuic acid (3,4-dihydroxybenzoic acid) 50 are
either by oxidation of veratraldehyde 45, methylation of va- two other important intermediates that can be obtained by
nillic acid 5 to veratric acid methyl ester 48 followed by a using vanillin 4 as starting material. Lange29 has reported a
smooth ester hydrolysis to give the compound 46, or by synthetic procedure to protocatechualdehyde 49 starting from
methylation of acetovanillone 6 to obtain acetoveratrone 47 vanillin 4. In this process vanillin 4 is treated with anhydrous
which is oxidized using the haloform reaction to give veratric aluminium chloride and pyridine in CH2Cl2 under reflux for
acid 46. Such a process was recently improved and optimized 24 h, followed by treatment with dilute hydrochloric acid
(15-20%) at a temperature around 25-30 C. In this process,
(20) Mucke, H. A. M.; Castaner, J. Drugs Future 2000, 25(1), 29. the organic phase contains the unreacted vanillin 4, whereas
(21) Steiner, G.; Bach, A.; Bialojan, S.; Greger, G.; Hege, H.-G.;.Hoger, T.;
Jochims, K.; Munschauer, R.; Neumann, B.; Teschendorf, H.-J.; Traut, M.; the aqueous phase is extracted with ethyl ether to give 3,4-
Unger, L.; Gross, G. Drugs Future 1998 23(2), 191. dihydroxybenzaldehyde 49 in high yields, Scheme 12.
(22) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(23) Pearl, I. A. J. Am. Chem Soc. 1946, 68, 2180.
(24) Seeger, E.; Kottler, A. (Dr. T. Thomae Gesellschaft). DE 963 424, 1957. (27) Bjrsvik, H.-R.; Norman, K. Org. Process Res. DeV. 1999, 3, 341.
(25) Sankey, G.. H.; Whiting, K. D. E. (Minnesota 3M Lab Ltd.). DE 2 024 (28) Bjrsvik, H.-R.; Liguori, L.; Minisci, F. Org. Process Res. DeV. 2001, 5,
049, 1970. 136.
(26) (Orgamol SA, Evionnnaz, Sc.). GB 1 030 022 1966. (29) Lange, R. G. J. Org. Chem. 1962, 27, 2037.

Vol. 6, No. 3, 2002 / Organic Process Research & Development 283

 Bjrsvik et al.30 have recently reported another process Scheme 16
(Scheme 14) to protocatechualdehyde 49, although with cate-
Scheme 14

chol 53 as starting material. Catechol 53 is reacted with gly-

oxylic acid 54 in basic medium in the presence of aluminium
oxide to obtain the corresponding mandelic acid derivative
55. When the mandelic acid derivative 55 is subjected to
copper(II) oxidation, protocatechualdehyde 49 is obtained
in good yield. Protocatechualdehyde 49 can be used for the
synthesis of two very useful second-generation fine chemi- The process to itopride 58 is composed of the three
cals, namely, heliotropin (benzo[1,3]dioxole-5-carbaldehyde) synthetic steps outlined in Scheme 16. The intermediate 4-(2-
51 and iso-vanillin (3-hydroxy-4-methoxybenzaldehyde) 52 dimethylaminoethoxy)benzaldehyde 61 is obtained by react-
(Scheme 12), both serving as flavouring and fragrance agents ing p-hydroxybenzaldehyde 7 (which also is a first-
as well as intermediates for the synthesis of several phar- generation fine chemical produced from the lignin oxidation,
maceutical chemicals. Much attention has been focused on although in small amounts) with N-(2-chloroethyl)dimethyl-
iso-vanillin 52 as a synthetic building block for the synthesis amine 62 in potassium carbonate dissolved in acetone. The
of several PDE4 inhibitors, that are used in the treatment of aldehyde 61 is then reacted with ammonia in ethanol over
chronic obstructive pulmonary disease and asthma.31 Raney nickel, to obtain [2-(4-aminomethylphenoxy)ethyl]-
The pathway to protocatechuic acid 50 reported by Pearl23 dimethylamine 63 that in the last step is reacted with veratric
is a composite process comprising a concurrent demethyla- acid chloride 56 in toluene to obtain itopride 58. The product
tion and oxidation by treating vanillin 4 in fused KOH at a is stabilized as a hydrochloride salt made by treatment with
temperature in the range 245-255 C for 30 min, diluting hydrochloric acid when the amidation step is finished.
with water, and concluding the process with acidification with In the synthesis of mebeverine 59 [3,4-dimethoxybenzoic
hydrochloric acid. Moreover, oxidation of the corresponding acid 4-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}-
aldehyde 49 may also be a synthetic path to follow, although butyl ester], veratric acid chloride 56 is also used as a
protection of the free hydroxylic groups may be necessary. building block. In the first step 4-methoxyphenylacetone 64
Veratric acid chloride 56 (3,4-dimethoxybenzoic acid is reacted with ethylamine 65 and hydrogenated over plati-
chloride) is obtained from veratric acid 46 by treating the num, yielding ethyl-[2-(4-methoxyphenyl)-1-methylethyl]-
carboxylic acid with thionyl chloride, phosgene, or with amine 66 that is in turn reacted with the acid chloride ethyl
triphosgene 57, Scheme 15. 3-chloro formylpropionate 67 to give the amide N-ethyl-N-
[2-(4-methoxyphenyl)-1-methylethyl]succinamic acid ethyl
Scheme 15
ester 68. The ester group of this intermediate is reduced using
lithium aluminium hydride to give the corresponding alcohol
4-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}butan-
1-ol 69. The alcohol 69 in the last step is reacted with veratric
acid chloride 56 to form the ester linkage of the final product,
mebeverine 59. The complete process is outlined in Scheme
17.
Veratric acid chloride 56 is used as a building block in
Vesnarinone 60 is also obtained from a linear multistep
the synthesis of a variety of pharmaceutical chemicals:
synthetic process. In this process, all of the steps, except
itopride32,33 [N-[4-(2-dimethylaminoethoxy)benzyl]-3,4-dimeth-
the last one, build an intermediate, 6-piperazin-1-yl-3,4-
oxybenzamide] 58, a gastric prokinetic agent (peristaltic
dihydro-1H-quinolin-2-one 76, that is reacted with veratric
stimulant), mebeverine34,35 59, an antispasmodic, and
acid chloride 56 in the ultimate step. p-Nitroaniline 70 is
vesnarinone36-38 60, a cardiotonic.
monoacetylated using acetic acid anhydride 29 and reduced
(30) Bjrsvik, H.-R., Liguori, L.; Minisci, F. Org. Process Res. DeV. 2000, 4, by hydrogenation over platinium on charcoal to give p-
534. aminoacetanilide 71. Reacting this intermediate with -ethoxy-
(31) Sorbera, L. A.; Leeson, P. A.; Castaner, J. Drugs Future 2000, 25(12),
1261. acryloyl chloride 72 gives N-(4-acetylaminophenyl)-3-eth-
(32) Yasuo, I.; Hideo, K.; Eiichi, K.; Nobuo, O.; Hiroyuki, N.; Jun, S. (Hokuriku
Pharmaceutical). EP 0 306 827, 1989. (36) Kazuyuki, N.; Michiaki, T.; Yang Yung H.; Hidenori, O. (Otsuka
(33) Goldberg, M. W.; Teitel, S. (Hoffmann-La Roche Inc.). U.S. Patent 2,- Pharmaceutical Co., Ltd.). DE 31 42 982, 1983.
879,293, 1959. (37) Kazuyuki, N.; Michiaki, T.; Yang Yung, H,; Hidenori, O. (Otsuka
(34) Kralt, T.; Moed, H. D.; Lindner, A.; Asma, W. J. (N.V. Philips). DE 1 126 Pharmaceutical Co., Ltd.). U.S. Patent 4,415,572, 1982.
889, 1958. (38) Tominaga, M.; Yo, E.; Ogawa, H.; Yamashita, S.; Yabuuchi, Y.; Nakagawa,
(35) (N.V. Philips). GB1 009 082, 1965. K. Chem. Pharm. Bull 1984, 32(6), 2100.

284 Vol. 6, No. 3, 2002 / Organic Process Research & Development

Scheme 17 Scheme 19

synthetic path39-42 starting from veratraldehyde 45. The first

step is a reduction of the carbonyl group to the corresponding
alcohol carried out by dissolving veratraldehyde 45 in ethyl
ether, after which the reducing agent LiAlH4 is added. The
thus obtained 3,4-dimethoxybenzyl alcohol 78 is in the
oxyacrylamide 73 that is treated with sulfuric acid followed following step converted to 3,4-dimethoxybenzyl chloride
by hydrogenation on platinum on charcoal. The intermediate 79 [4-(2-chloroethyl)-1,2-dimethoxybenzene], a step that may
74 [N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acetamide] is be performed following several different procedures. For
then treated with hydrochloric acid and reacted with bis(2- example, 3,4-dimethoxybenzyl alcohol 78 is dissolved in
bromoethyl)amine hydrobromide 75 to give 6-piperazin-1- dichloromethane and reacted with concentrated HCl. The
yl-3,4-dihydro-1H-quinolin-2-one 76 that in the final step is final step of the synthesis of homoveratronitrile 77 is the
reacted with veratric acid chloride 56 to give vesnarinone introduction of the cyano group. This is carried out by
60. The complete process is given in Scheme 18. refluxing 3,4-dimethoxybenzyl chloride 79 and NaCN in
benzene and water. The process to homoveratronitrile 77
Scheme 18
from veratraldehyde 45 is shown in Scheme 19.
Homoveratronitrile 77 can, as mentioned above, be used
as a building block in the synthesis of several pharmaceutical
chemicals. Papaverine 80, an antispasmodic and vasodilator,
is one such substance. The synthetic path to papaverine 80
includes two different compounds derived from lignosul-
fonate. In addition to homoveratronitrile 77, 2-(3,4-dimethoxy-
phenyl)ethylamine 81 is also used. The compound 81 is
obtained by reduction of homoveratronitrile 77. The reduction
(hydrogenation) can be performed over Raney nickel as
shown in Scheme 19. (3,4-Dimethoxyphenyl)acetic acid 82
is obtained from homoveratronitrile 77 by hydrolysis in
strong mineral acid (e.g., example sulfuric acid).
The synthetic path to papaverine43,44 80 is shown in
Scheme 20. The two substances 81 and 82 are reacted at
elevated temperature (160 C) in decahydronaphthalene 83
to obtain 2-(3,4-dimethoxyphenyl)-N-[2-(3,4-dimethoxyphen-
yl)ethyl]acetamide 84. The intermediate 84 [2-(3,4-dimeth-
oxyphenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide] is
treated with POCl3 in the following step to give the 3,4-
dihydroisoquinoline derivative 85, that in the last step is
treated with Pd in 1,2,3,4-tetrahydronaphthalene 86 at ele-
6. Second- and Third-Generation Fine Chemicals From
(39) Anand, R. C.; Ranjan, H. Bull. Chem. Soc. Jpn. 1985, 58, 791.
Lignosulfonate and Pharmaceutical Chemicals (40) Jung, M. E.;. Long-Mei, Z. Tetrahedron Lett. 1983, 24(42), 4533.
6.1. Synthesis and Application of Homoveratronitrile, (41) Ogura, F.; Nakao, A.; Nakagawa, M. Bull. Chem. Soc. Jpn. 1979, 52, 1165.
(42) Mueller, J.; Wiersdorff, W.-W.; Burst, W.; Dralle, H.; Schaeffner, E.;
Homoveratrylamine, and 3,4-Dimethoxyphenylacetic Acid. Steinkamp, R. (BASF AG). DE 3 527 338, 1987.
Homoveratronitrile 77 [(3,4-dimethoxyphenyl)acetonitrile] is (43) Budesinsky Z.; Protiva, M. Synthesizche Arzneimittel; Akademie-Verlag:
Berlin 1961; p 87.
a versatile compound for synthesis of several pharmaceutical (44) Mauvernay, R. Y. (Centre Europeen de Recherches). U.S. Patent 3,823,-
chemicals. It can be synthesized following a four-step 234, 1974.

Vol. 6, No. 3, 2002 / Organic Process Research & Development 285

Scheme 20 Scheme 21

vated temperature to give papaverine 80 [1-(3,4-dimethoxy- Scheme 22

benzyl)-6,7-dimethoxyisoquinoline].
Verapamil45-47 87, also known as iproveratril, is a
coronary vasodilator and another pharmaceutical chemical
that is produced from homoveratronitrile and 2-(3,4-
dimethoxyphenyl)ethylamine.
Verapamil 87 is synthesized by reacting homoveratroni-
trile 77 with isopropyl chloride in the presence of sodamide
to give 2-(3,4-dimethoxyphenyl)-3-methylbutyronitrile 88
that is one of two intermediates in the short convergent
synthesis of verapamil 87. The other intermediate is syn-
thesized from 2-(3,4-dimethoxyphenyl)ethylamine 81 that is
monomethylated using dimethylsulphate to give [2-(3,4-
dimethoxyphenyl)ethyl]methylamine 89, which is further
reacted with 1-bromo-3-chloropropane 43 to yield the second
building block (3-chloropropyl)-[2-(3,4-dimethoxyphenyl)-
ethyl]methylamine 90. The two intermediates 88 and 90 are
in the last step coupled in the presence of sodamide to give
87. The process is outlined in Scheme 21.
Homoveratrylamine 81 is a very versatile fine chemical,
which can be used in several synthetic processes, thus
providing a range of different pharmaceutical chemicals. In
the following, a series of synthetic processes for a wide range
of pharmaceutical substances is presented. Common to all
of these is that homoveratrylamine 81 is a key building block.
The antiemetic and tranquilizer, benzquinamide48-51 99, can
be obtained via an eight-step linear synthesis (Scheme 22).
Homoveratrylamine 81 is reacted with malonic acid diethyl
ester to give N-[2-(3,4-dimethoxyphenyl)ethyl]malonamic
acid ethyl ester 91. Treatment of this product with POCl3
gives a dehydroisoquinolin derivative 92 which upon hy- Reacting this intermediate with ethyl acrylate 94 followed
drogenation over Pd/C gives (6,7-dimethoxy-1,2,3,4-tetrahy- by treatment with sodium, gives the hexahydro-2H-pyrido-
droisoquinolin-1-yl)acetic acid ethyl ester 93. [2,1-a]isoquinoline derivative 96 that on treatment with dieth-
(45) Dengel, F. (Knoll AG Chemische Fabriken). DE 1 154 810, 1963.
ylamine gives the hexahydro-2H-pyrido[2,1-a]isoquinoline
(46) Dengel, F. (Knoll AG Chemische Fabriken). DE 1 158 083, 1963. carboxamide derivative 97. The keto function is reduced by
(47) Dengel, F. (Knoll AG Chemische Fabriken). U.S. Patent 3,261,859, 1966. hydrogenation over Raney nickel, and the synthesis is com-
(48) Tretter, J. R. (Pfizer & Co., Inc.). U.S. Patent 3,053,845, New York, 1962.
(49) Lombardino, J. G.; McLamore, W. M. (Pfizer & Co, Inc.). U.S. Patent pleted by acetylation using acetic anhydride (Scheme 22).
3,055,894, 1962. Denopamine 100, which is a 1-receptor agonist and orally
(50) Tretter, R. (Pfizer & Co, Inc.). BE 621 895, 1963.
(51) Brossi, A.; Lindlar, H.; Walter, M.; Schnider, O. HelV. Chim. Acta 1958, active cardiostimulant, is also synthesized using 81 as a
41, 119. building block in a two-step synthetic process. 1-(4-Benzyl-
286 Vol. 6, No. 3, 2002 / Organic Process Research & Development
Scheme 23 Scheme 25

lignosulfonates. The compound can be applied in a wide

range of pharmaceutical chemicals used in some different
therapeutic areas. (3,4-Dimethoxyphenyl)acetone 109 is syn-
thesized from veratraldehyde 45 by treatment with nitroeth-
ane to obtain the intermediate 1-(3,4-dimethoxyphenyl)-2-
nitro-1-propene 110 which is then reduced by refluxing for
several hours in the presence of Fe/FeCl3 6H2O and concen-
trated hydrochloric acid.54-56 The process is given in Scheme
26.

Scheme 26

oxyphenyl)-2-chloroethanone 101 is reacted with 81 to form

1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylami-
no]ethanone 102. The benzylic ketone is reduced by NaBH4
to obtain a racemic mixture of the alcohol 103, that is then
separated by racemic resolution using D(-)-acetylphenylala-
nine. The last step of this process is hydrogenation over
Pd-C to remove the benzyl moiety used to protect the phen- Carbidopa 111, a decarboxylase inhibitor used in levodopa
olic group. The outline of the process is given in Scheme therapy, is synthesized from 109. The derivative 109 is, in
23. the first step of the synthetic process, treated with sodium
The cardiotonic substance dobutamine52,53, 105 is synthe- hydrogen sulfite and reacted with potassium cyanide and
sized in a two-step process starting with the reaction of 81 hydrazine to obtain 3-(3,4-dimethoxyphenyl)-2-hydrazino-
and 4-(4-methoxyphenyl)butan-2-one 106 and hydrogenation 2-methylpropionitrile 112. In the following steps, the nitrile
over Pd-C. The following step is treatment with hydrogen- group is hydrolyzed to the carboxylic acid, and the phenolic
bromide in acetic acid, which gives the free phenolic groups hydroxyl groups are demethylated by treatment with the
on the aromatics. The process is outlined in Scheme 24. strong mineral acids, hydrochloric and hydrobromic acids.
The last step is constituted by racemate resolution to obtain
Scheme 24
carbidopa 111. The process is shown in Scheme 27.

Scheme 27

Dopamine 108, a sympathomimetic, is obtained from The antispasmodic and vasodilator dimoxyline57 114 is
homoveratrylamine 81 in one step, namely treatment with also synthesized using 109. The first step of the process is
hydrogen bromide, to demethylate the phenolic hydroxy the reaction of 109 with hydroxylamine to obtain 1-(3,4-
groups (Scheme 25). dimethoxyphenyl)propan-2-one oxime 115, which is then
6.2. Synthesis and Application of (3,4-Dimethoxyphe- treated with NH3 over Raney nickel to yield 2-(3,4-
nyl)acetone. (3,4-Dimethoxyphenyl)acetone [1-(3,4-dimethox-
yphenyl)propan-2-one] 109 is another very versatile fine (54) Pearl, I. A.; Beyer, D. L. J. Org. Chem. 1951, 16, 221.
(55) Shepard, E. R.; Noth, J. F.; Porter, H. D.; Simmans, C. K. J. Am. Chem.
chemical that can be derived from the oxidation products of Soc. 1952, 74, 4611.
(56) Chuksanova, A. A.; Sergeeva, L. L.; Shorygina, N. N. Otdel. Khim. Nauk
(52) Tuttle, R. R.; Mills, J. (Eli Lilly & Co.). DE 2 317 710, 1973. 1959, 2219.
(53) Tuttle, R. R.; Mills, J. (Eli Lilly and Co.). U.S. Patent 3 987 200, 1976. (57) Shepard, E. E. (Eli Lilly & Co.). U.S. Patent 2,728,769, 1955.

Vol. 6, No. 3, 2002 / Organic Process Research & Development 287

Scheme 28 Scheme 30

ester. This is carried out by means of ethanol and hydro-

chloric acid. The processes to methyldopa 120 and methyl-
dopate 121 are shown in Scheme 29.
6.3. Synthesis and Application of 4,5-Dimethoxyan-
thranilic Acid. 4,5-Dimethoxyanthranilic acid [2-amino-4,5-
dimethoxybenzoic acid] 125 has been used in the synthesis
of the two antihypertensive compounds: prazosin58-61 126
dimethoxyphenyl)-1-methylethylamine 116. In the subse- and terazosin62-65 127 (R-blocker). The preparation66,67 of
quent step, this substance is reacted with (4-ethoxy-3- 4,5-dimethoxyanthranilic acid 125 can be performed via a
methoxyphenyl)acetic acid 117 at elevated temperature, three-step synthetic process.67 The first step is to prepare
giving the amide N-[2-(3,4-dimethoxyphenyl)-1-methyl- 6-nitroveratraldehyde 128 by nitration of veratraldehyde 45
ethyl]-2-(4-ethoxy-3-methoxyphenyl)acetamide 118, which with a subsequent oxidation of the formyl group in 128 with
is treated with phosphorus oxychloride and then with Pd-C potassium permanganate to give the corresponding benzoic
to give dimoxyline 114. The process is outlined in Scheme acid 129. The product 129 is dissolved in ethanol, and
28. catalytic reduction using Adams platinum catalyst provides
Methyldopa 120 and methyldopate 121 are both antihy- the pure amino acid 125 in high yield. The process is given
pertensive agents. The synthesis of these compounds starts in Scheme 30.
by the reaction of 109 with potassium cyanide and am- Prazosin58 126 can be synthesized by reaction of 125 with
monium carbonate to obtain 5-(3,4-dimethoxybenzyl)-5- sodium cyanate, to give 6,7-dimethoxyquinazoline-2,4-diol
methylimidazolidine-2,4-dione 122. Treatment of 122 with 130 which is then dichlorinated in the subsequent step, using
barium hydroxide yields 2-amino-3-(3,4-dimethoxyphenyl)- POCl3 and PCl5. Treatment with NH3 gives 2-chloro-6,7-
2-methylpropionic acid 123. Some different synthetic path- dimethoxyquinazolin-4-ylamine 132 that is reacted with
ways may be followed from this point of the process. furan-2-yl-piperazin-1-ylmethanone 133 to yield the target
An example given in the Scheme 29 shows how the molecule prazosin 126, see Scheme 31.
intermediate 123 is treated with HBr to liberate (demethylate) Terazosin 127 is also prepared following a short conver-
the phenolic groups, and this is followed by a racemate gent synthetic process starting from 4,5-dimethoxyanthranilic
resolution step based on selective crystallization. The acid 125 to obtain 2-chloro-6,7-dimethoxyquinazolin-4-
synthetic process to methyldopate 121 consists of only one ylamine 132, following a synthetic path similar to that of
more synthetic step, namely, building the methyldopa ethyl the process to prazosin 126. This compound serves as one
of two key intermediates. The other key intermediate
Scheme 29
piperazin-1-yl-(tetrahydro-furan-2-yl)methanone 134 is ob-
tained by reacting piperazine 135 with furan-2-carbonyl
chloride 136, giving furan-2-yl-piperazin-1-ylmethanone 137
which is then hydrogenated over Raney nickel to give the
compound 134, Scheme 32.

(58) Hess, H.-J. E. (Pfizer & Co. Inc.). U.S. Patent 3,511,836, 1970.
(59) Hess, H.-J. E. (Pfizer & Co. Inc.). U.S. Patent 3,635,979, 1972.
(60) Hess, H.-J. E. (Pfizer & Co. Inc.). U.S. Patent 3,663,706, 1972.
(61) Hess, H.-J. E. (Pfizer & Co. Inc.). DE 1 620 138, 1970.
(62) Winn, M.; Kyncl, J.; Dunnigan, S. A.; Jones, P. H. (Abbott Laboratories).
DE 2 646 186, 1977.
(63) Winn, M.; Kyncl, J.; Dunnigan, S. A.; Jones, P. H. (Abbott Laboratories).
U.S. Patent 4,026,894, 1977.
(64) Roteman, R. (Abbott Laboratories). DE 2 831 112, 1981.
(65) Roteman, R. (Abbott Laboratories). U.S. Patent 4,251,532, 1979.
(66) Heidelberger, N.; Jacobs, W. A. J. Am. Chem. Soc. 1919, 41, 2131.
(67) Fetscher, C. A.; Bogert, M. T. J. Org. Chem. 1939, 4, 71.

288 Vol. 6, No. 3, 2002 / Organic Process Research & Development

Scheme 31 Scheme 33

Scheme 32
product 138 in 95% yield, Scheme 33. The reaction can also
be performed using PPA (polyphosphoric acid), albeit PPMA
is superior since PPA is very troublesome to handle due to
the viscosity. Several other methods for construction of the
indanone framework have also been reported in the chemical
literature.69-71
The synthesis72,73 of 3-(3,4-dimethoxyphenyl)propionic
acid 139 can be performed by reacting veratraldehyde 45
and malonic acid in the presence of pyridine and piperidine
first at 80 C than at reflux. The reaction is quenched by
pouring the reaction mixture into cold water followed by
acidifying with concentrated hydrochloric acid. The obtained
product, 3,4-dimethoxycinnamic acid [3-(3,4-dimethoxyphe-
nyl)acrylic acid] 140, is isolated by filtration and purified
by recrystallization from aqueous ethanol (90%). The 3-(3,4-
dimethoxyphenyl)propionic acid 139, is obtained by reduc-
tion of 140 (e.g., by hydrogenation over Raney nickel),74
Scheme 33.
Similar to many of the other derivatives from lignosul-
fonate, 5,6-dimethoxyindan-1-one 138 is also very versatile.
It is used in the preparation of truxenes as mesogens for
discotic liquid crystal,75 and it is a key intermediate in an
organic process76 to donepezil hydrochloride 143 that is used
for the treatment of cognitive disorder and as an acetylcholin-
esterase inhibitor. It is used as the active ingredient in the
anti-Alzheimer drug Aricept. The pharmaceutical chemical
143 is synthesized by reacting 5,6-dimethoxyindan-1-one 138
with 1-benzylpiperidine-4-carbaldehyde 141 in the presence
of BuLi, diisopropylamine, and tetrahydrofuran. The interme-
diate 2-(1-benzyl-piperidin-4-ylmethylene)-5,6-dimethoxyin-
dan-1-one 142 is hydrogenated over Pd-C and treated with
HCl in methylene chloride and ethyl acetate to obtain done-
6.4. Synthesis and Application of 3-(3,4-Dimethoxy-
pezil hydrochloride 143. The process is outlined in Scheme
phenyl)acrylic Acid, 3-(3,4-Dimethoxyphenyl)propionic
34.
Acid, and 5,6-Dimethoxyindan-1-one. 5,6-Dimethoxyindan-
1-one 138 belongs to another class of third-generation fine (69) Kusama, H.; Narasaka, K. Bull. Soc. Chem. Jpn. 1995, 68, 2379.
chemicals that may be obtained from lignosulfonate. The (70) Taniguchi, K.; Yoshimura, T. Tokuno; Kosugi, T. (Fukuju Pharmaceutical
Co., Ltd.). JP 11302216, 1999.
synthetic process68 to 5,6-dimethoxyindan-1-one 138 is (71) Laurain N.; Saint Jalmes, L. (Rhone Poulenc Chimie). FR 278 8764, 2000.
performed by treating 3-(3,4-dimethoxyphenyl)propionic acid (72) De Silva, S. O.; Ahmad, I.; Snieckus, V. Can. J. Chem. 1979, 57, 1598.
(73) Koo, J.; Fish, M. S.; Walker, G. N.; Blake, J. J. Org. Synth. Coll. 1963,
139 with PPMA (phosphorus pentoxide methanesulphonic IV, 327.
acid) at a temperature of 100 C. After only few minutes, (74) Tuttle, R. E.; Mills, J. (Lilly, Eli, and Co.) DE 2,317,710, 1973.
the reaction mixture can be worked up, affording the pure (75) Sato, Y.; Takimoto, J. (Nippon Oil Co., Ltd.). JP 11092427, 1999.
(76) Kunizou, H.; Yoshiharu, Y.; Hiroo, O.; Yuoichi, I.; Norio, K.; Takashi,
K.; Michiko, K.; Atsuhiki, K.; Atsushi, S.; Yutaka, T.; Kiyomi, Y.; Shin,
(68) Cho, H.; Matsuki, S. Heterocycles 1996 43, 127. A.; Mansion, K.; Hachiro, S. (Eisai Co Ltd.). EP 296 560, 1988.

Vol. 6, No. 3, 2002 / Organic Process Research & Development 289

Scheme 34 substances, only a very few of the first-generation fine
chemicals have been isolated for further synthetic applica-
tions. Even though only a very few of the first-generation
fine chemicals from oxidation of lignosulfonates have been
isolated, a huge variety of organic processes to pharmaceuti-
cal chemicals are based on them. Future discovery and
optimization of more selective depolymerization processes
of lignosulfonates may extend the employment of such fine
chemicals as building blocks.

Acknowledgment
We thank the Norwegian Research Council and the
7. Conclusions University of Bergen for financial support to our research.
When browsing the chemical literature it is interesting to Professor George Francis is acknowledged for discussions
see how simple old molecules such as vanillin 4, vanillic and linguistic support during the preparation of this review.
acid 5, and acetovanillone 6 are still used as substrates for We will also direct a thank to Dr. Thomas Hu at Paprican,
new drugs and other fine chemicals. Canada, who encouraged us to write this review.
Degradation of the complex materials, lignosulfonates,
affords a large variety of compounds 4-18 (Scheme 5) that
Received for review October 1, 2001.
may be potential building blocks for more complex molecular
entities. Due to the low achieved yields of most of these OP010087O

290 Vol. 6, No. 3, 2002 / Organic Process Research & Development