An improved new path to synthesize gemfibrozil

Article abstract of DOI:10.14233/ajchem.2015.17491

A new route has been developed for synthesis of gemfibrozil in good yield with high purity. The obtained gemfibrozil was characterized by using IR, ¹H NMR, ¹³C NMR and mass spectral studies. According to Biopharmaceutical Classification System, gemfibrozil is classified under class-II drugs (low solubility-high permeability) and an antihyperlipidimic. So it's admirable to synthesize the intention molecule in easy and economical way.

Full text of DOI:10.14233/ajchem.2015.17491

Asian Journal of Chemistry; Vol. 27, No. 3 (2015), 925-928
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.17491
An Improved New Path to Synthesize Gemfibrozil
1
2,*
1
RAMBABU NUNNA , N.D. JAYANNA and D. RAMACHANDRAN
1
2
Department of Chemistry, Acharya Nagarjun University, Nagarjuna Nagar, Guntur-522 510, India
Department of Chemistry, Sahyadri Science College (Autonomous), Shimoga-577 203, India
*
Corresponding author: E-mail: jayanna07@gmail.com
Received: 1 March 2014; Accepted: 18 May 2014;
Published online: 19 January 2015;
AJC-16696
A new route has been developed for synthesis of gemfibrozil in good yield with high purity. The obtained gemfibrozil was characterized
1
13
by using IR, H NMR, C NMR and mass spectral studies.According to Biopharmaceutical Classification System, gemfibrozil is classified
under class-II drugs (low solubility-high permeability) and an antihyperlipidimic. So it's admirable to synthesize the intention molecule
in easy and economical way.
Keywords: Gemfibrozil, Antihypolipidimic, Lopid.
sses. In view of the high-volume requirement, huge revenues
associated with this molecule and disadvantages from the
reported processes, there arises a need to develop an alternative
process for gemfibrozil, meeting with all regulatory aspects.
INTRODUCTION
Gemfibrozil, 2,2-dimethyl-5-(2,5-dimethylphenoxy)-
pentanoic acid, is an pharmaceutical drug used for prevention
and treatment of atherosclerosis. It was developed by Parke-
1
Davis & Co. (USA) . Gemfibrozil is used for the treatment of
EXPERIMENTAL
adult patients with very high elevations of serium triglyceride
levels (types IV and V hyperlipidemia) who are at risk of
developing pancreatitis (inflammation of pancreas) and who
do not respond adequately to a strict diet. Gemfibrozil, a fibric
acid antilipemic agent similar to clofibrate, is used to treat
hyperlipoproteinemia and as a second line therapy for type
IIb hypercholesterolemia. It reduces triglyceride levels, low
density lipoprotien (LDL), very low density lipoprotien
Melting points were recorded on electro-thermal melting
1
13
point apparatus and are uncorrected. H NMR and C NMR
spectra were recorded on Bruker 300 MHz spectrometer in
IISc, Bangalore, India. The chemical shifts are shown in δ
values (ppm) with tetramethylsilane as an internal standard.
LC-MS were obtained using C 18 column on Shimadzu, LCMS
2010A, Japan. The FT-IR spectra of the compounds were taken
inABB FTLA spectrometer in the range between 4000 to 500
(
VLDL) levels and increase high density lipoprotien (HDL)
2
,3
-1
levels . Gemfibrozil increase the activity of extra hepatic
lipoprotein lipase (LL), thereby increasing lipoprotein
triglyceride lipolysis. Chylomicrons are degraded, very low
density lipoprotiens are converted to low density lipoprotiens
and low density lipoprotiens are converted to high density
cm . The column chromatography was performed using silica
gel (230-400 mesh). Silica gel GF254 plates from Merck were
used for TLC and spots located either by UV or dipping in
potassium permanganate solution. The chemicals were pur-
chased from Sigma-Aldrich Co and from SD Fine chemicals.
The solvents for column chromatography were of reagent
grade and were purchased from commercial source.
4
-6
lipoprotiens . Gemfibrozil also inhibits the synthesis and
increases the clearance of apolipoprotein B, a carrier molecule
for very low density lipoprotien.
General procedure
Reports are available in the literature related to the various
synthetic routes for the preparation of gemfibrozil. These
Preparation of allyl isobutyrate )1): Conc.H
2
SO (3.33 g,
4
7
processes reported have restricted application in the industry
0.033 mol) was added drop wise to a flask containing isobutyric
acid (100 g, 1.135 mol) and allyl alcohol (79.11 g 1.362 mol)
because of less overall yield, number of purifications and
the stringent regulatory requirement to meet the quality of a
finished drug substance. To minimize the cost constraints and
number of purifications, we avoided tedious work-up proce-
at room temperature under N atmosphere. The reaction
2
mixture was heated to reflux at 95 ºC for 5 h. The completion
of reaction was monitored by TLC. After completion the

926 Nunna et al.
Asian J. Chem.
reaction, mixture was cooled to room temperature and was
added saturated solution of sodium bicarbonate. Organic layer
was separated. Aqueous layer was extracted with Hexane (2 ×
The resulting mixture was heated to reflux at 110 °C with
stirring. Thereafter, bromoester (50 g, 0.224 mol) was added
drop wise at 110 °C over period of 2 h. After completion of
addition stirring was continued at 110 °C for further 16 h.
Completion of reaction was monitored by TLC.After comple-
tion of reaction, reaction mass was cooled to room temperature.
Organic layer was separated, aqueous layer was extracted with
toluene (2 × 50 mL). The combined organic layer was washed
with 10 % sodium hydroxide solution (2 × 50 mL), dried with
sodium sulphate. Toluene was distilled off using line vacuum
to get 56.8 g (96.1 %) of gem-methyl ester as a brown liquid
with GC purity 90 %. The crude ester was distilled under
reduced pressure (vacuum = 1.3 mm).
5
0 mL) and dried with sodium sulphate. Hexane was distilled
off at atmospheric pressure to get 113.32 g (78.15 %) of allyl
isobutyrate as a yellow liquid with GC purity 96.76 %.
Preparation of 2,2-dimethy1-4-pentanoic acid (DMP)
(
2): To a four necked flask equipped with condenser and
nitrogen inlet, added sodium hydride (27.12 g, 1.13 mol) and
toluene (340 mL, 3 vol). The resulting mixture was heated to
1
10 ºC with stirring. Thereafter, allyl isobutyrate (113 g, 0.88
mol) was added drop wise over period of 5 h.After the addition,
stirring was continued at 110 ºC for further 3 h. The completion
of reaction was monitored by TLC.After completion of reaction,
the reaction mixture was cooled to room temperature and
Anal. Calcd for (%) C16
9.15, Found: C 72.65, H 9.13,; IR (KBr, νmax, cm ): 3030 (C-H
aromatic stretching), 2870 (C-H methylene stretching), 1732
H
23
O (264.3 g/ mol): C 72.69, H
3
-1
2
0 mL of methanol was added to decompose unreacted sodium
hydride. After dissolving insoluble matters with addition of
26 mL of water, toluene and aqueous layer were separated
1
(ester stretching), 1585 (C=C); H NMR (CDCl
3
) ppm: δ 1.2
2
(s, 3H), δ 1.3 (s, 3H), δ 1.7 (m, 2H), δ 1.8 (m, 2H), δ 2.2 (s,
3H, 6C), δ 2.3 (s, 3H, 1C), δ 3.7 (s, 3H, methoxy), δ 4.0 (s,
from each other. Aqueous layer was washed with 100 mL of
toluene and separated from each other. Aqueous layer was
acidified to a pH-1 with conc. HCl (36 mL). The formed oil
layer was recovered and the aqueous layer was extracted with
hexane (100 mL). Combined organic layer was dried with
sodium sulphate. Hexane was distilled off at atmospheric
pressure to get 92.3 g (82 %) of 2,2-dimethyl-4-pentenoic acid
as a brown liquid with GC purity 99.23 %.
13
2H), δ 6.7-7.0 (3H, Ar H); C NMR (CDCl ) ppm): 164.10,
3
158.49, 149.05, 142.32, 136.41, 135.0, 130.96, 128.47, 128.26,
128.04, 126.99, 125.56, 122.93, 121.20, 119.93, 110.61,
107.02 (17 Ar-C), 55.90 (methoxy); M 276.1.
General procedure for the synthesis of gemfibrozil (6):
To a flask containing water (9.97 mL), NaOH (9.97 g, 0.25
mol) and TBAB (4.3 g, 10 %), gem-methyl ester (43 g, 0.162
Synthesis of 5-bromo-2-,2-dimethyl-pentanoic acid (3):
mol) was added at room temperature under N atmosphere.
2
2
,2-Dimethyl-1,4-pentanoic acid (92 g, 0.718 mol) was added
The resulting mixture was heated to reflux at 73-75 °C with
stirring for 2-3 h. Completion of reaction was monitored by
TLC.After completion of reaction, methanol was distilled off.
Reaction mass was cooled to room temperature, followed by
addition of water.Again mass was cooled to 0-5 °C. The resul-
ting sodium salt of gemfibrozil was filtered, washed with
toluene. The salt was dissolved in water taken in another flask,
added charcoal and heated to reflux for 0.5 h. Hot reaction
mass was filtered through hyflo and washed with hot water.
Filtrate was cooled to 5-10 °C and acidified with conc. HCl
(22 mL) and resulting solid was filtered suck dried. The solid
was dissolved in methanol taken in another flask, added
charcoal and heated to reflux for 0.5 h. Hot reaction mass was
filtered through hyflo and washed with hot methanol. Filtrate
was cooled to 5-10 °C. Resulting solid was filtered, suck dried.
Dried under vacuum at 50 °C to get 31.6 g (77.6 %) of gemfi-
brozil as a white solid with LC purity 99.5 %. m.p. 59-61 °C.
to a flask containing hexane (644 mL, 7 vol) and benzoyl per-
oxide (0.92,1 %). 64 g of HBr gas was bubbled into the reaction
solution at 0-5 °C over period of 3 h. After completion of
bubbling stirring continued for further 2 h. Completion of
reaction was monitored by TLC.After completion of reaction,
the reaction mixture was washed with 100 mL water. The hexane
layer was separated, dried with sodium sulphate. Hexane was
distilled off at atmospheric pressure to get 112.6 g (75 %) of
5
-bromo-2,2-dimethyl-pentanoic acid as a brown liquid.
Synthesis of 5-bromo-2,2-dimethyl-pentanoic acid
methyl ester (4): 4.48 mL of conc. H
to a flask containing methanol (224 mL, 2 vol) and 5-bromo-
,2-dimethyl-pentanoic acid (112 g, 0.535 mol) at room tempe-
2
SO
4
was added drop wise
2
rature. The resulting mixture was heated to reflux at 60-70° C
for 16 h. The completion of reaction was monitored by TLC.
After completion of reaction methanol was distilled of at
atmospheric pressure. Reaction mass was cooled to room
temperature, followed by addition of saturated sodium bicar-
bonate solution. Organic layer was separated, aqueous layer
was extracted with hexane (2 × 50 mL). The combined organic
layer was washed with water (100 mL), dried with sodium
sulphate. Hexane was distilled off at atmospheric pressure to
get 113.52 g (95 %) of 5-bromo-2,2-dimethyl-pentanoic acid
methyl ester as a brown liquid with GC purity 75.6 %. The
crude ester was distilled under reduced pressure (vacuum =
Anal. Calcd for (%) C16
8.86, Found: C 71.93, H 8.81; IR (KBr, νmax, cm ): 2917 (broad
band centering due to OH stretching vibrations of carboxylic
H
23
O (264.3 g/mol): C 71.97, H
3
-1
acid, along with weaker C-H stretching bands), 1703 (C=O
1
stretching); H NMR (CDCl
3
) ppm: δ 1.25 (s, 6H), δ 1.76 (m,
4H), δ 2.17 (s, 3H), δ 2.3 (s, 3H), δ 6.6 (s, 1H, Ar H), δ 6.67
13
(d, 1H, Ar H), δ 7.0 (d, 1H, Ar H); C NMR (CDCl
3
) ppm:
184.81, 156.99, 136.45, 130.33, 123.65, 120.77, 112.05, 67.97,
+1
42.0, 36.91, 25.17, 24.98, 21.40, 15.74; M 251.0.
1
.3 mm).
Synthesis of gem-methyl ester 5: To a flask containing
RESULTS AND DISCUSSION
toluene (125 mL, 2.5 v) and xylenol (27.39 g, 0.224 mol),
potassium carbonate (34.65 g, 0.251 mol) and TBAB (5 g,
The present improved method is start with synthesis of
allyl butyrate followed by rearrangement reaction to form
compound 2. The addition of hydrogen bromide to the com-
1
0 %) were added at room temperature under N atmosphere.
2

Vol. 27, No. 3 (2015)
An Improved New Path to Synthesize Gemfibrozil 927
O
O
O
OH
O
OH
+
conc. H SO4
NaH, Toluene, 3 h
2
OH
5
h
2
1
HBr, Hexane, 5 h Dibenzoylperoxide
O
O
OH
O
OH
MeOH
K CO , TBAB
O
O
2
3
+
Toluene, 16 h
conc. H SO , 16 h
2
4
O
5
Br
3
Br
4
NaOH,TBAB, H O, 3 h
2
conc. HCl
O
O
OH
6
Scheme-I
pound resulted in the formation of compound 3, followed by
the esterification reaction. The compound 4 on treating with
xylenol to form gem-methyl ester. The formation of compound
confirmed by the spectral analysis. The alkali hydrolysis of
gem-methyl ester yield the final compound gemfibrozil (5)
Spanish authors used the Hailer-Bauer reaction of ketone
15
cleavage to synthesize 5 . The Grignard reactions have been
16
patented by other Spanish authors in fewer yields (70 %).
Apart from these reports, gemfibrinozil (5) has been synthesized
by the hydrolysis of gem-ester (Scheme-II). But, preparation
of gem-ester leads to more cycle time and more volume, Higher
effluent generations and low output of gemfibrozil. Consi-
dering the literature data and the results, we proposed a novel
scheme for synthesis of gemfibrozil (5) for less in economically
and improve with respect to cycle time, reaction volume and
energy cost and effluent reductions. The mass analysis of
gemfibrozil (5) and synthesized intermediate compounds
showed exact molecular ion peak of corresponding molecular
weights. The characterizations of the final molecule gemfibrozil
(
Scheme-I).
The final step of synthesis of 5 using this proposed scheme
involves specific production difficulties. As follows from the
8
literature, the yields are 55-60 % at the step of O-alkylation
9
with 1,3-dibromopropane and 70-76 % . Thus, by this tech-
nique the total yield of gemfibrozil is 39-46 %. There are several
techniques of synthesis of gemfibrozil and its derivatives repor-
ted with some modifications in the patent literature. Spanish
10
patent describes synthesis 5 by alkylation of corresponding
potassium salt with 5-bromo-2,2-dimethylpentanamide,
followed by the alkaline hydrolysis of the intermediate amide
to 5. A method for obtaining 5 by oxidation of respective
aldehyde; other method reported that, N-isobutylidene-
dicyclohexylamine followed by the hydrolysis of the imine
1
13
(5) based on the careful comparison of IR, H NMR, C NMR
and mass spectral data.
O
O
O
O
NaOH, IBA
Conce.HCl
11
formed . The Warner-Lambert Company has improved the
OH
O
12
method developed by Parke Davis for obtaining 5 . In this
patent, isobutyl isobutyrate undergoes the reaction with lithium
diisopropylamide in THF in the presence of styrene. The resul-
ting anion reacts with 1-bromo-3-chloropro-pane to yield
isobutyl 5-chloro-2,2-dimethylpentanoate, which was treated
with sodium 2,5-dimethylphenolate in a DMF/toluene mixture
in the presence of NaI and the ester formed was hydrolyzed to
Scheme-II
Conclusion
The formation of gemfibrozil moiety with the ease and
procedural simplicity are the key aspects of the synthesis. An
improved process has been developed for synthesis of
gemfibrozil with an overall yield of 80 and 99.9 % purity. The
5
. The total yield (for two steps) of gemfibrozil is 80 %. Malonic
1
3,14
acid derivatives also used for synthesis of gemfibrozil
.

928 Nunna et al.
Asian J. Chem.
4
5
.
.
Y.A. Kesaniemi and S.M. Grundy, JAMA, 251, 2241 (1984).
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the reported processes, with the use of low cost starting material
and avoided the multisteps.
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Heinsalmi, P. Helo, J.K. Huttunen, P. Kaitaniemi and P. Koskinen,
JAMA, 260, 641 (1988).
6
7
.
.
J. Lewis, Multicenter Pract. Cardiol., 9, 99 (1983).
P.L. Creger, 2,2-Dimethyl-{11-aryloxy-alkanoic acids and salts and
esters thereof), US Patent 3,674,836 (1972).
ACKNOWLEDGEMENTS
The authors are thankful to the Director, IISc, Bangalore
for providing spectral data and valuable cooperation for this
work.
8
.
Organic Synthesis Coll., 1, 435 (1941).
9. Organic Synthesis Coll., 50, 58 (1970).
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