FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
“PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE PIPERINE”
2. APPLICANT
(a) NAME: CIPLA LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: Cipla House, Peninsula Business Park, Ganpatrao Kadam
Marg, Lower Parel, Mumbai 400013, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it has to be performed.

2
Technical filed:
The present invention relates to substantially pure piperine and an improved process
for the preparation of piperine. More specifically, the invention provides a process
for the preparation of substantially pure piperine, having low concentrations of
isomeric impurities.
Background of the invention:
Piperine, the technical grade active ingredient, is naturally occurring in the black
pepper plant, Piper nigrum L. The amount of piperine varies in plants belonging to
the Piperaceae family; it constitutes 2% to 7.4% of both black pepper and white
pepper (Piper nigrum L.; Ravindran 2003; Peter 2006; Parthasarathy and others
2008), although some reports pointed to higher piperine content of black pepper up
to 9% (Gaikar and Raman 2002; Agarwal 2010), 4% of long pepper (Piper longum
L.) fruits, and 4.5% of Balinese long pepper fruits (Piper retrofractum Vahl; Gaikar
and Raman 2002). The piperine content of pepper can be influenced by many
environmental factors including climate, growing conditions, and its place of origin
(Peter 2006).
Piperine, as the most abundant alkaloid in pepper, was first isolated from the extract
of pepper by Hans Christian Ørsted in 1819. It was extracted as a yellow crystalline
compound with a melting point of 128 to 130°C. The chemical structure of piperine
was later identified as piperoylpiperidine, with the chemical formula of C17H19NO3,
and with the IUPAC name 1-(5-[1,3-benzodioxol- 5-yl]-1-oxo-2,4-pentadienyl)
piperidine.
Piperoylpiperidine (piperine) exists as 4 isomeric structures: piperine (trans-trans
isomer)(I), isopiperine (cis-trans isomer), chavicine (cis-cis isomer), and
isochavicine (trans-cis isomer), as illustrated in Figure 1; however, the 3 geometric
isomers isopiperine, chavicine and isochavicine have almost no pungency.
Figure 1
3
Piperine has been used in herbal medicine as an anti-inflammatory, anti-arthritic,
and anti-depressant. Moreover, it has been reported to act as a bioenhancer, a
compound used in combination with a pharmaceutical in order to increase drug
bioavailability, in combination with propranolol, theophylline, ciprofloxacin, and
tetracycline. Recently, piperine was used as a bioenhancer with the antitubercular
drug, rifampicin. The combined therapy of the drug with piperine has enabled the
therapeutic dose of rifampicin by 50%.
Various process are disclosed in the prior art to obtain high purity piperine.
US5744161 teaches an extraction process of piperine from black pepper, having
assay by HPLC 98%. Isolatation of piperine from a suitable oleoresin material
obtained from the fruit or plant of the Piperaceae family is disclosed.
4
US 6054585 discloses a process to recover piperine from resin of black pepper,
wherein a mixture of 0.9 kg of urea, and 0.3 kg of resin of black pepper are refluxed
in ethanol or methanol, the resultant filtrate is concentrated to yield piperine and
some unreacted urea, which is further recrystallized to yield 75 g of 98% pure
piperine.
US 6365601 discloses a two-step process for the extraction of piperine from plants
of piper species using aqueous hydrotrope solution. The isolated piperine has
recovery of 58.8% (716 mg.) based on the amount of piperine present in the dried
fruit with a purity of 98%.
Linchan Huaxue Yu Gongye (2008), 28(2), 6-10 discloses Preparative separation
and purification of piperine from Piper nigrum Linn. by high-speed counter-current
chromatography with a 2-2-phase solvent system composed of petroleum ether (60-
90°C)-Ethyl acetate-methanol-water (1:0.8:1:0.8, vol. ratio), wherein pieperine is
obtained at 99.1% purity.
CN 104311530 A discloses a method of extracting high purity piperine comprising
(1) grinding pepper fruit to obtain 60 mesh powder, adding 95% ethanol soln.,
immersing for 0.5 h, refluxing in 80°C water bath for 2 h, collecting the filtrate and
the filter residue, (2) vacuum distilling and concentrating the filtrate, (3) immersing
the filter residue in 95% ethanol for 0.5 h, refluxing, vacuum filtering, collecting
the filtrate, (4) combining the filtrate, vacuum distilling and concentrating, (5)
regulating pH to 4 with 6.0 mol/L HCl, stewing for 4 h, centrifugating for 10 min,
removing the undissolved substance, (6) regulating pH to 11 with 10% sodium
hydroxide, (7) adding distilled water, cooling for 4 h, (8) centrifugating at 1200 rpm
for 10 min to obtain crude piperine, (9) recrystallizing the crude piperine in acetone
for 2-3 times, and (10) washing the obtained solid with ethyl ether, and vacuum
drying to obtain high-purity piperine with a content of 98.9% and a purity of
99.96%. However, the process disclosed is not only cumbersome but also there is
no enabling disclosure.
5
The processes disclosed in the prior art suggest extraction of Piper nigrum oleoresin
containing piperine and other volatile oils using large volume of solvents. Piperine
containing oleoresin is then solvent extracted and recrystallized to obtain pure
piperine. Further, the extraction process is not selective as other compounds like
gums, polysaccharides and resins are also extracted together reducing the purity of
piperine. Hence, requires repetitive recrystallization to obtain piperine with a
maximum purity of 99.1%. Thus, the post extraction processing to purify piperine
is cumbersome and uneconomical. These conventional processes are carried out
using several steps which often present difficult operating conditions and result in
a high cost of production.
An alternative synthetic route is disclosed in number of literature which involves a
Wittig -Horner reaction of piperonal (II) with an appropriate phosphorane. The
complete synthesis is shown below in scheme 1.
Scheme 1
In the first Arbusov reaction, the phosphonate ester (VII) is prepared from methyl
4-bromo-2-Butanoate (VI) and triethylphosphite by reacting at 120-130˚C. The
product, methyl 4-(diethoxyphosphinyl)-2-Butanoate (VII), is reacted in the second
step with freshly prepared sodium methoxide to generate the phosphonate
6
carbanion in the presence of piperonal (III). The phosphonate carbanion undergoes
a Wittig type reaction with the piperonal (III) to form the trans alkene, methyl
piperate ((E, E)-5-(3,4-methylenedioxyphenyl)-2,4-pentadienoate) (VIII). Finally,
reaction of methyl piperate (VIII) with piperidine in the presence of sodium
methoxide in refluxing methanol solution for 40 hours gives piperine (I).
The process suffers many disadvantages.
1. Methyl 4-bromo-2-butenoate is very expensive and usually contaminated to
some extent with 2(5H)-furanone, a side product of its synthesis and
purification. The boiling points of the two compounds are nearly the same, so
it is not possible to separate them by distillation. The starting material used in
this experiment, may contain as much as 15% of the 2(5H)-furanone which
does not interfere with the reaction but might be present in the product as a
significant impurity.
2. Triethyl phosphate has an extremely disagreeable odour. Because of the
exothermic reaction at high temperature of 120-130˚C, the toxicity of ethyl
bromide and the stench of triethylphosphite, this Wittig -Horner reaction
should be carried out in a fume hood.
3. Excessive use of reagents for example piperidine 11 equivalents and sodium
methoxide 4.5 equivalents.
4. Poor yield of 20% leads to high product cost thus not suitable for industrial
scale up.
In another modification piperine is produced by reacting methyl- 2-butanoate with
NBS in the presence of CCl4 and benzoyl peroxide to yield methyl 4-bromo-2-
butenoate (VI). Wittig reaction of triethyl phosphite with the piperonal (III) to form
the trans alkene, methyl piperate ((E, E)-5-(3,4-methylenedioxyphenyl)-2,4-
pentadienoate) (VIII). Hydrolysis of the ester to piperic acid (VIIIA) and further
condensation with piperidine using dry benzene and oxalyl chloride to yield
piperine (I).This process also suffers from many disadvantages such as use of toxic
7
and flammable CCl4, benzoyl peroxide, carcinogenic benzene, oxalyl chloride and
dimethoxyethane.
Further, the prior art processes are silent on the isomeric purity of the piperine.
These patents/literature do not provide any insight about the presence of isomeric
impurities as well as disclosure of any purity of the final product.
Owning to the broad spectrum of multiple uses of piperine, it would be a significant
contribution to the art, to provide substantially pure piperine free from these and
other impurities and processes for preparing such pure piperine which has high
purity and high yield.
Object of the invention:
An object of the invention is to provide substantially pure piperine.
Yet another object of the invention is to provide a process to prepare substantially
pure piperine.
Yet another object of the invention is to provide a process to prepare substantially
pure piperine , wherein piperine obtained is having purity of more than 99.5%.
Yet another object of the invention is to provide substantially pure piperine, wherein
piperine obtained is having isomeric purity of more than 99.0%.
Yet another object of the present invention is to provide a process which is simple,
economical and suitable for industrial scale up.
8
Summary of the invention:
In line with the above objectives, the present invention provides a method for
preparing substantially pure piperine of formula (I).
More preferably, the invention provides a synthetic method for preparing
substantially pure piperine, which process comprises;
a) reacting crotonic acid (V) with a chlorinating agent to provide crotonoyl chloride
(IV);
b) reacting crotonoyl chloride (IV) with piperidine to provide (2E)-1(1-
piperidinyl)-2-buten-1-one (III); or
b’) reacting methyl crotonate (IVA) with piperidine to provide (2E)-1(1-
piperidinyl)-2-buten-1-one (III);
c) reacting (2E)-1(1-piperidinyl)-2-buten-1-one (III) with piperonyl aldehyde (II)
in the presence of a suitable phase transfer catalyst to provide piperine having a
purity of greater than 99.5%; and/or
d) optionally, crystallizing from a suitable solvent to get the piperine having desired
purity.
In another aspect, the present invention provides substantially pure piperine having
a purity of greater than 99.5%
In a further aspect, the present invention provides substantially pure piperine,
having isomeric purity of more than 99.0%.
In a further aspect, the present invention provides substantially pure piperine, free
from genotoxic impurities (GTIs).
In yet another aspect, the present invention provides pharmaceutical composition
comprising substantially pure piperine.
9
In yet embodiment of the present invention, there is provided use of substantially
pure piperine as a pharmacokinetic booster or enhancer to boost the effectiveness
of the drugs.
Accordingly, there is provided a pharmaceutical composition comprising at least
one drug and substantially pure piperine and use of the said composition for
enhancing bioavailability, blood levels and efficacy of the drug.
Brief description of the drawings:
Fig.1 shows a typical x-ray powder diffraction spectrum of crystalline solid of pure
piperine
Fig.2 shows a FTIR spectrum of crystalline solid of pure piperine
Fig.3 shows a Differential Scanning Calorimetry (DSC) thermogram of crystalline
solid of pure piperine
Detailed Description of the invention:
The present invention provides a process for the preparation of substantially pure
piperine of Formula (I).
Formula I
The term "substantially pure piperine" in the specification refers to piperine having
purity (measured by HPLC) above 99.5%, preferably above 99.7%, and more
preferably above 99.9%.
As used herein, the term "substantially pure" refers to a substance that has
preferably between about 95% and 100% of one form (trans-trans isomer) and
between about 5% and 0% of the other form, more preferably between about 99%
and 100% of one form (trans-trans isomer) and between about 1% and 0% of the
10
other form, and, most preferably, between about 99.9% and 100% of one form
(trans-trans isomer) and about 0.1% and 0% of the other form.
In an embodiment, the present invention provides substantially pure piperine having
purity (measured by HPLC) more than 99.5% and isomeric purity more than 99%.
In an embodiment, the process for the preparation of substantially pure piperine is
as depicted below in scheme 2.
Scheme 2
In an embodiment, crotonic acid is reacted with a chlorinating agent selected from
thionyl chloride, oxalyl chloride, Phosphorous trichloride, Phosphorous
pentachloride, Phosphorous oxychloride.
11
The chlorination reaction is preferably performed in the presence of a suitable
solvent selected from alcohol (Cl-4) or Ketones (C3-6) or organic solvents (C 1-8
alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents
(Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether,
tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters
(Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a
temperature ranging from about 0°C to about 100°C, preferably about 10°C to
about 80°C, more preferably about 20° C. to about 50°C; preferably, for about an
hour to about 25 hours, more preferably about 10 hours to about 20 hours, most
preferably about 12 hours to about 16 hours.
After completion of the reaction, the solvent is further distilled off to obtain
crotonoyl chloride (IV).
The crotonoyl chloride (IV) is then reacted with piperidine to provide (2E)-1(1-
piperidinyl)-2-buten-1-one (III). The reaction is preferably performed in the
presence of a solvent at a temperature ranging from about 0°C to about 50°C,
preferably about 10°C to about 40°C, more preferably about 20°C to about 30°C;
preferably, for about an hour to about 25 hours, more preferably about an hour to
about 20 hours, most preferably about an hour to about 10 hours.
Preferably the reaction mass is washed with first mixture of water and brine, then
5% dil HCl; followed by 5% sodium bicarbonate solution and washed with mixture
of water and brine. The organic solvent is further distilled off to obtain (2E)-1(1-
piperidinyl)-2-buten-1-one (III).
In one embodiment, condensation is carried out by isolating intermediate crotonoyl
chloride (IV) and reacting with piperidine. In another embodiment, condensation is
carried out in-situ without isolating the intermediate crotonoyl chloride (IV).
12
Alternately, methyl crotonate (IVA) may be reacted with piperidine in the presence
of suitable base to obtain (2E)-1(1-piperidinyl)-2-buten-1-one (III). Suitable base
may be selected from organic and inorganic bases such as sodium methoxide,
sodium t-butoxide, triethylamine, diisoproylamine and the like.

The reaction is preferably performed in the presence of a suitable solvent selected
from polar and nonpolar solvents; at a temperature ranging from about 0°C to about
100°C, preferably about 10°C to about 80°C, more preferably at about 30° C. to
about 60°C; preferably, for about an hour to about 25 hours, more preferably about
10 hours to about 20 hours, most preferably about 12 hours to about 16 hours.
In an embodiment, (2E)-1(1-piperidinyl)-2-buten-1-one (III) is reacted with
piperonyl aldehyde (II) in the presence of a suitable phase transfer catalyst to
provide piperine (I). The pH of the reaction mass is maintained by using a suitable
base. The base can be selected from the group consisting of one or more of alkali
metal hydroxide, metal amides, metal alkoxides, amine bases, and alkali metal
hydrides.
Examples of suitable bases are: sodium hydroxide, potassium hydroxide, sodium
hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide, sodium methoxide, sodium ethoxide and potassium tbutoxide. Most preferably, the base is selected from the group consisting of sodium
hydroxide and potassium hydroxide. Preferably, aqueous base such as aqueous
NaOH/KOH solution is added over a period of 30 mins to 1 hour.
Suitable phase transfer catalyst is selected from benzyl triethyl ammonium chloride,
tetrabutyl ammonium bromide, aliquat 336, benzyl trimethyl ammonium chloride,
methyl tricapryl ammonium chloride, methyl tributyl ammonium chloride, and
methyl trioctyl ammonium chloride or mixtures thereof.
13
The reaction is preferably performed in the presence of a suitable solvent selected
from DMSO, DMF, or mixtures thereof; at a temperature ranging from about 0°C
to about 50°C, preferably about 10°C to about 40°C, more preferably about 20°C
to about 30°C; preferably, for about an hour to about 25 hours, more preferably
about 10 hours to about 20 hours, most preferably about 10 hours to about 15 hours.

In an embodiment piperine is optionally purified in the suitable solvent or solvents
mixture thereof. A suitable solvent is selected from polar solvent and nonpolar
solvents selected form toluene, ethanol, IPA, ethyl acetate, acetone and mixture
thereof.
The purity (measured by HPLC) of the piperine obtained according to the present
invention is preferably about above 99%, more preferably about above 99.5% and
still more preferably about above 99.9%; and contains the isomeric impurities
isopiperine, chvicine and isochavicine below detection limit and meeting the ICH
guidelines.
In yet another embodiment of the invention related to a process for the preparation
of substantially pure piperine, wherein substantially pure piperine contains the
genotoxic impurities, such as shown below in scheme 3,
14
individually and collectively below 50 ppm thereby meeting the ICH
guidelines.The piperine obtained by the process of the present invention is further
characterized by XRD, which is found to be substantially similar with crystalline
Form I of piperine.
In an embodiment crystalline Form I of piperine is characterised by
a) X-ray powder diffraction(XRPD) pattern substantially as shown in figure 1;
b) IR substantially as shown in figure 2; and
c) DSC substantially as shown in figure 3.
In an embodiment, piperine obtained by the process of the present invention is
further hydrogenated to obtain tetrahydropiperine (Ia). The reaction is preferably
carried out in the presence of a suitable catalyst, polar protic solvent and in the
presence of a hydrogen source. Preferably, the catalyst is selected from Pd/C, Pt/C,
PtO2, Ru and the like. Preferably, the polar protic solvent is selected from the group
consisting of a C1-C5 alcohol (such as methanol, ethanol, isopropanol, butanol, and
tert-butanol), acetonitrile, water, and mixture thereof. Most preferably, the solvent
is methanol.
In an embodiment, piperine obtained by the process of the present invention is
further hydrolysed to piperic acid (Ib). The hydrolysis is preferably performed using
an aqueous acid or aqueous base solution in the presence of a suitable solvent.
The process of the present invention is advantageous over prior art processes as the
reaction steps are conducted at low temperature, reduces reaction hours, minimises
large handling of reaction solvents and thus making it economical for industrial
scale up.
Other features and embodiments of the invention will become apparent by the
following examples which are given for illustration of the invention rather than
limiting its intended scope. Various changes and modifications to the disclosed
embodiments will be apparent to those skilled in the art.
15
EXAMPLE
Example 1:
Preparation of (E) -1-(Piperidin-1-yl) but-2-en-1-one ( III)
To a well stirred mixture of crotonic acid (100 gms, 1.16 moles) DMF (1.0ml) in
dichloromethane 500 ml was added thionyl chloride (100 ml, 1.34 moles) dropwise
under N2 atmosphere at 25-30°C and stirred for 14 hours at 30-35°C. After
completion, reaction mass was concentrated and diluted with MDC (1000 ml) and
cooled to 0°C. Piperidine (310.0ml, 3.15 moles) was added drop wise over a period
of 3 hours below 10°C. The reaction mixture was then agitated at 25-30° C for 7
hrs. After completion, the reaction mixture was filtered and filtrate was sequentially
washed with water (2 x 500 ml), 5% dil HCl 500 ml, 5% sodium bicarbonate (500
ml) and finally with brine solution (500 ml). Organic layer was evaporated to obtain
title compound as dark brown colored oil.
Yield: 110.0gms
HPLC Purity: 95%
Example 2:
Preparation of (E) -1-(Piperidin-1-yl)but-2-en-1-one ( III)
To a well stirred mixture of crotonic acid (50 gms, 0.580 moles) DMF (1.0ml) in
toluene (500 ml) was added thionyl chloride (50 ml, 0.670 moles) dropwise under
N2 atmosphere at 25-30°C and stirred for 10 hours at 35-40°C. After completion of
the reaction additional 250 ml toluene is added to reaction mass. Piperidine (150.0
ml, 0.500 moles) was added drop wise over a period of 3 hours below 10°C. The
reaction mixture was then agitated at 25-30° C for 7 hrs. The progress of the reaction
was monitored by HPLC. After completion, the reaction mixture was filtered and
filtrate was sequentially washed with water (2 x 250 ml), 5% dil HCl (250 ml), 5%
Sodium bicarbonate (250 ml) and finally with brine solution (250 ml). Organic layer
was evaporated to obtain title compound as dark brown colored oil.
Yield: 65.0gms
HPLC Purity: 95%
16
Example 3:
Preparation of piperine (I)
To a well stirred mixture of (E) -1-(Piperidin-1-yl) but-2-en-1-one (100.0gm, 0.653
moles), benzyl triethyl ammonium chloride (27.0gm, 0.118 moles) in DMSO (1000
ml) was added piperonyl aldehyde (88.0gm, 0.586 moles) at 25-30°C. Aq. NaOH
(4.7gm 0.118 moles in 100 ml water) was added drop wise over a period of 45 min.
The reaction mixture was then stirred at 25-30°C for 12-15 hours. After completion
of reaction it was quenched in water (5000 ml) and further stirred at 25°C for 2.0
hrs. The precipitated solid was isolated by filtration, washed with water and dried
under vacuum at 55-60 °C to yield title compound piperine as yellow solid.
The crude piperine was purified by crystallization from 500 ml toluene to obtain
crystalline solid.
Yield: 89.0gm.
HPLC Purity: 99.95%
Example 4:
Preparation of Tetrahydro Piperine ( Ia)
To a 1.0 lit hydrogenator, piperine (15.0 gms, 0.052 moles) along with methanol
(140ml) was charged at 25-300
C. In another beaker slurry of 10% Pd/C (1.5 gm, 50
% wet) in 10.0 ml of methanol was prepared and charged into above reaction mass
at 25-300
C. The hydrogen pressure (40-50 PSI) was applied and maintained
reaction at 40-450
C for 10-12 hrs. Reaction mixture was cooled to 25-300
C and
filtered through hyflo to remove catalyst and the bed was washed with methanol
(15 ml). Distilled out methanol under vacuum below 450
C. Added n-Heptane (100
ml) and stirred for 12-13hrs. The precipitated solid was isolated by filtration,
washed with n-Heptane and dried under vacuum at 35-40 °C to obtain title
compound tetrahydropiperine as white solid.
Yield: 14.0 gms,
Purity: 99.5%

17
Example 5:
Preparation of Piperic acid (Ib)
Charged piperine (15.0gm, 0.052 moles) with ethylene glycol( 150 ml) at 25-300
C
into reaction flask, added potassium Hydroxide (13.3 gm, 0.238 moles) at 25-300
C.
Temperature of the reaction was increased to 1150
C and maintained for 14-15 hrs.
After completion of reaction, the reaction mixture was cooled to 15-200
C and added
water (150 ml) into reaction mixture followed by acidification with 15.0 ml of
Conc. HCl. Reaction mixture was stirred further for 1.0 hr at 15-200
C and the
precipitated solid was filtered, washed with water. Wet cake was charged into
reaction flask along with methanol (55 ml) and stirred for 1.0 hr. at 25-300
C. The
solid was isolated by filtration, washed with 15 ml of methanol and under vacuum
at 25-30°C to give title compound piperic acid.
Yield: 7.0 gm.
HPLC Purity: 96.5%

Example 6:
Preparation of (E) -1-(Piperidin-1-yl)but-2-en-1-one ( III)
To a well stirred mixture of sodium methoxide (16.2 gm, 0.300 mole) in toluene
(400 ml) was added under piperidine (40 gms, 0.405 mole) under nitrogen
atmosphere at room temperature. The temperature was increased to 55°C and stirred
for 1 hr and then added methyl crotonate (50 gms, 0.500 mole) dropwise within a
period of 30 min. The reaction mixture was stirred further at 55-60°C for 12 to 15
hrs and then cooled to room temperature. The reaction mixture was quenched with
water (500 ml). The organic layer was separated and washed with water and brine
solution and concentrated to obtain title compound.
Yield: 41 gms
HPLC Purity ~ 50%.

18
Example 7:
Preparation of (E) -1-(Piperidin-1-yl)but-2-en-1-one ( III)
To a well stirred mixture of crotonic acid (100 gms, 1.16 moles) DMF (2.0ml) in
toluene (3000 ml) was added thionyl chloride (200 ml, 1.387 moles) dropwise under
N2 atmosphere at 25-35°C and stirred for 2 hours at 35-40°C. After completion of
the reaction, the reaction mixture was cooled to 5-10°C. Piperidine (690.0 ml, 2.3
moles) was added drop wise over a period of 3 hours below 10°C. The reaction
mixture was then agitated at 25-30° C for 1 hr. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was diluted with water
(1400 ml) and stirred at 25-30° C for 15-20 min. The organic layer separated,
washed with water (1400 ml), 5% dil HCl (1400 ml), 5% Sodium bicarbonate (1400
ml) and finally with water (1400 ml). Organic layer was evaporated to obtain title
compound as oil.
Yield: 240 gms
Example 8:
Preparation of piperine (I)
To a well stirred mixture of (E) -1-(Piperidin-1-yl) but-2-en-1-one (225.0gm, 1.468
moles), benzyl triethyl ammonium chloride (67.0gm, 0.294 moles) in DMSO (2250
ml) was added piperonyl aldehyde (198.5gm, 1.322 moles) at 25-30°C. The reaction
mixture was stirred for 15-20 mins and aq. NaOH (24.0 gm 0.6 moles in 225 ml
water) was added drop wise over a period of 45 min. The reaction mixture was then
stirred at 25-30°C for 5 hours. After completion of reaction it was quenched in water
(6750 ml) and further stirred at 25°C for 1.0 hr. The precipitated solid was isolated
by filtration, washed with water and dried under vacuum at 55-60 °C to obtain title
compound piperine as yellow solid.
Yield: 301.0 gm
Toluene purification:
The crude piperine (265 gm) was dissolved in 2650 ml toluene at 45-500
C. Treated
with charcoal 926.5 gm) for 30 min at 45-500
C. The reaction mixture was filtered
19
and the clear filtrate was evaporated to obtain residue. The residue was stirred in
1060 ml toluene at 60-650
C for 30 min. The reaction mixture was cooled to 25-
300
C and further chilled to 0-50
C and stirred for 1 hr. The precipitated solid was
isolated by filtration, and dried under vacuum at 55-60°C for 12-15 hrs to obtain
title compound Piperine as yellow solid.
Yield: 210 gm
HPLC Purity: 99.6 %
Other isomers<0.02%
IPA purification:
Piperine (180 gm) was dissolved in 1440 ml IPA at 60-650
C. The reaction mixture
was stirred for 30 mins, gradually cooled to 25-300
C and further chilled to 0-50
C
and stirred for 1 hr. The precipitated solid was isolated by filtration, and dried under
vacuum at 55-60°C for 12-15 hrs to obtain title compound Piperine as yellow solid.
Yield: 145 gm
HPLC Purity: 99.95%
Other isomers<0.02%

20
We claim,
1. A process for the preparation of substantially pure piperine of Formula (I)
comprising the steps of;
a) reacting crotonic acid (V)
with a chlorinating agent to provide crotonoyl chloride (IV);
;
b) reacting crotonoyl chloride (IV) with piperidine to provide (2E)-1(1-
piperidinyl)-2-buten-1-one (III)
O
N
(2E)-1(1-piperidinyl)-2-buten-1-one ( III) ;
or
b’) reacting methyl crotonate (IVA)
21
with piperidine to provide (2E)-1(1-piperidinyl)-2-buten-1-one (III);
c) reacting (2E)-1(1-piperidinyl)-2-buten-1-one (III) with piperonyl
aldehyde (II)
in the presence of a suitable phase transfer catalyst to provide
substantially pure
piperine; and
d) optionally, crystallizing the piperine from a suitable solvent to get the
desired purity.

2. The process according to claim 1, wherein chlorinating agent is selected from
thionyl chloride, oxalyl chloride, Phosphorous trichloride, Phosphorous
pentachloride and Phosphorous oxychloride.
3. The process according to claim 2, wherein the chlorination reaction is carried
in the presence of a suitable solvent selected from alcohols (C1-4), ketones
(C3-6), organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene),
halogenated organic solvents (methylene dichloride, ethylene dichloride),
ethers (methyl tertiary butyl ether, tetrahydrofuran, di-isopropyl ether ),
sulphoxides (dimethyl sulphoxide), esters (ethyl acetate, benzyl acetate,
isoamyl acetate), water and mixtures thereof.
4. The process according to claim 2 or 3, wherein the chlorination reaction is
carried at a temperature ranging from about 0°C to about 100°C, preferably
about 10°C to about 80°C, more preferably about 20° C. to about 50°C.
22
5. The process according to any of the preceding claims 1 to 4, wherein, the
crotonoyl chloride (IV) is not isolated.
6. The process according to claim 1, wherein the reaction of step b) is carried at a
temperature ranging from about 0°C to about 50°C, preferably about 10°C to
about 40°C, more preferably about 20°C to about 30°C.
7. The process according to claim 1, wherein the step b’) is carried in the presence
of a base selected from organic and inorganic bases such as sodium methoxide,
sodium t-butoxide, triethylamine, diisoproylamine and the like, in a solvent
selected from the group consisting of polar and nonpolar solvents.
8. The process according to claim 7, wherein the step b’) is carried at a
temperature ranging from about 0°C to about 100°C, preferably about 10°C to
about 80°C, more preferably about 30° C. to about 60°C.
9. The process according to claim 1, wherein the phase transfer catalyst is
selected from the group consisting of benzyl triethyl ammonium chloride,
tetrabutyl ammonium bromide, aliquat 336, benzyl trimethyl ammonium
chloride, methyl tricapryl ammonium chloride, methyl tributyl ammonium
chloride, and methyl trioctyl ammonium chloride or mixtures thereof.
10. The process according to claim 1, wherein the pH of the reaction mass in step
c) is maintained by using a suitable base selected from the group consisting of
one or more of alkali metal hydroxide, metal amides, metal alkoxides, amine
bases, and alkali metal hydrides.
11. The process according to any of the claims claim 9 or claim 10, wherein the
reaction is performed in the presence of a suitable solvent selected from DMSO,
DMF, or mixtures thereof; at a temperature ranging from about 0°C to about
50°C, preferably about 10°C to about 40°C, more preferably about 20°C to
about 30°C.
23
12. The process according to claim 1, wherein the crystallization solvent is selected
from polar solvent and nonpolar solvents selected from the group consisting of
toluene, ethanol, IPA, ethyl acetate acetone and mixture thereof.
13. Substantially pure piperine having a purity of greater than 99.5%.
14. Substantially pure piperine having a purity of greater than 99.7%.
15. Substantially pure piperine having a purity of greater than 99.9%.
16. Substantially pure piperine having HPLC purity of greater than 99.5% and
isomeric purity of greater than 99%.
17. Substantially pure piperine having HPLC purity of greater than 99.5% and
isomeric purity of greater than 99%, according to claim 16, wherein genotoxic
impurities are individually and collectively below 50 ppm and meeting the ICH
guidelines.
18. A substantially pure crystalline piperine having a purity greater than 99.5% is
characterized by at least one of;
a) X-ray powder diffraction(XRPD) substantially as shown in figure 1;
b) IR substantially as shown in figure 2; and
c) DSC substantially as shown in figure 3.
19. A pharmaceutical composition comprising substantially pure piperine.