DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
docosanol, which is represented by the following structural formula-1.
5
Formula-1
Background of the Invention:
Docosanol (C22H45OH) is a fatty alcohol, is known as behenyl alcohol or 1-docosanol.
It is developed by Avanir Pharmaceuticals for the treatment of cold sores 10 and fever blisters
caused by herpes simplex virus, marketed by Glaxo Smith kline with brand name Abreva
10% topical cream in USA .
Generally higher fatty alcohol are extracted from plants and some other natural
15 products. However, fatty alcohol mixtures having a chain length range of C18 (octadecanol) to
C22 (docosanol) . These are produced industrially by means of fatty acid or fatty acid ester
under high pressure hydrogenation. There are some reports with higher fatty acid reduction,
as Bleyberg, Ulrich, Ber.64,2504 (1931); and Francis et al, Proc.Roy.Soc (London) A158,691
(1937). The disadvantages of the methods are source of higher fatty acid is extremely limited,
20 and that raw materials from natural sources always provide fatty acid mixtures. Industrial
production of fatty alcohols from fatty acids in large quantity can not be achieved due to the
limited availability of fatty acids.
Long-chain fatty alcohols up to a chain length of approximately C30 are also produced
on an industrial scale by means of Zieglerf s method starting from aluminum, hydrogen, and
25 ethylene. Here, triethylaluminum is subjected with ethylene to a growth reaction, by which is
meant the step wise insertion of ethylene into the aluminum alkyl group and after oxidation
to the aluminum alkoxide and hydrolysis. The raw alcohol obtained with Zieglerfs method
contains impurities, such as for example parafins, olefins, ethers, esters, and aldehydes.
However, it is not suitable for the separation of linear alcohols from branched alcohols.
30
Docosanol was first disclosed in Ber.41, 1475 (1908), Prepared from Bouveault and
Blanks method from ethylerucate.
3
The Indian Journal of Chemistry, 1996, 35B, 1239 discloses a process for preparation
of docosanol which involves, reduction of 6-docosenoic acid by using Pd/C, H2 gas to
produce docosanoic acid, which is esterfied with methanol, by reduction of the resulting
methyl docosanoate using lithium aluminium hydride . The major draw back associated with
the above process is more number of steps and usage of lithiumaluminium 5 hydride for
reduction, which is very costly and pyrophoric reagent.
The Journal of Biological Chemistry 1924, 59, 905-921 discloses a process for
preparation of docosanol.
The prior art processes are having disadvantages for long chain alcohol synthesis.
10 Hence, there is a continuous need to develop a chemical process for synthesis of long chain
alcohols specifially for docosanol. Which is useful for commercial manufacturing with high
yields and purity.
The present application describes an improved processes for the preparation of the
compound of formula-1.
15 Brief Description :
The first aspect of the present invention is to provide a novel process for the
preparation of the compound of formula-1, comprising of reacting the compound of formula-
2 with suitable reagents in a step wise manner.
The second aspect of the present invention to provide a compound of formula-6a.
20 The third aspect of the present invention provide a process for the preparation of a
compound of formula-6a.
The fourth aspect of the present invention is to provide a novel process for the
preparation of the compound of formula-1, comprising of reacting the compound of
formula-8 with suitable reagents, suitable solvents in a step wise manner.
25 The fifth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1, comprising of reacting the compound of formula-
9 with suitable reagents, suitable solvents in a step wise manner.
The sixth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1, comprising of reacting the compound of formula-
30 9 with suitable reagents, suitable solvents in a step wise manner.
4
The seventh aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1, comprising of reacting the compound of formula-
16 with suitable reagents, suitable solvents in a step wise manner.
The eighth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1, comprising of reacting 5 the behenic acid with
alcohol in presence of acid, followed by reduction by using suitable reagents, suitable
solvents in a step wise manner.
Brief description of the drawings:
10 Figure 1: Illustrates the PXRD pattern of crystalline form of compound of formula-1.
Figure 2: Illustrates the IR spectrum of crystalline form of compound of formula-1.
Detailed Description:
As used herein the term gsuitable solventh used in the present invention refers to
15 ghydrocarbon solventsh such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; gether solventsh such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
20 ether, 1,2-dimethoxy ethane and the like; gester solventsh such as methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; gpolar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; gchloro solventsh such as dichloromethane,
dichloroethane, chloroform, carbon tetrachloride and the like; gketone solventsh such as
25 acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; gnitrile solventsh such as
acetonitrile, propionitrile, isobutyronitrile and the like; galcoholic solventsh such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
30 monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; gpolar
solventsh such as water or mixtures thereof.
5
As used herein the present invention the term gsuitable baseh refers to inorganic or
organic base. Inorganic base refers to galkali metal carbonatesh such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; galkali metal bicarbonatesh such as
sodium bicarbonate, potassium bicarbonate and the like; galkali metal hydroxidesh such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and 5 the like; galkali metal
alkoxidesh such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
10 and organic bases like dimethylamine, diethylamine, diisopropyl amine,
diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term g oxidisingh agent used in the present invention refers to the reagent is selected
from Pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), Dessmertin
15 periodinane (DMP), Swern oxidation (oxalylchloride, triethylamine and DMSO),
collinsreagent (CrO3, Pyridine), (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO);
The term greducingh agent used in the present invention refers suitable reducing reagents are
selected from lithium aluminium hydride, sodiumborohydride, BF3 etheratesolution,
diisobutyl aluminium hydride (DIBAL-H), catalytic hydrogenation using Pd/C, Ray-nickel;
20
The first aspect of the present invention provides a novel process for the preparation
of compound of formula-1,
25
Formula-1
comprising of ;
a) oxidizing the compound of formula-2
30 with a suitable oxidizing agent in a suitable solvents to provide the compound of formula-3,
6
Formula-3
b) reacting the compound obtained in step-a) with suitable reagent the compound of
formula-4 in presence of suitable solvent to provide the 5 compound of formula-6,
R: Methyl, Ethyl
Formula-4
Formula-6
10 c) reducing the compound obtained in step-b) using suitable agent, in a suitable solvent to
provide the compound of formula-1,
d) purifying the compound obtained in step-c) in a suitable solvent to provide the
compound of formula-1.
Wherein in step-a) the suitable solvent is selected from ester solvents, chloro solvents, ether
15 solvents, polar aprotic solvents, nitrile solvents, or any mixture thereof; the suitable oxidizing
agent is selected from Pyridinium chlorochromate (PCC), Pyridinium dichromate (PDC),
Dess mertin periodinane (DMP), Swern oxidation (oxalylchloride, triethylamine, DMSO),
collins reagent (CrO3, Pyridine), 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO); suitable
temperature 0-60o C, preferably 15-50o C; most preferably 25-30o C ;
20 in step-b) suitable reagents are selected from (2-ethoxy-2-oxoethylene) triphenyl
phosphonium, (2-methoxy-2-oxoethylene) triphenylphosphonium; the suitable solvent is
selected from ester solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile
solvents, polar solvents, dimethylformamide, dimethylsulfoxide or any mixture thereof;
suitable solvent dichloromethane, toluene;
25 in step-c) suitable agents are selected from catalytic hydrogenation using Pd/C, Raney nickel,
and reducing agents lithium aluminium hydride, sodium borohydride, BF3 etherate solution,
diisobutyl aluminium hydride (DIBAL-H); suitable solvents selected from ether solvents,
7
protic solvents and aprotic solvents, water or any mixture thereof; preferred solvent ether
solvents; suitable temperature 0-80o C, preferably 10-75o C; most preferably 25-60oC;
step-d) the suitable solvent is selected from ketone solvents, ester solvents, alcohol solvents,
chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents,
dimethylformamide, dimethylsulfoxide or any mixture thereof; preferred 5 solvent methylene
dichloride;
Preferred embodiment of the present invention provides an improved process for the
preparation of the compound of formula-1 comprising of ;
a) reacting icosanol the compound of formula-2 and pyridinium chlorochromate (PCC) in
10 methylenedichloride to provide icosanal the compound of formula-3,
b) reacting the compound obtained in step-a) with the compound of formula-4a in
methylenedichloride to provide (E/Z)-ethyl docos-2-enoate the compound of formula-6a,
Formula-4a
15 c) reacting the compound obtained in step-b) with lithium aluminium hydride in tetrahydro
furan to provide docosanol the compound of formula-1.
Other embodiment of the present invention provide an improved process for the
preparation of the compound of formula-1 comprising of ;
a) reacting icosanol the compound of formula-2 and pyridinium chlorochromate (PCC) in
20 methylenedichloride to provide icosanal the compound of formula-3,
b) reacting the compound obtained in step-a) with (2-ethoxy-2-oxoethylene) triphenyl
phosphonium the compound of formula-4a in methylenedichloride to provide (E/Z)-ethyl
docos-2-enoate the compound of formula-6a,
c) reacting the compound obtained in step-b) using Pd/C in tetrahydrofuran under hydrogen
25 gas pressure to provide ethyl docosanoate the compound of formula-7a,
d) reacting the compound obtained in step-c) using sodium borohydride in tetrahydrofuran to
provide docosanol the compound of formula-1,
e) purifying the obtained docosanol in methylenedichloride.
The second aspect of the present invention provides a novel (E/Z)-Ethyl docos-2-enoate the
30 compound of formula-6a. Which is the main intermediate for the preparation of docoasnol.
8
Formula-6a
The third aspect of the present invention provides a process for the preparation of E/Z
ethyl docos-2-enoate the compound of formula-6a comprising of ;
a) reacting icosanal the compound of formula-3 with the compound of 5 formula-5 in presence
of zinc dust, tetrahydrofuran to provide (E/Z)-ethyl docos-2-enoate the compound of
formula-6a,
b) purifying the compound obtained in step-a) in methanol to provide (E/Z)-ethyl docos-2-
enoate.
10 The process of the present invention can be represented schematically as follows:
9
In another embodiment of the present invention compound of formula-7 can be
prepared by reacting behenic acid with alcoholic solvent in presence of suitable acid.
In another embodiment of the present invention compound of formula-7 can be
prepared by reacting behenic acid with alcoholic solvent in presence of thionylchloride or
oxalylchloride or NŒ-ethylcarbodiimide 5 hydrochloride (EDC)
The fourth aspect of the present invention provides an improved process for the
preparation of the compound of formula-1 comprising of ;
a) oxidizing the compound of formula-8 with a suitable oxidizing agent in a suitable
solvents to provide the compound of formula-9,
10 b) reacting the compound obtained in step-a) with suitable reagent, the compound of
formula-10 in suitable solvent to provide the compound of formula-11,
Formula-10
c) reducing the compound obtained in step-b) using suitable reagent in a stepwise manner or
15 in a single step in a suitable solvent provide the compound of formula-1,
d) purifying the compound obtained in step-c) in a suitable solvent to provide the compound
of formula-1.
wherein, in step-a) the suitable solvent is selected from ketone solvents, ester solvents, chloro
solvents, ether solvents, polar aprotic solvents, nitrile solvents, or any mixture thereof; the
20 suitable oxidizing reagent is selected from Pyridinium chlorochromate (PCC), Pyridinium
dichromate (PDC), Dessmartin periodinane (DMP), Swern oxidation (oxalylchloride,
triethylamine, DMSO), collins reagent (CrO3, Pyridine), 2,2,6,6-Tetramethylpiperidin-1-
yl)oxyl(TEMPO); suitable temperature 0-60o C, preferably 15-50o C; most preferably 25-30o
C ; in step-b) the suitable solvent is selected from ester solvents, chloro solvents, ether
25 solvents, polar aprotic solvents, nitrile solvents, polar solvents, dimethylformamide,
dimethylsulfoxide or any mixture thereof; suitable solvent dichloromethane, toluene;
preferred solvent dichloromethane; in step-c) suitable agents are selected from catalytic
hydrogenation using Pd/C, Raney nickel, and reducing agents lithium aluminium hydride,
sodium borohydride, BF3 etherate solution, diisobutyl aluminium hydride (DIBAL-H);
30 suitable solvents selected from ether solvents, protic solvents and aprotic solvents, water
10
mixture thereof; preferred solvent ether solvents ; suitable temperature 0-80o C, preferably
10-75o C; most preferably 25-70oC;
step-d) the suitable solvent is selected from ketone solvents, ester solvents, alcohol solvents,
chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents,
dimethylformamide, dimethylsulfoxide or any mixture thereof; 5 suitable solvents
methylenedichloride;
The process of the present invention can be represented schematically as follows:
10
11
The fifth aspect of the present invention provides an improved process for the
preparation of docosanol the compound of formula-1 comprising of ;
a) reacting the compound of formula-9 with the compound of formula-12 in suitable solvent
to provide the compound of formula-13,
5
R: Methyl, Ethyl
Formula-12
b) reacting the compound obtained in step-a) using suitable reducing agent in step wise
manner or in single step in suitable solvent to provide docosanol the compound of formula-1,
c) purifying the compound obtained in step-c) in a suitable solvent 10 to provide the compound
of formula-1.
wherein, in step-a,b) the suitable solvent is selected from ester solvents, alcohol solvents,
chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents,
dimethylformamide, dimethylsulfoxide or any mixture thereof; step-b) suitable agents are
15 selected from catalytic hydrogenation using Pd/C, raney nickel, and reducing agents lithium
aluminium hydride, sodium borohydride, BF3 etherate solution, diisobutyl aluminium hydride
(DIBAL-H); suitable solvents selected from ether solvents, water or any mixture thereof;
preferred solvent ether solvent; suitable temperature 0-80o C, preferably 10-75o C; most
preferably 25-70oC;
20
The process of the present invention can be represented schematically as follows:
12
The sixth aspect of the present invention provide an improved 5 process for the
preparation of the compound of formula-1comprising of ;
a) reacting the compound of formula-9 with the compound of formula-14 in suitable solvent
to provide compound of formula-15,
10
Formula-14
R'= Hydrogen, acetyl, benzyl, dihydropyran.
b) reacting the compound obtained in step-a) using suitable agent in step wise manner or in
15 single step in suitable solvent to provide the compound of formula-1,
c) purifying the compound obtained in step-c) in a suitable solvent to provide the compound
of formula-1.
wherein, in step-a,b) the suitable solvent is selected from ester solvents, alcohol solvents,
chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents,
20 dimethylformamide, dimethylsulfoxide or any mixture thereof; step-b) suitable reducing
reagents are selected from Pd/C, raney nickel, lithium aluminium hydride, sodium
borohydride, BF3 etherate solution, diisobutyl aluminium hydride (DIBAL-H); suitable
solvents selected from ether solvents, protic solvents and aprotic solvents, water or any
mixture thereof; preferred solvent ether solvent; suitable temperature 0-80o C, preferably 10-
25 75oC; most preferably 25-70oC;
13
The process of the present invention can be represented schematically as follows:
5
The seventh aspect of the present invention provide an improved process for the
preparation of the compound of formula-1 comprising of ;
a) reacting the compound of formula-16 with the compound of formula-17 in a suitable
solvent to provide the compound 10 of formula-15,
Formula-17
R'= Hydrogen, acetyl, benzyl, dihydropyran.
15
b) reacting the compound obtained in step-a) using suitable agent in step wise manner or in
single step in suitable solvent to provide the compound of formula-1,
c) purifying the compound obtained in step-b) in a suitable solvent to provide the compound
of formula-1.
14
wherein, in step-a,b) the suitable solvent is selected from ester solvents, alcohol solvents,
chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents,
dimethylformamide, dimethylsulfoxide or any mixture thereof; step-b) suitable agents are
selected from catalytic hydrogenation using Pd/C, Raney nickel, and reducing agents lithium
aluminium hydride, sodium borohydride, BF3 etherate solution, diisobutyl 5 aluminium hydride
(DIBAL-H); suitable solvents selected from ether solvents, water or any mixture thereof;
preferred solvent ether solvent; suitable temperature 0-80o C, preferably 10-75o C; most
preferably 25-70oC;
10 The process of the present invention can be represented schematically as follows:
The eighth aspect of the present invention provide an improved process for the
15 preparation of the compound of formula-1 comprising of;
a) optionally purifying behenic acid in a suitable solvent,
b) esterifying behenic acid in a suitable alcohol in presence of acid,
c) reducing the compound obtained in step-b) with a suitable reducing reagent, solvent,
d) optionally purifying the compound obtained in step-c) to get docosanol.
15
wherein, in step-a) the suitable solvent is selected from ester solvents, alcohol solvents,
chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents,
dimethylformamide, dimethylsulfoxide or any mixture thereof; preferably tetrahydrofuran;
wherein, in step-b) suitable solvent is alcoholic solvent, selected form methanol, ethanol,
isopropanol, butanol, propanol; wherein, in step-c) suitable reducing 5 reagents are selected
from lithium aluminium hydride, sodium borohydride, BF3 etherate solution, diisobutyl
aluminium hydride (DIBAL-H); suitable solvents selected from ether solvents, protic
solvents and aprotic solvents, water or any mixture thereof; preferably: tetrhydrofuran,
methanol; wherein step-d) the suitable solvent is dichloromethane, chloroform,
10 tetrahydrofuran, ethanol, methanol, isopropanol, ethers, ketone solvents, ester solvents, polar
solvents and mixture thereof; preferably dichloromethane.
Other embodiment of the present invention is a process for preparation of Docosanol
compound of formula-1 comprising of ;
a) purifying behenic acid in a tetrahydrofuran,
15 b) esterifying behenic acid in methanol in presence of sulfuric acid,
c) reducing the compound obtained in step-b) with sodiumborohydride in tetrahydrofuran
and methanol,
d) purifying the compound obtained in step-c) with dichloromethane to get the compound of
formula-1.
20 Other embodiment of the present invention is a process for preparation of Docosanol
compound of formula-1 comprising of :
a) purifying behenic acid in a tetrahydrofuran,
b) esterification of behenic acid in methanol in presence of thionylchloride,
c) Reducing the compound obtained in step-b) with sodiumborohydride in tetrahydrofuran
25 and methanol,
e) purifying the compound obtained in step-c) in dichloromethane to get the compound of
formula-1.
30
16
The process of the present invention can be represented schematically as follows:
Docosanol and its polymorphs produced by the present invention can be further micronized
or milled to get the desired particle size to achieve desired solubility 5 profile based on
different forms of pharmaceutical composition requirements. Techniques that may be used
for particle size reduction include, but not limited to ball, roller and hammer mills, and jet
mills. Milling or micronization may be performed before drying, or after the completion of
drying of the product.
10 PXRD analysis of docosanol was carried out using BRUKER D8 ADVANCED/AXS
X-Ray diffractometer using Cu Kƒ¿ radiation of wavelength 1.5406 A‹ and continuous scan
speed of 0.03‹/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not
15 be construed as limitation of the scope of the invention.
17
Examples:
Example-1: Preparation of the compound of formula-2.
A round bottom flask was charged with pyridinium chloro chromate (70 gm), methylene
dichloride (200 ml) stirred for 30 min. A solution of the compound of 5 formula-2 (50.0 gm) in
methylene dichloride (150 ml) was added slowly to the above reaction mixture at 25-35oC
and stirred for 4 hr at same temperature. The reaction mixture was diluted with 10% NaOH
aqueous solution (200 ml) and stirred for 30 min, separated the organic layer. The organic
layer was washed with water, brine solution and solvent was distilled under reduced pressure
10 to get the title compound.
Yield: 33.0 gr.
Example-2: Preparation of the compound of formula-6a.
A round bottom flask was charged with the compound of formula-4a ( 39.0 gm), dichloro
methane (75 ml) stirred for 30 min. A solution of the compound of formula-3 (25 gm) in
15 dichloro methane (250 ml) was added slowly to the above reaction mixture at 0-5o C and
stirred for 30 min at same temperature and for 3 hr at 40oC. The reaction mixture was
evaporated, diluted with methanol (125 ml) and stirred for 30 min at 60o C. The reaction
mixture was cooled to 25-35oC, the obtained solid was filtered, washed with methanol (20
ml) and dried to get the title compound.
20 Yield: 24.0 gm.
Example-3: Preparation of the compound of formula-7a.
An auto clave vessel was charged with the compound of formula-6a (30.0 gm), tetrahydro
furan (250 ml) and a solution of Pd/C (5%, 5.0 gr) in THF (50 ml). The reaction mixture was
flushed with nitrogen, and stirred under hydrogen pressure at 3.0 kg/cm2 for 4 hrs at 25-35oC.
25 the reaction mixture was filtered through hyflow bed washed with tetrahydrofuran (30 ml).
The filtrate was evaporated under reduced pressure to get the crude material. The crude
material was stirred in isopropanol (80 ml) for 45 min at 25-35oC, the obtained solid was
filtered and washed with isopropanol (10 ml), dried the material to get the title compound.
Yield: 20.0 gm.
30 Example-4: Preparation of the compound of formula-1.
A round bottom flask was charged with the compound of formula-7a ( 20.0 gm), tetrahydro
furan (100 ml) stirred for 20 min. The solution was cooled to 0-5o C, sodium borohydride
18
(6.03 gm) was added in portion wise under nitrogen atmosphere, followed by methanol (20
ml) and stirred for 6 hr at 25-35oC. The reaction mixture was cooled to 5-10o C, adjust the pH
below 1.0 using aq.HCl (10 ml) and stirred for 30 min. The aqueous layer was extracted
with methylene dichloride (2 X 100 ml), the combined organic layer was dried and
evaporated to get crude material. The obtained crude material was 5 recrystallized using
dichloromethane , filtered the obtained solid and washed with dichloromethane , dried to get
the title compound.
Yield: 9.0 gm.
Example-5: Preparation of the compound of formula-1.
10 A round bottom flask was charged with lithium aluminium hydride (8.0 gm), tetrahydro
furan (250 ml) and the suspension was stirred for 1 hr. A solution of (E/Z)-Ethyl docos-2-
enoate ( 50.0 gm) the compound of formula-6A in tetrahydrofuran (250 ml) was added dropwise
to the above suspension at 20o C and heated the reaction mixture to 45oC and maintained
at the same temperature for 6 hr. The reaction mixture was cooled to 5-10oC and quenched
15 with saturated aq.sodium sulphate solution, Con.sulphuric acid (5 ml) drop wise and stirred
for 15 min to separate the organic layer. Organic layer was washed with brine solution, dried
and evaporated the solvent to provide the crude compound. The obtained crude material was
purified using methylene dichloride to get the title compound.
Yield: 14.0 gm.
20 Example-6: Preparation of the compound of formula-3.
A round bottom flask was charged with TEMPO (0.1 gm), dichloromethane (30 ml) and
stirred for 10 min, the reaction mixture cooled to -5oC, charged with the compound of
formula-2 (10.0 gm), potassium bromide (1.0 gm), sodium bicarbonate (4.0 gr) and sodium
hypochloride (5 ml) simultaneously, stirred at 25-35oC for 4 hr. The reaction mixture was
25 quenched with hypo (10% solution, 50 ml) and stirred for 30 min. The organic layer was
separated and aqueous layer was extracted with dichloromethane. The combined organic
layer was dried and distilled off to get the title compound.
Yield: 5.0 gr.
Example-7: Preparation of the compound of formula-1.
30 A round bottom flask was charged with the compound of formula-7a ( 5.0 gm), toluene (85
ml) and stirred for 10 min. A solution of diisobutyl aluminum hydride (DIBAL-H) in toluene
(5.7 gm) was added drop wise to the above reaction mixture under nitrogen atmosphere and
19
stirred for 4 hrs at 25-35oC. The reaction mixture was cooled to 5o C and adjusted pH ~ 1.5
using 10% aqueous HCl (15 ml), followed by water (300 ml), toluene (200 ml) were added
and stirred for 30 min. The organic layer was separated and washed with water, brine
solution. The organic layer was distilled off to get the title compound.
5 Yield: 5.0 gr.
Example-8: Purification of the compound of formula-18.
A round bottom flask was charged with the compound of formula-18 (200 gr), tetrahydro
furan (600 ml) and stirred for 15 min, heated to 45-55‹C and stirred for 20 min. The solution
was cooled to 15-25‹C, filtered the obtained solid. The wet compound was purified several
10 times by using tetrahydrofuran to get the pure compound of formula-18.
Yield: 80 gr.
Example-9: Purification of the compound of formula-18.
A round bottom flask was charged with the compound of formula-18 (50 gr), acetone (120
ml) and stirred for 15 min, heated to reflux and stirred for 20 min. The solution was cooled to
15 15-25‹C, filtered the obtain solid and dried to get the title compound.
Yield: 12 gr.
Example-10: Purification of the compound of formula-18.
A round bottom flask was charged with the compound of formula-18 (50 gr), acetonitrile
(150 ml) and stirred for 15 min, heated to reflux and stirred for 20 min. The solution was
20 cooled to 15-25‹C, filtered the obtained solid and dried to get the title compound.
Yield: 18 gr.
Example-11: Preparation of the compound of formula-7a.
A round bottom flask was charged with the compound of formula-18 (100 gr), methanol
(400 ml). Slowly added sulfuricacid (1.15 gr) to the reaction mixture and stirred for 15 min,
25 heated to 60-70‹C and stirred for 14 hr. Cooled the reaction mixture to 15-25‹C, filtered the
obtained solid, washed with methanol (100 ml) and dried to get the title compound.
Yield: 100 gr.
Example-12: Preparation of the compound of formula-7b.
A round bottom flask was charged with the compound of formula-18 (100 gr), ethanol (400
30 ml) stirred for 10 min. Slowly added sulfuricacid (1.15 gr) to the reaction mixture stirred for
15 min, heated to 70-80‹C and stirred for 14 hr. Cooled the reaction mixture to 15-25‹C,
filtered the obtain solid and washed with ethanol (100 ml) dried to get the title compound.
20
Yield: 95 gr.
Example-13: Preparation of the compound of formula-7a.
A round bottom flask was charged with the compound of formula-18 (100 gr), methanol
(400 ml) stirred for 10 min. Thionylchoride (21.3 ml) was added drop wise addition to the
reaction mixture, heated to 60-70‹C and stirred for 1 hr. Cooled the 5 reaction mixture to 15-
25‹C, distilled off the solvent furthter diluted with water and extracted with MDC. The
combined organic layer was dried and evaporated to get the title compound.
Yield: 88 gr.
Example-14: Preparation of the compound of formula-1.
10 A round bottom flask was charged with the compound of formula-7a (100 gr), tetrahydro
furan (400 ml) stirred for 10 min. Sodium borohydride (53.34 gr) was added to the reaction
mixture at 15-25‹C, followed by drop wise addition of methanol (200 ml) to the reaction
mass, stirred for 6 hr at 60-70‹C. The reaction mixture was cooled to 10-20‹C quenched
with water (1000 ml), dichloromethane (1000 ml) and adjusted the pH to 5-6 using dilute HCl.
15 The reaction mixture was heated to 30-40‹C and seperated the organic layer. The aqueous
layer was extracted with dichloromethane (200 ml), the combined organic layers were dried
and distilled off the solvent. The obtained crude material was purified by using dichloro
methane (200 ml) and dried to get the title compound.
Yield: 85 gr. ,CLAIMS:1. A process for preparation of Docosanol compound of formula-1
comprising of ;
a) purifying behenic acid in a suitable solvent,
b) esterification of behenic acid in alcohol in presence 5 of sulfuric acid,
c) reducing the compound obtained in step-b) with a suitable reducing agent in a suitable
solvent,
d) optionally purifying the compound obtained in step-c) in a sauitable solvent to get the
compound of formula-1.
10 2. The process as claimed in claim 1 step-a) the suitable solvent is selected from ester
solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile
solvents, polar solvents, dimethylformamide, dimethylsulfoxide or any mixture thereof;
preferably tetrhydrofuran.
3. The process as claimed in claim 1 step-b) suitable solvent is alcoholic solvent, selected
15 form methanol, ethanol, isopropanol, butanol, propanol;
4. The process as claimed in claim 1 step-c) reducing agents are selected form lithium
aluminium hydride, sodium borohydride, BF3 etherate solution, diisobutyl aluminium hydride
(DIBAL-H) or mixture thereof. Suitable solvents is selected from ether solvents, protic
solvents and aprotic solvents, water or mixture thereof; Preferably : tetrahydrofuran and
20 methanol.
5. The process as claimed in claim 1 step-d) the suitable solvent is dichloromethane,
chloroform, tetrahydrofuran, ethanol, methanol, isopropanol, ethers, ketone solvents, ester
solvents, polar solvents and mixture thereof. Preferably dichloromethane.
6. A process for preparation of Docosanol compound of formula-1
25 comprising of ;
a) purifying behenic acid in a tetrahydrofuran,
b) esterifying behenic acid in methanol in presence of sulfuric acid,
c) reducing the compound obtained in step-b) with sodiumborohydride in tetrahydrofuran
and methanol,
30 d) purifying the compound obtained in step-c) with dichloromethane to get the compound of
formula-1.
22
7. A process for preparation of Docosanol compound of formula-1
comprising of ;
a) purifying behenic acid in a tetrahydrofuran,
b) esterifying behenic acid in methanol in presence of thionylchloride,
c) reducing of compound obtained in step-b) with sodiumborohydride 5 in tetrahydrofuran and
methanol,
d) purifying the compound obtained in step-c) in dichloromethane to get the compound of
formula-1.
8. A composition comprising Docosanol obtained as per the process claimed in claim 1 to 7,
10 along with atleast one pharmaceutical acceptable excipient.
9. A compound for Formula-6a
15 Formula-6a