U.S. patent application number 16/008360 was filed with the patent office on 2018-10-11 for process for the preparation of lomitapide.
The applicant listed for this patent is Parthasaradhi Reddy Bandi, Vamsi Krishna Bandi, Mukunda Reddy Jambula, Rathnakar Reddy Kura. Invention is credited to Parthasaradhi Reddy Bandi, Vamsi Krishna Bandi, Mukunda Reddy Jambula, Rathnakar Reddy Kura.
Application Number | 20180291773 16/008360 |
Document ID | / |
Family ID | 55027786 |
Filed Date | 2018-10-11 |
United States Patent
Application |
20180291773 |
Kind Code |
A1 |
Bandi; Parthasaradhi Reddy ;
et al. |
October 11, 2018 |
PROCESS FOR THE PREPARATION OF LOMITAPIDE
Abstract
The present invention relates to a process for preparing
Lomitapide or its pharmaceutically acceptable salt thereof having
high purity with acceptable levels of impurities.
Inventors: |
Bandi; Parthasaradhi Reddy;
(Hyderabad, IN) ; Kura; Rathnakar Reddy;
(Hyderabad, IN) ; Bandi; Vamsi Krishna;
(Hyderabad, IN) ; Jambula; Mukunda Reddy;
(Hyderabad, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bandi; Parthasaradhi Reddy
Kura; Rathnakar Reddy
Bandi; Vamsi Krishna
Jambula; Mukunda Reddy |
Hyderabad
Hyderabad
Hyderabad
Hyderabad |
|
IN
IN
IN
IN |
|
|
Family ID: |
55027786 |
Appl. No.: |
16/008360 |
Filed: |
June 14, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15542391 |
Jul 7, 2017 |
|
|
|
16008360 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 211/58 20130101;
C07C 2603/18 20170501; C07C 51/367 20130101; C07C 67/293 20130101;
C07C 231/12 20130101; C07C 69/157 20130101; C07C 231/02 20130101;
C07C 62/32 20130101; C07C 231/02 20130101; C07C 235/40 20130101;
C07C 231/12 20130101; C07C 233/59 20130101; C07C 67/293 20130101;
C07C 69/157 20130101; C07C 51/367 20130101; C07C 62/32
20130101 |
International
Class: |
F01L 1/245 20060101
F01L001/245; F01L 1/24 20060101 F01L001/24 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 2014 |
IN |
5536/CHE/2014 |
Claims
1-10. (canceled)
11. The process for the preparation of salt of piperidinyl biphenyl
carboxamide derivative of compound of formula III, ##STR00025##
wherein X represents an acid salt. which comprises: i) condensing
4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid of Formula
VIII ##STR00026## with 4-amino-1-benzyl piperidine of Formula IX
##STR00027## to yield benzylpiperidine biphenyl carboxamide
derivative of Formula X; ##STR00028## ii) optionally isolating the
compound of Formula X; iii) optionally purifying the compound of
Formula X; iv) converting the compound of Formula X to the acid
salt of piperidinyl biphenyl carboxamide derivative of formula
III.
12. The process as claimed in claim 11, wherein solvent used in
step i) selected from the group comprising of methanol, ethanol,
isopropanol, methylene chloride, dimethyl formamide, ethyl acetate,
isopropyl acetate, acetonitrile, heptane, toluene, n-heptane,
n-hexane, diisopropyl ether, tetrahydrofuran, 1,4-dioxane or
mixture thereof.
13. The process as claimed in claim 11, wherein debenzylation in
step iv) carried out using a metal catalyst is selected from the
group comprising of palladium and platinum.
14. The process as claimed in claim 11, wherein acid used in step
iv) selected from the group comprising of hydrochloric acid,
hydrobromic acid, acetic acid and formic acid.
15. The process as claimed in claim 11, wherein acid salt of
compound of Formula III is selected from the group comprising of
hydrochloric acid salt, hydrobromic acid salt, acetic acid salt and
formic acid salt.
16-17. (canceled)
18. The process as claimed in claim 11, wherein solvent used in
step i) selected from the group comprising of methanol, ethanol,
methylene chloride, acetonitrile, acetone, ethylacetate, dimethyl
formamide or mixture thereof.
19. The process as claimed in claim 11, wherein solvent used in
step ii) selected from the group comprising of methanol, ethanol,
methylene chloride, acetonitrile, acetone, ethyl acetate,
n-heptane, n-hexane, toluene, dimethyl formamide or mixture
thereof.
20. The process as claimed in claim 11, wherein acid used in step
iii) selected from the group comprising of methane sulfonic acid,
acetic acid, formic acid, oxalic acid, hydrochloric acid, hydro
bromic acid.
21. The process as claimed in claim 11, wherein solvent used in
step iii) selected from the group comprising of methanol, ethanol,
isopropyl alcohol, methylene chloride, acetonitrile, acetone, ethyl
acetate, n-heptane, n-hexane, toluene or mixture thereof.
22. The process as claimed in claim 11, wherein solvent used in
step iv) selected from the group comprising of methanol, ethanol,
isopropyl alcohol, methylene chloride, acetonitrile, acetone, ethyl
acetate, n-heptane, n-hexane, toluene or mixture thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing
Lomitapide or its pharmaceutically acceptable salt thereof having
high purity with acceptable levels of impurities.
BACKGROUND OF THE INVENTION
[0002] Lomitapide chemically known as
N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4'(trifluoromethyl)[1,1'-biphenyl]-2--
yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide
having the following structure designated as Formula 1.
##STR00001##
[0003] Lomitapide is marketed as its mesylate salt under the trade
name Juxtapid.RTM. as capsule; oral having dosage strengths Eq 5MG
Base, Eq 10MG Base and EQ 20MG Base, which inhibits the microsomal
triglyceride transfer protein (MTP or MTTP) which is necessary for
very low-density lipoprotein (VLDL) assembly and secretion in the
liver.
[0004] Lomitapide and its pharmaceutically acceptable salts were
disclosed in U.S. Pat. No. 5,712,279 A. This patent also discloses
the preparation of Lomitapide by two different methods, which are
shown below:
##STR00002## ##STR00003##
[0005] The process for the preparation of
9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula II, comprises reacting 9-Fluorene carboxylic acid of
Formula IV with 1,4-Dibromobutane in presence of n-BuLi in
tetrahydrofuran, then chlorination with oxalyl chloride to form
acid chloride compound as a crude oil, followed by amidation with
2,2,2-trifluoroethylamine hydrochloride in presence of
triethylamine to yield
9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula II.
[0006] The process for the preparation of piperidinyl biphenyl
carboxamide derivative of Formula IIIa, comprises by reacting
4'-(trifluoromethyl)-2-biphenyl carboxylic acid of Formula VIII
with oxalyl chloride in methylene chloride and dimethyl formamide,
thereafter condensed with 4-amino-1-benzylpiperidine of Formula IX
in presence of triethylamine in methylene chloride to yield
N-(1-benzylpiperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxa-
mide of Formula X, which is deprotected using palladium/carbon in
methanol and cyclohexane.
[0007] Lomitapide has been prepared by condensing bromobutyl
9H-fluorene carboxamide derivative of Formula II with piperidinyl
biphenyl carboxamide derivative of formula IIIa in
dimethylformamide or by condensing bromobutyl 9H-fluorene
carboxamide derivative of Formula II with 4-tert-Boc-amino
piperidine to give
9-(4-(4-aminopiperidin-yl)butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-c-
arboxamide and thereafter condensed with
4'-(trifluoromethyl)-2-biphenyl carboxylic acid in the presence of
triethylamine.
[0008] Lomitapide hydrochloride salt has been prepared by purifying
Lomitapide free base by Column Chromatography (SiO.sub.2, MeOH:
MeCl.sub.2) and thereafter reacting with etheral HCl in
Methanol.
[0009] The present inventors have found that the prior-art process
is not suitable commercially or on industrial scale as the process
yields Lomitapide having dimer impurities, shown below designated
as Formula A and Formula B.
##STR00004##
[0010] Further the process involves purification using column
chromatography, which is not suitable in the commercial scale
production.
[0011] Further, the process shown for the intermediate preparation
yields the intermediate compound having less purity and low yields,
as the reaction doesn't go complete.
[0012] Further, the present inventors has also observed that the
Lomitapide prepared by the prior-art process yields Lomitapide
having the purity of .ltoreq.85% (by HPLC), which needs further
purifications and hence the process is not suitable
economically.
[0013] U.S. Pat. No. 5,760,246 A discloses the synthesis of
9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula II, which is as shown below:
##STR00005##
[0014] Alkylation of
N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide has been carried
out by protecting alkane in presence of a base, wherein protecting
group is selected from the group consisting of
t-Bu(CH.sub.3).sub.2Si or t-Bu(Ph).sub.2Si, followed by
deprotection and bromination. The present inventors have repeated
the process and found that the obtained intermediate compound has
less purity, low yields, commercially not feasible and economically
not cost effective.
[0015] In view of the above, there is a need for the improved,
cost-effective, industrially applicable process for the preparation
of Lomitapide or its pharmaceutically acceptable salt thereof as
well as its intermediates having high yield, purity as well as
acceptable levels of impurities.
Objectives
[0016] One objective of the present invention is to provide a
process for the preparation of Lomitapide or its pharmaceutically
acceptable salt thereof, which is industrially applicable, having
high yield and purity with the acceptable levels of impurities.
[0017] Another objective of the present invention is to provide a
process for the preparation of Lomitapide or its pharmaceutically
acceptable salt thereof, which is cost effective and suitable
economically.
[0018] Another objective of the present invention also provides
intermediate compounds, which are useful in the preparation of
Lomitapide or its pharmaceutically acceptable salt thereof.
SUMMARY OF THE INVENTION
[0019] The present invention provides a process for the preparation
of Lomitapide or its pharmaceutically acceptable salt thereof,
##STR00006##
wherein X represents an acid salt, which comprises, [0020] i)
condensing bromobutyl 9H-fluorene carboxamide derivative of Formula
II
[0020] ##STR00007## with salt of piperidinyl biphenyl carboxamide
derivative of Formula III
##STR00008## [0021] wherein X represents an acid salt to yield
Lomitapide freebase; [0022] ii) optionally purifying Lomitapide
freebase; [0023] iii) optionally converting Lomitapide Free base to
its pharmaceutically acceptable salt thereof; and [0024] iv)
optionally purifying Lomitapide pharmaceutically acceptable salt
thereof.
[0025] In another embodiment of the present invention provides a
process for the preparation of bromobutyl 9H-fluorene carboxamide
derivative of Formula II,
##STR00009##
which comprises: [0026] i) condensing 9H-fluorene-9-carboxylic acid
of Formula IV
[0026] ##STR00010## with 4-bromobutyl acetate to yield
9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of Formula V;
##STR00011## [0027] ii) optionally isolating the compound of
Formula V; [0028] iii) reacting the compound of Formula V with
alkali hydroxide solution to yield
9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of Formula VI;
[0028] ##STR00012## [0029] iv) reacting the compound of formula VI
with 2,2,2-trifluoroethane-1-amine hydrochloride salt to yield
9-(4-hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-carboxylic
acid of Formula VII;
[0029] ##STR00013## [0030] v) reacting the compound of formula VII
with bromine to yield bromobutyl 9H-fluorene carboxamide derivative
of Formula II; and [0031] vi) optionally purifying the compound of
Formula II.
[0032] In another embodiment of the present invention provides a
process for the preparation of salt of piperidinyl biphenyl
carboxamide derivative of formula III,
##STR00014##
wherein X represents an acid salt. which comprises: [0033] i)
condensing 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid
of Formula VIII
[0033] ##STR00015## with 4-amino-1-benzyl piperidine of Formula
IX
##STR00016## to yield benzylpiperidine biphenyl carboxamide
derivative of Formula X;
##STR00017## [0034] ii) optionally isolating the compound of
Formula X; [0035] iii) optionally purifying the compound of Formula
X; [0036] iv) converting the compound of Formula X to the acid salt
of piperidinyl biphenyl carboxamide derivative of formula III.
[0037] In another embodiment of the present invention provides
intermediate compound, 9-(4-acetoxybutyl-9H-fluorene-9-carboxylic
acid of Formula V
##STR00018##
which is useful in the preparation of Lomitapide or its
pharmaceutically acceptable salt thereof.
[0038] In another embodiment of the present invention provides
intermediate compound, 9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic
acid of Formula VI
##STR00019##
which is useful in the preparation of Lomitapide or its
pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The present invention relates to a process for the
preparation of Lomitapide or its pharmaceutically acceptable salt
thereof with acceptable levels of impurities, which comprises:
reacting the bromobutyl 9H-fluorene carboxamide derivative of
Formula II with salt of piperidinyl biphenyl carboxamide of Formula
III in a solvent selected from the group comprising of alcohols,
halogenated hydrocarbons, polar aprotic solvents, non-polar
solvents, wherein alcohols are selected from the group comprising
of aliphatic alcohols or aromatic alcohols, halogenated
hydrocarbons are selected from the group comprising of chlorinated
hydrocarbons, polar aprotic solvents are selected from the group
comprising of organic nitriles, amides, ketones, ethereal solvents,
esters in presence of a base selected from the group comprising of
alkyl amines or organo or inorgano metallic reagents, metal
hydrides, metal hydroxides or metal alkoxides to give Lomitapide
Free base and optionally purifying Lomitapide Free base. Optionally
converting Lomitapide free base to its pharmaceutically acceptable
salt thereof by reacting Lomitapide Free base with an acid in a
solvent selected from the group comprising of alcohols, halogenated
hydrocarbons, polar aprotic solvents, non-polar solvents to yield
Lomitapide pharmaceutically acceptable salt thereof and optionally
purifying Lomitapide pharmaceutically acceptable salt thereof.
##STR00020##
wherein X represents an acid salt.
[0040] In another embodiment of the present invention, aliphatic
alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol, pentanol, isobutanol,
tertiary butanol, cyclopropanol, cyclobutanol, cyclopentanol,
cyclohexanol or mixtures thereof, aromatic alcohols are selected
form the group comprising of phenols, benzylalcohol or mixtures
thereof; chlorinated hydrocarbons are selected from the group
comprising of chloroform, ethylene chloride, methylene dichloride
or mixtures thereof; organic nitriles are selected from the group
comprising of aliphatic nitriles such as C.sub.2-C.sub.8 nitrile;
Ketones are selected from the group comprising of aliphatic ketones
such as acetone, dimethyl formamide, methyl ethyl ketone, methyl
isobutyl ketone, cyclobutanone, cyclopentanone, cyclohexanone or
mixtures thereof; esters are selected from the group comprising of
methyl acetate, ethyl acetate, isopropyl acetate, isopropyl acetate
or mixtures thereof; non-polar solvents are selected from the group
comprising of butane, pentane, hexane, heptane, toluene, n-hexane,
n-heptane; and ethereal solvents are selected from the group
comprising of dimethyl ether, diethyl ether, diisopropyl ether,
tetrahydrofuran, 1,4-dioxane and the like.
[0041] In another embodiment throughout the invention, the mixture
of solvents means two or more solvents.
[0042] In another embodiment of the present invention, obtained
Lomitapide or its pharmaceutically acceptable salt can be
optionally purified by conventional methods.
[0043] The present invention also relates to a process for the
preparation of bromobutyl 9H-fluorene carboxamide derivative of
Formula II, which comprises: condensing 9H-fluorene-9-carboxylic
acid of Formula IV with 4-bromobutyl acetate in a solvent selected
from alcohols, halogenated hydrocarbons, polar aprotic solvents,
non-polar solvents, wherein alcohols are selected from the group
comprising of aliphatic alcohols or aromatic alcohols, halogenated
hydrocarbons are selected from the group comprising of chlorinated
hydrocarbons, polar aprotic solvents are selected from the group
comprising of organic nitriles, amides, ketones, ethereal solvents,
esters in presence of a base selected from the group comprising of
alkyl amines or organo or inorgano metallic reagents, metal
hydrides, metal hydroxides or metal alkoxides to yield
9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of Formula V and
optionally isolating the compound of Formula V thereafter reacting
with alkali hydroxide solution in a solvent to yield
9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of Formula VI.
Reacting the compound of formula VI with
2,2,2-trifluoroethane-1-amine hydrochloride salt in a solvent to
yield
9-(4-hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-carboxylic
acid of Formula VII and is reacting with bromine in a solvent to
yield bromobutyl 9H-fluorene carboxamide derivative of Formula II
and optionally purifying the compound of Formula II.
##STR00021##
[0044] In another embodiment of the present invention, aliphatic
alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol, pentanol, isobutanol,
tertiary butanol, cyclopropanol, cyclobutanol, cyclopentanol,
cyclohexanol or mixtures thereof, aromatic alcohols are selected
form the group comprising of phenols, benzylalcohol or mixtures
thereof; chlorinated hydrocarbons are selected from the group
comprising of chloroform, ethylene chloride, methylene dichloride
or mixtures thereof; organic nitriles are selected from the group
comprising of aliphatic nitriles such as C.sub.2-C.sub.8 nitrile;
Ketones are selected from the group comprising of aliphatic ketones
such as acetone, dimethyl formamide, methyl ethyl ketone, methyl
isobutyl ketone, cyclobutanone, cyclopentanone, cyclohexanone or
mixtures thereof; esters are selected from the group comprising of
methyl acetate, ethyl acetate, isopropyl acetate, isopropyl acetate
or mixtures thereof; non-polar solvents are selected from the group
comprising of butane, pentane, hexane, heptane, toluene, n-hexane,
n-heptane and ethereal solvents are selected from the group
comprising of dimethyl ether, diethyl ether, diisopropyl ether,
tetrahydrofuran, 1,4-dioxane and the like.
[0045] In another embodiment of the present invention, alkali
hydroxides used throughout the invention are selected form the
group comprising of sodium hydroxide, potassium hydroxide and the
like.
[0046] The present invention also relates to a process for the
preparation of piperidinyl biphenyl carboxamide derivative or acid
salt thereof of Formula III, which comprises: condensing
4'-(trifluoromethyl)-2-biphenyl carboxylic acid of Formula VIII
with 4-amino-1-benzylpiperidine of Formula IX in a solvent is
selected from alcohols, halogenated hydrocarbons, polar aprotic
solvents, non-polar solvents, wherein alcohols are selected from
the group comprising of aliphatic alcohols or aromatic alcohols,
halogenated hydrocarbons are selected from the group comprising of
chlorinated hydrocarbons, polar aprotic solvents are selected from
the group comprising of organic nitriles, amides, ketones, ethereal
solvents or esters to yield
N-(1-benzylpiperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxa-
mide of Formula X and optionally isolating and purifying the
compound of Formula X. The obtained compound of Formula X is
debenzylated using a metal catalyst to give the compound of Formula
IIIa and is reacted with an acid selected from organic or inorganic
acids to yield the compound of formula III.
##STR00022##
wherein X represents an acid salt.
[0047] In another embodiment of the present invention, aliphatic
alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol, pentanol, isobutanol,
tertiary butanol, cyclopropanol, cyclobutanol, cyclopentanol,
cyclohexanol or mixtures thereof, aromatic alcohols are selected
form the group comprising of phenols, benzylalcohol or mixtures
thereof; chlorinated hydrocarbons are selected from the group
comprising of chloroform, ethylene chloride, methylene dichloride
or mixtures thereof; organic nitriles are selected from the group
comprising of aliphatic nitriles such as C.sub.2-C.sub.8 nitrile;
Ketones are selected from the group comprising of aliphatic ketones
such as acetone, dimethyl formamide, methyl ethyl ketone, methyl
isobutyl ketone, cyclobutanone, cyclopentanone, cyclohexanone or
mixtures thereof; esters are selected from the group comprising of
methyl acetate, ethyl acetate, isopropyl acetate, isopropyl acetate
or mixtures thereof; non-polar solvents are selected from the group
comprising of butane, pentane, hexane, heptane, toluene, n-hexane,
n-heptane and ethereal solvents are selected from the group
comprising of dimethyl ether, diethyl ether, diisopropyl ether,
tetrahydrofuran, 1,4-dioxane and the like.
[0048] In another embodiment of the present invention, alkyl amines
used throughout the invention are selected form the group
comprising of diethylamine, triethylamine and the like; organo or
inorgano metallic reagents used throughout the invention are
selected form the group comprising of n-butyl lithium, sec-butyl
lithium, t-butyl lithium and the like; metal hydrides used
throughout the invention are selected form the group comprising of
sodium hydride, potassium hydride and lithium hydride and the like;
metal hydroxides used throughout the invention are selected form
the group comprising of sodium hydroxide, potassium hydroxide,
lithium hydroxide and the like; metal alkoxides used throughout the
invention are selected form the group comprising of sodium
methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide
and the like.
[0049] In another embodiment of the present invention, acid salt
used throughout the invention is selected from the group comprising
of organic acid salts like acetate salt, formate salt, oxalate,
methane sulfonate salt; inorganic acid salts like hydrochloride
salt, hydrobromide salt and the like.
[0050] In another embodiment of the present invention, metal
catalyst used throughout the invention is selected form the group
comprising of palladium and platinum and the like.
[0051] In another embodiment of the present invention provides a
compound, 9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of
Formula V useful in the process for the preparation of Lomitapide
or its pharmaceutically acceptable salt thereof.
##STR00023##
[0052] In another embodiment of the present invention, obtained
compound of formula V can be optionally isolated and purified by
conventional methods.
[0053] In another embodiment of the present invention provides a
compound, 9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of
Formula VI useful in the process for the preparation of Lomitapide
or its pharmaceutically acceptable salt thereof.
##STR00024##
[0054] In another embodiment of the present invention, obtained
compound of formula VI can be optionally isolated and purified by
conventional methods.
[0055] The invention of the present application will be explained
in more detail with reference to the following examples, which
should not be construed as limiting the scope of the invention in
any manner.
EXAMPLES
Preparation of
9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl-9H-fluorene-9-carboxamide
of Formula III
[0056] To a solution of 9-fluorecarboxylic acid (50 g, 240 mmol) in
THE (1200 mL) at 0.degree. C., was added dropwise a solution of
n-butyl lithium (2.5M, 211 mL, 530 mmol) in THF. The yellow
reaction was stirred at 0.degree. C. for 1 h, then
1,4-dibromobutane (31.3 mL, 260 mmol) was added dropwise over 30
min. The reaction was stirred at 0.degree. C. for 30 min, then the
reaction was warmed to RT for 30 h. HCl solution (1N, 500 mL) was
added, then extracted with dichloromethane (3.times.750 mL) to give
9-(4-bromobutyll)-9H-fluorene-9-carboxylic acid (71 g, 85%) as a
white solid.
[0057] To a solution of above obtained acid (60 g, 173 mmol) and
DMF (100 .mu.L) in CH.sub.2Cl.sub.2 (600 mL) under argon at
0.degree. C. was added oxalyl chloride (104 mL, 2.0M in
CH.sub.2Cl.sub.2, 208 mmol) drop wise. The reaction was stirred at
0.degree. C. for 10 min, then warmed to RT and stirred for 1.5 h.
The reaction was concentrated to give the crude acid chloride as
yellow oil. To a suspension of 2,2,2-trifluoroethylamine
hydrochloride (25.9 g, 191 mmol) in CH.sub.2Cl.sub.2 (500 mL) at
0.degree. C. under argon was added triethylamine (73 mL, 521 mmol)
followed by drop wise addition of a solution of the crude acid
chloride in CH.sub.2Cl.sub.2(15 mL). The reaction was stirred at
0.degree. C. for 1 h, diluted with CH.sub.2Cl.sub.2 (500 mL), and
washed with water (2.times.300 mL), 1N HCl (2.times.300 mL) to give
80 g of an oil which was purified by flash chromatography on silica
gel (2.5 kg). The crude product was loaded in a mixture of
CH.sub.2Cl.sub.2 and hexane, and eluted with a step gradient of 10%
EtOAc/hexane (4L) to 15% EtOAc/hexane (2L) to 20% EtOAc/hexane
(4L). Pure fractions were combined and evaporated to give
9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl-9H-fluorene-9-carboxamide
of formula II as a white solid.
[0058] Yield: 52.5 gm.
[0059] Chromatographic purity (by HPLC): .ltoreq.90%.
[0060] Dimer impurity A: 12.11%.
Preparation of
N-(1-Piperidin-4-yl)-4,-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide
Compound of Formula IIIa
[0061] To a slurry of 4'-(trifluoromethyl)-2-biphenyl carboxylic
acid of Formula VIII (50.0 g, 190 mmol) in methylene chloride (500
ml) was added the oxalyl chloride (28.7 ml, 330 mmol) followed by
DMF (5 drops). The reaction mixture was stirred and the residue was
dissolved in methylene chloride (400 ml). This solution was added
drop wise to a solution of 4-amino-1-benzylpiperidine of Formula IX
(36.4 ml, 180 mmol) and triethylamine (65.4 ml, 470 mmol) in
methylene chloride (300 ml). The reaction was diluted with
methylene chloride (600 ml) and washed with saturated NaHCO.sub.3
and 1N KOH. The organic layer was dried with Na.sub.2SO.sub.4, and
the solvent removed to give a white solid. This solid was
recrystallized from hot EtOH (1 L) and washed with heptane to give
N-(1
-benzylpiperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-c-
arboxamide compound of Formula X as a white solid (59.1 g, 75.6%
yield). The mother liquor was concentrated to dryness and
recrystallized from hot EtOH (300 ml) and washed with heptane to
give
N-(1-benzylpiperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxa-
mide compound of Formula X as a white solid.
[0062] Yield: 12.7 gm.
[0063] To a solution of benzylpiperidinyl biphenyl carboxamide
derivative of Formula X (59.0 g, 130 mmol) in methanol (300 ml) and
ethanol (300 ml) was added the cyclohexene (150 ml, 1.5 mol) and
20% palladium hydroxide on carbon (11.8 g). The reaction was heated
to reflux (80.degree. C.) and stirred at that temperature 2.5 h.
The hot mixture was filtered and washed with methanol and then
solvent was removed to give
N-(1-piperidin-4-yl)-4,-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide
compound of Formula IIIa as a white solid.
[0064] Yield: 46.7 gm.
[0065] Chromatographic purity (by HPLC): .ltoreq.91%.
[0066] Dimer impurity B: 6%.
Preparation of Lomitapide Free Base
[0067] To a stirred solution of
N-(1-piperidin-4-yl)-4,-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide
compound of Formula Ma (18.0 g, 49 mmol) in dimethyl formamide (100
ml) at room temperature was added potassium carbonate (12.6 g, 49
mmol) followed by
9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl-9H-fluorene-9-carboxamide
of formula II (21.0 g, 49 mmol). The reaction was heated to
50.degree. C. and stirred at that temp under argon 24 h. After
cooling, the reaction was filtered to remove potassium carbonate,
and the filter cake was rinsed with ethyl acetate. The filtrate was
partitioned between 20% heptane in ethyl acetate and water. The
organic layer was dried (Na.sub.2SO.sub.4) and the solvent removed
in vacuo to give a solid (30 g). This solid was recrystallized from
300 ml 25% ethyl acetate in heptane to give Lomitapide Free base as
an off-white solid (27.0 g, 78.9% yield).
[0068] Yield: 27.0 gm.
[0069] Chromatographic purity (by HPLC): .ltoreq.85%.
Example 1
Preparation of 9-(4-Acetoxybutyl)-9H-fluorene-9-carboxilic Acid of
Formula V
[0070] Tetrahydrofuran (1700 ml) was added to the
9H-fluorene-9-carboxylic acid (100 gm) at room temperature then the
reaction mass was cooled to -20 to -30.degree. C. n-butyl lithium
(67 gm) was added slowly at -20 to -30.degree. C. for 60 to 90
minutes and maintained for 60 to 70 minutes at -20 to -30.degree.
C. 4-bromobutyl acetate (185 gm) was added then the reaction mass
was cooled to room temperature and maintained for 17 hours. After
completion of the reaction, DM water was added to the reaction
mixture and stirred for 30 minutes at room temperature to yield
9-(4-acetoxybutyl)-9H-fluorene-9-carboxilic acid of Formula V.
Example 2
Preparation of 9-(4-Hydroxybutyl)-9H-fluorene-9-carboxilic Acid of
Formula VI
[0071] To the above reaction mixture, 10% NaOH solution was added
at room temperature. After completion of the reaction, reaction
mass was washed with dichloromethane and pH was adjusted to 1 to
1.5 with 50% HCl solution. Filtered the solid and washed with DM
water then dried at room temperature to yield crude
9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid. Charged
Dichloromethane to the above solid at room temperature and stirred
for 5 to 6 hours at room temperature. Filtered the solid and washed
with dichloromethane then dried the material to yield pure
9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of formula VI.
[0072] Yield: 107 gm.
[0073] Chromatographic purity (by HPLC): 96.6%.
Example 3
Preparation of
9-(4-Hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula VII
[0074] Charged dichloromethane (500 ml) to the above solid (100 gm)
at room temperature and then cooled to 0 to 10.degree. C.
2,2,2-trifluoroethan-1-amine HCl salt (57 gm) was added and
followed by adding DM water and dichloromethane (200 ml). 10% NaOH
solution was added at 0 to 10.degree. C. and the layers ware
separated. The aqueous layer was washed with dichoromethane (200
ml). Combined the layers and charged 3-(ethylimino
methyleneamino)-N,N-dimethyl-propan-1-amine HCl (EDC1.HCl) (71 gm).
Reaction mass was maintained for 1 hour to 1 hour 30 minutes at 0
to 10.degree. C. and filtered the mass then washed with
dichloromethane. Distilled off the solvent completely and added
acetonitrile (300 ml) to the obtained product and added slowly DM
water then stirred for 14 hours to 15 hours. Filtered the solid and
washed with diisopropyl ether (300 ml) and dried to yield
9-(4-Hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula VII.
[0075] Yield: 90 gm
[0076] Chromatographic purity (by HPLC): 97.3%.
Example 4
Preparation of
9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula II
[0077] To the above 9H-fluorene-9-carboxamide derivative of formula
VII (100 gm), triphenylphosphine (144 gm) and dichloromethane (500
ml) were added at 25 to 30.degree. C. then cooled to 0.degree. C.
to 10.degree. C. Bromine solution (88 gm of bromine and 400 ml of
dichloromethane) was added to the above reaction mixture then
maintained for 15 to 30 minutes at 0.degree. C. to 10.degree. C.
Reaction mixture was heated to 25 to 30.degree. C. After the
completion of reaction, sodium thiosulphate solution was added and
stirred for 10 minutes then layers were separated. Organic layer
was washed with 10% NaOH solution and DM water then distilled the
layer followed by drying. diisopropyl ether (800 ml) was added and
stirred for hours at 20 to 30.degree. C. Filtered the solid and
washed with diisopropyl ether (600 ml). Distilled the solid and
filtered the reaction mixture and washed with dichloromethane (1000
m1). Filtered the solid and washed with hexane then dried to yield
9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula II.
[0078] Yield: 85 gm.
[0079] Chromatographic purity (by HPLC): 98.6%.
Example 5
Preparation of
N-(1-Benzylpiperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxa-
mide of Formula X
[0080] Charged 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic
acid of Formula VIII (100 gm) and acetonitrile (1000 ml) at 25 to
30.degree. C. and then stirred for 5 minutes to 10 minutes. Charged
4-amino-1-benzylpiperidine of Formula IX (70 gm) to the above
reaction mixture and stirred for 5 minutes to 10 minutes at 25 to
30.degree. C. Hydroxybenzotriazole (HOBT) (7 gm) was added and
stirred for 5 minutes to 10 minutes at 25 to 30.degree. C. To the
above reaction mixture, EDC.HCl (80 gm) and acetonitrile (500 ml)
were added at 25 to 30.degree. C. and then stirred for 3 hours to 3
hours 30 minutes. Filtered the solid and washed with acetonitrile
(300 ml) and then dried the material at 35 to 40.degree. C. for 5
to 6 hours to yield
N-(1-benzylpiperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxa-
mide of Formula X.
[0081] Yield: 140 gm
[0082] Chromatographic purity (by HPLC): 99%.
Example 6
Preparation of Hydrochloride salt of
N-(1-Piperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide
of Formula III
[0083] To the benzylpiperidinyl biphenyl carboxamide derivative of
Formula X (100 gm) compound, added methanol (1200 ml) and 10% Pd/C
in DM water. Reaction mixture was heated to 45 to 55.degree. C. and
maintained for 3 hours to 3 hours 30 minutes. The reaction mixture
was cooled to 25 to 30.degree. C. and filtered the material and
washed with methanol (400 ml). Methanol was distilled-off
completely at 45 to 50.degree. C. Methanol (200 ml) was added at 25
to 30.degree. C. and stirred for 5 minutes at room temperature.
Conc.Hydrochloric acid (200 ml) was added and stirred for 15
minutes to 20 minutes at 30 to 35.degree. C. DM water was added and
maintained for 1 hour to 1 hour 30 minutes at 30 to 35.degree. C.
and filtered the solid then washed with water. Dried the material
to yield hydrochloride salt of
N-(1-Piperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide
of Formula III.
[0084] Yield: 60 gm
[0085] Chromatographic purity (by HPLC): 97.8%.
Example 7
Preparation of Lomitapide Free Base
[0086] Charged
N-(1-piperidin-4-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide
hydrochloride salt of Formula III (100 gm) and dimethyl formamide
(300 ml) to the
9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
of Formula II (121 gm) at 25 to 30.degree. C. and stirred for 15 to
20 minutes. Triethylamine (78 gm) was added to the above reaction
mixture for 30 minutes to 45 minutes at room temperature. The
reaction mixture was maintained for 21 hours to 23 hours at 25 to
30.degree. C. Filtered the sold and washed with dimethyl formamide
(100 ml) and the layers were separated. DM Water was added to the
organic layer and then combined the layers at 25 to 30.degree. C.
Maintained the reaction mixture for 6 hours to 7 hours at room
temperature and filtered the solid and washed with water.
Acetonitrile was added and heated to 75 to 80.degree. C. The
obtained clear solution was cooled to room temperature and stirred
for 90 hour 120 minutes at 25 to 30.degree. C. Filtered the solid
and washed with acetonitrile and dried the compound to yield
Lomitapide Free base.
[0087] Yield: 60 gm.
[0088] Chromatographic purity (by HPLC): 99.8%.
Example 8
Preparation of Lomitapide Mesylate
[0089] Charged methanol (250 ml) at to Lomitapide free base (50 gm)
at 25 to 30.degree. C. and cooled to 0 to -10.degree. C. Methane
sulfonic acid (6 gm) was added at 0 to -10.degree. C. for 30
minutes to 45 minutes. Maintained the above obtained reaction
mixture at 0 to -10.degree. C. for 45 minutes to 60 minutes.
Activated carbon was added at 0 to -10.degree. C. and maintained
for 30 minutes to 60 minutes. Filtered the material and washed with
methanol (200 ml) and methanol was distilled off completely at 35
to 40.degree. C. and followed by drying to yield Lomitapide
Mesylate.
[0090] Yield: 55 gm.
* * * * *