WO2016012934A1 - Process for making lomitapide mesylate - Google Patents

Process for making lomitapide mesylate Download PDF

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Publication number
WO2016012934A1
WO2016012934A1 PCT/IB2015/055508 IB2015055508W WO2016012934A1 WO 2016012934 A1 WO2016012934 A1 WO 2016012934A1 IB 2015055508 W IB2015055508 W IB 2015055508W WO 2016012934 A1 WO2016012934 A1 WO 2016012934A1
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Prior art keywords
formula
lomitapide
solvent
process according
group
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PCT/IB2015/055508
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French (fr)
Inventor
Lakshmana Rao Vadali
Eswara Reddy YERVA
Govardhana Phani Sharma VEMAVARAPU
Padala Bhaskar RAO
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Mylan Laboratories Ltd
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Publication of WO2016012934A1 publication Critical patent/WO2016012934A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates generally to the field of pharmaceutical sciences, and more specifically to providing an improved process for preparing lomitapide and its pharmaceutically acceptable salts.
  • the present invention further relates to amorphous forms of pharmaceutically acceptable salts (e.g., mesylate) of lomitapide.
  • Lomitapide mesylate which has the IUPAC name N-(2,2,2-trifluoroethyl)-9-[4-[4- [[[4'(trifluoromethyl) [ 1 , 1 '-biphenyl] -2-yl]carbonyl] amino] - 1 -piperidinyl] butyl] -9H-fluorene- 9-carboxamide, methane sulfonic acid salt is a microsomal triglyceride transfer protein ("MTP”) inhibitor.
  • MTP microsomal triglyceride transfer protein
  • Lomitapide mesylate is marketed in the United States as JUXTAPID® and is indicated for use as an adjunct to a low-fat diet and other lipid-lowering treatments to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia.
  • JUXTAPID® is formulated as a hard gelatin capsule in strengths of 5, 10, and 20 mg and is administered orally at a dosage of 5 to 60 mg/day.
  • the present invention provides a method for the simple and efficient preparation of lomitapide using simple bases.
  • the processes disclosed herein also provide novel intermediates that may be formed during the preparation of lomitapide.
  • the present invention further provides pharmaceutically acceptable salts (e.g., mesylate) of lomitapide in an amorphous form.
  • pharmaceutically acceptable salts e.g., mesylate
  • the present invention provides an improved process for the preparation of lomitapide.
  • One aspect of the present invention provides a process for the preparation of lomitapide which includes the steps of: a) reacting formula 2 with formula 9 to give formula 3 ;
  • step a) to step e) above may be carried out in the presence of a base and a suitable solvent.
  • the present invention further provides pharmaceutically acceptable salts (e.g., mesylate) of lomitapide in amorphous form.
  • pharmaceutically acceptable salts e.g., mesylate
  • Another aspect of the present invention provides a process of preparing lomitapide mesylate that includes the steps of: a) reacting lomitapide free base with methane sulfonic acid in a solvent; b) removing the solvent; and c) isolating lomitapide mesylate.
  • FIGURE 1 is an X-ray powder diffractogram of the amorphous form of lomitapide mesylate.
  • the present invention provides an improved process for the preparation of lomitapide which may be carried out according to Scheme-I below.
  • Scheme-I may be broken down into steps as below: a) reacting formula 2 with formula 9 to give formula 3 ;
  • a substituent represented as 'R' in the scheme above may be a Ci_5 straight or branched alkyl group.
  • suitable Ci_5 straight or branched alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, and isobutyl.
  • One of skill in the art would be familiar with other C 1-5 straight or branched alkyl groups that may be used in the context of the present invention.
  • a substituent represented as 'X' in the scheme above is a leaving group, which may be the same or different in each occurrence.
  • Suitable leaving groups may be, for example, halides or sulfonyl ester groups.
  • Suitable halides include fluoride, chloride, bromide, and iodide.
  • suitable sulfonyl ester groups include O-mesyl, O-tosyl, and O-trifluoromethanesulfonyl groups.
  • step a) may be performed by reacting formula 2 with formula 9 in the presence of a base and a solvent to give formula 3.
  • Formula 9 is a 1,4- di-halo butane, for example, 1,4-di-fluorobutane, 1,4-di-chlorobutane, 1,4-di-bromobutane, or 1 ,4-di-iodobutane.
  • formula 2 is substituted with a methyl group in the 'R' position (methyl 9H-fluorene-9-carboxylate) and is reacted with 1,4-dibromo butane (formula 9) to form a formula 3a (methyl 9-(4-bromobutyl)-9H- fluorene-9-carboxylate), shown below, which is a resulting embodiment of formula 3.
  • step a) may be carried out in the presence of a base and a solvent.
  • the base used in step a) may be an inorganic base or an organic base.
  • suitable inorganic bases include potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 C0 3 ), barium carbonate (BaCCh), potassium bicarbonate (KHCO 3 ), sodium carbonate (NaHCC ⁇ ), barium carbonate (BaCC ⁇ ), cesium carbonate (CSCO 3 ), calcium carbonate (CaCC ⁇ ), sodium hydroxide (NaOH), potassium hydroxide (KOH), and mixtures thereof.
  • Suitable organic bases include, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine, and mixtures thereof.
  • the solvent used in step a) may be, for example, an ether solvent, a ketone solvent, a polar aprotic solvent, or mixtures thereof.
  • suitable ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • Suitable ketone solvents include, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
  • Suitable polar aprotic solvents include, for example, dimethylformamide, acetonitrile, and dimethylsulfoxide. In some embodiments of the present invention, dimethyl formamide was found to be a particularly useful solvent.
  • step b) may be performed by condensing formula 3 with formula 4 in the presence of a base and a solvent to give formula 5.
  • formula 3 is formula 3a (methyl 9-(4-bromobutyl)-9H-fluorene-9-carboxylate), described above.
  • the reaction of formula 3a with formula 4 results in formula 5a (methyl 9- ⁇ 4-[4-( ⁇ [4'- (trifluoromethyl)biphenyl-2-yl]carbonyl ⁇ amino )piperidin-l-yl]butyl ⁇ -9H-fluorene-9- carboxylate) shown below, which is a resulting embodiment of formula 5.
  • step b) may be carried out in the presence of a base and a solvent.
  • the base used in step b) may be inorganic or organic.
  • suitable inorganic bases include potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 C0 3 ), barium carbonate (BaC0 3 ), potassium bicarbonate (KHC0 3 ), sodium carbonate (NaHC0 3 ), barium carbonate (BaC0 3 ), cesium carbonate (CsC0 3 ), calcium carbonate (CaC0 3 ), sodium hydroxide (NaOH), potassium hydroxide (KOH) and mixtures thereof.
  • Suitable organic bases include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and mixtures thereof.
  • the solvent used in step b) may be, for example, an ether solvent, a ketone solvent, a polar aprotic solvent, or mixtures thereof.
  • suitable ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • suitable ketone solvents including acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
  • Suitable polar aprotic solvents include, for example, dimethylformamide, acetonitrile, and dimethylsulfoxide. In some embodiments of the present invention, dimethyl formamide was found to be a particularly useful solvent.
  • formula 5, which was formed in step b) may optionally be converted into an acid addition salt before proceeding to step c).
  • Suitable acids useful for the formation of salts include, for example, hydrochloric acid, hydrobromic acid, benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p- toluenesulfonic acid, methanesulfonic acid, and malic acid.
  • hydrochloric acid was found to be a particularly useful acid for converting formula 5 to an acid addition salt.
  • step c) may be performed by converting formula 5 (or an acid addition salt thereof) into formula 6 by reacting formula 5 with a base and a solvent.
  • suitable bases for step c) include sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 C0 3 ), potassium bicarbonate (KHCO 3 ), sodium carbonate (NaHCC ⁇ ), barium carbonate (BaCC ⁇ ), cesium carbonate (CSCO 3 ), calcium carbonate (CaCC ⁇ ), and mixtures thereof.
  • sodium hydroxide (NaOH) was found to be particularly useful base.
  • suitable solvents for step c) include alcohols, ether solvents, chlorinated solvents, ketone solvents, and mixtures thereof.
  • suitable alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol.
  • suitable ether solvents include, for example, methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • suitable chlorinated solvents include chloroform, dichloromethane, and dichloroethane.
  • Suitable ketone solvents include, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
  • formula 5 is formula 5a (methyl 9- ⁇ 4-[4-( ⁇ [4'-(trifluoromethyl)biphenyl-2-yl] carbonyl ⁇ amino)piperidin- 1 -yl]butyl ⁇ - 9H-fluorene-9-carboxylate), described above.
  • a mixture of methanol and tetrahydrofuran was found to be a particularly useful solvent mixture for carrying out the conversion of step c).
  • step d) may be performed by amidating formula 6 to form lomitapide (formula 1).
  • this conversion may be achieved by first converting formula 6 into its acid halide (not shown in the above schemes) in the presence of a halogenating agent and a halogenated solvent. The acid halide of formula 6 may then be amidated to make lomitapide.
  • formula 6 is converted into its acid chloride by treating formula 6 with a chlorinating agent in a solvent.
  • Suitable chlorinating agents include, for example, thionyl chloride (SOCl 2 ), phosphoryl chloride (POCI 3 ), phosphorous trichloride (PCI 3 ), phosphorous pentachloride (PCI 5 ), and mixtures thereof.
  • the solvent may be a chlorinated solvent, for example, chloroform, dichloromethane, dichloroethane, or mixtures thereof. In particularly useful embodiments of the present invention, dichloromethane was found to be a particularly useful solvent.
  • the acid halide form of formula 6 may next be amidated in the presence of a base and a solvent to complete step d) and give lomitapide.
  • the acid chloride of formula 6 is amidated with 2,2,2-trifluoro ethylamine or a salt thereof.
  • Suitable bases for amidating the acid halide of formula 6 include, for example, triethylamine, diisopropylethylamine, N- methylmorpholine, pyridine, lutidine, DBU, DBN, picoline, and mixtures thereof.
  • triethylamine was found to be particularly useful base.
  • the solvent may be a chlorinated solvent, for example, chloroform, dichloromethane, dichloroethane, or mixtures thereof. In particularly useful embodiments of the present invention, dichloromethane was found to be a particularly useful solvent.
  • the amidation of formula 6 to give lomitapide of formula 1 may alternatively be carried out by processes well-known in the art, for example, by using coupling agents.
  • Suitable coupling agents include, for example, EDCI and DCC.
  • Amidation may also be carried out using a mixture of anhydrides and appropriate reagents, for example, ethylchloroformate.
  • One of skill in the art will be familiar with various methods by which the amidation of step e) may be achieved.
  • lomitapide (formula 1) may be optionally converted into a pharmaceutically acceptable salt as in step e).
  • Acids useful for the formation of pharmaceutically acceptable salts include, for example, hydrochloric acid, hydrobromic acid, methanesulfonic acid, benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluenesulfonic acid, and malic acid. Methanesulfonic acid was found to be a particularly useful acid in forming a salt of lomitapide.
  • Another aspect of the present invention provides novel intermediate compounds of formula 3, formula 5, and formula 6 shown below.
  • a substituent represented as "R” in the scheme above may be a C 1-5 straight or branched alkyl group.
  • suitable C 1-5 straight or branched alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, and isobutyl.
  • Ci_5 straight or branched alkyl groups that may be used in the context of the present invention.
  • Another aspect of the present invention provides novel compounds of formula 3 a and formula 5a and the usage of formula 3a and formula 5a for the preparation of lomitapide or pharmaceutically acceptable salts thereof.
  • the compound of formula 3 or 3 a may be hydrolyzed to yield formula 3b according to the processes well known in the art.
  • formula 3b may be further converted into lomitapide or its pharmaceutically acceptable salts by conventional methods, such as those disclosed in U.S. Patent No. 5,739,135.
  • lomitapide mesylate may be prepared by reacting lomitapide free base with methanesulfonic acid in a solvent. The solvent may then be subsequently removed by methods well known in the art, providing lomitapide mesylate. The composition may then be optionally treated with a non-polar solvent to improve the purity and quality of the product.
  • lomitapide mesylate may be prepared by the following process: a) reacting lomitapide free base with methanesulfonic acid in a solvent ;
  • step a) above may be carried out by reacting lopitamide free base with methanesulfonic acid in a solvent.
  • the resulting solution may then be stirred over a period of about 2 to about 5 hours.
  • the solvent used in step a) may be, for example, aliphatic alcohols, ester solvents, ether solvents, chlorinated solvents, ketone solvents, polar solvents, and mixtures thereof.
  • Suitable aliphatic alcohols include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol.
  • ester solvents examples include ethyl acetate, methyl acetate, and butyl acetate.
  • useful ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • Suitable chlorinated solvents include, for example, chloroform, dichloromethane, and dichloroethane.
  • ketone solvents examples include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
  • polar solvents examples include water, dimethylformamide, acetonitrile, and dimethylsulfoxide.
  • methanol, acetone, ethyl acetate, and isopropyl alcohol were found to be particularly useful solvents.
  • step b) may be carried out by removing the solvent using methods well known to one of skill in the art, for example, under reduced pressure, to obtain a solid residue.
  • step c) may be optionally performed by treating the solid residue formed in step b) with a non-polar solvent to obtain pure lomitapide mesylate.
  • non-polar solvents include n-hexane, cyclohexane, n-heptane, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof.
  • diisopropyl ether, n-hexane, or a mixture of diisopropyl ether and n-hexane were all found to be particularly useful solvents.
  • Another aspect of the present invention provides a process for the preparation of amorphous lomitapide mesylate which may include the following steps: a) reacting lomitapide free base with methanesulfonic acid in a solvent; b) removing the solvent; c) adding a non-polar solvent; and d) isolating amorphous lomitapide mesylate.
  • step a) above may be carried out by reacting lopitamide free base with methansolfonic acid in a solvent.
  • the resulting solution may thenbe stirred over a period of about 2 to about 5 hours.
  • the solvent used in step a) may be, for example, aliphatic alcohols, aromatic alcohols, ester solvents, ether solvents, chlorinated solvents, ketone solvents, polar solvents, and mixtures thereof.
  • Suitable aliphatic and aromatic alcohols include, for example, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol.
  • ester solvents examples include ethyl acetate, methyl acetate, and butyl acetate.
  • useful ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran.
  • Suitable chlorinated solvents include, for example, chloroform, dichloromethane, and dichloroethane.
  • ketone solvents examples include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
  • polar solvents examples include water, dimethylformamide, acetonitrile, and dimethylsulfoxide.
  • methanol, acetone, ethyl acetate, and isopropyl alcohol were found to be particularly useful solvents.
  • step b) may be carried out by removing the solvent using methods well known to one of skill in the art, for example, under reduced pressure, to obtain a solid residue.
  • step c) may be performed by treating the solid residue formed in step b) with a non-polar solvent to obtain pure lomitapide mesylate.
  • non-polar solvents include n-hexane, cyclohexane, n-heptane, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof.
  • diisopropyl ether, n-hexane, or a mixture of diisopropyl ether and n- hexane were all found to be particularly useful solvents.
  • the amorphous form of lomitapide mesylate of the present invention may be characterized by its powder X-ray diffraction (PXRD) pattern.
  • PXRD powder X-ray diffraction
  • the X-ray diffraction pattern of the amorphous form of lomitapide mesylate was measured on a BRUKER D-8 Discover powder diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • FIG. 1 shows the PXRD pattern of amorphous lomitapide mesylate.
  • the lomitapide mesylate compositions disclosed herein may be formulated in a variety of dosage forms for delivery to human and non-human patients.
  • Lomitapide mesylate may be formulated in an oral dosage form, such as a tablet, capsule, or liquid.
  • the dosage form may be formulated as an immediate- release, extended-release, sustained-release, or delayed-release formulation.
  • modified- release properties may be obtained through employing coatings and/or matrices that enable modified release of lomitapide mesylate.
  • lomitapide mesylate may be incorporated into dosage forms with a variety of excipients well known in the art, for example, pre-gelatinized starch, sodium starch glycolate, microcrystalline cellulose, lactose monohydrate, silicon dioxide, and magnesium stearate. Coatings of formulations in capsule form may contain gelatin and titanium dioxide.
  • dosage forms may have from about 5 to about 60 milligrams of lomitapide. In particularly useful embodiments of the present invention, dosage forms have 5, 10, or 20, 30, 40, or 60 milligrams of lomitapide mesylate.
  • Lomitapide may also be included in an injectable formulation, using methods and components well known to those of skill in the art.
  • Lomitapide mesylate When administered to human and non-human patients, formulations of lomitapide mesylate may be adjusted to compensate for the age, weight, and physical condition of the patient.
  • Lomitapide mesylate may be administered over a wide dosage range from about 5 to about 500 milligrams per day with about 5 to about 60 milligrams having particular utility.
  • Lomitapide mesylate of the present invention may be administered in combination with, prior to, or after dosing regimens of other lipid-modifying compounds, for example, mipomersen (KYNAMRO ® ), atorvastatin (LIPITOR ® ), ezetimibe (ZETIA ® ), and fenofibrate (TRICOR ® ).
  • the lomitapide mesylate of the present invention When administered to patients, the lomitapide mesylate of the present invention may be useful for preventing, treating, or stabilizing atherosclerosis. Additionally, the lomitapide mesylate of the present invention may be useful in lowering serum lipid levels, such as cholesterol or triglyceride levels. The lomitapide mesylate of the present invention may also be useful in the prevention, treatment, or stabilization of hypercholesterolemia, hypertriglyceridiemia, hyperlipidemia, pancreatitis, hyperglycemia, and obesity, in addition to diseases and disorders that are precipitated by or associated with those conditions. Those conditions may be genetically linked or idiopathic.
  • Example 8 Preparation of hydrochloride salt of formula 5a (methyl 9- ⁇ 4-[4-( ⁇ [4'- (trifluoromethyl)biphenyl-2-yl]carbonyl ⁇ amino)piperidin-l-yl]butyl ⁇ -9H-fluorene-9- carboxylate hydrochloride)
  • the formed precipitate was filtered and dried to yield 9- ⁇ 4-[4-( ⁇ [4'-(trifluoromethyl)biphenyl-2-yl] carbonyl ⁇ amino)piperidin- 1 -yl]butyl ⁇ -9H- fluorene-9-carboxylate as an off white solid.
  • the obtained solid was dissolved in toluene, and HC1 was added followed by water at RT and stirred at same temperature for 4 h. The resulting solid was filtered and washed with toluene, water and dried to yield substantially pure formula 5a as an off white solid.
  • Example 12 Preparation of lomitapide of formula 1 (N-(2,2,2-trifluoroethyl)-9- ⁇ 4-[4- ( ⁇ [4'-(trifluoromethyl)biphenyl-2-yl]carbonyl ⁇ amino)piperidin-l-yl]butyl ⁇ -9H-fluorene-
  • Example 13 Preparation of lomitapide of formula 1 (N-(2,2,2-trifluoroethyl)-9- ⁇ 4-[4- ( ⁇ [4'-(trifluoromethyl)biphenyl-2-yl]carbonyl ⁇ amino)piperidin-l-yl]butyl ⁇ -9H-fluorene-

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Abstract

The present disclosure provides a process for lomitapide and its pharmaceutically acceptable salts. The present disclosure further provides pharmaceutically acceptable salts (e.g., 5 mesylate) of lomitapide in amorphous form.

Description

PROCESS FOR MAKING LOMITAPIDE MESYLATE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application, in its entirety, claims the benefit of earlier Indian provisional patent applications No. 3561/CHE/2014 filed on July 21, 2014 and 4418/CHE/2014 filed on Sep 09, 2014.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates generally to the field of pharmaceutical sciences, and more specifically to providing an improved process for preparing lomitapide and its pharmaceutically acceptable salts. The present invention further relates to amorphous forms of pharmaceutically acceptable salts (e.g., mesylate) of lomitapide.
BACKGROUND OF THE INVENTION
Lomitapide mesylate, which has the IUPAC name N-(2,2,2-trifluoroethyl)-9-[4-[4- [[[4'(trifluoromethyl) [ 1 , 1 '-biphenyl] -2-yl]carbonyl] amino] - 1 -piperidinyl] butyl] -9H-fluorene- 9-carboxamide, methane sulfonic acid salt is a microsomal triglyceride transfer protein ("MTP") inhibitor. The chemical structure of lomitapide mesylate is shown below:
Lomitapide Mesylate
Lomitapide mesylate is marketed in the United States as JUXTAPID® and is indicated for use as an adjunct to a low-fat diet and other lipid-lowering treatments to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia. JUXTAPID® is formulated as a hard gelatin capsule in strengths of 5, 10, and 20 mg and is administered orally at a dosage of 5 to 60 mg/day.
U.S. Patent Nos. 5,712,279 and 5,739,135, which are hereby incorporated by reference, disclose methods of preparing lomitapide and its intermediates. These processes include drawbacks such as employing chemicals that may be difficult to handle. Therefore, there is a need in the art for a simpler process for preparing lomitapide.
The present invention provides a method for the simple and efficient preparation of lomitapide using simple bases. The processes disclosed herein also provide novel intermediates that may be formed during the preparation of lomitapide.
The present invention further provides pharmaceutically acceptable salts (e.g., mesylate) of lomitapide in an amorphous form.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of lomitapide.
One aspect of the present invention provides a process for the preparation of lomitapide which includes the steps of: a) reacting formula 2 with formula 9 to give formula 3 ;
Figure imgf000003_0001
b) condensing formula 3 with formula 4 to give formula 5;
Figure imgf000003_0002
c) converting formula 5 into formula 6;
Figure imgf000004_0001
Formula 5 Formula 6
d) amidating formula 6 to give lomitapide of formula 1; and
Figure imgf000004_0002
e) optionally converting lomitapide of formula 1 into a pharmaceutically acceptable salts of lomitapide.
Within the context of the present invention, step a) to step e) above may be carried out in the presence of a base and a suitable solvent.
The present invention further provides pharmaceutically acceptable salts (e.g., mesylate) of lomitapide in amorphous form.
Another aspect of the present invention provides a process of preparing lomitapide mesylate that includes the steps of: a) reacting lomitapide free base with methane sulfonic acid in a solvent; b) removing the solvent; and c) isolating lomitapide mesylate.
BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of preferred embodiments of the disclosure shown in the accompanying drawing figures, wherein: FIGURE 1 is an X-ray powder diffractogram of the amorphous form of lomitapide mesylate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of lomitapide which may be carried out according to Scheme-I below.
Figure imgf000005_0001
Figure imgf000005_0002
SCHEME-I where 'R' and 'X' in are defined as disclosed below.
For ease of discussion, Scheme-I may be broken down into steps as below: a) reacting formula 2 with formula 9 to give formula 3 ;
Figure imgf000005_0003
b) condensing formula 3 with formula 4 to give formula 5
Figure imgf000006_0001
c) converting formula 5 into formula 6;
Figure imgf000006_0002
Formula 5 Formula 6
d) amidating formula 6 to give lomitapide of formula 1 ; and
Figure imgf000006_0003
e) optionally converting lomitapide of formula 1 into a pharmaceutically acceptable salt.
Within the context of the present invention, a substituent represented as 'R' in the scheme above may be a Ci_5 straight or branched alkyl group. Examples of suitable Ci_5 straight or branched alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, and isobutyl. One of skill in the art would be familiar with other C1-5 straight or branched alkyl groups that may be used in the context of the present invention.
Within the context of the present invention, a substituent represented as 'X' in the scheme above is a leaving group, which may be the same or different in each occurrence. Suitable leaving groups may be, for example, halides or sulfonyl ester groups. Suitable halides include fluoride, chloride, bromide, and iodide. Examples of suitable sulfonyl ester groups include O-mesyl, O-tosyl, and O-trifluoromethanesulfonyl groups.
According to the present invention, step a) may be performed by reacting formula 2 with formula 9 in the presence of a base and a solvent to give formula 3. Formula 9 is a 1,4- di-halo butane, for example, 1,4-di-fluorobutane, 1,4-di-chlorobutane, 1,4-di-bromobutane, or 1 ,4-di-iodobutane.
In a particularly useful embodiment of the present invention, formula 2 is substituted with a methyl group in the 'R' position (methyl 9H-fluorene-9-carboxylate) and is reacted with 1,4-dibromo butane (formula 9) to form a formula 3a (methyl 9-(4-bromobutyl)-9H- fluorene-9-carboxylate), shown below, which is a resulting embodiment of formula 3.
Figure imgf000007_0001
Formula 3a
According to the present invention, step a) may be carried out in the presence of a base and a solvent. The base used in step a) may be an inorganic base or an organic base. Examples of suitable inorganic bases include potassium carbonate (K2CO3), sodium carbonate (Na2C03), barium carbonate (BaCCh), potassium bicarbonate (KHCO3), sodium carbonate (NaHCC^), barium carbonate (BaCC^), cesium carbonate (CSCO3), calcium carbonate (CaCC^), sodium hydroxide (NaOH), potassium hydroxide (KOH), and mixtures thereof. Suitable organic bases include, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine, and mixtures thereof. Within the context of the present invention, the solvent used in step a) may be, for example, an ether solvent, a ketone solvent, a polar aprotic solvent, or mixtures thereof. Examples of suitable ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran. Suitable ketone solvents include, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Suitable polar aprotic solvents include, for example, dimethylformamide, acetonitrile, and dimethylsulfoxide. In some embodiments of the present invention, dimethyl formamide was found to be a particularly useful solvent.
According to the present invention, step b) may be performed by condensing formula 3 with formula 4 in the presence of a base and a solvent to give formula 5.
In a particularly useful embodiment of the present invention, formula 3 is formula 3a (methyl 9-(4-bromobutyl)-9H-fluorene-9-carboxylate), described above. The reaction of formula 3a with formula 4 results in formula 5a (methyl 9-{4-[4-({ [4'- (trifluoromethyl)biphenyl-2-yl]carbonyl} amino )piperidin-l-yl]butyl}-9H-fluorene-9- carboxylate) shown below, which is a resulting embodiment of formula 5.
Figure imgf000008_0001
Formula 5a
According to the present invention, step b) may be carried out in the presence of a base and a solvent. Within the context of the present invention, the base used in step b) may be inorganic or organic. Examples of suitable inorganic bases include potassium carbonate (K2CO3), sodium carbonate (Na2C03), barium carbonate (BaC03), potassium bicarbonate (KHC03), sodium carbonate (NaHC03), barium carbonate (BaC03), cesium carbonate (CsC03), calcium carbonate (CaC03), sodium hydroxide (NaOH), potassium hydroxide (KOH) and mixtures thereof. Examples of suitable organic bases include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and mixtures thereof. The solvent used in step b) may be, for example, an ether solvent, a ketone solvent, a polar aprotic solvent, or mixtures thereof. Examples of suitable ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran. Examples of suitable ketone solvents including acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Suitable polar aprotic solvents, include, for example, dimethylformamide, acetonitrile, and dimethylsulfoxide. In some embodiments of the present invention, dimethyl formamide was found to be a particularly useful solvent.
Within the context of the present invention, formula 5, which was formed in step b) may optionally be converted into an acid addition salt before proceeding to step c). Suitable acids useful for the formation of salts include, for example, hydrochloric acid, hydrobromic acid, benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p- toluenesulfonic acid, methanesulfonic acid, and malic acid. In some embodiments, hydrochloric acid was found to be a particularly useful acid for converting formula 5 to an acid addition salt.
According to the present invention, step c) may be performed by converting formula 5 (or an acid addition salt thereof) into formula 6 by reacting formula 5 with a base and a solvent. Examples of suitable bases for step c) include sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K2CO3), sodium carbonate (Na2C03), potassium bicarbonate (KHCO3), sodium carbonate (NaHCC^), barium carbonate (BaCC^), cesium carbonate (CSCO3), calcium carbonate (CaCC^), and mixtures thereof. In some embodiments, sodium hydroxide (NaOH) was found to be particularly useful base. Examples of suitable solvents for step c) include alcohols, ether solvents, chlorinated solvents, ketone solvents, and mixtures thereof. Examples of suitable alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol. Suitable ether solvents include, for example, methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran. Example of suitable chlorinated solvents include chloroform, dichloromethane, and dichloroethane. Suitable ketone solvents include, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone.
In a particularly useful embodiment of the present invention, formula 5 is formula 5a (methyl 9-{4-[4-({ [4'-(trifluoromethyl)biphenyl-2-yl] carbonyl } amino)piperidin- 1 -yl]butyl } - 9H-fluorene-9-carboxylate), described above. In some embodiments of the present invention, a mixture of methanol and tetrahydrofuran was found to be a particularly useful solvent mixture for carrying out the conversion of step c).
According to the present invention, step d) may be performed by amidating formula 6 to form lomitapide (formula 1). Within the context of the present invention, this conversion may be achieved by first converting formula 6 into its acid halide (not shown in the above schemes) in the presence of a halogenating agent and a halogenated solvent. The acid halide of formula 6 may then be amidated to make lomitapide.
In particularly useful embodiments of the present invention, formula 6 is converted into its acid chloride by treating formula 6 with a chlorinating agent in a solvent. Suitable chlorinating agents include, for example, thionyl chloride (SOCl2), phosphoryl chloride (POCI3), phosphorous trichloride (PCI3), phosphorous pentachloride (PCI5), and mixtures thereof. The solvent may be a chlorinated solvent, for example, chloroform, dichloromethane, dichloroethane, or mixtures thereof. In particularly useful embodiments of the present invention, dichloromethane was found to be a particularly useful solvent. Similarly, brominating agents and solvents, fluorinating agents and solvents, as well as iodating agents and solvents may alternatively be used. According to the present invention, the acid halide form of formula 6 may next be amidated in the presence of a base and a solvent to complete step d) and give lomitapide.
In particularly useful embodiments of the invention, the acid chloride of formula 6 is amidated with 2,2,2-trifluoro ethylamine or a salt thereof. Suitable bases for amidating the acid halide of formula 6 include, for example, triethylamine, diisopropylethylamine, N- methylmorpholine, pyridine, lutidine, DBU, DBN, picoline, and mixtures thereof. In some embodiments, triethylamine was found to be particularly useful base. The solvent may be a chlorinated solvent, for example, chloroform, dichloromethane, dichloroethane, or mixtures thereof. In particularly useful embodiments of the present invention, dichloromethane was found to be a particularly useful solvent.
Within the context of the present invention, the amidation of formula 6 to give lomitapide of formula 1 (step d) may alternatively be carried out by processes well-known in the art, for example, by using coupling agents. Suitable coupling agents include, for example, EDCI and DCC. Amidation may also be carried out using a mixture of anhydrides and appropriate reagents, for example, ethylchloroformate. One of skill in the art will be familiar with various methods by which the amidation of step e) may be achieved.
Within the context of the present invention, lomitapide (formula 1) may be optionally converted into a pharmaceutically acceptable salt as in step e). Acids useful for the formation of pharmaceutically acceptable salts include, for example, hydrochloric acid, hydrobromic acid, methanesulfonic acid, benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluenesulfonic acid, and malic acid. Methanesulfonic acid was found to be a particularly useful acid in forming a salt of lomitapide.
Another aspect of the present invention provides novel intermediate compounds of formula 3, formula 5, and formula 6 shown below.
Figure imgf000010_0001
Within the context of the present invention, a substituent represented as "R" in the scheme above may be a C1-5 straight or branched alkyl group. Examples of suitable C1-5 straight or branched alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, and isobutyl. One of skill in the art would recognize that other Ci_5 straight or branched alkyl groups that may be used in the context of the present invention.
Within the context of the present invention, the usage of compound of formula 3, formula 5, and formula 6 of the present invention may be useful in the preparation of lomitapide or its pharmaceutically acceptable salts.
Another aspect of the present invention provides novel compounds of formula 3 a and formula 5a and the usage of formula 3a and formula 5a for the preparation of lomitapide or pharmaceutically acceptable salts thereof.
Figure imgf000011_0001
Formula 5a
Within the context of the present invention, the compound of formula 3 or 3 a may be hydrolyzed to yield formula 3b according to the processes well known in the art.
Figure imgf000011_0002
Formula 3a Formula 3b
According to the present invention, formula 3b may be further converted into lomitapide or its pharmaceutically acceptable salts by conventional methods, such as those disclosed in U.S. Patent No. 5,739,135.
Another aspect of the present invention provides a process for the preparation of lomitapide mesylate. According to the present invention, lomitapide mesylate may be prepared by reacting lomitapide free base with methanesulfonic acid in a solvent. The solvent may then be subsequently removed by methods well known in the art, providing lomitapide mesylate. The composition may then be optionally treated with a non-polar solvent to improve the purity and quality of the product.
According to the present invention, lomitapide mesylate may be prepared by the following process: a) reacting lomitapide free base with methanesulfonic acid in a solvent ;
b) removing the solvent;
c) optionally adding non-polar solvent; and
d) isolating lomitapide mesylate.
According to the present invention, step a) above may be carried out by reacting lopitamide free base with methanesulfonic acid in a solvent. The resulting solution may then be stirred over a period of about 2 to about 5 hours. The solvent used in step a) may be, for example, aliphatic alcohols, ester solvents, ether solvents, chlorinated solvents, ketone solvents, polar solvents, and mixtures thereof. Suitable aliphatic alcohols include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol. Examples of suitable ester solvents include ethyl acetate, methyl acetate, and butyl acetate. Examples of useful ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran. Suitable chlorinated solvents, include, for example, chloroform, dichloromethane, and dichloroethane. Examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Examples of polar solvents include water, dimethylformamide, acetonitrile, and dimethylsulfoxide. In some embodiments of the present invention, methanol, acetone, ethyl acetate, and isopropyl alcohol were found to be particularly useful solvents.
Next, step b) may be carried out by removing the solvent using methods well known to one of skill in the art, for example, under reduced pressure, to obtain a solid residue.
Next, step c) may be optionally performed by treating the solid residue formed in step b) with a non-polar solvent to obtain pure lomitapide mesylate. Within the context of the present invention, examples of non-polar solvents include n-hexane, cyclohexane, n-heptane, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof. In certain embodiments, diisopropyl ether, n-hexane, or a mixture of diisopropyl ether and n-hexane were all found to be particularly useful solvents. Another aspect of the present invention provides a process for the preparation of amorphous lomitapide mesylate which may include the following steps: a) reacting lomitapide free base with methanesulfonic acid in a solvent; b) removing the solvent; c) adding a non-polar solvent; and d) isolating amorphous lomitapide mesylate.
According to the present invention, step a) above may be carried out by reacting lopitamide free base with methansolfonic acid in a solvent. The resulting solution may thenbe stirred over a period of about 2 to about 5 hours. The solvent used in step a) may be, for example, aliphatic alcohols, aromatic alcohols, ester solvents, ether solvents, chlorinated solvents, ketone solvents, polar solvents, and mixtures thereof. Suitable aliphatic and aromatic alcohols include, for example, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol. Examples of suitable ester solvents include ethyl acetate, methyl acetate, and butyl acetate. Examples of useful ether solvents include methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, and tetrahydrofuran. Suitable chlorinated solvents, include, for example, chloroform, dichloromethane, and dichloroethane. Examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Examples of polar solvents include water, dimethylformamide, acetonitrile, and dimethylsulfoxide. In some embodiments of the present invention, methanol, acetone, ethyl acetate, and isopropyl alcohol were found to be particularly useful solvents.
Next, step b) may be carried out by removing the solvent using methods well known to one of skill in the art, for example, under reduced pressure, to obtain a solid residue.
Next, step c) may be performed by treating the solid residue formed in step b) with a non-polar solvent to obtain pure lomitapide mesylate. Within the context of the present invention, examples of non-polar solvents include n-hexane, cyclohexane, n-heptane, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof. In certain embodiments, diisopropyl ether, n-hexane, or a mixture of diisopropyl ether and n- hexane were all found to be particularly useful solvents. The amorphous form of lomitapide mesylate of the present invention may be characterized by its powder X-ray diffraction (PXRD) pattern. Thus, the X-ray diffraction pattern of the amorphous form of lomitapide mesylate was measured.
The X-ray diffraction pattern of the amorphous form of lomitapide mesylate was measured on a BRUKER D-8 Discover powder diffractometer equipped with goniometer of Θ/2Θ configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
FIG. 1 shows the PXRD pattern of amorphous lomitapide mesylate.
The lomitapide mesylate compositions disclosed herein may be formulated in a variety of dosage forms for delivery to human and non-human patients. Lomitapide mesylate may be formulated in an oral dosage form, such as a tablet, capsule, or liquid. Depending on the physiological result intended, the dosage form may be formulated as an immediate- release, extended-release, sustained-release, or delayed-release formulation. Such modified- release properties may be obtained through employing coatings and/or matrices that enable modified release of lomitapide mesylate. Within the context of the present invention, lomitapide mesylate may be incorporated into dosage forms with a variety of excipients well known in the art, for example, pre-gelatinized starch, sodium starch glycolate, microcrystalline cellulose, lactose monohydrate, silicon dioxide, and magnesium stearate. Coatings of formulations in capsule form may contain gelatin and titanium dioxide. Within the context of the present invention, dosage forms may have from about 5 to about 60 milligrams of lomitapide. In particularly useful embodiments of the present invention, dosage forms have 5, 10, or 20, 30, 40, or 60 milligrams of lomitapide mesylate.
Lomitapide may also be included in an injectable formulation, using methods and components well known to those of skill in the art.
One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
When administered to human and non-human patients, formulations of lomitapide mesylate may be adjusted to compensate for the age, weight, and physical condition of the patient. Lomitapide mesylate may be administered over a wide dosage range from about 5 to about 500 milligrams per day with about 5 to about 60 milligrams having particular utility. Lomitapide mesylate of the present invention may be administered in combination with, prior to, or after dosing regimens of other lipid-modifying compounds, for example, mipomersen (KYNAMRO®), atorvastatin (LIPITOR®), ezetimibe (ZETIA®), and fenofibrate (TRICOR®).
When administered to patients, the lomitapide mesylate of the present invention may be useful for preventing, treating, or stabilizing atherosclerosis. Additionally, the lomitapide mesylate of the present invention may be useful in lowering serum lipid levels, such as cholesterol or triglyceride levels. The lomitapide mesylate of the present invention may also be useful in the prevention, treatment, or stabilization of hypercholesterolemia, hypertriglyceridiemia, hyperlipidemia, pancreatitis, hyperglycemia, and obesity, in addition to diseases and disorders that are precipitated by or associated with those conditions. Those conditions may be genetically linked or idiopathic.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.
Examples
Example 1: Preparation of formula 2a (methyl 9H-fluorene-9-carboxylate)
To a stirred solution of 9H-fluorene-9-carboxylic acid (10 g) in MeOH (50 mL), SOCl2 (10 mL) was added drop wise at 0 °C followed by DMF (catalytic amount) and stirred at 0 °C for 30 min. The reaction mixture was concentrated by distilling off MeOH and SOCl2 completely. The obtained crude was diluted with ethyl acetate and washed with 10 % NaHC03. The organic layer was separated and concentrated under reduced pressure to yield formula 2a as a pale brown solid (10 g).
Example 2: Preparation of formula 2a (methyl 9H-fluorene-9-carboxylate)
To a stirred solution of 9H-fluorene-9-carboxylic acid (10 g) in MeOH (50 mL), SOCI2 (5.2 mL) was added drop wise at 0 °C followed by DMF (catalytic amount) and stirred at room temperature (RT) for ~ 3h. The reaction mixture was quenched with ice cold water and stirred at same temperature for 30 minutes. The obtained solid was filtered and washed with water. The filtered solid was stirred with 5 % Sodium bicarbonate solution for 30 minutes. The solid was filtered and washed with water. The filtered solid was dried to yield formula 2a as an off-white solid (10 g).
1H NMR (CDC13): δ 7.8 (d, 2H), δ 7.65 (d, 2H), δ 7.45 (d, 2H), δ 7.35 (d, 2H), δ 4.9 (s, 1H), δ 3.75 (s, 3H)
Example 3: Preparation of formula 3a (methyl 9-(4-chlorobutyl)-9H-fluorene-9- carboxylate)
To a stirred solution of methyl 9H-fluorene-9-carboxylate (10 g) in DMF (50 mL), K2CO3 (6.0 g) was added at 0 °C and stirred at same temperature for 1 h. To the reaction mixture 1, 4-dibromo butane (5.3 mL) was added at 0 °C and stirred at room temperature (RT) for ~2h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure to yield crude methyl 9-(4-bromobutyl)-9H-fluorene-9-carboxylate. The crude was washed with cold MeOH to yield substantially pure formula 3a as a pale yellow solid (5 g).
Example 4: Preparation of formula 3a (methyl 9-(4-chlorobutyl)-9H-fluorene-9- carboxylate)
To a stirred solution of methyl 9H-fluorene-9-carboxylate (10 g) in DMF (25 mL), K2CO3 (6.2 g) was added at 0 °C and stirred at same temperature for 1 h. To the reaction mixture 1-bromo, 4-chloro butane (5.1 mL) was added at 0 °C and stirred at room temperature (RT) for 16h. The reaction mixture was quenched with ice cold water. The formed solid was filtered and washed with water. Filtered solid was crystallized in DMF: water (2: 1) to yield substantially pure methyl 9-(4-chlorobutyl)-9H-fluorene-9-carboxylate as a pale yellow solid (10 g).
1H NMR (CDC13): δ 7.8 (d, 2H), δ 7.55 (d, 2H), δ 7.5-7.3 (m, 4H), δ 3.59 (s, 3H), δ 3.2 (t, 2H), δ 2.35 (m, 2H), δ 1.7 (m, 2H), δ 0.9 (m, 2H)
Example 5: Preparation of formula 5a (methyl 9-{4-[4-({[4'-(trifluoromethyl)biphenyl- 2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylate)
To a stirred solution of N-(piperidin-4-yl)-4'-(trifluoromethyl)biphenyl-2- carboxamide (1.12 g) in DMF (10 mL), K2C03 (740 mg) was added at 0 °C and stirred at same temperature for 15 min. Then methyl 9-(4-bromobutyl)-9H-fluorene-9-carboxylate (1 g) was added at 0 °C and stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and stirred for lhr. The reaction mixture was filtered and dried to yield formula 5a as an off white solid (1.3 g).
Example 6: Preparation of formula 5a (methyl 9-{4-[4-({[4'-(trifluoromethyl)biphenyl- 2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylate)
To a stirred solution of methyl 9-(4-chlorobutyl)-9H-fluorene-9-carboxylate (5 g) in DMF (25 mL), K2C03 (2.2 g) was added followed by N-(piperidin-4-yl)-4'- (trifluoromethyl)biphenyl-2-carboxamide (5.5 g) and potassium Iodide (2.6 g) at room temperature and stirred at 70 °C for 24 h. The reaction mixture was quenched with ice cold water and stirred for lhr. The reaction mixture was filtered and dried to yield formula 5a as an off white solid (10 g).
1H MR (CDC13): δ 7.8 -7.2 (m, 17H), δ 5.1 (d, 1H), δ 3.75 (m, 1H), δ 3.55 (s, 3H), δ 2.5-2.3 (m, 4H), δ 2.0 (m, 2H), δ 1.8 (t, 2H), δ 1.6 (m, 2H), δ 1.3 (m, 2H), δ 1.0 (m, 2H), δ 0.6 (m, 2H).
Example 7: Preparation of hydrochloride salt of formula 5a (methyl 9-{4-[4-({[4'- (trifluoromethyl)biphenyl-2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9- carboxylate hydrochloride)
To a stirred solution of methyl 9-{4-[4-({ [4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylate (10 g) in toluene (100 mL), HC1 (20 mL) was added followed by water (80 mL) at RT and stirred at same temperature for 4 h. The obtained solid was filtered and washed with toluene, water and dried to yield substantially pure formula 5a as an off white solid.
Example 8: Preparation of hydrochloride salt of formula 5a (methyl 9-{4-[4-({[4'- (trifluoromethyl)biphenyl-2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9- carboxylate hydrochloride)
To a stirred solution of N-(piperidin-4-yl)-4'-(trifluoromethyl)biphenyl-2- carboxamide (1.12 g) in DMF (10 mL), K2C03 (740 mg) was added at 0 °C and stirred at same temperature for 15 min. To the reaction mixture, methyl 9-(4-bromobutyl)-9H- fluorene-9-carboxylate (1 g) was added at 0 °C and stirred at RT for 16 h. The reaction mixture was quenched with ice cold water. The formed precipitate was filtered and dried to yield 9-{4-[4-({ [4'-(trifluoromethyl)biphenyl-2-yl] carbonyl } amino)piperidin- 1 -yl]butyl } -9H- fluorene-9-carboxylate as an off white solid. The obtained solid was dissolved in toluene, and HC1 was added followed by water at RT and stirred at same temperature for 4 h. The resulting solid was filtered and washed with toluene, water and dried to yield substantially pure formula 5a as an off white solid.
Example 9: Preparation of formula 6 (9-{4-[4-({[4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylic acid)
To a stirred solution of formula 5 (methyl 9-{4-[4-({ [4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylate) (l lg) in MeOH:THF (1:2) (10 volumes), 10 % aqueous NaOH (100 ml) was added at 0 °C and stirred at -30 °C for 16 h. The reaction mixture was concentrated by distilling off MeOH:THF mixture. The crude was diluted with water and acidified with con. Hydrochloric acid. The reaction mass was filtered, dried and washed with toluene. The aqueous layer was separated and acidified with HC1 until pH = 3. The formed precipitate was filtered and dried to yield formula 6 as an off white solid (8 g).
Example 10: Preparation of formula 6 (9-{4-[4-({[4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylic acid)
To a stirred solution of formula 5 (methyl 9-{4-[4-({ [4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylate) (lOg) in MeOH:THF (1:2) (5 volumes), 10 % aqueous NaOH (50 ml) was added at 0 °C and stirred at room temperature for 24 h. The reaction mixture was cooled and acidified to pH=l with 50 % aqueous HC1. The reaction mixture was extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure to yield crude compound. The crude product was purified with acetone to yield substantially pure formula 6 as an off white solid (8 g).
1H MR (CDC13): δ 7.8 -7.2 (m, 17H), δ 6.2 (d, 1H), δ 3.8 (d, 1H), δ 2.5 (m, 4H), δ 2.5 (m, 2H), δ 1.9 (m, 2H), δ 1.5 (m, 4H), δ 1.2 (m, 2H), δ 0.6 (m, 2H)
Example 11: Preparation of formula 6 (9-{4-[4-({[4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylic acid)
To a stirred solution of formula 5 (methyl 9-{4-[4-({ [4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9-carboxylate hydrochloride) (1 g) in MeOH:THF (1: 1) (10 volumes), 10 % aqueous NaOH (10 volumes) was added at 0 °C and stirred at RT for 15 min. The reaction mixture was concentrated by distilling off MeOH:THF mixture. The crude was diluted with water and washed with toluene. The aqueous layer was separated and acidified with HC1 until pH = 3. The formed precipitate was filtered and dried to yield crude formula 6.
Example 12: Preparation of lomitapide of formula 1 (N-(2,2,2-trifluoroethyl)-9-{4-[4- ({[4'-(trifluoromethyl)biphenyl-2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-
9-carboxamide)
To formula 6 (2 g) in dichloromethane, SOCl2 (5 mL) was added followed by DMF (catalytic amount) at 0 °C and stirred at same temperature for 2 h. This reaction mixture was concentrated under reduced pressure to yield crude acid chloride of formula 6. In a separate flask, 2, 2, 2-tri fluoroethyl amine hydrochloride (900 mg) was charged and Et3N (2.2 mL) was added at 0 °C and stirred at same temperature for 15 min. Then the crude acid chloride dissolved in dichloromethane (10 mL) was added drop wise at 0 °C and stirred at RT for 1 h. The reaction mixture was quenched with 10 % NaHC03 and extracted with dichloromethane. The organic layer was separated and concentrated under reduced pressure to yield crude lomitapide as an off white solid (1.6 g).
Example 13: Preparation of lomitapide of formula 1 (N-(2,2,2-trifluoroethyl)-9-{4-[4- ({[4'-(trifluoromethyl)biphenyl-2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-
9-carboxamide)
To formula 6 (5 g) in MDC (50 ml), triethyl amine (1.4 ml) was added at 0 °C and stirred at same temperature for 15 minutes. To this, ethylchloroformate (1.0 mL) was added at 0 °C and stirred at same temperature for 90 minutes. In a separate flask, 2, 2, 2- trifluoroethyl amine hydrochloride (3.3 g) was charged and MDC (33 ml) was added. To this, 5 % NaOH solution (33 mL) was added at 0 °C and stirred at same temperature for 90 minutes. The organic layer was separated and anhydride was added to the reaction mixture at 0 °C and stirred at same temperature for ~3 hours and quenched with brine solution. The organic layer was separated and concentrated under reduced pressure to yield lomitapide as an off white solid (5 g).
1H MR (CDC13): δ 7.8 (m, 2H), δ 7.7 (m, 3H), δ 7.5-7.3 (m, 11H), δ 5.35 (m, 1H), δ 5.1 (d, 1H), δ 3.7 (m, 3H), δ 2.4 (m, 2H), δ 2.1-1.5 (m, 8H), δ 1.3 (m, 2H), δ 1.1 (m, 2H), δ 0.6 (m, 2H) Example 14: Preparation of N-(2,2,2-trifluoroethyl)-9-{4-[4-({[4'- (trifluoromethyl)biphenyl-2-yl]carbonyl}amino)piperidin-l-yl]butyl}-9H-fluorene-9- carboxamide methanesulfonate (lomitapide mesylate)
To a stirred solution of lomitapide (1 g) in MeOH (10 mL) methane sulfonic acid (145 mg) was added at RT and stirred at same temperature for 3 h. This reaction mixture was concentrated under reduced pressure to yield crude lomitapide mesylate. This crude was triturated with diisopropyl ether to yield substantially pure lomitapide mesylate as an off white solid.
1H MR (CDC13): δ 10.3 (m, 1H), δ 7.8-7.2 (m, 16H), δ 6.5 (d, 1H), δ 5.35 (m, 1H), δ 3.9 (d, 1H), δ 3.7 (m, 2H), δ 3.4 (m, 2H), δ 2.7-2.5 (m, 5H), δ 2.4 (m, 2H), δ 2.22 (m, 4H), δ 2.1-2.0 (m, 2H), δ 1.6 (m, 2H), δ 0.7 (m, 2H).
Example 15: Preparation of lomitapide mesylate
To 10 g of lomitapide in methanol (50 ml), methane sulfonic acid (1.6 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent was removed under vacuum to obtained crude material was stirred in diisopropyl ether (-100 ml) and filtered to give off white solid. The solid was further dried at 45°C under vacuum to give lomitapide mesylate (9.5 g) as amorphous material.
Example 16: Preparation of lomitapide mesylate
To 10 g of lomitapide in methanol (50 ml), methane sulfonic acid (1.6 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum to obtained crude material was stirred in n-hexane (-100 ml) and filtered to give off white solid. The solid was further dried at 45 °C under vacuum to give lomitapide mesylate (9.5 g) as amorphous material.
Example 17: Preparation of lomitapide mesylate
To 10 g of lomitapide in acetone (50 ml), methane sulfonic acid (1.6 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum to obtained crude material was stirred in diisopropyl ether (-100 ml) and filtered to give off white solid. The solid was further dried at 45 °C under vacuum to give lomitapide mesylate (9.5 g) as amorphous material. Example 18: Preparation of lomitapide mesylate
To 10 g of lomitapide in acetone (50 ml), methane sulfonic acid (1.6 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum to obtained crude material was stirred in n-hexane (-100 ml) and filtered to give off white solid. The solid was further dried at 45°C under vacuum to give lomitapide mesylate (9.5 g) as amorphous material.
Example 19: Preparation of lomitapide mesylate
To 5 g of lomitapide in ethyl acetate (50 ml), methane sulfonic acid (0.8 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum to obtained crude material was stirred in diisopropyl ether (-100 ml) and filtered to give off white solid. The solid was further dried at 45 °C under vacuum to give lomitapide mesylate (4.5 g) as amorphous material.
Example 20: Preparation of lomitapide mesylate
To 5 g of lomitapide in ethyl acetate (50 ml), methane sulfonic acid (0.8 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum to obtained crude material was stirred in n-hexane (-100 ml) and filtered to give off white solid. The solid was further dried at 45 °C under vacuum to give lomitapide mesylate (4.5 g) as amorphous material.
Example 21: Preparation of lomitapide mesylate
To 5 g of lomitapide in isopropyl alcohol (25 ml), methane sulfonic acid (0.8 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum to obtained crude material was stirred in diisopropyl ether (-100 ml) and filtered to give off white solid. The solid was further dried at 45°C under vacuum to give lomitapide mesylate (4.5 g) as amorphous material.
Example 22: Preparation of lomitapide mesylate
To 5 g of lomitapide in isopropyl alcohol (25 ml), methane sulfonic acid (0.8 g) was added and the reaction mass was stirred for 2-3 hrs. The solvent removed in vacuum and obtained crude material was stirred in n-hexane (-100 ml) and filtered to give off white solid. The solid was further dried at 45°C under vacuum to give lomitapide mesylate (4.5 g) as amorphous material.

Claims

We claim:
A process for the preparation of lomitapide comprising the steps
a) reacting Formula 2 with Formula 9 to give Formula 3;
Figure imgf000023_0001
Formula 2
b) condensing Formula 3 with Formula 4 to give Formula 5;
Figure imgf000023_0002
c) converting Formula 5 into Formula 6; and
Figure imgf000023_0003
Formula 5 Formula 6
d) amidating Formula 6 to give lomitapide of Formula 1,
Figure imgf000023_0004
wherein R is a Ci_5 straight alky group or a Ci_5 branched alkyl group and X is a leaving group.
2. The process according to claim 1, further comprising converting lomitapide of formula 1 into a pharmaceutically acceptable salt of lomitapide after the amidating step.
3. The process according to claim 1, wherein the step-a is carried out in the presence of a base and a solvent.
4. The process according to claim 1, wherein the step-b is carried out in the presence of a base and a solvent.
5. The process according to claim 3 or 4, wherein the base is an inorganic base or an organic base.
6. The process according to claim 5, wherein the inorganic base is selected from the group consisting of potassium carbonate (K2CO3), sodium carbonate (Na2C03), barium carbonate (BaC03), potassium bicarbonate (KHC03), sodium carbonate (NaHC03), barium carbonate (BaC03), cesium carbonate (CsC03), calcium carbonate (CaC03), sodium hydroxide (NaOH), potassium hydroxide (KOH), and mixtures thereof.
7. The process according to claim 5, wherein the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and mixtures thereof.
8. The process according to claims 3 or 4, wherein the solvent is selected from the group consisting of methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, dimethylformamide, acetonitrile, dimethylsulfoxide, and mixtures thereof.
9. The process according to claim 1, wherein the step-c is carried out in the presence of a base and a solvent.
10. The process according to claim 9, wherein the base is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K2CO3), sodium carbonate (Na2C03), potassium bicarbonate (KHCO3), sodium carbonate (NaHC03), barium carbonate (BaC03), cesium carbonate (CsC03), calcium carbonate (CaC03), and mixtures thereof.
11. The process according to claim 9, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and mixtures thereof.
12. A process for the preparation of lomitapide mesylate comprising the steps of: a) reacting lomitapide free base with methane sulfonic acid in a first solvent; b) removing the first solvent; c) optionally adding the second solvent; and d) isolating lomitapide mesylate.
13. The process according to claim 12, where the first solvent is a polar solvent.
14. The process according to claim 13, wherein the polar solvent is selected from the group consisting of aliphatic alcohols, aromatic alcohols, ester solvents, ether solvents, chlorinated solvents, ketone solvents, and mixtures thereof.
15. The process according to claim 12, wherein the second solvent is a non-polar solvent.
16. The process according to claim 15, wherein the second solvent is selected from the group consisting of n-hexane, cyclohexane, n-heptane, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether and 1,4-dioxane, and mixtures thereof.
17. Amorphous lomitapide mesylate.
18. The amorphous lomitapide mesylate of claim 17, which has an X-ray powder diffraction pattern as shown in Figure 1.
19. A compound of Formula 3
Figure imgf000026_0001
Formula 3
wherein R is a C1-5 straight alky group or a C1-5 branched alkyl group and X is a leaving group.
20. A compound of Formula 5
Figure imgf000027_0001
wherein R is a C1-C5 straight alkyl group or a C1-C5 branched alkyl group.
21. A compound of Formula 6
Figure imgf000027_0002
Formula 6
22. Use of compounds claimed in claims 19-21 for the preparation of lomitapide or its pharmaceutically acceptable salts.
PCT/IB2015/055508 2014-07-21 2015-07-21 Process for making lomitapide mesylate WO2016012934A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105523994A (en) * 2016-02-03 2016-04-27 南京华威医药科技开发有限公司 Crystal form III of lomitapide mesylate
EP3107540A4 (en) * 2014-02-17 2017-08-30 Hetero Research Foundation Polymorphs of lomitapide and its salts
US10138206B2 (en) * 2014-10-09 2018-11-27 Glenmark Pharmaceuticals Limited Amorphous form of lomitapide mesylate

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US5712279A (en) 1995-02-21 1998-01-27 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
WO1999063929A2 (en) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein

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GB830825A (en) * 1957-01-18 1960-03-23 Wellcome Found Improvements in and relating to diquaternary compounds
US5739135A (en) 1993-09-03 1998-04-14 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
US5712279A (en) 1995-02-21 1998-01-27 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
WO1999063929A2 (en) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3107540A4 (en) * 2014-02-17 2017-08-30 Hetero Research Foundation Polymorphs of lomitapide and its salts
US10138206B2 (en) * 2014-10-09 2018-11-27 Glenmark Pharmaceuticals Limited Amorphous form of lomitapide mesylate
CN105523994A (en) * 2016-02-03 2016-04-27 南京华威医药科技开发有限公司 Crystal form III of lomitapide mesylate
CN105523994B (en) * 2016-02-03 2018-06-05 南京华威医药科技集团有限公司 Methanesulfonic acid Lome Tapai crystal form III

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