WO2002088069A2 - Compounds useful as intermediates for 4-aminoquinoline derivatives - Google Patents

Compounds useful as intermediates for 4-aminoquinoline derivatives Download PDF

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Publication number
WO2002088069A2
WO2002088069A2 PCT/IB2002/001217 IB0201217W WO02088069A2 WO 2002088069 A2 WO2002088069 A2 WO 2002088069A2 IB 0201217 W IB0201217 W IB 0201217W WO 02088069 A2 WO02088069 A2 WO 02088069A2
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Prior art keywords
compound
formula
benzyl
solution
reaction
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PCT/IB2002/001217
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French (fr)
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WO2002088069A3 (en
WO2002088069A9 (en
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David Burns Damon
Robert Wayne Dugger
Robert William Scott
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Pfizer Products Inc.
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Priority to AU2002253448A priority Critical patent/AU2002253448B2/en
Priority to KR1020037014135A priority patent/KR100591998B1/en
Priority to EP02722569A priority patent/EP1383734B1/en
Priority to CA002445693A priority patent/CA2445693A1/en
Priority to MXPA03009936A priority patent/MXPA03009936A/en
Priority to IL15754602A priority patent/IL157546A0/en
Priority to BR0209238-7A priority patent/BR0209238A/en
Priority to JP2002585373A priority patent/JP3924250B2/en
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to HU0304041A priority patent/HU225777B1/en
Priority to DE60209004T priority patent/DE60209004T2/en
Publication of WO2002088069A2 publication Critical patent/WO2002088069A2/en
Publication of WO2002088069A3 publication Critical patent/WO2002088069A3/en
Publication of WO2002088069A9 publication Critical patent/WO2002088069A9/en
Priority to HK04105255A priority patent/HK1062294A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4

Definitions

  • COMPOUNDS USEFUL AS INTERMEDIATES FIELD OF THE INVENTION This invention relates to compounds useful as intermediates for cholesteryl ester transfer protein (CETP) inhibitors and methods for the preparation thereof.
  • CETP cholesteryl ester transfer protein
  • Atherosclerosis and its associated coronary artery disease is the leading cause of mortality in the industrialized world.
  • CAD coronary artery disease
  • CHD coronary heart disease
  • LDL-C Low HDL-C is also a known risk factor for CHD (Gordon, D. J., et al.: "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15).
  • dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
  • cholesteryl ester transfer protein activity affects all three.
  • the net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
  • PCT application publication number WO 00/02887 discloses the use of catalysts comprising certain novel ligands for transition metals in transition metal-catalyzed carbon-heteroatom and carbon-carbon bond formation.
  • One aspect of this invention is the compound of formula III,
  • Another aspect of this invention is the compound of formula IV,
  • a further aspect of this invention is compounds of formula VI,
  • R is selected from methyl, benzyl and substituted benzyl.
  • R is selected from methyl, benzyl and substituted benzyl.
  • R in the compounds of formula VI and the compounds of formula VII is selected from methyl, benzyl and benzyl substituted with one or more substituents each independently selected from (CrC 3 )alkyl, (C ⁇ -C 3 )alkyloxy and a halogen.
  • a further aspect of this invention is methods for preparing the compound of formula III, above, comprising coupling trifluoromethylbenzene that is para-substituted with a halogen or O-triflate with the compound of formula II,
  • said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a transition metal, preferably palladium.
  • said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a phosphine ligand, preferably a dialkylphosphinobiphenyl ligand, more preferably selected from 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl and 2-dicyclohexylphosphino-2'-methylbiphenyl.
  • a phosphine ligand preferably a dialkylphosphinobiphenyl ligand, more preferably selected from 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl and 2-dicyclohexylphosphino-2'-methylbiphenyl.
  • Another aspect of this invention is methods for preparing the compound of formula IV, above, comprising hydrolyzing the above compound of formula III, with a hydrolyzing agent selected from an acid and a base, preferably an acid, more preferably sulfuric acid with water, to form the compound of formula IV.
  • a hydrolyzing agent selected from an acid and a base, preferably an acid, more preferably sulfuric acid with water, to form the compound of formula IV.
  • a further aspect of this invention is methods for preparing compounds of formula VI, above, comprising combining the compound of formula IV, above, with a compound of formula V,
  • R is selected from methyl, benzyl and substituted benzyl, in the presence of a base, preferably lithium t-butoxide, to form compounds of formula VI.
  • An additional aspect of this invention is methods for preparing compounds of formula VII, above, comprising reducing the above compounds of formula VI, wherein R is selected from methyl, benzyl and substituted benzyl, with a reducing agent, preferably sodium borohydride in the presence of a Lewis acid, preferably calcium ions or magnesium ions, to form a reduced compound and cyclizing the reduced compound under acidic conditions to form a compound of formula VII.
  • a reducing agent preferably sodium borohydride in the presence of a Lewis acid, preferably calcium ions or magnesium ions
  • substituted benzyl with respect to compounds of formula V, VI and VII means benzyl that is substituted on the benzene ring with one or more substituents such that such substitution does not prevent: (a) the reaction of the applicable formula V compound with the compound of formula IV to form the applicable formula VI compounds, (b) the reduction and cyclization of the applicable formula VI to form the applicable formula VIIB compound, (c) the acetylation of the formula VIIB compound to form the formula VIIIB compound or (d) the deprotection step to remove the applicable substituted benzyloxycarbonyl group in forming the formula IB compound from the compound of formula VIIIB.
  • Preferred substituents are (C ⁇ -C 3 )alkyl and (C ⁇ -C 3 )alkoxy and halogens.
  • Chemical structures herein are represented by planar chemical structure diagrams that are viewed from a perspective above the plane of the structure.
  • a wedge line ( ⁇ ) appearing in such chemical structures represents a bond that projects up from the plane of the structure.
  • the formula III compound is prepared by combining the chiral isomer compound of formula II ((R)-3-amino- pentanenitrile) with trifluoromethylbenzene that is para-substituted with a halogen or O-triflate (-O-S(O) 2 CF 3 ) in the presence of a metal catalyst, preferably Pd.
  • a metal catalyst preferably Pd.
  • the coupling reaction occurs in the presence of a ligand, preferably a phosphine ligand, and a base.
  • a preferred phosphine ligand is a dialkylphosphinobiphenyl ligand, preferably selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl) and 2- dicyclohexylphosphino-2'-methylbiphenyl.
  • the reaction is preferably performed at a temperature of about 60°C to about 110°C.
  • the formula II chiral isomer may be prepared from (R)-2-amino-1-butanol (CAS# 005856-63- 3) by methods known to those skilled in the art according to Scheme A and as described in Example 9 of the Experimental Procedures.
  • the formula IV compound is prepared by hydrolyzing the nitrile of the formula III compound.
  • the hydrolysis may be performed in acidic or basic conditions.
  • the preferred method of hydrolysis is under acidic conditions, preferably using sulfuric acid and water.
  • preferred bases are hydroxy bases, preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkoxy bases, preferably methoxide and ethoxide.
  • it is preferably to use a peroxide.
  • the hydrolysis reaction is preferably performed at a temperature of about 20°C to about 40°C.
  • the formula VI compound is prepared by reacting the amide of the formula IV compound with a formula V chloroformate in the presence of a base, preferably lithium t-butoxide. The reaction is preferably performed at a temperature of about 0°C to about 35°C. If the formula VI compound having R as methyl is desired, then methyl chloroformate is used as the formula V compound. If the formula VI compound having R as benzyl is desired, then benzyl chloroformate is used.
  • the formula VII compound is prepared by reacting the imide of the formula VI compound with a reducing agent, preferably sodium borohydride, in the presence of a Lewis acid activator, preferably calcium or magnesium ions to produce a reduced intermediate.
  • the reaction to make the reduced intermediate is preferably performed at a temperature of about -20°C to about 20°C. Under acidic conditions, the intermediate diastereoselectively cydizes to form the tetrahydroquinoline ring of formula VII.
  • the cyclization step is preferably performed at about 20°C to about 50°C.
  • the CETP inhibitor of formula IA is prepared by acylating the compound of formula VII wherein R is methyl at the tetrahydroquinoline nitrogen with ethyl chloroformate in the presence of a base, preferably pyridine, to form the compound of formula VI 11 A.
  • the reaction is preferably performed at a temperature of about 0°C to about 25°C.
  • the formula IA CETP inhibitor is prepared by alkylating the formula VIM compound, wherein R is methyl, with a 3,5-bis(trifluoromethyl)benzyl halide, preferably 3,5-bis(trifluoromethyl)benzyl bromide in the presence of a base, preferably an alkoxide or hydroxide, and more preferably potassium t- butoxide.
  • a base preferably an alkoxide or hydroxide, and more preferably potassium t- butoxide.
  • the preferred temperature range of the reaction is about 25°C to about 75°C.
  • the CETP inhibitor of formula IB is prepared by acylating compound
  • R is benzyl or substituted benzyl at the tetrahydroquinoline nitrogen with isopropyl chloroformate in the presence of a base, preferably pyridine, to form the compound of formula VIIIB.
  • a base preferably pyridine
  • the preferred temperature of this reaction is about 0°C to about 25°C.
  • the CETP inhibitor of formula IB may then be prepared from the formula VIIIB compound by first treating compound VIIIB with an excess of a hydrogen source (e.g., cyclohexene, hydrogen gas or ammonium formate) in the presence of a suitable catalyst in a polar solvent (e.g. ethanol) to remove the benzyloxycarbonyl group.
  • a hydrogen source e.g., cyclohexene, hydrogen gas or ammonium formate
  • the 3,5-bis-trifluoromethylbenzyl group of the formula IB compound may then be introduced by treating the amine and an acid, such as acetic acid, with 3,5-bis-trifluoromethyl-benzaldehyde followed by treatment with a hydride source, such as sodium triacetoxyborohydride. Then, the amino group is acetylated by methods known by those skilled in the art to form the formula IB compound.
  • a hydride source such as sodium triacetoxyborohydride.
  • the procedure for preparing the compound of formula IB from the compound of formula VIIIB is further described in Example 46 of commonly assigned U.S. Patent No. 6,140,343. The disclosure of U.S. Patent No. 6,140,343 is incorporated herein by reference.
  • reaction solution was cooled to room temperature and filtered through Celite®. The solids were rinsed with toluene (3 x 2L) and the filtrate was collected. All filtrates were combined to afford a crude solution of the title compound.
  • Example 2 (3R)-3-(4-Trifluoromethyl-phenylamino)-Dentanoic acid amide
  • Aqueous sulfuric acid (8.2 L sulfuric acid and 1.1 L water premixed and cooled to 35 °C or less) was added to the crude toluene solution of (3R)-3-(4- trifluoromethyl-phenylamino)-pentanenitrile from Example 1.
  • the resulting bilayer was stirred well and heated to 35 °C for 17 hours.
  • the lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95 L water and 10.7 kg sodium hydroxide) and diisopropyl ether (IPE) (40 L).
  • aqueous sodium hydroxide 95 L water and 10.7 kg sodium hydroxide
  • IPE diisopropyl ether
  • the reaction tank was then charged with lithium t-butoxide solution (18-20% in THF, 24.6 kg, -58 mol) at such a rate as to maintain the internal temperature below 10 °C and preferably at a temperature of about 5 °C.
  • lithium t-butoxide solution 18-20% in THF, 24.6 kg, -58 mol
  • the reaction was quenched by the addition of 1.5 M hydrochloric acid (36 L).
  • the aqueous layer was removed, and the organic phase extracted with saturated NaCI/water solution (10 L).
  • the aqueous layer was removed and the organic phase was concentrated by distillation under vacuum and at a temperature of about 50°C until the volume was reduced to about 24 L.
  • Cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50°C under vacuum until the volume of solution in the vessel was reduced to 24 L.
  • a second portion of cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50°C under vacuum until the volume of solution in the vessel was reduced to 24 L.
  • the solution was seeded with (3R)-[3-(4- trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid methyl ester and allowed to granulate while stirring for 2 hours.
  • a solution of 3.3 M aqueous magnesium chloride solution (4.68 kg MgCI 2 *6H 2 O in 7 L water) was added at such a rate that the internal temperature did not exceed -5 °C.
  • the reaction solution was warmed to 0 °C for 45 min.
  • the reaction was quenched by transferring the reaction mixture to a 200 L tank containing methylene chloride (70 L), and 1M hydrochloric acid/citric acid solution (5.8 L concetrated hydrochloric acid, 64 L water, and 10.5 kg citric acid).
  • the headspace of the tank was purged with nitrogen gas. This bilayer was stirred at room temperature for two hours. The phases were separated and the lower organic product layer was removed.
  • the organic phase was returned to the reaction vessel and extracted with an aqueous citric acid solution (6.3 kg citric acid, 34 L water). The mixture was stirred for 1 hour and allowed to settle overnight. The layers were separated and to the organic was added Darco® activated carbon (G-60 grade, 700 g) (Atlas Powder Co., Wilmington, DE) and the solution was stirred for 30 minutes. The mixture was then filtered through Celite®, and the carbon was rinsed twice with methylene chloride (14L and 8L). The filtrate was distilled while periodically adding hexanes so as to displace the methylene chloride with hexanes to a total final volume of 70 L (112 L total hexanes used). Product crystallized during the displacement.
  • aqueous citric acid solution 6.3 kg citric acid, 34 L water.
  • the mixture was stirred for 1 hour and allowed to settle overnight.
  • the layers were separated and to the organic was added Darco® activated carbon (G-60 grade, 700 g) (Atlas Powder
  • Example 7 (3RH3-(4-Trifluoromethyl-phenylaminoVpentanoyl1-carbamic acid benzyl ester A clean, dry and nitrogen gas purged flask was charged with (3R)-3-(4- trifluoromethyl-phenylamino)-pentanoic acid amide (20.11 g, 77.27 mmol) and isopropyl ether (100 mL) and the mixture was cooled to -12°C. Benzyl chloroformate (13.25 mL, 92.8 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (185.5 mL).
  • the lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0°C. Fifteen minutes after the completion of base addition, the reaction was quenched by adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO ), filtered, and concentrated under partial vacuum (at 40 °C) to a total volume of 100 mL. Additional isopropylether (200 mL) was added and the solution was again concentrated under partial vacuum (at 40 °C) to a total volume of 100 mL.
  • the internal temperature was maintained below - 5°C by adjusting the addition rate. Once all of the magnesium solution was added, the solution temperature was raised to 0°C and stirred for 30 minutes. The reaction was then quenched by the addition of methylene chloride (115 mL), 1 N hydrochloric acid (115 mL) and citric acid (14.02 g, 72.97 mmol). This bilayer was stirred at room temperature. After 3.75 hours, the cyclization reaction was found to be complete by HPLC analysis and the phases were separated. Water (58 mL) and citric acid (8.41 g, 43.77 mmol) were added to the organic layer and the mixture was stirred at room temperature for 45 minutes.
  • Methanesulfonyl chloride (184.1 mL) was added to the reaction mixture over a 30-minute period. After stirring for 1 hour, the reaction mixture was combined with the filtrate from Run # 1 and filtered. The solids where washed with 400 mL ethyl acetate. Hexanes (12 L) were added to the filtrate. The mixture was cooled in an ice/water bath. After about 2.5 hours the solids were isolated by filtration, washed with hexanes (2 L) and dried under vacuum to afford the title compound (971.57 g ).
  • Step 2 (l-Cvanomethyl-propyD-carbamic acid tert-butyl ester.
  • Sodium cyanide 24.05 g was added to dimethylformamide (DMF) (500 L) and the mixture was stirred at 35°C for 30 minutes.
  • Tetrabutyl ammonium bromide was added and the reaction mixture was stirred at 35°C for two hours.
  • Methanesulfonic acid 2-tert-butoxycarbonylamino-butyl ester (101.23 g) was added and the reaction mixture was stirred at 35°C overnight. The mixture was then partitioned between two liters water and one liter isopropyl ether.
  • Step 3 (R)-3-Aminopentanenitrile methanesulfonic acid salt.
  • Methane sulfonic acid (71 g) was added to a solution of (l-cyanomethyl-propyl)-carbamic acid tert-butyl ester in tetrahydrofuran (530 mL).
  • the reaction mixture was heated to 40°C for approximately 30 minutes.
  • the temperature was raised to 45°C and stirred for approximately one hour.
  • the temperature was raised again to 65°C and the reaction mixture was stirred for five hours.
  • the mixture was allowed to cool to ambient temperature.
  • the resulting solids were isolated by filtration to afford the title compound (41.53 g).

Abstract

This invention relates compounds of formulae Wherein A is CN,CONH2 OR CONHCOOR, R being methyl or optionally substituted benzyl, useful as intermediates for cholesteryl ester transfer protein (CETP) inhibitors and methods for the preparation thereof.

Description

COMPOUNDS USEFUL AS INTERMEDIATES FIELD OF THE INVENTION This invention relates to compounds useful as intermediates for cholesteryl ester transfer protein (CETP) inhibitors and methods for the preparation thereof.
BACKGROUND OF THE INVENTION
Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S.
Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D. J., et al.: "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15).
High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues resulting in reduced compliance. Fibrates and the HMG-CoA reductase inhibitors raise HDL-C only modestly. As a result, there is a significant unmet medical need for a well-tolerated agent which can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.
PCT application publication number WO 00/02887 discloses the use of catalysts comprising certain novel ligands for transition metals in transition metal-catalyzed carbon-heteroatom and carbon-carbon bond formation.
Commonly assigned U.S. Patent No. 6,140,343, the disclosure of which is incorporated herein by reference, discloses, inter alia, the CETP inhibitor, c/'s-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, and processes for the preparation thereof (e.g., procedure disclosed in Example 46).
Commonly assigned U.S. Patent No. 6,197,786, the disclosure of which is incorporated herein by reference, discloses, inter alia, the CETP inhibitor, c/s-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, and processes for the preparation thereof (e.g., procedure disclosed in Example 7).
SUMMARY OF THE INVENTION
One aspect of this invention is the compound of formula III,
Figure imgf000003_0001
Another aspect of this invention is the compound of formula IV,
Figure imgf000003_0002
IV. A further aspect of this invention is compounds of formula VI,
Figure imgf000004_0001
VI. wherein R is selected from methyl, benzyl and substituted benzyl.
An additional aspect of this invention is compounds of formula VII,
Figure imgf000004_0002
VII,
wherein R is selected from methyl, benzyl and substituted benzyl.
In a preferred embodiment of the compound aspects of this invention, R in the compounds of formula VI and the compounds of formula VII is selected from methyl, benzyl and benzyl substituted with one or more substituents each independently selected from (CrC3)alkyl, (Cι-C3)alkyloxy and a halogen.
A further aspect of this invention is methods for preparing the compound of formula III, above, comprising coupling trifluoromethylbenzene that is para-substituted with a halogen or O-triflate with the compound of formula II,
Figure imgf000004_0003
to form the compound of formula III.
In a preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a transition metal, preferably palladium.
In another preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a phosphine ligand, preferably a dialkylphosphinobiphenyl ligand, more preferably selected from 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl and 2-dicyclohexylphosphino-2'-methylbiphenyl.
In an additional preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a base, preferably cesium carbonate.
Another aspect of this invention is methods for preparing the compound of formula IV, above, comprising hydrolyzing the above compound of formula III, with a hydrolyzing agent selected from an acid and a base, preferably an acid, more preferably sulfuric acid with water, to form the compound of formula IV.
A further aspect of this invention is methods for preparing compounds of formula VI, above, comprising combining the compound of formula IV, above, with a compound of formula V,
O cr Λ o-" Rκ v, wherein R is selected from methyl, benzyl and substituted benzyl, in the presence of a base, preferably lithium t-butoxide, to form compounds of formula VI.
An additional aspect of this invention is methods for preparing compounds of formula VII, above, comprising reducing the above compounds of formula VI, wherein R is selected from methyl, benzyl and substituted benzyl, with a reducing agent, preferably sodium borohydride in the presence of a Lewis acid, preferably calcium ions or magnesium ions, to form a reduced compound and cyclizing the reduced compound under acidic conditions to form a compound of formula VII. The term "substituted benzyl" with respect to compounds of formula V, VI and VII means benzyl that is substituted on the benzene ring with one or more substituents such that such substitution does not prevent: (a) the reaction of the applicable formula V compound with the compound of formula IV to form the applicable formula VI compounds, (b) the reduction and cyclization of the applicable formula VI to form the applicable formula VIIB compound, (c) the acetylation of the formula VIIB compound to form the formula VIIIB compound or (d) the deprotection step to remove the applicable substituted benzyloxycarbonyl group in forming the formula IB compound from the compound of formula VIIIB. Preferred substituents are (Cι-C3)alkyl and (Cι-C3)alkoxy and halogens.
Chemical structures herein are represented by planar chemical structure diagrams that are viewed from a perspective above the plane of the structure. A wedge line ( ~~~ ) appearing in such chemical structures represents a bond that projects up from the plane of the structure.
DETAILED DESCRIPTION OF THE INVENTION Reaction Scheme A illustrates the process for preparing the chiral isomer of formula II from (R)-2-amino-1-butanol. Scheme B illustrates the process of preparing the cholesterol ester transfer protein inhibitors of formula IA and formula IB.
SCHEME A
Figure imgf000007_0001
NaCN, Bu4NBr DMF
Figure imgf000007_0002
SCHEME B
Figure imgf000008_0001
According to Scheme B, the formula III compound is prepared by combining the chiral isomer compound of formula II ((R)-3-amino- pentanenitrile) with trifluoromethylbenzene that is para-substituted with a halogen or O-triflate (-O-S(O)2CF3) in the presence of a metal catalyst, preferably Pd. For optimal coupling, the coupling reaction occurs in the presence of a ligand, preferably a phosphine ligand, and a base. A preferred phosphine ligand is a dialkylphosphinobiphenyl ligand, preferably selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl) and 2- dicyclohexylphosphino-2'-methylbiphenyl. The reaction is preferably performed at a temperature of about 60°C to about 110°C. The formula II chiral isomer may be prepared from (R)-2-amino-1-butanol (CAS# 005856-63- 3) by methods known to those skilled in the art according to Scheme A and as described in Example 9 of the Experimental Procedures.
The formula IV compound is prepared by hydrolyzing the nitrile of the formula III compound. The hydrolysis may be performed in acidic or basic conditions. The preferred method of hydrolysis is under acidic conditions, preferably using sulfuric acid and water. For hydrolysis with base, preferred bases are hydroxy bases, preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkoxy bases, preferably methoxide and ethoxide. Also, for hydrolysis with base, it is preferably to use a peroxide. The hydrolysis reaction is preferably performed at a temperature of about 20°C to about 40°C.
The formula VI compound is prepared by reacting the amide of the formula IV compound with a formula V chloroformate in the presence of a base, preferably lithium t-butoxide. The reaction is preferably performed at a temperature of about 0°C to about 35°C. If the formula VI compound having R as methyl is desired, then methyl chloroformate is used as the formula V compound. If the formula VI compound having R as benzyl is desired, then benzyl chloroformate is used. The formula VII compound is prepared by reacting the imide of the formula VI compound with a reducing agent, preferably sodium borohydride, in the presence of a Lewis acid activator, preferably calcium or magnesium ions to produce a reduced intermediate. The reaction to make the reduced intermediate is preferably performed at a temperature of about -20°C to about 20°C. Under acidic conditions, the intermediate diastereoselectively cydizes to form the tetrahydroquinoline ring of formula VII. The cyclization step is preferably performed at about 20°C to about 50°C.
The CETP inhibitor of formula IA is prepared by acylating the compound of formula VII wherein R is methyl at the tetrahydroquinoline nitrogen with ethyl chloroformate in the presence of a base, preferably pyridine, to form the compound of formula VI 11 A. The reaction is preferably performed at a temperature of about 0°C to about 25°C.
The formula IA CETP inhibitor is prepared by alkylating the formula VIM compound, wherein R is methyl, with a 3,5-bis(trifluoromethyl)benzyl halide, preferably 3,5-bis(trifluoromethyl)benzyl bromide in the presence of a base, preferably an alkoxide or hydroxide, and more preferably potassium t- butoxide. The preferred temperature range of the reaction is about 25°C to about 75°C. The CETP inhibitor of formula IB is prepared by acylating compound
VII wherein R is benzyl or substituted benzyl at the tetrahydroquinoline nitrogen with isopropyl chloroformate in the presence of a base, preferably pyridine, to form the compound of formula VIIIB. The preferred temperature of this reaction is about 0°C to about 25°C. The CETP inhibitor of formula IB may then be prepared from the formula VIIIB compound by first treating compound VIIIB with an excess of a hydrogen source (e.g., cyclohexene, hydrogen gas or ammonium formate) in the presence of a suitable catalyst in a polar solvent (e.g. ethanol) to remove the benzyloxycarbonyl group. The 3,5-bis-trifluoromethylbenzyl group of the formula IB compound may then be introduced by treating the amine and an acid, such as acetic acid, with 3,5-bis-trifluoromethyl-benzaldehyde followed by treatment with a hydride source, such as sodium triacetoxyborohydride. Then, the amino group is acetylated by methods known by those skilled in the art to form the formula IB compound. The procedure for preparing the compound of formula IB from the compound of formula VIIIB is further described in Example 46 of commonly assigned U.S. Patent No. 6,140,343. The disclosure of U.S. Patent No. 6,140,343 is incorporated herein by reference. EXPERIMENTAL PROCEDURES
Melting points were determined on a Buchi melting point apparatus.
NMR spectra were recorded on a Varian Unity 400 (Varian Co., Palo Alto,
CA). Chemical shifts are expressed in parts per million downfield from the solvent. The peak shapes are denoted as follows: s=singlet; d=doublet; t=triplet; q=quartet; m=multiplet; bs=broad singlet.
Example 1
(3R)-3-(4-Trifluoromethyl-phenylamino)-pentanenitrile
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (R)- 3-aminopentanenitrile methanesulfonic acid salt (3000 g, 15.44 mol), sodium carbonate (2.8 kg, 26.4 mol), and methylene chloride (21 L). The heterogeneous mixture was stirred well for at least 2 hours. The mixture was filtered and the filter was rinsed with methylene chloride (3 x 2 L). The resulting filtrate was placed in a clean, dry, and nitrogen gas purged 50 L glass reaction tank. The methylene chloride was removed by distillation until the internal temperature reached 50-53°C to afford the free-based amine as a thin oil. The tank was then cooled to room temperature and charged with toluene (20 L), chloro-4-(trifluoromethyl)benzene (4200 g, 23.26 mol), and cesium carbonate (7500 g, 23.02 mol). The solution was sparged with nitrogen gas for 1 hour. Near the time of completion of the sparging, fresh catalyst solution was prepared by charging a 2L round-bottom flask, equipped with stir bar and flushed with nitrogen gas, with 2-dicyclohexylphosphino-2'-
(N,N-dimethylamino)biphenyl (68 g, 0.17 mol), phenylboronic acid (28 g, 0.23 g), and tetrahydrofuran (1.2 L) followed by palladium acetate (26 g, 0.12 mol). The catalyst solution was stirred at room temperature under nitrogen atmosphere for 15 minutes. The catalyst solution was added to the 50L reaction tank with the use of a cannula (excluding air). The mixture was heated to 79°C internal temperature under nitrogen atmosphere for 16 hours.
The reaction solution was cooled to room temperature and filtered through Celite®. The solids were rinsed with toluene (3 x 2L) and the filtrate was collected. All filtrates were combined to afford a crude solution of the title compound.
Example 2 (3R)-3-(4-Trifluoromethyl-phenylamino)-Dentanoic acid amide Aqueous sulfuric acid (8.2 L sulfuric acid and 1.1 L water premixed and cooled to 35 °C or less) was added to the crude toluene solution of (3R)-3-(4- trifluoromethyl-phenylamino)-pentanenitrile from Example 1. The resulting bilayer was stirred well and heated to 35 °C for 17 hours. The lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95 L water and 10.7 kg sodium hydroxide) and diisopropyl ether (IPE) (40 L). After extraction and removal of the aqueous layer, the organic layer was combined and extracted with saturated aqueous NaHCO3 (10 L). The organic phase from the resulting bilayer was concentrated by distillation to a volume of 19 L. The solution was then cooled to room temperature and seeded with (3R)-3-(4- trifluoromethyl-phenylamino)-pentanoic acid amide and allowed to granulate for 3 hours while stirring. To the heterogenous mixture was added cyclohexane (38 L) and the mixture was granulated for an additional 11 hours. The solids were filtered, rinsed with cyclohexane (4 L), dried under vacuum at 40 °C to afford 3021 g (75 %) of the title compound.
1H NMR (400 MHz, CDCI3): 0.98 (t, 3, J=7.5), 1.60-1.76 (m, 2), 2.45 (d, 2, J=5.8), 3.73-3.80 (m, 1 ), 5.53(br s, 1 ), 5.63 (br s, 1 ), 6.65, (d, 2, J=8.7), 7.39 (d, 2, J=8.7) 13C NMR (100 MHz, CDCI3): 10.74, 27.80, 40.02, 51.95, 112.63, 118.9 (q, J=32.7), 125.18 (q, J=271.0), 126.93 (q, J=3.8), 150.17, 174.26
Example 3 (3R)-f3-(4-Trifluoromethyl-phenylamino)-pentanoyll-carbamic acid methyl ester A clean, dry and nitrogen gas purged 100 L glass tank was charged with (3R)- 3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (6094 g, 23.42 mol), isopropyl ether (30 L) and methyl chloroformate (2.7 kg, 29 mol). The resulting slurry was cooled to 2°C. The reaction tank was then charged with lithium t-butoxide solution (18-20% in THF, 24.6 kg, -58 mol) at such a rate as to maintain the internal temperature below 10 °C and preferably at a temperature of about 5 °C. Ten minutes after addition of base was complete, the reaction was quenched by the addition of 1.5 M hydrochloric acid (36 L). The aqueous layer was removed, and the organic phase extracted with saturated NaCI/water solution (10 L). The aqueous layer was removed and the organic phase was concentrated by distillation under vacuum and at a temperature of about 50°C until the volume was reduced to about 24 L. Cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50°C under vacuum until the volume of solution in the vessel was reduced to 24 L. A second portion of cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50°C under vacuum until the volume of solution in the vessel was reduced to 24 L. While holding the temperature at 50 °C, the solution was seeded with (3R)-[3-(4- trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid methyl ester and allowed to granulate while stirring for 2 hours. The solution was then cooled slowly (over 1.5 hours) to room temperature and allowed to granulate while stirring for 15 hours. The mixture was filtered. The resulting solids were rinsed with cyclohexane (10 L) and dried under vacuum at 40°C to afford 7504 g of the title compound (94%). m.p.=142.3-142.4 °C.
1H NMR (400 MHz, d6-Acetone): 0.96 (t, 3, J=7.4), 1.55-1.75 (m, 2), 2.86 (dd, 1 , J=6.6, 16.2, 2.96 (dd, 1 , J=6.2, 16.2), 3.69 (s, 3), 3.92-3.99 (m, 1), 5.49 (br d, 1 , J=8.7), 6.76 (d, 2, J=8.7), 7.37 (d, 2, J=8.7), 9.42 (br s, 1 ). 13C NMR (100 MHz, CDCI3): 10.62, 28.10, 40.19, 51.45, 53.42, 112.54, 118.98 (q, J=32.70), 125.16 (q, J=270.2), 126.90 (q, J=3.8), 150.10, 152.71 , 173.40.
Example 4 (2R. 4S)-(2-Ethyl-6-trifluoromethyl-1.2.3.4-tetrahvdro-quinolin-4-yl)-carbamic acid methyl ester A clean, dry and nitrogen gas purged 100 L glass tank was charged (3R)-[3- (4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid methyl ester (7474 g) followed by 2B ethanol (46 L) and water (2.35 L). Sodium borohydride (620 g) was added to the solution in one portion. Nitrogen gas purging is maintained. The mixture was stirred at room temperature for 20 minutes and then cooled to -10 °C. A solution of 3.3 M aqueous magnesium chloride solution (4.68 kg MgCI2*6H2O in 7 L water) was added at such a rate that the internal temperature did not exceed -5 °C. Once addition was completed, the reaction solution was warmed to 0 °C for 45 min. The reaction was quenched by transferring the reaction mixture to a 200 L tank containing methylene chloride (70 L), and 1M hydrochloric acid/citric acid solution (5.8 L concetrated hydrochloric acid, 64 L water, and 10.5 kg citric acid). The headspace of the tank was purged with nitrogen gas. This bilayer was stirred at room temperature for two hours. The phases were separated and the lower organic product layer was removed. After aqueous layer removal, the organic phase was returned to the reaction vessel and extracted with an aqueous citric acid solution (6.3 kg citric acid, 34 L water). The mixture was stirred for 1 hour and allowed to settle overnight. The layers were separated and to the organic was added Darco® activated carbon (G-60 grade, 700 g) (Atlas Powder Co., Wilmington, DE) and the solution was stirred for 30 minutes. The mixture was then filtered through Celite®, and the carbon was rinsed twice with methylene chloride (14L and 8L). The filtrate was distilled while periodically adding hexanes so as to displace the methylene chloride with hexanes to a total final volume of 70 L (112 L total hexanes used). Product crystallized during the displacement. Once a stable distillation temperature was reached, the solution was cooled and granulated while stirring at room temperature for 10 hours. The solids were filtered off, rinsed with hexanes (14 L), and dried at 40 °C under vacuum to afford the title compound (5291 g). (80%). m.p.=139.0-140.5°C. 1H NMR (400 MHz, d6-Acetone): 1.00 (t, 3, J=7.5), 1.51-1.67 (m, 3), 2.19 (ddd, 1 , J=2.9, 5.4, 12.4), 3.44-3.53 (m, 1 ), 3.67 (s, 3), 4.89-4.96(m, 1), 5.66 (br s, 1 ), 6.56 (br d, 1 , J=8.7), 6.65 (d, 1 , J=8.7), 7.20 (d, 1 , J=8.7), 7.30 (br s,
1 )-
13C NMR (100 MHz, CDCI3): 9.88, 29.24, 35.47, 48.09, 52.42, 52.60, 113.66, 118.90 (q, J=33.1 ), 121.40, 124.08 (q, J=3.8), 125.08 (q, J=270.6), 125.70 (q, J=3.8), 147.68, 157.30.
Example 5
(2R. 4S)-2-Ethyl-4-methoxycarbonylamino-6-trifluoromethyl-3,4-dihydro-2/-/- αuinoline-1-carboxylic acid ethyl ester A clean, dry and nitrogen gas purged 100 L glass tank was charged with (2R,
4S)-(2-ethyl-6-trifluoromethyl-1 ,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (5191 g, 17.17 mol), methylene chloride (21 L), and pyridine
(4.16 L, 51.4 mol). The reaction vessel was cooled to -10°C. Ethyl chloroformate (4.10 L, 42.9 mol) was slowly added at such a rate that the internal temperature did not exceed -5°C. The reaction solution was brought to 0°C and held for 20 hours. The reaction was quenched by adding to a mixture of diisopropyl ether (IPE) (36 L), methylene chloride (6.2 L) and 1.5M hydrochloric acid solution (52 L). The resulting phases were separated and the organic layer was extracted with 1 M sodium hydroxide solution (15 L). The resulting phases were separated and the organic layer was washed with saturated aqueous sodium chloride NaCI (15 L). The resulting phases were separated and the organic layer was concentrated by distillation to a volume of 40 L. Crystallization initiated at lower volume. The methylene chloride was displaced with IPE by distilling the mixture and periodically adding IPE to maintain a constant volume at 40L until a temperature of 68°C was maintained (46 L total IPE used). The mixture was cooled and allowed to granulate with stirring at room temperature for 19 hours. The solids were filtered, rinsed with IPE (8 L), and dried under vacuum at 40°C to afford 5668 g of the title compound (88%). m.p.=157.3-157.6°C.
1H (400 MHz,d6-Acetone): 0.84 (t, 3, J=7.5), 1.26 (t, 3, J=7.0), 1.44-1.73 (m, 3), 2.59 (ddd, 1 , J=4.6, 8.3,12.9), 3.67 (s, 3), 4.14-4.28 (m, 2), 4.46-4.54 (m, 1 ), 4.66-4.74 (m, 1), 6.82 (br d, 1 , J=9.1 ), 7.53 (s, 1 ), 7.58 (d, 1 , J=8.3), 7.69 (d, 1 , J=8.3).
13C NMR (100 MHz, CDCI3): 9.93, 14.55, 28.46, 38.08, 46.92, 52.64, 53.70, 62.42, 120.83 (q, J=3.4), 124.32 (q, J=271.7), 124.36 (q, J=3.4), 126.38, 126.46 (q, J=32.7), 134.68, 139.65, 154.66, 156.85.
Example 6 (2R. 4S)-4-r(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino1-2-ethyl- 6-trifluoromethyl-3.4-dihvdro-2 -/-αuinoline-1-carboxylic acid ethyl ester A clean, dry and nitrogen gas purged 100 L glass tank was charged with (2R, 4S)-2-ethyl-4-methoxycarbonylamino-6-trifluoromethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid ethyl ester (5175 g, 13.82 mol), CH2CI2 (20 L), and potassium t-butoxide (1551 g, 13.82 mol) at room temperature. The mixture was stirred for five minutes. 3,5-Bis(trifluromethyl)benzylbromide (3.50 L, 19.1 mol) was added to the mixture in one portion. The internal temperature was maintained between 20-25 °C for 1.5 hours. After 2.3 hours of reaction time, an additional charge of potassium t-butoxide (46.10 g, 0.41 mol) was added. After a total reaction time of 4.5 hours, the reaction was quenched. 1 ,4-Diazabicyclo[2.2.2]octane (DABCO) (918 g, 8.18 mol) was added to the reaction solution and the mixture was stirred for 1 hour. IPE (40 L) and 0.5 M hydrochloric acid (30 L) were added to the reaction mixture. The resulting organic and aqueous phases were separated and the organic layer was extracted with 0.5M hydrochloric acid (2 x 30 L). The resulting organic and aqueous phases were then separated and the organic layer was extracted with saturated aqueous sodium chloride (15 L) and the resulting organic and aqueous phases were separated. Anhydrous magnesium sulfate (3.5 kg) was added to the organic layer and the mixture was stirred for 30 minutes. The mixture was then filtered (0.5 micron filter) into a 50 L glass tank with IPE wash (8 L) in two portions. The filtrate was concentrated under vacuum to a total volume of 12 L with internal temperature of 35 °C resulting in an oil. 2B Ethanol (25 L) was added to the oil and the solution was concentrated under vacuum to a volume of 12 L. To the solution was added 2B ethanol (15 L) and the solution was again concentrated under vacuum to a volume of 12 L. The solution was cooled to room temperature and seeded with (2R, 4S)-4- [(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3 g). The solution was granulated for about 38 hours, filtered, and rinsed with 2B ethanol (4 L + 2L). The solids were dried under vacuum (no heat) to afford 4610 g (55%) of the title compound. The mother liquor from the above filtration was concentrated under vacuum (solution temp = 62 °C) to a final volume of 6 L and cooled to 38°C. The solution was seeded with (2R, 4S)-4- [(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6- trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.5 g) and allowed to cool and granulate while stirring for 19 hours. The mixture was filtered and the solids rinsed with 2B EtOH (2.5 L). The resulting cake was dried under vacuum (no heat) to provide 1422 g (17%) of the title compound as the second crop. Combined recovery was 6032 g (73%).
Example 7 (3RH3-(4-Trifluoromethyl-phenylaminoVpentanoyl1-carbamic acid benzyl ester A clean, dry and nitrogen gas purged flask was charged with (3R)-3-(4- trifluoromethyl-phenylamino)-pentanoic acid amide (20.11 g, 77.27 mmol) and isopropyl ether (100 mL) and the mixture was cooled to -12°C. Benzyl chloroformate (13.25 mL, 92.8 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (185.5 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0°C. Fifteen minutes after the completion of base addition, the reaction was quenched by adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO ), filtered, and concentrated under partial vacuum (at 40 °C) to a total volume of 100 mL. Additional isopropylether (200 mL) was added and the solution was again concentrated under partial vacuum (at 40 °C) to a total volume of 100 mL. After cooling, the solution was seeded with (3R)-[3-(4-trifluoromethyl- phenylamino)-pentanoyl]-carbamic acid benzyl ester and allowed to stir at room temperature overnight. The remaining solvent was displaced with cyclohexane using partial vacuum distillation (45 °C bath, 200 mL followed by 100 mL), the resultant slurry was cooled and stirred for 40 minutes, filtered, and dried to provide 25.8714 g (85%) of the title compound, m.p. 100.6-101.4 °C.
1H NMR (400 MHz d6-acetone): 0.96 (t, 3, J=7.5), 1.57-1.75 (m, 2), 2.87 (dd, 1 , J=6.6, 16.2), 2.97 (dd, 1 , J=6.2, 16.2), 3.94-4.00 (m, 1 ), 5.16 (s, 2), 5.50 (br s, 1 ), 6.75 (d, 2, J=5.7), 7.33-7.43 (m, 7), 9.52 (br s, 1 ). 13C NMR (100 MHz CDCI3): 10.66, 28.13, 40.28, 51.47, 68.25, 112.52, 118.91 (q, J=32.3), 125.21 (q, J=269.9), 126.92 (q, J=3.8), 128.64, 128.98, 129.04, 135.05, 150.12, 152.12, 173.52.
Example 8 (2R. 4S)-(2-Ethyl-6-trifluoromethyl-1.2.3,4-tetrahvdro-αuinolin-4-yl)-carbamic acid benzyl ester
A clean, dry and nitrogen gas purged flask was charged with (3R)-[3-(4- trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester (11.51 g, 29.18 mmol) and 95% ethanol (80 mL) and the solution was cooled in an ice/acetone bath (~ -12 °C). Sodium borohydride (0.773 g, 20.4 mmol) was then added to the solution. The internal temperature of the reaction was -11.5 °C. To the reaction flask was slowly added a solution of MgCI2*6H2O (6.23 g, 30.6 mmol, in 13 mL H2O). The internal temperature was maintained below - 5°C by adjusting the addition rate. Once all of the magnesium solution was added, the solution temperature was raised to 0°C and stirred for 30 minutes. The reaction was then quenched by the addition of methylene chloride (115 mL), 1 N hydrochloric acid (115 mL) and citric acid (14.02 g, 72.97 mmol). This bilayer was stirred at room temperature. After 3.75 hours, the cyclization reaction was found to be complete by HPLC analysis and the phases were separated. Water (58 mL) and citric acid (8.41 g, 43.77 mmol) were added to the organic layer and the mixture was stirred at room temperature for 45 minutes. The phases were separated and g-60 Darco® activated charcoal (1.52 g) (Atlas Powder Co., Wilmington, DE) was added to the organic layer. After stirring for 45 minutes, the solution was filtered through Celite® and washed with methylene chloride (2 x 15 mL). The filtrate was then displaced with hexanes (approximately 350 mL) by distillation under atmospheric pressure and concentration of the mixture to a total volume of 230 mL. The mixture was stirred at room temperature for 14 h, filtered, and dried to afford 9.0872 g (82%) of the title compound. m.p. 154.0-155.2 °C.
1H NMR (400 MHz d6-acetone): 1.00 (t, 3, J=7.5), 1.51-1.69 (m, 3), 2.17-2.26 (m, 1 ), 3.46-3.54 (m, 1), 4.96 (ddd, 1 , J=5.4, 9.5, 11.6), 5.14 (d, 1 , J=12.9), 5.20 (d, 1 , J=12.9), 5.66 (br s, 1 ), 6.65 (d, 1 , J=8.3), 6.71 (br d, 1 , J=9.1 ), 7.20 (dd, 1 , J=1.9, 8.9), 7.30-7.43 (m, 6). 13C NMR (100 MHz CDCI3): 9.89, 29.24, 35.34, 48.16, 52.44, 67.27, 113.70, 118.85 (q, J=32.7), 121.37, 124.12 (q, J=3.8), 125.14 (q, J=270.6), 125.72 (q, J=3.8), 128.38, 128.51 , 128.86, 136.57, 147.71 , 156.74.
Example 9 (R)-3-Aminopentanenitrile methanesulfonic acid salt Step 1 : Methanesulfonic acid 2-tert-butoxycarbonylamino-butyl ester- Run #1 : BOC anhydride (515.9 g) in ethyl acetate (400 mL) was added to a solution of R-(-)-2-amino-1-butanol (200.66 g) in ethyl acetate (1105 mL) via an addition funnel. The reaction mixture was stirred for approximately 30 minutes. Tetramethylethylenediamine (TMEDA) (360 mL) was added and the reaction mixture was cooled to approximately 10°C. Methanesulfonyl chloride (184.7 mL) was added to the reaction mixture over a 30-minute period. After stirring for 1 hour, the reaction mixture was filtered and the filtrate was collected. Run #2: BOC anhydride (514.5 g) in ethyl acetate (400 mL) was added to a solution of R-(-)-2-amino-1-butanol (200.12 g) in ethyl acetate (1101 mL) via an addition funnel. The reaction mixture was stirred for approximately 30 minutes. Tetramethylethylenediamine (TMEDA) (359.1 mL) was added and the reaction mixture was cooled to approximately 10°C. Methanesulfonyl chloride (184.1 mL) was added to the reaction mixture over a 30-minute period. After stirring for 1 hour, the reaction mixture was combined with the filtrate from Run # 1 and filtered. The solids where washed with 400 mL ethyl acetate. Hexanes (12 L) were added to the filtrate. The mixture was cooled in an ice/water bath. After about 2.5 hours the solids were isolated by filtration, washed with hexanes (2 L) and dried under vacuum to afford the title compound (971.57 g ).
Step 2: (l-Cvanomethyl-propyD-carbamic acid tert-butyl ester. Sodium cyanide (24.05 g) was added to dimethylformamide (DMF) (500 L) and the mixture was stirred at 35°C for 30 minutes. Tetrabutyl ammonium bromide was added and the reaction mixture was stirred at 35°C for two hours. Methanesulfonic acid 2-tert-butoxycarbonylamino-butyl ester (101.23 g) was added and the reaction mixture was stirred at 35°C overnight. The mixture was then partitioned between two liters water and one liter isopropyl ether. The resulting organic and aqueous phases were separated and washed sequentially with watner and a saturated solution of sodium chloride in water. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford a solid (65.22 g). The solid (61.6 g) was transferred to a flask equipped with an overhead stirrer. Hexane was added and the flask was heated to 65°C. After all the solids were in solution, the mixture was cooled to ambient temperature. The mixture was stirred overnight. The resulting solids were isolated by filtration to afford the title compound (52.32
9)-
Step 3: (R)-3-Aminopentanenitrile methanesulfonic acid salt. Methane sulfonic acid (71 g) was added to a solution of (l-cyanomethyl-propyl)-carbamic acid tert-butyl ester in tetrahydrofuran (530 mL). The reaction mixture was heated to 40°C for approximately 30 minutes. The temperature was raised to 45°C and stirred for approximately one hour. The temperature was raised again to 65°C and the reaction mixture was stirred for five hours. The mixture was allowed to cool to ambient temperature. The resulting solids were isolated by filtration to afford the title compound (41.53 g).

Claims

1. The compound of formula III,
Figure imgf000021_0001
The compound of formula IV,
Figure imgf000021_0002
IV.
A compound of formula VI,
Figure imgf000021_0003
VI. wherein R is selected from methyl, benzyl and substituted benzyl.
A compound of formula VII,
Figure imgf000021_0004
VII,
wherein R is selected from methyl, benzyl and substituted benzyl.
5. A compound of claim 3 or 4 wherein R is selected from methyl, benzyl and benzyl substituted with one or more substituents each independently selected from (CrC3)alkyl, (d-C3)alkyloxy and a halogen.
6. A method for preparing the compound of formula III,
Figure imgf000022_0001
III, comprising coupling trifluoromethylbenzene that is para-substituted with a halogen or O-triflate with the compound of formula II,
Figure imgf000022_0002
II, to form the compound of formula III.
7. A method of claim 6 wherein said trifluoromethylbenzene compound is combined with said compound of formula II in the presence of a phosphine ligand.
8. A method of claim 7 wherein said phosphine ligand is a dialkylphosphinobiphenyl ligand.
9. A method of claim 8 wherein said phosphine ligand is selected from 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and 2- dicyclohexylphosphino-2'-methylbiphenyl.
10. A method of claim 6 wherein said coupling comprises combining said trifluoromethylbenzene compound with said compound of formula II in the presence of a base.
11. A method for preparing the compound of formula IV,
Figure imgf000022_0003
IV, comprising hydrolyzing the compound of formula III,
Figure imgf000023_0001
with a hydrolyzing agent selected from an acid and a base to form the compound of formula IV.
12. A method for preparing a compound of formula VI,
Figure imgf000023_0002
VI, comprising combining the compound of formula IV,
Figure imgf000023_0003
IV, with a compound of formula V,
Figure imgf000023_0004
V, wherein R is selected from methyl, benzyl and substituted benzyl, in the presence of a base to form a compound of formula VI.
13. A method of claim 12 wherein said base is lithium t-butoxide.
14. A method for preparing a compound of formula VII,
PCT/IB2002/001217 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives WO2002088069A2 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
BR0209238-7A BR0209238A (en) 2001-04-30 2002-04-08 Compounds useful as intermediates
EP02722569A EP1383734B1 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives
CA002445693A CA2445693A1 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives
MXPA03009936A MXPA03009936A (en) 2001-04-30 2002-04-08 Compounds useful as intermediates.
IL15754602A IL157546A0 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives
AU2002253448A AU2002253448B2 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives
JP2002585373A JP3924250B2 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives
KR1020037014135A KR100591998B1 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatives
HU0304041A HU225777B1 (en) 2001-04-30 2002-04-08 Compounds useful as intermediates for 4-aminoquinoline derivatwes and process for producing them
DE60209004T DE60209004T2 (en) 2001-04-30 2002-04-08 COMPOUNDS USE AS INTERMEDIATE CHOLESTERYTERESTRANSFERPROTEIN (CETP) INHIBITORS
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002924A1 (en) * 2002-06-28 2004-01-08 Pcbu Services, Inc. Preparation of chiral amino-nitriles
WO2004007741A1 (en) * 2002-07-12 2004-01-22 Kaneka Corporation PROCESS FOR PRODUCING OPTICALLY ACTIVE β-AMINONITRILE COMPOUND AND AMIDE COMPOUND AS ANTIPODE THEREOF
WO2004074255A2 (en) * 2003-02-18 2004-09-02 Takasago International Corporation Method for producing an optically active tetrahydroquinoline
WO2004083166A1 (en) * 2003-03-17 2004-09-30 Kaneka Corporation Processes for production of (r)-3-[4-(trifluoromethyl)- phenylamino]pentanamide derivatives
WO2005100321A1 (en) * 2004-04-07 2005-10-27 Millennium Pharmaceuticals, Inc. Pgd2 receptor antagonists for the treatment of inflammatory diseases
US7211672B2 (en) 2002-10-04 2007-05-01 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US7223859B2 (en) 2003-03-17 2007-05-29 Pfizer Inc. Method for producing (R)-3-[4-(trifluoromethyl) phenylamino]-pentanoic acid amide derivative
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
WO2008112166A2 (en) 2007-03-09 2008-09-18 Indigene Pharmaceuticals Inc. Combination of metformin r-(+) lipoate and antihyperlipidemic agents for the treatment of diabetic hyperglycemia and diabetic complications
US7504508B2 (en) 2002-10-04 2009-03-17 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
EP2154132A1 (en) 2006-03-30 2010-02-17 Mitsubishi Tanabe Pharma Corporation A process for preparing tetrahydroquinoline derivatives
EP2316447A1 (en) 2003-09-26 2011-05-04 Japan Tobacco, Inc. Method of inhibiting remnant lipoprotein production
US7951950B2 (en) 2005-02-24 2011-05-31 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US9867811B2 (en) 2011-07-08 2018-01-16 Novartis Ag Method of treating atherosclerosis in high triglyceride subjects

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197786B1 (en) * 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US20090181966A1 (en) * 2002-10-04 2009-07-16 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
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WO2006012093A1 (en) * 2004-06-24 2006-02-02 Eli Lilly And Company Compounds and methods for treating dyslipidemia
DE102004031656A1 (en) * 2004-06-30 2006-01-19 Merck Patent Gmbh Tetrahydroquinolines
WO2006069162A1 (en) * 2004-12-20 2006-06-29 Reddy Us Therapeutics, Inc. Novel heterocyclic compounds and their pharmaceutical compositions
CA2610205A1 (en) * 2005-06-20 2006-12-28 Astrazeneca Ab Process for the production of (alkoxycarbonylamino)alkyl sulfonates
DE102006032391A1 (en) * 2006-07-04 2008-01-17 Merck Patent Gmbh fluorosurfactants
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JP2011256110A (en) * 2008-09-30 2011-12-22 Takeda Chem Ind Ltd Manufacturing method of hexahydropyrroloquinoline
AR077208A1 (en) * 2009-06-30 2011-08-10 Lilly Co Eli ACID DERIVATIVES TRANS-4 - [[(5S) -5 - [[[3,5-BIS (TRIFLUOROMETIL) PHENYLE] METHYL] (2-METHYL-2H-TETRAZOL-5-IL) AMINO) -2,3, 4,5-TETRAHIDRO-7,9-DIMETIL-1H-1-BENZAZEPIN-1-IL) METHYL) -CYCLHEXANCARBOXYL AND ITS CRYSTALLINE FORMS, PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND IT, ITS USE TO PREPARE A MEDICAM
WO2012141487A2 (en) 2011-04-12 2012-10-18 Chong Kun Dang Pharmaceutical Corp. Cycloalkenyl aryl derivatives for cetp inhibitor
NZ708079A (en) 2013-01-31 2016-07-29 Chong Kun Dang Pharm Corp Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as cetp inhibitors
CA2926010A1 (en) * 2013-11-11 2015-05-14 Lonza Ltd Method for preparation of cyano compounds of the 13th group with a lewis acid
EP4083022A1 (en) * 2014-08-12 2022-11-02 NewAmsterdam Pharma B.V. Process for preparing synthetic intermediates for preparing tetrahydroquinoline derivatives
CN105294559B (en) * 2015-06-24 2017-11-14 厦门法茉维特动物药业有限公司 A kind of synthetic method of the aminoquinolines of medicine intermediate 4

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000017164A1 (en) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors
WO2000017165A1 (en) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5035813B2 (en) 1998-07-10 2012-09-26 マサチューセッツ インスティテュート オブ テクノロジー Ligands for metals and improved metal catalyst processes based on them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000017164A1 (en) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors
WO2000017165A1 (en) * 1998-09-17 2000-03-30 Pfizer Products Inc. 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TATEE T ET AL: "Isoxazole derivatives as centrally acting muscle relaxants. III. Synthesis and activity of conformationally restricted analogs" CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 35, no. 9, September 1987 (1987-09), pages 3676-3690, XP002217378 *

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Publication number Priority date Publication date Assignee Title
WO2004002924A1 (en) * 2002-06-28 2004-01-08 Pcbu Services, Inc. Preparation of chiral amino-nitriles
WO2004007741A1 (en) * 2002-07-12 2004-01-22 Kaneka Corporation PROCESS FOR PRODUCING OPTICALLY ACTIVE β-AMINONITRILE COMPOUND AND AMIDE COMPOUND AS ANTIPODE THEREOF
US7504508B2 (en) 2002-10-04 2009-03-17 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
US7211672B2 (en) 2002-10-04 2007-05-01 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
JP2006519783A (en) * 2003-02-18 2006-08-31 高砂香料工業株式会社 Process for producing optically active tetrahydroquinolines
WO2004074255A3 (en) * 2003-02-18 2004-11-25 Takasago Perfumery Co Ltd Method for producing an optically active tetrahydroquinoline
US8188307B2 (en) 2003-02-18 2012-05-29 Takasago International Corporation Method for producing an optically active tetrahydroquinoline
WO2004074255A2 (en) * 2003-02-18 2004-09-02 Takasago International Corporation Method for producing an optically active tetrahydroquinoline
US7601842B2 (en) 2003-02-18 2009-10-13 Takasago International Corporation Method for producing an optically active tetrahydroquinoline
US7223859B2 (en) 2003-03-17 2007-05-29 Pfizer Inc. Method for producing (R)-3-[4-(trifluoromethyl) phenylamino]-pentanoic acid amide derivative
WO2004083166A1 (en) * 2003-03-17 2004-09-30 Kaneka Corporation Processes for production of (r)-3-[4-(trifluoromethyl)- phenylamino]pentanamide derivatives
EP2316447A1 (en) 2003-09-26 2011-05-04 Japan Tobacco, Inc. Method of inhibiting remnant lipoprotein production
EP2319509A1 (en) 2003-09-26 2011-05-11 Japan Tobacco, Inc. Method of Inhibiting remnant lipoprotein production
WO2005100321A1 (en) * 2004-04-07 2005-10-27 Millennium Pharmaceuticals, Inc. Pgd2 receptor antagonists for the treatment of inflammatory diseases
US7951950B2 (en) 2005-02-24 2011-05-31 Millennium Pharmaceuticals, Inc. PGD2 receptor antagonists for the treatment of inflammatory diseases
EP2154132A1 (en) 2006-03-30 2010-02-17 Mitsubishi Tanabe Pharma Corporation A process for preparing tetrahydroquinoline derivatives
US8084611B2 (en) 2006-03-30 2011-12-27 Mitsubishi Tanabe Pharma Corporation Process for preparing tetrahydroquinoline derivatives
WO2008112166A2 (en) 2007-03-09 2008-09-18 Indigene Pharmaceuticals Inc. Combination of metformin r-(+) lipoate and antihyperlipidemic agents for the treatment of diabetic hyperglycemia and diabetic complications
US9867811B2 (en) 2011-07-08 2018-01-16 Novartis Ag Method of treating atherosclerosis in high triglyceride subjects

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