MXPA00011855A - Method for making (-)-(2r,4s)-4- [(3,5-bis- trifluoromethyl-benzyl)- methoxycarbonylamino]- 2-ethyl-6- trifluoromethyl-3,4-dihydro- 2h-quinoline- 1-carboxylic acid ethyl ester - Google Patents

Abstract

A process for preparing (-)-(2R,4S)-4Ä(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminoÜ- 2-ethyl-6-trifluoromethyl-3,4- dihydro-2H- quinoline-1- carboxylic acid ethyl ester comprising combining (-)-(2R,4S)-4 (3,5-bis-trifluoromethyl- benzylamino) -2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H- quinoline-1- carboxylic acid ethyl ester, 4-toluene-sulfonate and sodium carbonate in tetrahydrofuran at a temperature of about 20 DEG C to about 25 DEG C in the presence of methyl chloroformate.

Description

PROCEDURE FOR THE OBTAINING OF 1, 2,3,4- TETRAHIDRQQUINOLINAS 4-CARBOXIAM1NQ-2-SUBSTITUTE BACKGROUND OF THE INVENTION This invention relates to inhibitors of cholesteryl ester transfer protein (CETP) and to a process for obtaining such inhibitors. Arteriosclerosis 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 changes in diet and drug therapies, coronary heart disease (CHD) remains the most common cause of death in the United States, where cardiovascular diseases appear in 44% of the total deaths, with 53% of them associated with coronary arteriosclerotic diseases. The risk of developing this condition has been shown to be strongly correlated with certain lipid levels in the plasma. Although high LDL cholesterol may be the best known form of dyslipidemia, it is far from being the only major lipid contributing to coronary heart disease (CHD). The low level of HDL cholesterol is also a known risk factor for coronary heart disease (Gordon, DJ, et al .: "High-density Lipoprotein Cholesterol and Cardiovascular Disease"), Circulation, (1989), 79: 8-15) . High levels of LDL cholesterol and triglycerides have been positively correlated, while high levels of HDL cholesterol have been negatively correlated with the risk of developing cardiovascular diseases. Thus, dyslipidemia is not a unique risk profile for coronary heart disease but may be constituted by one or more alterations of lipids. Among many factors controlling the plasma levels of these disease conditioning principles, the activity of the protein that transfers the cholesteryl ester (CETP) affects the other three. The role of this 70,000 Daltons plasma glycoprotein found in various animal species, including humans, is the transfer of cholesteryl ester and triglycerides between the lipoprotein particles, including high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoproteins (VLDL), chylomicrons. The net result of CEPT activity is a decrease in HDL cholesterol and an increase in LDL cholesterol. This effect on the profile of lipoproteins is believed to be pro-arteriogenic, especially in subjects whose lipid profile constitutes a high risk of coronary disease. There are no therapies to raise HDL completely satisfactory. Niacin can significantly increase HDL, but it presents serious tolerance problems that reduce adaptability. Fibrates and the HMG-CoA reductase inhibitors increase HDL cholesterol only moderately. As a result there is a medical need for a well-tolerated agent that can significantly raise plasma HDL levels, thereby reversing or slowing the progression of arteriosclerosis. The common assignment request E.U.A. No. 09 / 391,152 filed September 7, 1999 and titled 1, 2,3,4-tetrahydroquinoline 4-carboxyamino-2-substituted, which description is incorporated herein by reference, refers to compounds of the following general formula : Specifically, the compound [2R, 4S] 4 - [(3,5-bis-trisflouoromethyl-benzyl) -methoxycarbonyl-amino] -2-etl-6-trifluoromethyl-3,4-dihydro is described. -2H-quinoline-1-carboxylic acid. A method for the preparation of this compound in Example 7 is also described. Thus, although there is a variety of anti-arteriosclerosis therapies, there is a continuing need and a continuing search in this field for the art of compounds for the treatment of arteriosclerosis, and methods suitable for the preparation of such compounds.

BRIEF DESCRIPTION OF THE INVENTION One aspect of the present invention is 4- (3,5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 4-toluenesulfonate. Another aspect of the present invention is the ethyl ester of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethylbenzyl) -2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1-carboxyls or pharmaceutically acceptable salts thereof, preferably the salts of 4-toluenesulfonate thereof. Another aspect of the present invention is the c-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and pharmaceutically acceptable salts thereof, preferably the (-) di-benzoyl-L-tartrate salt or the (-) di-p-toluoyl-L-tartaric acid salt thereof. Another aspect of the invention relates to the process for the preparation of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl acid ethyl ester. -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid comprising the combination of 4-toluenesulfonate of (-) - (2R, 4S) -4- (3,5-bis-) ethyl ester trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, and sodium carbonate in tetrahydrofuran at a temperature from about 20 ° C to about 25 ° C in the presence of chloroformate methyl.

Another aspect of the present invention relates to the process of preparation of the ester 4-toluenesulfonate of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethylene-benzylamine) -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, comprising: a. combination of 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) - dibenzoyl-L-tartaric acid (anhydrous) or (-) acid ethyl ester -di-p-toluoyl-L-tartaric to form the (-) - dibenzoyl-L-tartaric acid salt or the di-p-toluoyl-L-tartaric acid salt thereof; b. Combination of the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis (trifluoromethyl) benzaldehyde, followed by the addition of sodium triacetoxyborohydride; and c. addition of 4-toluenesulfonic acid monohydrate. Preferably the (-) - dibenzoyl-L-tartaric acid (anhydrous) is used. Another aspect of the present invention relates to a process for the preparation of the 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising; the combination of cis-4-benzyloxycarbonylamino-2-ethyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium / carbon to form a suspension and heating of the resulting suspension at a temperature of about 35 ° C to about 60 ° C for about 30 minutes to about 3 hours.

Another aspect of the present invention relates to a process for the preparation of cis- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid ester R. that R 1 is benzyl, t-butyl or C 1 -C 4 alkyl, which comprises: the combination of a R 1 -vinylcarbamic acid, (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine and 4-toluenesulfonic acid monohydrate in toluene at a temperature of about 50 ° C to about 90 ° C. Preferably the process includes the additional step of combining the R 1 ester of the resulting cis- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ester with pyridine and chloroformate. ethyl in dichloromethane to prepare the cis-4-R 1 -oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. Another aspect of the present invention relates to a process for the preparation of the ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid comprising: a. the combination of vinyl carbamic R 1 acid, wherein R 1 is benzyl, (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine acid and 4-toluene sulfonic acid monohydrate in toluene a temperature of about 50 ° C to about 90 ° C to prepare the R1 ester of cis- (2-etl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) carbamic, wherein R1 is benzyl; b. the combination of the resultant cis- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ester R1 with pyridine and ethyl chloroformate in dichloromethane to prepare the ethyl ester of the cis-4-R 1 -oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. c. the combination of the cis-4-R1-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium / carbon to form a suspension and heating the resulting suspension to a temperature of from about 35 ° C to about 60 ° C for about 30 minutes to about 3 hours to prepare the ethyl ester of 4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid; d. combination of 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) - dibenzoyl-L-tartaric acid or (-) - di-p-toluoyl-L-tartaric to form the (-) - dibenzoyl-L-tartaric acid salt or the di-p-toluoyl-L-tartaric acid salt thereof; and. Combination of the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis- (trifluoromethyl) benzaldehyde, followed by the addition of sodium triacetoxyborohydride to form a product; F. combination of said product and 4-toluenesulfonic acid monohydrate to prepare the 4-toluenesulfonate of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl acid ethyl ester -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; and g. Combination of the ethyl ester of (-) - (2R, 4S) -4- (3,5-bis-trif) -oromethyl-benzyl-amino) -2-ethyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid, tosylate salt, methyl chloroformate and sodium carbonate in tetrahydrofuran at a temperature from about 20 ° C to about 25 ° C in the presence of methyl chloroformate. In contrast to the procedure described in example 7 of the application of E.U.A. No. 09 / 391,152, the four intermediates II, V, VI and VII are easily isolated and purified as crystalline material. The formation of III produces a purer product since the reaction is carried out with pure starting material II. The resolution by classical formation of the diastomer salt is much easier to scale than the use of chiral chromatography. In addition, the crystallization of the final products (for example, the anhydrous form, the ethanolate form) is facilitated by the high purity of the compound of formula VII. As used herein the term mammals refers to all mammals that contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans. Some other mammals, for example, dogs, cats, cattle, goats, sheep and horses have no CETP in their plasma and are not included in this document. The term ethanolate refers to an ethanol of solvation. By "pharmaceutically acceptable" it is meant that the carriers, carriers, diluents or excipients, and / or salts must be compatible with the other ingredients of the formulation, and not deteriorate the container thereof. As used herein, the terms "reaction inert solvent" and "inert solvent" refer to a solvent or mixture of solvents that does not interact with the starting materials, reactants, intermediates or products in a manner that would affect negatively to the performance of the desired product. Other aspects and advantages will become apparent from the specification and claims of the invention.

DETAILED DESCRIPTION OF THE INVENTION In general the compound of the present invention, [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3, ethyl ester, 4-Dihydro-2H-quinoline-1-carboxylic acid, can be obtained by processes including procedures analogous to those known in the chemical arts, particularly in light of the description herein. Certain procedures for obtaining the compound of the present invention are provided as further aspects thereof and are described below, being included in the experimental part.

SCHEME According to the above scheme, the amine of formula II can be prepared by the combination of benzotriazole, 4- (trifluoromethyl) aniline (I) and propionaldehyde in a non-polar solvent such as toluene at room temperature (from about 20 ° C to about 30 ° C for about 0.5 hours to about 3 hours). The ester of formula III can be prepared by the combination of the R1 ester of vinyl carbamic acid (in which R1 is benzyl, t-butyl or alkyl (C? -C)), the amine of formula II and p-toluenesulfonic acid monohydrate in an inert solvent such as toluene at elevated temperature (from about 50 ° C to about 90 ° C) for about 0.5 hours to about 3 hours. Preferably R1 is benzyl. The compound of formula IV can be prepared by combining the ester of formula III, ethyl chloroformate and an amine base such as pyridine in an inert, non-nucleophilic solvent such as dry dichloromethane resulting in an exothermic reaction. The compound of formula V can be prepared by treating the product of the above reaction in the form of ammonium, palladium on carbon in a polar and protic solvent such as methanol at a temperature of about 35 ° C to about 60 ° C for about 0.5 hours to approximately 3 hours. The reaction sequence proceeds via preparation of the classical formation of the diastomer salt by the combination of 4-amino-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and the (-) - dibenzoyl-L-tartaric acid (anhydrous) followed by the addition of an alcoholic solvent such as ethanol at room temperature (eg from about 20 ° C to about 30 ° C) for about 1 to about 24 hours to form the (-) - dibenzoyl-L-tartaric acid salt thereof. Alternatively, (-) - di-p-toluoyl-L-tartaric acid can be used in place of (-) - dibenzoyl-L-tartaric acid. The compound of formula VII can be prepared by treatment of the salt of formula VI, 1,2-dichloroethane and an aqueous base such as sodium hydroxide with 3,5-bis (trifluoromethyl) benzaldehyde followed by the addition of sodium triacetoxyborohydride at room temperature ( for example, from about 20 ° C to about 30 ° C) for about 1 to about 24 hours. The 4-toluenesulfonic acid monohydrate is then added at room temperature (for example from about 20 ° C to about 30 ° C). The compound of formula VIII can be prepared by the combination of the ethyl ester of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3 , 4-dihydro-2H-quinoline-1-carboxylic acid and sodium carbonate in tetrahydrofuran at room temperature (eg, from about 20 ° C to about 25 ° C) in the presence of methyl chloroformate. A crystalline form of the ethanolate of the above compound can be prepared from the amorphous compound by recrystallization from ethanol / water at a temperature from about 20 ° C to about 25 ° C, preferably at room temperature for about 0.5 hours to about 18 hours . Typically the range is between about 3% and about 10% ethanol and about 90% to about 97% water. Preferably the ratio is from about 10% to about 90% ethanol / water. Alternatively, the crystalline form of ethanolate can be prepared using procedures analogous to those described above but without the use of ethanol alone. The filtered materials are typically granulated for about 2 hours to about 24 hours followed by air drying. The amorphous form of the [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro ethyl ester compound -2H-quinoline-1-carboxylic acid is prepared as described in example 10 below of the present document. An anhydrous crystalline form of the above compound can be prepared from the amorphous compound by recrystallization from hexanes (solvent consisting of hexane isomers (e.g., n-hexane, cyclohexane, methylpentane, etc.)) at a temperature of about 40 ° C to about 80 ° C, preferably 60 ° C followed typically by granulation of the filtrate for about 2 to about 24 hours and followed by drying at air.

Alternatively, the anhydrous crystal can be prepared from the crystalline form of the ethanolate (described above) using procedures analogous to the immediately preceding process.

In addition, the performance of this process can be improved by azeotropic ethanol distillation of the hexanes. It is observed that since the anhydrous and ethanolate crystals have different energy levels, the seeding with the anhydrous or ethanolate form can determine the isolated crystalline form. As is known in the art, the presence of seed crystals in the air in a laboratory can be a sufficient "seeding" element. In one embodiment the anhydrous crystals can be obtained using hexanes and the resulting anhydrous crystals can be used to seed the production of more anhydrous crystals from the ethanol. A preferred dosage is from about 0.1 to 100 mg / kg / day of the compound prepared by the process of the present invention, preferably the anhydrous crystals. An especially preferred dosage is about 0.1 to 10 mg / kg / day. The compound of the present invention can be used for the treatment of arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human either male or female). The compound of the present invention can also be used in combination with a second compound. The second compound may be an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion of the microsomal triglyceride transfer protein, a PPAR activator, a bile acid reuptake inhibitor, an inhibitor of the absorption of cholesterol, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant. The dosage of the compound of the present invention to be administered will generally vary according to principles well known in the art taking into account the severity of the disease to be treated and the route of administration. In general, the compound will be administered to a warm-blooded animal (such as a human, farm animal or companion animal) so that an effective dose is received, typically a daily dose administered in one or divided portions, for example a dose in the range of from about 0.01 to about 100 mg / kg of body weight / day, preferably from about 0.1 to about 10 mg / kg of body weight / day. The above dosages are exemplary of the middle case; there may, of course, be particular cases where greater or lesser dosing intervals are required, such deviations are within the scope of the present invention. The compound of the present invention is orally administrable and suitably used in combination with a pharmaceutically acceptable carrier, carrier or diluent, suitable for oral dosage forms. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile organic or aqueous solutions. The active compound will be present in said composition in an amount sufficient to provide the desired dosage in the range described herein. Thus, for oral administration the compound may be combined with a suitable solid or liquid carrier, diluent or liquid to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavors, sweeteners and the like. The tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, gum arabic, corn starch or gelatin.; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a unit dosage form is a capsule, for example a gel capsule, it may contain, in addition to or in place of the materials of the above type, a liquid carrier such as a fatty glyceride or mixtures of fatty glycerides, such as olive oil. , or Migloyl ™ or Capmul ™ glycerides. Other materials may be present as coatings or to modify the physical form of the dosage unit. For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. The compound of the present invention can also be administered parenterally. For parenteral administration the compound may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Injectable solutions prepared in this manner can be administered intravenously, intraperitoneally, subcutaneously or intramuscularly. Pharmaceutical forms suitable for injectable use include sterile solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to ensure that it presents an easy injectability. It must be stable under the conditions of obtaining and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. They can be sterilized, for example, by filtration through a filter that retains bacteria, by incorporation of sterilizing agents in the compositions or by irradiation or heating of the compositions when said irradiation or heating is compatible with the formulation of the medicament. Additional pharmaceutical formulations may include, inter alia, suppositories, sublingual tablets, topical dosage forms and the like and those prepared according to procedures that are commonly known in the art.

EXAMPLES The melting points were determined with a Thomas Hoover melting point apparatus or a DSC apparatus. Unless otherwise specified, CDCI3 was used for the NMR (nuclear magnetic resonance) spectra. Schwarzkopf Microanalytical Laboratory carried out the microanalysis. All reagents and solvents were obtained commercially and used without purification.

EXAMPLE 1 (1-Benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) anr? Ina A two-liter, four-neck flask was charged under a nitrogen atmosphere with benzotriazole (36.96 g, 310 mmol 1.0 eq.) And dry toluene (400 mL). A solution of 4- (trifluoromethyl) aniline (39.1 ml, 310 mmol, 1.0 eq.) And 50 ml of toluene was added at room temperature for one minute. Then a propionaldehyde solution at room temperature (24.6 ml, 341 mmoles, 1.1 eq.) And 50 ml of toluene was added over 20 minutes. There was an exotherm of 23 ° C to 30 ° C during this addition. After stirring 24 hours, n-heptane (500 ml) was added, and the suspension was stirred an additional hour. The suspension was filtered, the solids were washed with n-heptane (1 x 100 ml, then 1 x 200 ml, and dried). (1-Benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine was isolated in the form of bright white needles (81.3 g, 82%). After 24 hours, a second batch of filtrate was isolated (8.7 g, 9%). Melting point (m.p.): 130-132 ° C; 1 H NMR (proton nuclear magnetic resonance) (DMSO-dβ, 400 MHz) d 0.82 (t, 3 H, J = 7.5 Hz), 2.25 (m, 2 H), 6.49 (m, 1 H), 6.80 (d, 2 H) , J = 8.7 Hz), 7.35 (m, 3H), 7.50 (m, 1 H), 7.88 (d, 1 H, J = 8.3 Hz), 7.99 (m, 1 H), 8.09 (d, 1 H, J = 8.5 Hz); 13C NMR (nuclear magnetic resonance of carbon 13) (DMSO-d6, 100 MHz) d 49.32, 146.19, 131.46, 127.73, 126.8, 125.33, (c, J = 270 Hz), 124.44, 119.88, 118.27 (c, J = 31.7 Hz), 112.91, 111.56, 71.03, 28.08, 10.29; DEPT spectrum: quaternary carbons d 149.32, 146.19, 131.46, 125.33, 118.27; carbons CH d 127.73, 126.8, 124.44, 119.88, 112.91, 111.56, 71.03; carbons CH2 d 28.08; carbons CH3 d 10.29; IR (maximum) 3292 (s), 3038 (m), 2975 (m), 1621 (s), 1331 (s), 1114 (vs); Anal, calculated for C 16 H 5 N 4 F 3: C, 59.99; H, 4.72; N, 17.49. Found (first batch): C, 60.16; H, 4.74; N, 17.86. Found (second round): C, 59.97; H, 4.66; N, 17.63.

EXAMPLE 2 Benzyl Ester of cis- (2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) carbamic acid A one-liter, four-neck flask was charged under a nitrogen atmosphere with N-vinylcarbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 eq.) And dry toluene (500 ml). (1-Benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amina (50.0 g, 156 mmol, 1.0 eq.) And p-toluenesulfonic acid monohydrate (279 mg, 1.56 mmol) were added. , 0.01 eq.), And the mixture was heated to 70 ° C. After 2 hours, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 ml) was added. The mixture was washed with 1 N NaOH 1 x 200 ml, 1 x 200 ml H 2 O, 1 x 200 ml brine and dried (MgSO 4). The mixture was filtered and the solids were washed with 1 x 50 ml ethyl acetate. The filtrate was concentrated to approximately 250 ml. 500 ml of toluene was added and the mixture was concentrated to about 500 ml. 500 ml of n-heptane was added, the suspension was stirred 1 h, filtered through a Buchner funnel, and dried. The cis- (2-ethyl-l-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): m.p. 155-157 ° C; 1 H NMR (DMSO-d 6, 400 MHz) d 0.92 (t, 3 H, J = 7.5 Hz), 1.5 (m, 3 H), 2.00 (m, 1 H), 3.35 (m, 1 H), 4.77 (m, 1 H), 5.07 (d, 1H, J = 12.5 Hz), 5.15 (d, 1 H, J = 12.5 Hz), 6.35 (s, 1 H), 6.61 (d, 1 H, J = 8.5 Hz), 7.12 (s, 1 H), 7.18 (dd, 1 H, J = 1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1 H, = 9.1 Hz); 13C NMR (DMSO-d6, 100 MHz) d 157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (c, J = 270 Hz), 125.06, 123.50, 121.73, 1 15.2 (c, J = 31.7 Hz), 1 13.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum quaternary carbons d 157.03, 149.02, 137.79, 125.9, 121.73, 1 15.2 carbons CH d 128.82, 128.23, 128.03, 125.06, 123.50, 1 13.33, 53.09, 47.83 carbons CH2 d 65.85, 34.02, 28.68; carbons CH3 d 9.93; IR (maximum) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542 (vs), 1088 (vs); MS (mass spectroscopy) (APCI +) (chemical ionization at atmospheric pressure) m / z (relative intensity) 379 (M + H +, 53), 228 (100); Anal, calcd for C2oH2? N2O2F3: C, 63.48; H, 5.59; N, 7.40. Found: C, 63.69; H, 6.06; N, 7.36.

EXAMPLE 3 Cis-4-benzyloxycarbonylamino-2-ethyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A three-liter, four-neck flask was charged under a nitrogen atmosphere with cis- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (96.0) g, 254 mmoles, 1.0 eq.), dry dichloromethane (720 ml) and dry pyridine (103 ml, 1.227 moles, 5.0 eq.). A solution of ethyl chloroformate (121 ml, 1.27 moles, 5.0 eq.) In dry dichloromethane (240 ml) was added slowly over 4 hours. The addition was exothermic and required a reflux condenser. Once the addition of chloroformate was complete, the reaction was cooled in an ice bath and 1350 ml of 1 N NaOH was added. The mixture was stirred for 15 minutes and then transferred to a separatory funnel. The layers were separated and the aqueous extract was washed with 1 x 11 dichloromethane. The combined dichloromethane layers were washed with 1 N HCl 1 x 1350 mL, 1 x 1 1 saturated aqueous NaHCO3, 1 x 1 L brine and dried (Na2SO ). The mixture was filtered, and the filtrate was concentrated to an orange oil. 570 ml of absolute ethanol were added and the solution was concentrated. The solids were dissolved in 1370 ml of absolute ethanol. 570 ml of H 2 O were added dropwise over 45 minutes. The resulting fine suspension was stirred for 18 hours and filtered. The solids were washed with a cold mixture of absolute ethanol / water 7: 3 (1 x 250 ml, then 1 x 100 ml) and dried (under vacuum, 45 ° C) to give the ethyl ester of cis-4- acid. benzyloxycarbonylamino-2-ethyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as a white crystalline solid (94.54 g, 83%): mp 92-96 ° C; 1 H NMR (CDCl 3, 400 MHz) d 0.84 (t, 3 H, J = 7.4 Hz), 1.28 (t, 3 H, J = 7.0 Hz), 1.4 (m, 2 H), 1.62 (m, 1 H), 2.53 ( m, 1 H), 4.23 (m, 2H), 4.47 (m, 1 H), 4.79 (m, 1 H), 5.01 (d, 1 H, J = 9.2 Hz), 5.18 (m, 2H), 7.4 (m, 5H), 7.5 (m, 2H), 7.57 (m, 1 H); 13C NMR (CDCI3, 100 MHz) d 155.97, 154.43, 139.44, 136.21, 134.33, 128.61, 128.33, 126.32, (c, J = 31.7 Hz), 126.18, 124.22, 124.19, 124.12 (c, J = 273 Hz), 120.74, 120.70, 67.22, 62.24, 53.47, 46.79, 37.75, 28.25, 14.38, 9.78; DEPT spectrum: quaternary carbons d 155.97, 154.43, 139.44, 136.21, 134.33, 126.32, 124.12; carbon atoms CH d 128.61, 128.33, 128.22, 126.18, 124.22, 124.19, 120.74, 120.70, 53.47, 46.79; carbons CH2 d 67.22, 62.24, 37.75, 28.25; carbons CH3 d 14.38, 9.78; IR (maximum) 3304 (s), 3067 (m), 3033 (m), 2982 (m), 2932 (m), 1723 (s), 1963 (s), 1545 (s); MS (mass spectroscopy) (APCI +) m / z (relative intensity) 415 (M + H +, 21), 300 (100); Anal, calculated for C 23 H 25 N 2 O 4 F 3: C, 61.33; H, 5.60; N, 6.22. Found: C, 61.07; H, 5.69; N, 6.22.

EXAMPLE 4 C / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A one-liter, four-neck flask was charged under a nitrogen atmosphere with cis-4-benzyloxycarboxylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1 g. , 89 mmoles, 1.0 eq.), Methanol (400 ml), and ammonium formate (14.0 g, 223 mmoles, 2.5 eq.). 10% Pd / C with 50% moisture (4.0 g) was added, and the suspension was heated at 40 ° C for 1 hour. After 1.5 hours, the mixture was cooled to room temperature and filtered with celite. The cake was washed with 2 x 100 ml methanol. The filtrate was concentrated to about 75 ml, transferred to a separatory funnel, and diluted with 400 ml of ethyl acetate. The mixture was washed with saturated aqueous solution of 1 x 125 ml NaHCO 3, 1 x 100 ml brine and dried (Na 2 SO 4). The mixture was filtered and the filtrate was concentrated to a clear oil. The oil was crystallized from 100 ml of n-heptane to give the ethyl ester of c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester. carboxylic acid as a white crystalline solid (26.05 g, 93%): mp 61.5-63.5 ° C; H NMR (CDCl 3, 400 MHz) d 0.79 (t, 3 H, J = 7.4 Hz), 1.24 (m, 4 H), 1.42 (m, 1 H), 1.51 (br s, 2 H), 1.62 (m, 1 H) ), 2.46 (m, 1 H), 3.73 (m, 1 H), 4.17 (m, 2H), 4.36 (m, 1 H), 7.44 (m, 2H), 7.66 (m, 1 H); 13C NMR (CDCI3, 100 MHz) d 154.6, 139.3, 138.9, 126.3, (c, J = 32 Hz), 125.7, 124.3, (c, J = 271 Hz), 123.5, 1 19.8, 61.96, 54.16, 46.91, 41.50, 28.85, 14.38, 9.60; DEPT spectrum: quaternary carbons d 154.6, 139.3, 138.9, 126.3, 124.3; carbons CH d 125.7, 123.5, 1 19.8, 54.16, 46.91; carbons CH2 d 61.96, 41.50, 28.85; carbons CH3 d 14.38, 9.60; IR (maximum) 3350 (s), 3293 (m), 2972 (s), 1697 (vs); MS (APCI +) m / z (relative intensity) 358 (M + H + CH 3 CN +, 55), 317 (M + H +, 7), 300 (100); Anal, calculated for C? 5H19N2? 2F3: C, 56.96; H, 6.06; N, 8.86. Found: C, 56.86; H, 6.28; N, 8.82.

EXAMPLE 5 Salt herni - (-) - dibenzoyl-L-tartrate ethyl ester of (-) - (2R, 4S) -4-amino-S-ethyl-β-trifluoromethyl-S-dihydro-SH-quinoline- l -carboxyl A one liter, four-neck flask was charged under a nitrogen atmosphere with cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-qui ethyl ester. noline-1-carboxylic acid (24.0 g, 75.9 mmol, 1.0 eq.) and (-) - dibenzoyl-L-tartaric acid (anhydrous) (27.19 g, 75.9 mmol, 1.0 eq.). 300 ml of approximately 97% ethanol (prepared by adding 10.5 ml of H2O to 500 ml of absolute ethanol, mixed and 300 ml). The mixture was stirred at room temperature for 18 hours and then filtered. The solids were washed with approximately 97% ethanol 1 x 48 ml and dried to give hemi - (-) - dibenzoyl-L-tartrate acid ethyl ester salt (-) - (2R, 4S) -4-amino-2-etiI-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as a white crystalline solid (14.77 g, 39%): mp: 189.5-191.5 ° C (dec); 1 H NMR (DMSO-d 6, 400 MHz) d 0.62 (t, 3 H, J = 7.3 Hz), 1.16 (t, 3H, J = 7.1 Hz), 1.3 (m, 3H), 2.5 (m, 1 H), 4.1 (m, 4H), 5.63 (s, 1 H, methine proton in DBTA), 7.47 (m, 2H, protons aromatics of DBTA), 7.6 (m, 3H, aromatic protons of DBTA), 7.68 (s, 1 H), 7.95 (m, 2H), 8.2 (br s, NH3 +, not integrated); 13C NMR (DMSO-de, 100 MHz) d 169.85, 165.53, 154.10, 140.14, 134.59, 133.51, 130.74, 129.69, 128.98, 126.74, 124.82 (c, J = 31.7 Hz), 124.69 (c, J = 271 Hz) , 124.50, 120.90, 74.49, 62.14, 53.51, 45.94, 38.81, 28.23, 14.63, 9.58; DEPT spectrum: quaternary carbons d 169.85, 165.53, 154.10, 140.14, 134.59, 130.74, 124.82, 124.69; carbons CH d 133.51, 126.69, 128.98, 126.74, 124.50, 120.90, 74.49, 53.51, 45.94; carbons CH2 d 62.14, 38.81, 28.23; carbons CH3 d 14.63, 9.58; IR (maximum) 3278 (m), 2400-3100 (band), 1703 (vs); MS (APCI +) m / z (relative intensity) 358 (M + H + CH 3 CN +, 55), 317 (M + H +, 7), 300 (100); Anal, calculated for Ci5H19N2? 2F3.C9H7O4: C, 58.18; H, 5.29; N, 5.65. Found: C, 57.99; H, 5.15; N, 5.64; HPLC (high performance liquid chromatography) chiral: mobile phase n-hexane: 2-propanoLHOAc 950: 50: 2, flow 1.50 ml / min, column temperature 40 ° C, packing AD 4.6 x 250 mm, approximate concentration of the shows 0.5 mg / ml in about n-hexane: 2-propanol 1: 1. The authentic recemato shows a retention time of 7.5 minutes and 10.0 minutes. Hemi - (-) - dibensoyl-L-tartrate salt of (-) - (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-qui ethyl ester Nol-1-carboxylic acid: 10.0 minutes, 88.9%, 7.5 minutes «1%, 2.0 minutes (versus solvent) 1 1 1.1%; [α] D = -153 (c = 1.07, CH 3 OH).

EXAMPLE 6 (-) - (2R, 4S) -4-R (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4- ethyl ester tosylate dihydro-2H-quinoline-1-carboxylic acid The hemi - (-) - dibenzoyl-L-tartrate salt of (-) - (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydroxyethyl ester was suspended. 2H-quinoline-1-carboxylic acid (13.0 g, 26.2 mmol, 1.0 eq.) In 1,2-dichloroethane (260 ml) in a 500 ml separatory funnel. The mixture was washed with 1 N 1 x 65 ml NaOH, 1 x 65 ml brine and dried (MgSO). The mixture was filtered, concentrated to approximately 80 ml and transferred to a 250 ml three-necked flask. 3,5-Bis (trifluoromethyl) benzaldehyde (4.53 ml, 27.5 mmol, 1.05 eq.) Was added and the mixture was stirred for 1 hour at room temperature under nitrogen. Sodium triacetoxyborohydride (1.1 g, 52.4 mmol, 2.0 eq.) Was added in one portion, and the white suspension was stirred for 18 hours. 50 ml of 1,2-dichloroethane and 50 ml of 2N NaOH were added, and the aqueous phase was extracted with 1,2 x dichloroethane 2 x 50 ml. The combined organic extracts were washed with 1 N HCl 1 x 31 ml, saturated aqueous NaHCO3 1 x 50 ml, brine 1 x 50 ml and dried (Na2SO4). The mixture was filtered and concentrated to a clear oil. The oil was dissolved in methanol (71 ml). P-Toluenesulfonic acid monohydrate (5.23 g, 27.5 mmol, 1.05 eq.) Was added. After 5 minutes, 284 ml of isopropyl ether were added. The solution was concentrated to approximately 35 ml, transferred to a 500 ml three-necked flask (mechanically stirred), and diluted with 284 ml of isopropyl ether.

In 10 minutes a white non-thick suspension was formed. After stirring 3 hours, the suspension was filtered and the cake was washed with 2 x 70 ml isopropyl ether. After drying, the tosylate salt of the ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -2-ethyl ester was isolated. -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid as a white solid (16.18 g, 86% total yield): mp 191-192 ° C; 1 H NMR (DMSO-d6l 400 MHz) d 0.78 (t, 3H, J = 7.5 Hz), 1.21 (t, 3H, J = 7.0 Hz), 1.5 (m, 3H), 2.24 (s, 3H), 3.08 (m, 1 H), 4.17 (m, 2H), 4.41 (m, 1 H), 4.50 (m, 2H) ), 4.79 (m, 1 H), 7.04 (d, 2H, J = 7.9 Hz, 7.42 (d, 2H, J = 7.9 Hz), 7. 7 (m, 2H), 7.81 (s, 1 H), 8.21 (s, 1 H), 8.35 (s, 2H), 9.58 (br s, 1 H), 9.83 (br s, 1 HOUR); 13 C NMR (DMSO-de, 100 MHz) d 154.00, 145.46, 140.21, 138.39, 135.33, 132.51, 131.62, 130.79 (c, J = 33.2 Hz), 128.49, 127.40, 125.82, 125.36, 124.99 (c, J = 31.7 Hz), 124.59 (c, J = 271 Hz), 123.69 (c, J = 273 Hz), 123.44, 120.33, 62.32, 53.99, 53.79, 47.98, 33.30, 28.61, 21.13, 14.63, 9.58; DEPT spectrum: Quaternary carbons d 154.00, 145.46, 140.21, 138.39, 135.33, 130.79, 124.99, 124.59, 123.69; carbons CH d 132.51, 131.62, 128.49, 127.40, 125.82, 125.36, 123.44, 120.33, 53.99, 53.79; carbons CH2 d 62.32, 47.98, 33.30, 28.61; carbons CH3 d 21.13, 14.63, 9.58; IR (maximum) 2300-3100 (width), 2974 (m), 2731 (m), 2620 (m), 2455, 1714 (s), 1621 (m), 1283 (vs), 1169 (vs), 1126 ( vs); MS (ES +) m / z (relative intensity) 584 (M + H + CH 3 + CN +, 100), 543 (M + H +, 80); Anal, calcd for C 24 H 23 N 2 2 2 F 9.C 7 H 8 O 3 S: C, 52.1 1; H, 4.37; N, 3.92. Found: C, 52.15; H, 4.22; N, 3.69; [a] D = -77.9 (c = 1.05, CH3OH).

EXAMPLE 7 (M2R, 4S) -4-R (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic monoethanolate Na2CO3 (s) (6.75 g, 63.7 mmol, 3.5 eq.) Was added to a room temperature solution of (-) - (2R, 4S) -4 - [(3,5-bis) ethyl ester tosylate salt. -trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (13.0 g, 18.2 mmol, 1.0 eq.) in dry tetrahydrofuran (130 ml). Methyl-chloroformate was added (3.51 ml, 45.5 mmol, 2. 5 eq.) Drop by drop for 2 minutes. After 24 hours, the mixture was concentrated to 65 ml, diluted with 260 ml of ethyl acetate and transferred to a separatory funnel. The mixture was washed with 1 N HCl (evolution of CO2) 1 x 90 ml, saturated NaHC? 3 aqueous 1 x 90 ml, brine 1 x 90 ml, and dried (MgSO4). Filtration and concentration of the filtrate gave a clear oil which was distilled with 2B ethanol, 3 x 33 ml. The oil was dissolved in 33 ml of 2B ethanol and seeded with a few milligrams of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl ethyl ester. -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic monoethanolate. After stirring for 18 hours at room temperature, the suspension was filtered and dried to give the ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic monoethanolate with a white crystalline powder (8.66 g, 74%): mp 54-58 ° C; 1 H NMR (CDCl 3, 400 MHz, 55 ° C) d 0.73 (t, 3 H, J = 7.0 Hz), 1.20 (t, EtOH), 1.27 (t, 3H, J = 7.1 Hz), 1.42 (m, 2H), '1.66 (m, 1 H), 2.25 (br s, 1 H), 3.67 (c, EtOH), 3.79 (s, 3H), 4.2 (m, 3H), 4.33 (m, 1 H), 5.2 (br s, 2H), 7.12 (s, 1 H), 7.49 (d, 1 H, J = 8.3 Hz), 7.57 (d, 1 H, J = 8.5 Hz), 7.73 (s, 2H), 7.78 (s, 1 H); 13 C NMR (CDCl 3, 400 MHz) d 157.74, 154.37, 141.73, 140.05, 133.83, 132.14 (c, J = 33 Hz), 126.94, 124.49, 123.96 (c, J = 273 Hz), 123.13 (c, J = 273 Hz), 121.31, 119.17, 62.29, 58.28, 54.42, 53.71, 53.08, 46.67, 37.01, 29.02, 18.29, 14.32, 9.22 (note: the fourth quartet appears covered under the peak d 126.94, with J approximately 32 Hz); DEPT spectrum: quaternary carbons d 157.74, 154.37, 141 .73, 140.05, 133.83, 132.14, 123.96, 123.13; carbons CH d 126.94, 124.49, 121.31. 1 19.17, 54.42, 53.08; carbons CH2 d 62.29, 58.28, 46.67, 37.01, 29.02; carbons CH3 d 53.71, 18.29, 14.32, 9.22; IR (maximum) 3489 (s), 2974 (s), 2884 (m), 1701 (vs), 1280 (vs), 1 131 (vs); MS (ES +) m / z (relative intensity) 601 (M + H +, 100); Anal. Calculated for C26H25N20O4 9.C-2H6O: C, 52.01; H, 4.83; N, 4.33. Found: C, 51.84; H, 4.54; N, 4.33; Chiral HPLC: mobile phase n-hexane: 2-propanol: HOAc 950: 50: 2, flow: 1.0 ml / min, 254 nm packaging AD 4.6 x 250 mm, column temperature 40 ° C, sample concentration approximately 0.5 mg / ml in n-hexane: 2-propanol 90:10, retention times for the authentic racemate 3.6 and 4.6 min. The ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3 , 4-dihydro-2H-quinoline-1-carboxylic monoethanolate showed 4-6 minutes, 99.1% and 3.6 minutes, not detected; [afo-93.3 (c = 1.08, CH3OH).

EXAMPLE 8 Esthetic ester of (-M2R, 4S) -4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1- anhydrous carboxylic A 2.6 g portion of the ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6- was charged. trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (a mixture of predominantly amorphous material with traces of ethanolate in crystalline form; the title compound was also prepared analogously from pure amorphous material or pure ethanolate) in 13 milliliters of hexanes and heated until reaching the solution at 60 ° C. The heat was removed and the reaction was allowed to cool to room temperature over a period of one hour. The reaction was seeded with (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl ester. 3,4-dihydro-2H-quinoline-1-carboxylic acid anhydrous and granulated for 18 hours under ambient conditions. Alternatively, anhydrous crystals can be prepared from unplanted hexanes. The product was collected by filtration and air dried. Fusion microscopy: Appearance: powdery white powder.

EXAMPLE 9 (-) - (2R14S) -4-r (3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline ethyl ester -1 carboxylic monoethanolate 4.0 g of the ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl were dissolved. -3,4-dihydro-2H-quinoline-1-carboxylic acid in 3.5 ml of ethanol and was dissolved with ultrasound for 2 minutes until the solution was complete. A solid was formed to which 10 ml of ethanol was added and stirred overnight at room temperature. A white solid was filtered and collected on an LS paper filter of 0.22 microns followed by washing with 15 ml of ethanol. Fusion microscopy: Appearance: powdery white powder.

EXAMPLE 10 C / s-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of c / s-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was cooled. (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane in a water / ice bath while slowly adding methyl chloroformate (0.87 g, 9.2 mmol). After stirring overnight at room temperature, the reaction mixture was washed twice with 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel using a 5-10% mixture of ethyl acetate / hexanes as eluent to give 1.8 g of the title product. MS m / z 601 (M + + 1); 1 H NMR (coalescence of conformer mixture, CDCl 3) d 0.6-0.8 (ma, 3H), 1.3-1.5 (ma, 2H), 1.6-1.75 (ma, 1 H), 2.1-2.3 (mA, 1 H), 3.7 -3.9 (sa, 3H), 4.0-4.4 (ma, 4H), 5.0-5.6 (ma, 2H), 7.1 (s, 1 H), 7.4-7.6 (ma, 2H), 7.6, 7.8 (ma, 3H) ). The ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3 acid was prepared. , 4-dihydro-2H-quinoline-1-carboxylic acid in an optically enriched form by resolution of the corresponding racemate, or an intermediate in its synthesis, by conventional methods.

EXAMPLE 11 Ethyl ester of (-) - (2R, 4S) -4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-2-ethyl-β-trifluoromethyl-3,4 -hydroxy-2H-quinoline-1-carboxylic acid A crude solution of approximately 42 g of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] - ethyl ester was concentrated in vacuo. 2-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid in 500 ml of ethyl acetate (obtained via the procedure described in example 7) up to a volume of 100-135 ml. The remaining ethyl acetate was removed with EtOH 2B 3 x 220 ml to a final volume of 100-135 ml. This solution was seeded with a crystal of ethyl ester of the acid (-) - (2R), 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid. After stirring for 18 hours at room temperature the suspension was filtered and dried under vacuum to give 19.81 g of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) ethyl ester) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid. The melting point behavior was the same as that of the material prepared in Example 8 confirming that it was the natural anhydrous material.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. 4- (3,5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3,4-dithy-2H-quinoline-1-carboxylic acid ethyl ester - 4-toluenesulfonate. .

2 - The stereoisomer ethyl ester of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid or salts thereof.

3. The stereoisomer of claim 2 wherein the salt is 4-toluenesulfonate.

4. The (-) - di-p-toluoyl-L-tartaric acid salt of c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydrochloric acid ethyl ester -2H-quinoline-1-carboxylic acid.

5. The (-) dibenzoyl-L-tartrate salt of c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.

6.- The ethyl ester of (-) - (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid or salts thereof.

7. The stereoisomer of claim 6 wherein the salt is (-) di-benzole-L-tartrate.

8. The stereoisomer of claim 6 wherein the salt is the salt of (-) di-p-toluol-L-tartaric acid.

9. - A process for the preparation of the ethyl ester of (-) - (2R, 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6 -trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic compound comprising the combination of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethyl-benzylamino) ethyl ester) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, tosylate salt, sodium carbonate and methyl chloroformate in tetrahydrofuran at a temperature of about 20 ° C to about 25 ° C. 10.- A process for the preparation of 4-toluenesulfonate of the ethyl ester of (-) - (2R), 4S) -4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid comprising a. combination of 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) - dibenzoyl-L-tartaric acid (anhydrous) or (-) acid ethyl ester -di-p-toluoyl-L-tartaric to form the (-) - dibenzoyl-L-tartaric acid salt or the di-p-toluoyl-L-tartaric acid salt thereof; b. combination of the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis (trifluoromethyl) benzaldehyde, followed by the addition of sodium triacetoxyborohydride; and c. addition of 4-toluenesulfonic acid monohydrate. 1. The process of claim 10 wherein the ethyl ester of 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid and (-) acid are combined. -dibenzoyl-L-tartaric (anhydrous). 12. A process for the preparation of c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising the combination of c / s-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium / carbon to form a suspension and heating the resulting suspension to a temperature of about 35 ° C to about 60 ° C for about 30 minutes to about 3 hours. 13. A process for the preparation of the ester R 1 of c / s- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid, wherein R 1 is benzyl , t-butyl or (C -? - C4) alkyl, which comprises: the combination of an acid R 1 - vinyolcarboxy, (1-benzotriazol-1-yl-propyl) - (4- trifiuormethyl-phenol) -amine and 4-toluenesulfonic acid monohydrate in toluene at a temperature of about 50 ° C to about 90 ° C. 14. The process of claim 13 with the additional step of combining the ester R1 of the acid c / s- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tretrahydro-quinolin-4-yl) - Carboxylic acid with pyridine and ethyl chloroformate in dichloromethane to prepare the c / s-4-R 1 -oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolin-1-carboxylic acid ethyl ester. 15.- A process for the preparation of the ethyl ester of the acid (-) - (2R), 4S) -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic comprising a. the combination of vinyl carbamic R 1 acid, wherein R 1 is benzyl, (1-benzotriazol-1-yl-propyl) - (4-trifluoroemethyl-phenyl) -amine acid and 4-toluene sulphonic acid monohydrate in toluene at a temperature from about 50 ° C to about 90 ° C to prepare the ester R1 of c / s- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydroquinolin-4-yl) -carbamic acid, in the one that R1 is benzyl; b. the resulting R1 ester of the resulting c / s- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid ester with pyridine and ethyl chloroformate in dichloromethane to prepare the ester c / s-4-R1-oxocarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolin-1-carboxylic acid ethyl ester, c. the combination of c / s-4-R1-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium / carbon to form suspending and heating the resulting suspension at a temperature from about 35 ° C to about 60 ° C for about 30 minutes to about 3 hours to prepare the 4-amino-2-ethyl-6-trifluoromethyl-3-ethyl ester, 4-dihydro-2H-quinol-1-carboxylic acid; d. combination of 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) - dibenzoyl-L-tartaric acid or (-) - di-p-toluoyl-L-tartaric to form the salt of (-) - dibenzoii-L-tartaric acid or the salt of di-p-toluoyl-L-tartaric acid thereof; and. combination of the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis- (trifluoromethyl) benzaidehyde, followed by the addition of sodium triacetoxyborohydride to form a product; F. combination of the said product and 4-toluenesulfonic acid monohydrate to prepare the 4-toluene sulfonate of the ethyl ester of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethyl-benzyl) amino acid) -2-ethyl-6-trifluoromethyl) -3,4-dihydro-2H-quinoline-1-carboxylic acid; and g. Combination of the ethyl ester of (-) - (2R, 4S) -4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluorometii-3,4-dihydro-2H-quinoline-1 - carboxylic acid, tosylate salt, methyl chloroformate and sodium carbonate in tetrahydrofuran at a temperature of about 20 ° C to about 25 ° C.