HK1038007B

HK1038007B - Method for making 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline

Info

Publication number: HK1038007B
Application number: HK01107936.1A
Authority: HK
Inventors: D‧B‧达蒙; R‧W‧道格尔
Original assignee: 辉瑞产品公司
Priority date: 1999-11-30
Filing date: 2001-11-12
Publication date: 2005-04-08

Description

Process for preparing 4-carboxyamino-2-substituted-1, 2, 3, 4-tetrahydroquinolines

The present invention relates to Cholesteryl Ester Transfer Protein (CETP) inhibitors and methods of making such inhibitors.

Atherosclerosis and its associated Coronary Artery Disease (CAD) are major causes of death in the industrialized world. Despite attempts to alter secondary risk factors (smoking, obesity, lack of exercise) and to treat dyslipidemia (dyslipemia) by dietary modification and drug therapy, Coronary Heart Disease (CHD) remains the most common cause of death in the united states, with cardiovascular disease accounting for 44% of all causes of death, 53% of which are associated with atherosclerotic coronary heart disease.

The risk of developing these conditions has been shown to be closely related to certain plasma lipid levels. While elevated LDL-cholesterol may be the most recognized form of dyslipidemia, it is by no means the only important causative factor for lipid-related 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 HDL-cholesterol and triglyceride levels are positively correlated, while high HDL-cholesterol levels are negatively correlated with the risk of developing cardiovascular disease. Thus, dyslipidemia is not a single risk profile for CHD, but may consist of deviations in one or more lipids.

Of the many factors that control plasma levels of these disease-dependent elements, Cholesteryl Ester Transfer Protein (CETP) activity affects all three. In a variety of animals, including humans, it has been found that the effect of this 70,000 dalton plasma glycoprotein is to transfer cholesterol esters and triglycerides 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 decrease in HDL cholesterol and an increase in LDL cholesterol. This effect on the lipoprotein profile is believed to promote the formation of atherosclerosis, particularly in patients whose lipid profile may increase the risk of CHD.

There is no entirely satisfactory therapy for raising HDL. Niacin can significantly increase HDL, but presents serious tissue tolerance issues, thereby reducing compliance. Lipofethyl ester formulations (fibrites) and HMG CoA reductase inhibitors only slightly raise HDL-C. Thus, there is a clearly unmet need for well-tolerated drugs that can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

Commonly assigned U.S. application 09/391,152 entitled "4-carboxyamino-2-substituted-1, 2, 3, 4-tetrahydroquinoline" (filed 9/7/1999), the disclosure of which is incorporated herein by reference, relates to compounds of the general formula:

in particular, the compound [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is described. The preparation of this compound is also described in example 7.

Thus, despite the existence of a variety of anti-atherosclerotic therapies, there is a continuing need in the art and a continuing search for compounds useful in the treatment of atherosclerosis and methods of making such compounds.

In one aspect, the invention relates to 4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or its 4-tosylate salt.

In another aspect, the invention relates to (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof, preferably 4-tosylate.

In another aspect, the present invention relates to cis-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and pharmaceutically acceptable salts thereof, preferably its (-) di-benzoyl-L-tartrate salt or (-) di-p-toluoyl-L-tartrate salt.

In another aspect, the present invention relates to (-) (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and pharmaceutically acceptable salts thereof, preferably its (-) di-benzoyl-L-tartrate salt or its (-) di-p-toluoyl-L-tartrate salt.

In another aspect, the present invention relates to a process for the preparation of (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, the process comprises combining (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-tosylate and sodium carbonate in tetrahydrofuran at a temperature of from about 20 ℃ to about 25 ℃ in the presence of methyl chloroformate.

In another aspect, the present invention relates to a process for the preparation of (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-toluenesulfonate comprising,

a. combining 4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester with (-) dibenzoyl-L-tartaric acid (anhydrous) or (-) di-p-toluoyl-L-tartaric acid to form its (-) di-benzoyl-L-tartrate or (-) di-p-toluoyl-L-tartrate;

b. combining the formed salt, 1, 2-dichloroethane and aqueous base with 3, 5-bis (trifluoromethyl) benzaldehyde, and then adding sodium triacetoxyborohydride; and

c. 4-toluenesulfonic acid monohydrate was added.

Preferably, (-) dibenzoyl-L-tartaric acid (anhydrous) is used.

In another aspect, the present invention relates to a process for the preparation of 4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, which process comprises: cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate are mixed (combined) with palladium on carbon in methanol to form a slurry and the resulting slurry is heated at a temperature of from about 35 ℃ to about 60 ℃ for from about 30 minutes to about 3 hours.

In another aspect, the invention relates to cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid-R¹A process for the preparation of esters, wherein R¹Is benzyl, tert-butyl or C₁-C₄(alkyl) by reacting a vinyl-carbamic acid-R¹And (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine and 4-toluenesulfonic acid monohydrate are combined in toluene at a temperature of about 50 ℃ to about 90 ℃. Preferably the process further comprises reacting the cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid-R so formed¹Preparation of cis-4-R by combining the ester with pyridine and ethyl chloroformate in dichloromethane¹-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.

In another aspect, the present invention relates to a process for the preparation of (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, which process comprises,

a. reacting vinyl-carbamic acid-R¹(wherein R is¹Is benzyl), (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine and 4-toluenesulfonic acid monohydrate are combined in toluene at a temperature of about 50 ℃ to about 90 ℃ to produce cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid-R¹Esters (where R is¹Is benzyl);

b. the cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid-R that is formed is reacted with a base¹Esters with pyridine and chloroformic acidThe cis-4-R is prepared by the combination of ethyl ester in dichloromethane¹-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

c. cis-4-R¹-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate are mixed with palladium on carbon in methanol to form a slurry and the resulting slurry is heated at a temperature of about 35 ℃ to about 60 ℃ for about 30 minutes to about 3 hours to produce 4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

d. combining 4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester with (-) dibenzoyl-L-tartaric acid or (-) di-p-toluoyl-L-tartaric acid to form its (-) di-benzoyl-L-tartrate or (-) di-p-toluoyl-L-tartrate;

e. combining the formed salt, 1, 2-dichloroethane and aqueous base with 3, 5-bis (trifluoromethyl) benzaldehyde, and then adding sodium triacetoxyborohydride to form a product;

f. combining the product with 4-toluenesulfonic acid monohydrate to yield (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-toluenesulfonic acid salt; and

g. (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, tosylate, methyl chloroformate and sodium carbonate are combined in tetrahydrofuran at a temperature of from about 20 ℃ to about 25 ℃ in the presence of methyl chloroformate.

Unlike the process described in example 7 of U.S. application No. 09/391,152, the four intermediates II, V, VI and VII were readily isolated and purified in crystalline form. Since the reaction is carried out with pure starting material II, the formation of III results in a more pure product. Resolution by classical diastereomeric salt formation is easier to scale up than separation using chiral chromatography. Due to the high purity of the compound of formula VII, further crystallization of the final product (e.g. anhydrous form, ethanolate form) becomes easier.

The term "mammal" as used herein refers to all mammals that contain CETP in their plasma, e.g., rabbits and primates such as monkeys and humans. Certain other mammals, such as dogs, cats, cattle, goats, sheep and horses, contain no CETP in their plasma, and are never included.

The term "ethanolate" refers to solvated ethanol.

The term "pharmaceutically acceptable" means that the carrier, vehicle, diluent, excipient, and/or salt must be compatible with the other ingredients of the formulation and not deleterious to the user.

The expressions "reaction-inert solvent" and "inert solvent" as used herein refer to a solvent or mixture of solvents that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.

Other features and advantages will be apparent from the description and the claims, which describe the invention.

In general, the compound [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester of the present invention can be prepared by methods comprising analogous to the methods known in the chemical art, in particular according to the methods described herein. Certain methods for producing the compounds of the invention constitute further features of the invention and are described in the experimental section below.

Reaction scheme

According to the above reaction scheme, the amine of formula II can be prepared by combining benzotriazole, 4- (trifluoromethyl) aniline (I) and propionaldehyde in a non-polar solvent such as toluene at room temperature (about 20 ℃ to about 30 ℃) for about 0.5 to about 3 hours.

Esters of formula III can be prepared by reacting vinyl-carbamic acid R¹Esters (wherein R¹Is benzyl, tert-butyl or C₁-C₄(alkyl)), the amine of formula II and p-toluenesulfonic acid monohydrate are combined in an inert solvent such as toluene at elevated temperature (about 50 ℃ to about 90 ℃) for about 0.5 to about 3 hours. Preferably R¹Is 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 anhydrous dichloromethane, the reaction being exothermic.

The compounds of formula V can be prepared by treating the product of the foregoing reaction with ammonium formate, palladium on carbon in a polar protic solvent such as methanol at a temperature of about 35 ℃ to about 60 ℃ for about 0.5 to about 3 hours.

The reaction sequence proceeds by preparing the classical diastereomeric salt formed by combining 4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) dibenzoyl-L-tartaric acid (anhydrous), followed by addition of an alcoholic solvent such as ethanol at room temperature (e.g., about 20 ℃ to about 30 ℃) for about 1 to about 24 hours to form its (-) di-benzoyl-L-tartrate salt. Alternatively, (-) di-p-toluoyl-L-tartaric acid may be used instead of (-) dibenzoyl-L-tartaric acid.

The compound of formula VII may be prepared by treating the salt of formula VI, 1, 2-dichloroethane, and an aqueous base such as sodium hydroxide with 3, 5-bis (trifluoromethyl) benzaldehyde and then adding sodium triacetoxyborohydride at room temperature (e.g., about 20 ℃ to about 30 ℃) for about 1 hour to about 24 hours. 4-toluenesulfonic acid monohydrate is then added at room temperature (e.g., about 20 ℃ to about 30 ℃).

The compound of formula VIII can be prepared by combining (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and sodium carbonate in tetrahydrofuran at room temperature (about 20 ℃ to about 25 ℃) in the presence of methyl chloroformate. Crystalline ethanolate forms of the above compounds can be prepared from amorphous compounds by recrystallization from ethanol/water at a temperature of about 20 ℃ to about 25 ℃, preferably at room temperature, for about 0.5 hours to about 18 hours. Typical ranges are about 3% to about 10% ethanol and about 90% to about 97% water. Preferred ratios are about 10% to about 90% ethanol/water.

Alternatively, the crystalline ethanolate form may be prepared by a process similar to that described above but using ethanol alone. The filtered material is typically granulated for about 2 hours to about 24 hours and then air dried.

The amorphous form of the compound [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was prepared as described in example 10 below.

The anhydrous crystalline forms of the above compounds can be prepared from amorphous compounds by recrystallization from hexane (a solvent consisting of hexane isomers (e.g., n-hexane, cyclohexane, methylpentane, etc.) at a temperature of about 40 ℃ to about 80 ℃, preferably 60 ℃, followed by granulation of the filtered material for about 2 to about 24 hours and then air drying.

Alternatively, anhydrous crystals can be prepared from the ethanolate crystalline form (to be described below) in a manner similar to that described previously. In addition, the yield of the process can be increased by azeotroping ethanol from hexane.

It should be noted that since the anhydrous and ethanolate crystals have different energy levels, seeding with either the anhydrate or the ethanolate will determine the crystalline form isolated. It is known in the art that the presence of seeds in the air of a laboratory may be sufficient to "seed". In one embodiment, anhydrous crystals may be obtained with hexane and the obtained anhydrous crystals may be used as seed to produce further anhydrous crystals from ethanol.

The preferred dosage is about 0.1 to 100 mg/kg/day of the compound produced by the process of the present invention, preferably anhydrous crystals. A particularly preferred dosage is about 0.1-10 mg/kg/day.

The compounds of the invention are useful for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, myocardial ischemia, stroke, myocardial infarction, reperfusion injury, angioplasty restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human, either male or female).

The compounds of the present invention may also be used in combination with a second compound. The second compound may be an HMG-CoA reductase inhibitor, microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, PPAR activator, bile acid reuptake inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, lipid-removing ethyl ester formulation, nicotinic acid, ion exchange resin, antioxidant, ACAT inhibitor or bile acid sequestrant.

The dosage of the compounds of the invention administered will generally vary according to the severity of the condition being treated and the route of administration, according to principles well known in the art. Generally, the compounds will be administered to a warm-blooded animal (e.g., human, livestock or companion animal) in order to receive an effective dose, usually a daily dose administered in a single or divided doses, e.g., a dose of from about 0.01 to about 100 mg/kg/day body weight, preferably from about 0.1 to about 10 mg/kg/day body weight. The above dosages are only examples of the general case; of course, there may be specific instances where higher or lower dosages are required, and such variations are within the scope of the invention.

The compounds of the present invention may be administered orally and may therefore be used in combination with pharmaceutically acceptable carriers, excipients or diluents suitable for oral dosage forms. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound should be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage within the ranges described herein. Thus, for oral administration, the compounds may be mixed with suitable solid or liquid carriers, excipients, or diluents to form capsules, tablets, powders, syrups, solutions, suspensions and the like. If desired, the pharmaceutical compositions may also contain other ingredients such as flavoring agents, sweeteners, excipients, and the like.

Tablets, pills, capsules and the like may also contain binders such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; sweetening agents such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty acid glyceride or a mixture of fatty acid glycerides, e.g., olive oil or miglyoyl^TMOr Capmul^TMA glyceride.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or a mixture of 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 flavoring such as cherry or orange flavor.

The compounds of the invention may also be administered parenterally. For parenteral administration, the compounds may be mixed with sterile aqueous or organic vehicles to form injectable solutions or suspensions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly.

Pharmaceutical forms suitable for injectable administration include sterile solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the dosage form must be sterile and must be fluid to facilitate injection. It must be stable under the conditions of manufacture and storage and must be capable of preventing contamination by microorganisms such as bacteria and fungi. It must be sterilized, for example, by filtration through a bacteria retaining filter, by incorporating sterilizing agents into the composition, or by irradiating or heating the composition when radiation or heating is appropriate for the pharmaceutical formulation.

Other pharmaceutical preparations include suppositories, sublingual tablets, topical dosage forms and the like, which can be prepared according to art recognized methods.

Melting points were measured using a Thomas Hoover melting point apparatus or DSC apparatus. Unless otherwise stated, CDCl was used for NMR spectra₃. Microanalysis was performed by Schwarzkopf microanalysis laboratory. All reagents and solvents were obtained commercially and used without purification.

Example 1

(1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine

To a two-liter four-necked flask, under nitrogen, was added benzotriazole (36.96g, 310mmol, 1.0 eq.) and anhydrous toluene (400 mL). A solution of 4- (trifluoromethyl) aniline (39.1mL, 310mmol, 1.0 equiv.) and 50mL of toluene at room temperature was added over 1 minute. Then a solution of propionaldehyde (24.6mL, 341mmol, 1.1 equiv.) and 50mL of toluene at room temperature was added over 20 minutes. Exothermic heat was released during the addition, the temperature was from 23 ℃ to 30 ℃. After stirring for 24 hours, n-heptane (500mL) was added and the slurry was stirred for an additional 1 hour. The suspension was filtered and the solid was washed with n-heptane (1X 100mL, then 1X 200mL) and then dried. (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine (81.3g, 82%) was isolated as glossy, white needles. After 24 hours, a second crop of product (8.7g, 9%) was isolated from the filtrate. mp 130-;¹H NMR(DMSO-d6，400MHz)δ0.82(t，3H，J＝7.5Hz)，2.25(m，2H)，6.49(m，1H)，6.80(d，2H，J＝8.7Hz)，7.35(m，3H)，7.50(m，1H)，7.88(d，1H，J＝8.3Hz)，7.99(m，1H)，8.09(d，1H，J＝8.5Hz)；¹³c NMR (DMSO-d6, 100MHz) δ 149.32, 146.19, 131.46, 127.73, 126.8, 125.33(q, J270 Hz), 124.44, 119.88, 118.27(q, J31.7 Hz), 112.91, 111.56, 71.03, 28.08, 10.29; DEPT Spectroscopy: quaternary carbons δ 149.32, 146.19, 131.46, 125.33, 118.27; c.sub.d. of CH127.73，126.8，124.44，119.88，112.91，111.56，71.03；CH₂Carbon delta 28.08; CH (CH)₃Carbon delta 10.29; IR (drift) 3292(s), 3038(m), 2975(m), 1621(s), 1331(s), 1320(s), 1114 (vs); analytical calculation C₁₆H₁₅N₄F₃: c, 59.99; h, 4.72; n, 17.49. Found (first batch): c, 60.16; h, 4.74; and N, 17.86. Found (second batch): c, 59.97; h, 4.66; n, 17.63.

Example 2

Cis- (2-Ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester

To a one liter four-necked flask, under nitrogen, were added benzyl N-vinyl-carbamate (27.66g, 156mmol, 1.0 eq.) and anhydrous toluene (500 mL). (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine (50.0g, 156mmol, 1.0 equiv.) and p-toluenesulfonic acid monohydrate (297mg, 1.56mmol, 0.01 equiv.) were added, and the mixture was heated to 70 ℃. After 2 hours, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500mL) was added. 1X 200mL of 1N NaOH and 1X 200mL of H were used for mixing₂O, 1X 200mL brine, then dried (magnesium sulfate). The mixture was filtered and the solid was washed with 1 × 50mL ethyl acetate. The filtrate was concentrated to about 250 mL. 500mL of toluene was added and the mixture was concentrated to about 500 mL. 500mL of n-heptane was added, and then the slurry was stirred for 1 hour, filtered with a Buchner funnel and then dried. Cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (45.04g, 76%) was isolated as a white powder: mp155-157 ℃;¹H NMR(DMSO-d6，400MHz)δ0.92(t，3H，J＝7.5Hz)，1.5(m，3H)，2.00(m，1H)，3.35(m，1H)，4.77(m，1H)，5.07(d，1H，J＝12.5Hz)，5.15(d，1H，J＝12.5Hz)，6.35(s，1H)，6.61(d，1H，J＝8.5Hz)，7.12(s，1H)，7.18(dd，1H，J＝1.9，8.5Hz)，7.4(m，5H)，7.70(d，1H，J＝9.1Hz)；¹³C NMR(DMSO-d6，100MHz)δ157.03，149.02，137.79，128.82，128.23, 128.03, 125.9(q, J270 Hz), 125.06, 123.50, 121.73, 115.2(q, J31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT Spectroscopy: quaternary carbons δ 157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons δ 128.82, 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH (CH)₂Carbon δ 65.85, 34.02, 28.68; CH (CH)₃Carbon delta 9.93; IR (drift) 3430(m), 3303(s), 2951(m), 1686(vs), 1542(vs), 1088 (vs); MS (APC1+) M/z (relative intensity) 379(M + H)⁺53), 228 (100); analytical calculation C₂₀H₂₁N₂O₂F₃: c, 63.48; h, 5.59; n, 7.40; measured value: c, 63.69; h, 6.06, N, 7.36.

Example 3

Cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester

To a three-liter four-necked flask, under nitrogen, was added cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester (96.0g, 254mmol, 1.0 eq), anhydrous dichloromethane (720mL), and anhydrous pyridine (103mL, 1.27mol, 5.0 eq). A solution of ethyl chloroformate (121mL, 1.27mol, 5.0 equiv.) in dry dichloromethane (240mL) was added slowly over 4 hours. The feed was exothermic and a reflux condenser was required. When the addition of chloroformate was complete, the reaction was cooled in an ice bath and 1350mL of 1N NaOH was added. The mixture was stirred for 15 minutes and then transferred to a separatory funnel. The different layers were separated and the aqueous layer was extracted with 1X 1L of dichloromethane. The combined dichloromethane layers were washed with 1X 1350mL of 1N HCl, 1X 1L saturated aqueous sodium bicarbonate, 1X 1L brine, and then dried (sodium sulfate). The mixture was filtered and the filtrate was concentrated to an orange oil. 570mL of absolute ethanol was added and the solution was concentrated. The solid was dissolved in 1370mL of absolute ethanol and 570mL of water were added dropwise over 45 minutes. The resulting viscous slurry was stirred for 18 hours and then filtered. The solid was washed with cold 7: 3 absolute ethanol/water (1X 250mL, then 1X 100 m)L) then dried (vacuum oven, 45 ℃) to give cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white crystalline solid (94.54g, 83%): mp 92-96 ℃;¹H NMR(CDCl₃，400MHz)δ0.84(t，3H，J＝7.4Hz)，1.28(t，3H，J＝7.0Hz)，1.4(m，2H)，1.62(m，1H)，2.53(m，1H)，4.23(m，2H)，4.47(m，1H)，4.79(m，1H)，5.01(d，1H，J＝9.2Hz)，5.18(m，2H)，7.4(m，5H)，7.5(m，2H)，7.57(m，1H)；¹³C NMR(CDCl₃100MHz) δ 155.97, 154.43, 139.44, 136.21, 134.33, 128.61, 128.33, 128.22, 126.32(q, J ═ 31.7Hz), 126.18, 124.22, 124.19, 124.12(q, J ═ 273Hz), 120.74, 120.70, 67.22, 62.24, 53.47, 46.79, 37.75, 28.25, 14.38, 9.78; DEPT Spectroscopy: quaternary carbons δ 155.97, 154.43, 139.44, 136.21, 134.33, 126.32, 124.12; CH carbons δ 128.61, 128.33, 128.22, 126.18, 124.22, 124.19, 120.74, 120.70, 53.47, 46.79; CH (CH)₂Carbon δ 67.22, 62.24, 37.75, 28.25; CH (CH)₃Carbon δ 14.38, 9.78; IR (drift) 3304(s), 3067(m), 3033(m), 2982(m), 2932(m), 1723(s), 1693(s), 1545(s); MS (APCI +) M/z (relative intensity) 451(M + H)⁺2), 300 (100); analytical calculation C₂₃H₂₅N₂O₄F₃: c, 61.33; h, 5.60; and N, 6.22. Measured value: c, 61.07; h, 5.69; and N, 6.22.

Example 4

Cis-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

To a 1 liter four-necked flask, under nitrogen, was added cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1g, 89mmol, 1.0 eq), methanol (400mL) and ammonium formate (14.0g, 223mmol, 2.5 eq). 10% Pd/C (50% water wet) (4.0g) was added and the slurry was heated to 40 ℃ over 1 hour. After 1.5 hours, the mixture was cooled to room temperature and filtered through celite. The filter cake was washed with 2X 100mL of methanol.The filtrate was concentrated to about 75mL, transferred to a separatory funnel and then diluted with 400mL ethyl acetate. The mixture was washed with 1X 125mL of saturated aqueous sodium bicarbonate, 1X 100mL of brine, and then dried (sodium sulfate). The mixture was filtered and the filtrate was concentrated to a clear oil. The oil was crystallized from 100mL of n-heptane to give cis-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white crystalline solid (26.05g, 93%): mp61.5-63.5 ℃;¹H NMR(CDCl₃，400MHz)δ0.79(t，3H，J＝7.5Hz)，1.24(m，4H)，1.42(m，1H)，1.51(brs，2H)，1.62(m，1H)，2.46(m，1H)，3.73(m，1H)，4.17(m，2H)，4.36(m，1H)，7.44(m，2H)，7.66(m，1H)；¹³C NMR(CDCl₃100MHz) δ 154.6, 139.3, 138.9, 126.3(q, J ═ 32Hz), 125.7, 124.3(q, J ═ 271Hz), 123.5, 119.8, 61.96, 54.16, 46.91, 41.50, 28.85, 14.38, 9.60; DEPT Spectroscopy: quaternary carbons δ 154.6, 139.3, 138.9, 126.3, 124.3; CH carbons δ 125.7, 123.5, 119.8, 54.16, 46.91; CH (CH)₂Carbon δ 61.96, 41.50, 28.85; CH (CH)₃Carbon δ 14.38, 9.60; IR (drift) 3350(5), 3293(m), 2972(s), 1697 (vs); MS (ES +) M/z (relative intensity) 358(M + H + CH)₃CN⁺，55)，317(M+H⁺7), 300 (100); analytical calculation C₁₅H₁₉N₂O₂F₃: c, 56.96; h, 6.06; and N, 8.86. Measured value: c, 56.86; h, 6.28; and N, 8.82.

Example 5

(-) - (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester semi- (-) -dibenzoyl-L-tartrate

To a 1 liter flask, under nitrogen, was added cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (24.0g, 75.9mmol, 1.0 eq) and (-) dibenzoyl-L-tartaric acid (anhydrous) (27.19g, 75.9mmol, 1.0 eq). 300mL of about 97% ethanol was added (mixed by adding 10.5mL of water to 500mL of anhydrous ethanolPrepared and then measured out 300 mL). The mixture was stirred at room temperature for 18 hours and then filtered. The solid was washed with 1 × 48mL of about 97% ethanol and then dried to afford (-) (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester semi- (-) -dibenzoyl-L-tartrate as a white crystalline solid (14.77g, 39%): mp 189.5-191.5 deg.C (decomposition);¹h NMR (DMSO-d6, 400MHz) δ 0.62(t, 3H, J ═ 7.3Hz), 1.16(t, 3H, J ═ 7.1Hz), 1.3(m, 3H), 2.5(m, 1H), 4.1(m, 4H), 5.63(s, 1H, methine protons in DBTA), 7.47(m, 2H, aromatic H's of DBTA), 7.6(m, 3H, aromatic H's of DBTA), 7.68(s, 1H), 7.95(m, 2H), 8.2(br s, NH s), NH 95(m, 2H), c₃ ⁺No integration);¹³c NMR (DMSO-d6, 100MHz) δ 169.85, 165.53, 154.10, 140.14, 134.59, 133.51, 130.74, 129.69, 128.98, 126.74, 124.82(q, J ═ 31.7Hz), 124.69(q, J ═ 271Hz), 124.50, 120.90, 74.49, 62.14, 53.51, 45.94, 38.81, 28.23, 14.63, 9.58; DEPT Spectroscopy: quaternary carbons δ 169.85, 165.53, 154.10, 140.14, 134.59, 130.74, 124.82, 124.69; CH carbons δ 133.51, 129.69, 128.98, 126.74, 124.50, 120.90, 74.49, 53.51, 45.94; CH (CH)₂Carbon δ 62.14, 38.81, 28.23; CH (CH)₃Carbon δ 14.63, 9.58; IR (drift) 3278(m), 2400-; MS (ES +) M/z (relative intensity) 358(M + H + CH)₃CN⁺，55)，317(M+H⁺7), 300 (100); analytical calculation C₁₅H₁₉N₂O₂F₃·C₉H₇O₄: c, 58.18; h, 5.29; and N, 5.65. Measured value: c, 57.99; h, 5.15; n, 5.64; chiral HPLC: mobile phase 950: 50: 2 n-hexane: 2-propanol: HOAc, flow rate 1.50 mL/min, column temperature 40 ℃, chiralpak AD 4.6 × 250mm, sample concentration about 0.5mg/mL in about 1: 1 n-hexane: 2-propanol. Authentic racemates showed retention times of 7.5 minutes and 10.0 minutes. (-) - (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester semi- (-) -dibenzoyl-L-tartrate: 10.0 min, 88.9%, 7.5 min < 1%, 2.0 min (solvent front) 11.1%; [ alpha ] to]_D＝-153(c＝1.07，CH₃OH)。

Example 6

(-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl- 3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate

(-) -ethyl (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylate semi- (-) -dibenzoyl-L-tartrate (13.0g, 26.2mmol, 1.0 equiv.) was suspended in 1, 2-dichloroethane (260mL) in a 500mL separatory funnel. The mixture was washed with 1X 65mL of 1N NaOH and 1X 65mL of brine, then dried (magnesium sulfate). The mixture was filtered, concentrated to about 80mL, and then transferred to a 250mL three-neck flask. 3, 5-bis (trifluoromethyl) benzaldehyde (4.53mL, 27.5mmol, 1.05 equiv.) was added and the mixture was stirred at room temperature under nitrogen for 1 hour. Sodium triacetoxyborohydride (11.1g, 52.4mmol, 2.0 equiv.) was added in one portion and the white slurry was stirred for 18 hours. 50mL of 1, 2-dichloroethane and 50mL of 2N NaOH were added, and the aqueous layer was extracted with 2X 50mL of 1, 2-dichloroethane. The combined organic extracts were washed with 1X 31mL of 1N HCl, 1X 50mL of saturated aqueous sodium bicarbonate, and 1X 50mL of brine, and then dried (sodium sulfate). The mixture was filtered and concentrated to a clear oil. The oil was dissolved in methanol (71 mL). P-toluenesulfonic acid monohydrate (5.23g, 27.5mmol, 1.05 eq) was added. After 5 minutes 284mL of isopropyl ether were added. The solution was concentrated to about 35mL, transferred to a 500mL three-necked flask (mechanically stirred) and diluted with 284mL of isopropyl ether. A viscous white slurry formed in 10 minutes. After stirring for 3 hours, the slurry was filtered and the filter cake was washed with 2X 70mL of isopropyl ether. After drying, (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate was obtained as a white powder (16.18g, 86% overall yield): mp191-192 ℃;¹H NMR(DMSO-d6，400MHz)δ0.78(t，3H，J＝7.5Hz)，1.21(t，3H，J＝7.0Hz)，1.5(m，3H)，2.24(s，3H)，3.08(m，1H)，4.17(m，2H)，4.41(m，1H)，4.50(m，2H)，4.79(m，1H)，7.04(d，2H，J＝7.9Hz)，7.42(d，2H，J＝7.9Hz)，7.7(m，2H)，7.81(s，1H)，8.21(s，1H)，8.35(s，2H)，9.58(br s，1H)，9.83(brs，1H)；¹³c NMR (DMSO-d6, 100MHz) δ 154.00, 145.46, 140.21, 138.39, 135.33, 132.51, 131.62, 130.79(q, J ═ 33.2Hz), 128.49, 127.40, 125.82, 125.36, 124.99(q, J ═ 31.7Hz), 124.59(q, J ═ 271Hz), 123.69(q, J ═ 273Hz), 123.44, 120.33, 62.32, 53.99, 53.79, 47.98, 33.30, 28.61, 21.13, 14.63, 9.58; DEPT Spectroscopy: quaternary carbons δ 154.00, 145.46, 140.21, 138.39, 135.33, 130.79, 124.99, 124.59, 123.69; CH carbons δ 132.51, 131.62, 128.49, 127.40, 125.82, 125.36, 123.44, 120.33, 53.99, 53.79; CH (CH)₂Carbon δ 62.32, 47.98, 33.30, 28.61; CH (CH)₃Carbon δ 21.13, 14.63, 9.58; IR (drift) 2300-; MS (ES +) M/z (relative intensity) 584(M + H + CH)₃CN⁺，100)，543(M+H⁺80); analytical calculation C₂₄H₂₃N₂O₂F₉·C₇H₈O₃S: c, 52.11; h, 4.37; n, 3.92. Measured value: c, 52.15; h, 4.22; n, 3.69; [ alpha ] to]_D＝-77.9(c＝1.05，CH₃OH)。

Example 7

(-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]-2-ethyl group -6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester monoethanol compound

Sodium carbonate (S) (6.75g, 63.7mmol, 3.5 equiv.) is added to a solution of (-) - (2R, 4S) -4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate (13.0g, 18.2mmol, 1.0 equiv.) in anhydrous THF (130mL) at room temperature. Methyl chloroformate (3.51mL, 45.5mmol, 2.5 equiv.) was added dropwise over 2 minutes. After 24 hours, the mixture was concentrated to 65mL,diluted with 260mL ethyl acetate and then transferred to a separatory funnel. The mixture was diluted with 1X 90mL of 1N HCl (with CO)₂Overflow), 1X 90mL of saturated aqueous sodium bicarbonate solution and 1X 90mL of brine, followed by drying (magnesium sulfate). Filtration and concentration of the filtrate gave a clear oil which was co-stripped with 3X 33mL of 2B ethanol. The oil was dissolved in 33mL of 2B ethanol and a few mg of (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino group was introduced]-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate seed. After stirring at room temperature for 18 hours, the slurry was filtered and then dried to afford (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-group as a white crystalline powder]-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester monoethanol (8.66g, 74%): mp 54-58 ℃;¹H NMR(CDCl₃，400MHz，55℃)δ0.73(t，3H，J＝7.0Hz)，1.20(t，EtOH)，1.27(t，3H，J＝7.1Hz)，1.42(m，2H)，1.66(m，1H)，2.25(br s，1H)，3.67(q，EtOH)，3.79(s，3H)，4.2(m，3H)，4.33(m，1H)，5.2(br s，2H)，7.12(s，1H)，7.49(d，1H，J＝8.3Hz)，7.57(d，1H，J＝8.5Hz)，7.73(s，2H)，7.78(s，1H)；¹³C NMR(CDCl₃400MHz) δ 157.74, 154.37, 141.73, 140.05, 133.83, 132.14(q, J ═ 33Hz), 126.94, 124.49, 123.96(q, J ═ 273Hz), 123.13(q, J ═ 273Hz), 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 to be masked by the peak at δ 126.94, J being equal to about 32 Hz); DEPT Spectroscopy: quaternary carbons δ 157.74, 154.37, 141.73, 140.05, 133.83, 132.14, 123.96, 123.13; CH carbons δ 126.94, 124.49, 121.31, 119.17, 54.42, 53.08; CH (CH)₂Carbon δ 62.29, 58.28, 46.67, 37.01, 29.02; CH (CH)₃Carbon δ 53.71, 18.29, 14.32, 9.22; IR (drift) 3489(s), 2974(s), 2884(m), 1701(vs), 1280(vs), 1131 (vs); MS (ES +) M/z (relative intensity) 601(M + H)⁺100); analytical calculation C₂₆H₂₅N₂O₄F₉·C₂H₆O: c, 52.01; h, 4.83; n, 4.33. Measured value: c, 51.84; h, 4.54; n, 4.33; chiral HPLC: mobile phase 950: 50: 2 n-hexane: 2-propanol: HOAc, flow rate 1.0 mL/min, 254nm, chiralpak AD 4.6 × 250mm, column temperature 40 ℃, sample concentration of about 0.5mg/mL in 90: 10 n-hexane: 2-propanol, retention time of authentic racemate 3.6 and 4.6 minutes. (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]Ethyl-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylate monoethanol salt showed 4.6 min, 99.1% and 3.6 min, not determined; [ alpha ] to]_D＝-93.3(c＝1.08，CH₃OH)。

Example 8

Anhydrous (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]- 2-Ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

2.6g (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (mixture of mostly amorphous and trace crystalline forms of the ethanolate; the title compound can also be prepared in a similar manner from pure amorphous or pure ethanolate) was added to 13mL hexane and heated at about 60 ℃ to form a solution. The heating was stopped and the reaction was cooled to room temperature over 1 hour. The reaction solution was seeded with anhydrous (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and granulated at room temperature for 18H. Alternatively, anhydrous crystals can be obtained from hexane without seeding. The product was collected by filtration and air dried.

Melt microscopy (Fusion microscopy): type A oil- -dissolves at 50 ℃.

Dry- -clear melt at 86 ℃.

Appearance: free flowing white powder.

Example 9

4.0g (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was dissolved in 3.5mL ethanol and dissolved completely by sonication for 2 min. A white solid formed, to which 10mL of ethanol was added and stirred at room temperature overnight. The white powder was filtered and collected on a 0.22 μm LS filter paper and then washed with about 15mL ethanol.

And (3) molten glass microscope observation: type a oil-melts and dissolves at 43 ℃ with loss of water.

Dry- -clear melt at 43 ℃.

Appearance: free flowing white powder.

Example 10

Cis-4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl 3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: a solution of cis-4- (3, 5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.0g, 3.7mmol) and pyridine (0.58g, 7.4mmol) in 100mL of dichloromethane was cooled in an ice/water bath and methyl chloroformate (0.87g, 9.2mmol) was slowly added. 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 eluting with 5-10% ethyl acetate/hexane to give 1.8g of the title product. MS M/z 601 (M)⁺+1)；¹H NMR (agglomerated mixture of conformational isomers, CDCl)₃)δ0.6-0.8(bm，3H)，1.2-1.3(bm，3H)，1.3-1.5(bm，2H)，1.6-1.75(bm，1H)，2.1-2.3(bm，1H)，3.7-3.9(bs，3H)，4.0-4.4(bm，4H)，5.0-5.6(bm，2H)，7.1(s，1H)，7.4-7.6(bm，2H)，7.6-7.8(bm，3H)。

Optically enriched form of [2R, 4S ] -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is prepared by resolution of the corresponding racemate or intermediates in its synthesis by standard methods.

Example 11

Anhydrous (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino]- 2-Ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

A crude solution of about 42g (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in 500mL ethyl acetate (prepared by the method described in example 7) was concentrated in vacuo to a volume of 100 and 135 mL. The remaining ethyl acetate was replaced with 3X 220mL of 2B EtOH to a final volume of 100-135 mL. The solution was seeded with crystals of anhydrous (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. After 18H at room temperature, the slurry was filtered and dried in vacuo to give 19.81g of anhydrous (-) - (2R, 4S) -4- [ (3, 5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. The melting point characteristics were the same as for the material prepared by example 8, confirming the anhydrous nature of the material.

Claims

4- (3, 5-bis-trifluoromethylbenzylamino) -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or its 4-tosylate salt.
2. (-) di-p-toluoyl-L-tartrate salt of cis-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
3. (iv) cis-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (-) di-benzoyl L-tartrate.
(-) - (2R, 4S) -4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or a salt thereof.
5. The stereoisomer of claim 4, wherein the salt is (-) di-benzoyl-L-tartrate.
6. The stereoisomer of claim 4, wherein the salt is (-) di-p-toluoyl-L-tartrate.
7. A process for the preparation of cis-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, which process comprises: cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate are mixed with palladium/carbon in methanol to form a slurry and the resulting slurry is heated at a temperature of from 35 ℃ to 60 ℃ for from 30 minutes to 3 hours.
8. Preparation of cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid-R¹-a process for the preparation of esters, wherein R¹Is benzyl, tert-butyl or C₁-C₄(alkyl), the process comprising: reacting vinyl-carbamic acid-R¹And (1-benzotriazol-1-yl-propyl) - (4-trifluoromethyl-phenyl) -amine and 4-toluenesulfonic acid monohydrate are combined in toluene at a temperature of 50 ℃ to 90 ℃.
9. The process of claim 8, further comprising reacting the formed cis- (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid-R¹Preparation of cis-4-R by combining the ester with pyridine and ethyl chloroformate in dichloromethane¹-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.