HK1062294B - Compounds useful as intermediates for 4-aminoquinoline derivates - Google Patents

Description

Compounds useful as intermediates for 4-aminoquinoline derivatives

Technical Field

The present invention relates to compounds that are intermediates for Cholesteryl Ester Transfer Protein (CETP) inhibitors and processes for their preparation.

Background

Atherosclerosis and its associated Coronary Artery Disease (CAD) are the most mortality diseases in industrialized countries. In the united states, Coronary Heart Disease (CHD) remains the most common cause of death despite attempts to ameliorate secondary risk factors (smoking, obesity, lack of exercise) and to treat dyslipidemia by dietary and drug modification.

The risk of developing this condition has been shown to be closely related to certain blood lipid levels. While high LDL-C is the most obvious indicator of dyslipidemia, it is not suggested to be the only cause of CHD. Low HDL-C is also considered a risk factor for CHD (Gordon, D.J., et al: "High-Densitylipoprotein Cholesterol and Carbovasular Disease", Circulation, (1989), 79: 8-15).

High LDL-cholesterol and triglyceride levels are positively correlated with cardiovascular disease progression, while high levels of HDL-cholesterol are negatively correlated. Thus, dyslipidemia is not a single risk indicator for CHD, but includes one or more lipid abnormalities.

Of the many factors that control both plasma levels of these diseases, Cholesterol Ester Transfer Protein (CETP) activity has an effect on all three in a dependent manner. It has been found that this 70,000 dalton blood glucose protein plays a role in the transfer of cholesterol esters and triglycerides between lipoprotein particles in many animal species, including humans, including High Density Lipoproteins (HDL), Low Density Lipoproteins (LDL), Very Low Density Lipoproteins (VLDL) and chylomicrons. The end result of CETP activity is a decrease in HDL cholesterol and an increase in LDL cholesterol. This effect of lipoprotein levels is considered to be pro-atherogenic, especially in patients with increased risk of CHD due to lipid status.

Existing therapies for raising HDL are not entirely satisfactory. Nicotinic acid significantly increases HDL, but it has severe resistance leading to reduced activity. Fibrates (Fibrates) and HMG-CoA reductase inhibitors only marginally increase HDL-C. Thus, there is a clear unmet medical need for drugs that are well tolerated and that significantly increase plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

PCT application publication No. WO00/02887 discloses the use of catalysts containing certain novel ligands for transition metals in transition metal catalyzed carbon-heteroatom and carbon-carbon bond formation.

Commonly assigned U.S. patent 6,140,343, which is incorporated herein by reference, discloses inter alia CETP inhibitors, cis-4- [ acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isobutyl ester and methods for their preparation (e.g., as disclosed in example 46).

The commonly assigned U.S. patent 6,197,786, which is incorporated herein by reference, discloses inter alia CETP inhibitors, cis-4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and methods for their preparation (e.g., as disclosed in example 7).

Summary of The Invention

One aspect of the invention is a compound of formula III.

Another aspect of the invention is a compound of formula IV.

Yet another aspect of the invention is a compound of formula VI,

wherein R is selected from the group consisting of methyl, benzyl, and substituted benzyl.

Yet another aspect of the present invention is a compound of formula VII,

wherein R is selected from the group consisting of methyl, benzyl, and substituted benzyl.

In a preferred embodiment of these compounds of the invention, R of the compounds of formula VI and VII is selected from methyl, benzyl and benzyl substituted with one or more substituents each independently selected from (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy and halogen.

Another aspect of the present invention is a process for the preparation of a compound of formula III above, comprising coupling benzotrifluoride substituted in the para-position with halo or O-trifluoromethylsulfonate (O-triflate) with a compound of formula II,

to produce the compound shown in the formula III.

In a preferred embodiment of the process of the present invention for the preparation of the compound of formula III, the coupling reaction between said trifluorotoluene compound and said compound of formula II is carried out in the presence of a transition metal, preferably palladium.

In another preferred embodiment of the present invention with respect to the preparation method of the compound of formula III, the coupling reaction between the trifluoromethylbenzene compound and the compound of formula II is carried out in the presence of a phosphine ligand, preferably a dialkylphosphinobenzene ligand, more preferably selected from the group consisting of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl and 2-dicyclohexylphosphino-2' -methylbiphenyl ligand.

In a preferred embodiment of the present invention with respect to the process for preparing the compound of formula III, the coupling reaction between said trifluoromethylbenzene compound and said compound of formula II takes place in the presence of a base, preferably cesium carbonate.

Another aspect of the present invention is a process for preparing a compound of formula IV above comprising hydrolyzing a compound of formula III above with a hydrolyzing agent selected from the group consisting of an acid and a base, preferably an acid, more preferably sulfuric acid and water, to produce a compound of formula IV.

Yet another aspect of the present invention is a process for preparing a compound of formula VI above comprising coupling a compound of formula IV above with a compound of formula V above in the presence of a base, preferably lithium tert-butoxide, to form a compound of formula VI,

wherein R is selected from the group consisting of methyl, benzyl, and substituted benzyl.

Another aspect of the present invention is a process for preparing a compound of formula VII above, comprising reducing a compound of formula VI above (wherein R is selected from methyl, benzyl and substituted benzyl) with a reducing agent, preferably sodium borohydride, in the presence of a lewis acid, preferably calcium or magnesium ions, to produce a reduced compound, and cyclizing the reduced compound under acidic conditions to produce the compound of formula VII.

The term "substituted benzyl" in reference to compounds of formulas V, VI and VII means substituted on the phenyl ring with one or more substituentsA substituted benzyl group, which substituent does not hinder the following reaction: (a) reacting an appropriate compound of formula V with a compound of formula IV to form an appropriate compound of formula VI, (b) reducing and cyclizing the appropriate compound of formula VI to form an appropriate compound of formula VHB, (c) acylating the compound of formula VIIB to form a compound of formula VIIIB, or (d) subjecting the compound of formula VIIIB to a deprotection step to remove the appropriately substituted benzyloxycarbonyl group to form a compound of formula IB. A preferred substituent is (C)₁-C₃) Alkyl and (C)₁-C₃) Alkoxy and halogen.

The chemical structure is represented here by a planar chemical structure diagram, which is a view projected from above the plane of the structure. Wedge wire in such a chemical structureRepresenting a key protruding from the plane of the structure.

Detailed Description

Reaction scheme A illustrates a method for preparing a chiral isomer of formula II from (R) -2-amino-1-butanol. Reaction scheme B illustrates a method for preparing cholesteryl ester transfer protein inhibitors of formula IA and formula IB.

Scheme A

Scheme B

According to scheme B, the compound of formula III is prepared by reacting a chiral isomer compound of formula II ((R) -3-amino-valeronitrile) with a para-halogen or O-trifluoromethylsulfonate (O-triflate, -O-S (O) in the presence of a metal catalyst, preferably Pd₂CF₃) Substituted byTrifluoromethyl benzene is coupled. To optimize the coupling, the coupling reaction is carried out in the presence of a ligand, preferably a phosphine ligand, and a base. Preferred phosphine ligands are dialkylphosphinobenzene ligands, preferably selected from the group consisting of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl and 2-dicyclohexylphosphino-2' -methylbiphenyl. The reaction is preferably carried out at about 60 ℃ to about 110 ℃. Chiral isomers of formula II can be prepared according to scheme A from (R) -2-amino-1-butanol (CAS # 005856) -633 using methods known to those skilled in the art, as described in example 9 of the experimental procedure below.

The compound of formula IV is prepared by hydrolysis of the nitrile of the compound of formula III. The hydrolysis may be carried out under acidic or basic conditions. The preferred hydrolysis method is carried out under acidic conditions, preferably using sulfuric acid and water. For hydrolysis with a base, preferred bases are hydroxyl bases, preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkoxy bases, preferably methoxide and ethoxide. Also, for hydrolysis with alkali, it is preferred to use peroxide. The hydrolysis reaction is preferably carried out at about 20 ℃ to about 40 ℃.

The compound of formula VI is prepared by reacting the amide of the compound of formula IV with a chloroformate of formula V in the presence of a base, preferably lithium tert-butoxide. The reaction is preferably carried out at a temperature of from about 0 ℃ to about 35 ℃. If it is desired that R in the compound of formula VI is methyl, methyl chloroformate is used as the compound of formula V. If it is desired that R in the compound of formula VI is benzyl, benzyl chloroformate.

The compounds of formula VII are prepared by reacting the imide of the compound of formula VI with a reducing agent, preferably sodium borohydride, in the presence of a lewis acid activator, preferably calcium or magnesium ions, to form a reduced intermediate. This reaction to form the reduced intermediate is preferably carried out at about-20 ℃ to about 20 ℃. Under acidic conditions, the intermediate undergoes diastereoselective cyclization to form the tetrahydroquinoline ring of formula VII. The cyclization step is preferably carried out at about 20 ℃ to about 50 ℃.

CETP inhibitors of formula IA are prepared by acylating the nitrogen of tetrahydroquinoline on a compound of formula VII (R is methyl) with ethyl chloroformate in the presence of a base, preferably pyridine, to produce a compound of formula VIIIA. The reaction is preferably carried out at about 0 ℃ to about 25 ℃.

CETP inhibitors of formula IA are prepared by alkylating a compound of formula VII, wherein R is methyl, with 3, 5-bis (trifluoromethyl) benzyl halide, preferably 3, 5-bis (trifluoromethyl) benzyl bromide, in the presence of a base, preferably an alkoxide, more preferably a hydroxide. The reaction is preferably carried out at a temperature in the range of about 25 ℃ to about 75 ℃.

CETP inhibitors of formula IB are prepared by acylating the nitrogen of a tetrahydroquinoline of formula VII, wherein R is benzyl or substituted benzyl, with isopropyl chloroformate in the presence of a base, preferably pyridine, to form a compound of formula VIIIB. The reaction is preferably carried out at about 0 ℃ to about 25 ℃.

The CETP inhibitor of formula IB is then prepared from the compound of formula VIIIB by first treating the compound of formula VIIIB with an excess of a hydrogen source, such as cyclohexene, hydrogen or ammonium formate in the presence of a suitable catalyst in a polar solvent, such as ethanol, to remove the benzyloxycarbonyl group. The 3, 5-bis-trifluoromethylbenzyl group of formula IB can then be introduced by treatment with 3, 5-bis-trifluoromethyl-benzaldehyde with an amine and an acid such as acetic acid, followed by treatment with a hydride such as sodium triacetoxyborohydride. The amino group is then acylated to produce the compound of formula IB by methods known to those skilled in the art. Methods for preparing compounds of formula IB from compounds of formula VIIIB are also described in commonly assigned US6,140,343. The disclosure of US6,140,343 is incorporated herein by reference.

Experimental methods

Melting points were determined using a Buchi melting point apparatus. NMR spectra were recorded on a Varian Unity 400(Varian Co., Palo Alto, Calif.). Chemical shifts are expressed in ppm from the low magnetic field of the solvent. The peak pattern is represented by the following symbol: s is singlet; d is doublet; t is a triplet; q is quartet; m is multiplet; bs is a broad singlet.

Example 1

(3R) -3- (4-trifluoromethyl-phenylamino) -valeronitrile

A clean, dry, nitrogen-filled 100L glass jar was charged with (R) -3-aminopentanenitrile mesylate (3000g, 15.44mol), sodium carbonate (2.8kg, 26.4mol), and methylene chloride (21L). The heterogeneous mixture was stirred well for at least 2 hours. The mixture was filtered and the filtrate was rinsed with dichloromethane (3 × 2L). The resulting filtrate was placed in a clean, dry and nitrogen-filled 50L glass reaction tank. The dichloromethane was distilled off until the internal temperature reached 50-53 ℃ to give the free base amine as a thin oil. The pot was then cooled to room temperature and toluene (20L), chloro-4- (trifluoromethyl) benzene (4200g, 23.26mol) and cesium carbonate (7500g, 23.02mol) were added. The solution was sparged with nitrogen for 1 hour. Towards the completion of the gassing, a fresh catalyst solution was prepared by charging 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (68g, 0.17mol), phenylboronic acid (28g, 0.23g), and tetrahydrofuran (1.2L) into a 2L round bottom flask equipped with a stir bar and sparged with nitrogen, followed by palladium acetate (26g, 0.12 mol). The catalyst solution was stirred at room temperature under nitrogen for 15 minutes. The solution was added to a 50L reaction tank using a cannula (vented). The mixture was heated at an internal temperature of 79 ℃ for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and passed through Celite^*And (5) filtering. The solid was washed with toluene (3X 2L) and the filtrate was collected. All filtrates were combined to give a crude solution of the title compound.

Example 2

(3R) -3- (4-trifluoromethyl-phenylamino) -pentanoic acid amide

An aqueous sulfuric acid solution (8.2L sulfuric acid and 1.1L water premixed and cooled to 35 ℃ or less) was addedTo a crude toluene solution of (3R) -3- (4-trifluoromethyl-phenylamino) -valeronitrile of example 1. The resulting two-layer solution was stirred well and heated at 35 ℃ for 17 hours. The lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95L water and 10.7kg sodium hydroxide) and diisopropyl ether (IPE) (40L). After extraction and removal of the aqueous layer, the organic layers were combined and washed with saturated NaHCO₃Aqueous (10L) extraction. The organic phase in the resulting bilayer was concentrated by distillation to a volume of 19L. The solution was then cooled to room temperature and seeded with (3R) -3- (4-trifluoromethyl-phenylamino) -pentanoic acid amide and allowed to granulate for 3 hours with stirring. Cyclohexane (38L) was added to the heterogeneous mixture and the mixture was granulated for another 11 hours. The solid was filtered off, washed with cyclohexane (4L) and dried under vacuum at 40 ℃ to give 3021g (75%) of the title compound.

¹HNMR(400MHz，CDCl₃)：0.98(t，3，J＝7.5)，1.60-1.76(m，2)，2.45(d，2，J＝5.8)，3.73-3.80(m，1)，5.53(br s，1)，5.63(brs，1)，6.65(d，2，J＝8.7)，7.39(d，2，J＝8.7)

¹³CNMR(100MHz，CDCl₃)：10.74，27.80，40.02，51.95，112.63，118.9(q，J＝32.7)，125.18(q，J＝271.0)，126.93(q，J＝3.8)，150.17，174.26

Example 3

(3R) - [3- (4-trifluoromethyl-phenylamino) -pentanoyl]-carbamic acid methyl ester

A clean, dry, nitrogen-filled 100L glass jar was charged with (3R) -3- (4-trifluoromethyl-phenylamino) -pentanoic acid amide (6094g, 23.42mol), isopropyl ether (30L) and methyl chloroformate (2.7kg, 29 mol). The resulting slurry was cooled to 2 ℃. The reaction vessel was then charged with a lithium tert-butoxide solution (18-20% in THF, 24.6kg, about 58mol) at a rate such that the internal temperature was maintained below 10 deg.C, preferably about 5 deg.C. 10 minutes after the completion of the addition of the base, the reaction was quenched with 1.5M hydrochloric acid (36L). The aqueous layer was removed and the organic layer extracted with saturated NaCl/water solution (10L). The aqueous layer was removed and the organic phase was concentrated by distillation under vacuum and at about 50 ℃ until the volume was reduced to about 24L. Cyclohexane (48L) was added to the kettle and vacuum distilled at an internal temperature of about 45-50 deg.C until the volume of the solution in the kettle was reduced to 24L. A second portion of cyclohexane (48L) was added to the kettle and the still further vacuum distillation at an internal temperature of about 45-50 ℃ was repeated until the volume of the solution in the kettle was reduced to 24L. Seeds of (3R) - [3- (4-trifluoromethyl-phenylamino) -pentanoyl ] -carbamic acid methyl ester were seeded while the temperature was kept at 50 ℃ and stirred for 2 hours to form crystallites. The solution was then slowly cooled (1.5 hours) to room temperature and stirred for 15 hours to granulate. The mixture was filtered. The resulting solid was washed with cyclohexane (10L) and dried under vacuum at 40 deg.C to give 7504g (94%) of the title compound.

m.p.＝142.3-142.4℃

¹HNMR(400MHz，d₆-acetone): 0.96(t, 3, J ═ 7.4), 1.55 to 1.75(m, 2), 2.86(dd, 1, J ═ 6.6, 16.2), 2.96(dd, 1, J ═ 6.2, 16.2), 3.69(s, 3), 3.92 to 3.99(m, 1), 5.49(br d, 1, J ═ 8.7), 6.76(d, 2, J ═ 8.7), 7.37(d, 2, J ═ 8.7), 9.42(br s, 1).

¹³CNMR(100MHz，CDCl₃)：10.62，28.10，40.19，51.45，53.42，112.54，118.98(q，J＝32.70)，125.16(q，J＝270.2)，126.90(q，J＝3.8)，150.10，152.71，173.40。

Example 4

(2R, 4S) - (2-Ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid methyl ester

Charging (3R) - [3- (4-trifluoromethyl-phenylamino) -pentanoyl into a clean, dry, nitrogen-filled 100L glass jar]Methyl carbamate (7474g) followed by 2B ethanol (46L) and water (2.35L). Sodium borohydride (620g) was added to the above solution all at once. The nitrogen was continuously charged. The mixture was stirred at room temperature for 20 minutes, and thenIt was cooled to-10 ℃. 3.3M aqueous magnesium chloride solution (4.68kg MgCl) was added₂·6H₂O dissolved in 7L of water) at a rate such that the internal temperature does not exceed-5 ℃. Once the addition was complete, the reaction solution was warmed to 0 ℃ for 45 minutes. The reaction mixture was transferred to a 200L tank containing dichloromethane (70L) and a 1M hydrochloric acid/citric acid solution (5.8L concentrated hydrochloric acid, 64L water, and 10.5kg citric acid) to quench the reaction. The headspace of the tank was filled with nitrogen. The bilayer was stirred at room temperature for 2 hours. The phases were separated and the lower organic product was transferred. After removal of the aqueous layer, the organic phase was returned to the reaction vessel and extracted with aqueous citric acid (6.3kg citric acid, 34L water). The mixture was stirred for 1 hour and left overnight. Layering and adding Darco to the organic phase^*Activated charcoal (grade G-60, 700G, Atlas powder co., Wilmington, DE) and the solution was stirred for 30 minutes. The mixture was then filtered through Celite * and washed twice with dichloromethane (14L and 8L). The filtrate was distilled while periodically adding hexane to replace methylene chloride with hexane to a final total volume of 70L (total hexane used of 112L). The product crystallized out during the replacement. Once a stable distillation temperature was reached, the solution was cooled and granulated under stirring at room temperature for 10 hours. The solid was filtered off, washed with hexane (14L) and dried under vacuum at 40 ℃ to give the title compound (5291g) (80%).

m.p.＝139.0-140.5℃

¹HNMR(400MHz，d₆-acetone): 1.00(t, 3, J ═ 7.5), 1.51-1.67(m, 3), 2.19(ddd, 1, J ═ 2.9, 5.4, 12.4), 3.44-3.53(m, 1), 3.67(s, 3), 4.89-4.96(m, 1), 5.66(br s, 1), 6.56(br d, 1, J ═ 8.7), 6.65(d, 1, J ═ 8.7), 7.20(d, 1, J ═ 8.7), 7.30(br s, 1).

¹³CNMR(100MHz，CDCl₃)：9.88，29.24，35.47，48.09，52.42，52.60，113.66，118.90(q，J＝33.1)，121.40，124.08(q，J＝3.8)，125.08(q，J＝270.6)，125.70(q，J＝3.8)，147.68，157.30。

Example 5

(2R, 4S) -2-Ethyl-4-methoxycarbonylamino-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

In a clean, dry, nitrogen-filled 100L glass jar was charged (2R, 4S) - (2-ethyl-6-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid methyl ester (5191g, 17.17mol), dichloromethane (21L), and pyridine (4.16L, 51.4 mol). The reaction kettle was cooled to-10 ℃. Ethyl chloroformate (4.10L, 42.9mol) was added slowly at such a rate that the temperature in the kettle did not exceed-5 ℃. The temperature of the reaction solution was brought to 0 ℃ and maintained for 20 hours. The reaction was quenched by the addition of diisopropyl ether (IPE) (36L), dichloromethane (6.2L) and 1.5M hydrochloric acid solution (52L). The reaction layers were separated and the organic layer was extracted with 1M sodium hydroxide solution (15L). The reaction layers were separated and the organic layer was washed with saturated aqueous sodium chloride NaCl (15L). The resulting phases were separated and the organic layer was concentrated by distillation to a volume of 40L. Below this volume, crystallization begins to occur. The dichloromethane was replaced by IPE by distilling the mixture and periodically adding IPE until the volume remained constant at 40L with the temperature maintained at 68 ℃ (46L for IPE). The mixture was cooled and granulated at room temperature with stirring for 19 hours. The solid was filtered, washed with IPE (8L) and dried under vacuum at 40 ℃ to give 5668g of the title compound (88%).

m.p.＝157.3-157.6℃.

¹H(400MHz，d₆-acetone): 0.84(t, 3, J ═ 7.5), 1.26(t, 3, J ═ 7.0), 1.44-1.73(m, 3), 2.59(ddd, 1, J ═ 4.6, 8.3, 12.9), 3.67(s, 3), 4.14-4.28(m, 2), 4.46-4.54(m, 1), 4.66-4.74(m, 1), 6.82(br d, 1, J ═ 9.1), 7.53(s, 1), 7.58(d, 1, J ═ 8.3), 7.69(d, 1, J ═ 8.3).

¹³CNMR(100MHz，CDCl₃)：9.93，14.55，28.46，38.08，46.92，52.64，53.70，62.42，120.83(q，J＝3.4)，124.32(q，J＝271.7)，124.36(q，J＝3.4)，126.38，126.46(q，J＝32.7)，134.68，139.65，154.66，156.85。

Example 6

(2R, 4S) -4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]-2-ethyl-6-

Trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

In a clean, dry, nitrogen-filled 100L glass jar was charged (2R, 4S) -2-ethyl-4-methoxycarbonylamino-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (5175g, 13.82mol), CH at room temperature₂Cl₂(20L) and potassium tert-butoxide (1551g, 13.82 mol). The mixture was stirred for 5 minutes. To the mixture was added 3, 5-bis (trifluoromethyl) benzyl bromide (3.50L, 19.1mol) in one portion. The internal temperature was maintained at 20-25 ℃ for 1.5 hours. After 2.3 hours of reaction, potassium tert-butoxide (46.10g, 0.41mol) was additionally added. The reaction was stopped after a total of 4.5 hours. Adding 1, 4-diazabicyclo [2, 2 ] to the reaction solution]Octane (DABCO) (918g, 8.18mol), and the mixture was stirred for 1 hour. IPE (40L) and 0.5M hydrochloric acid (30L) were added to the reaction mixture. The resulting organic and aqueous phases were separated and the organic layer was extracted with 0.5M hydrochloric acid (2X 30L). The organic and aqueous phases were then separated and the organic phase was extracted with saturated aqueous sodium chloride (15L) and the resulting organic and aqueous phases were separated. Anhydrous magnesium sulfate (3.5kg) was added to the organic layer and the mixture was stirred for 30 minutes. The mixture was then filtered (0.5 micron filter) into a 50L glass jar and washed twice with IPE (8L). The filtrate was concentrated in vacuo at an internal temperature of 35 ℃ to a volume of 12L to give an oil. To the oil was added 2B ethanol (25L) and the solution was concentrated under vacuum to a volume of 12L. 2B ethanol (15L) was added to the solution and concentrated under vacuum to a volume of 12L. The solution was cooled to room temperature and (2R, 4S) -4[ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-was seeded]-2-Ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3g) seed crystals. The solution was granulated for about 38 hours, filtered, and washed with 2B ethanol (4L + 2L). Vacuum drying (Without heating) gave 4610g (55%) of the title compound. The mother liquor from the above filtration (solution temperature 62 ℃ C.) was concentrated in vacuo to a final volume of 6L and cooled to 38 ℃. Seeding (2R, 4S) -4[ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino in solution]-2-Ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.5g) seed crystals, which were cooled and granulated with stirring for 19 hours. The mixture was filtered and the solid was washed with 2B ethanol (2.5L). The resulting filter cake was dried in vacuo (no heating) to give 1422g (17%) of the second crop of the title compound. A combined total of 6032g (73%).

Example 7

(3R) - [3- (4-trifluoromethyl-phenylamino) -pentanoyl]-carbamic acid benzyl ester

In a clean, dry, nitrogen-filled flask was charged (3R) -3- (4-trifluoromethyl-phenylamino) -pentanoic acid amide (20.11g, 77.27mmol) and isopropyl ether (100mL) and the mixture was cooled to-12 ℃. Benzyl chloroformate (13.25mL, 92.8mmol) was then added, followed by 1.0M lithium tert-butoxide in THF (185.5 mL). The lithium tert-butoxide THF solution is added at such a rate that the internal temperature remains below 0 ℃. 15 minutes after the addition of the base, the reaction was quenched by the addition of a mixture of isopropyl ether (100mL) and 1.5M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride (130 mL). The phases were separated again and the organic layer was dried (MgSO₄) Filtered, and concentrated under partial vacuum (40 ℃) to a total volume of 100 mL. An additional isopropyl ether (200mL) was added and the solution was again concentrated under partial vacuum (40 ℃ C.) to a total volume of 100 mL. After cooling, (3R) - [3- (4-trifluoromethyl-phenylamino) -pentanoyl is seeded in solution]Seed crystals of benzyl carbamate and stir it at room temperature overnight. The remaining solvent was replaced by cyclohexane by partial vacuum distillation (bath temperature 45 ℃ C., 200mL followed by 100 mL). The resulting slurry was cooled and stirred for 40 minutes, filtered and dried to yield 25.8714g (85%) of the title compound.

m.p.100.6-101.4℃.

¹HNMR(400MHz d₆-acetone): 0.96(t, 3, J ═ 7.5), 1.57-1.75(m, 2), 2.87(dd, 1, J ═ 6.6, 16.2), 2.97(dd, 1, J ═ 6.2, 16.2), 3.94-4.00(m, 1), 5.16(s, 2), 5.50(br s, 1), 6.75(d, 2, J ═ 5.7), 7.33-7.43(m, 7), 9.52(br s, 1).

¹³CNMR(100MHz CDCl₃)：10.66，28.13，40.28，51.47，68.25，112.52，118.91(q，J＝32.3)，125.21(q，J＝269.9)，126.92(q，J＝3.8)，128.64，128.98，129.04，135.05，150.12，152.12，173.52。

Example 8

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

In a clean, dry nitrogen-filled flask, (3R) - [3- (4-trifluoromethyl-phenylamino) -pentanoyl]Benzyl carbamate (11.51g, 29.18mmol) and 95% ethanol (80mL), and the solution was cooled in an ice/acetone bath (ca. -12 ℃). Sodium borohydride (0.773g, 20.4mmol) was then added to the solution. The internal temperature of the reaction was-11.5 ℃. Slowly adding MgCl into the reaction flask₂·6H₂A solution of O (6.23g, 30.6mmol, dissolved in 13mL of water). The rate of addition was adjusted to maintain the internal temperature below-5 ℃. After all addition, the solution was raised to 0 ℃ and stirred for 30 minutes. The reaction was then quenched by the addition of dichloromethane (115mL), 1N hydrochloric acid (115mL), and citric acid (14.02g, 72.97 mmol). The layered solution was stirred at room temperature. After 3.75 hours, the reaction was analyzed by HPLC to observe that the cyclization reaction was complete and separated. Water (58mL) and citric acid (8.41g, 43.77mmol) were added to the organic layer, and the mixture was stirred at room temperature for 45 min. The phases were separated and g-60 Darco activated charcoal (1.52g) (Atlas Powderco., Wilmington, DE) was added to the organic layer. After stirring for 45 minutes, the solution was filtered through Celite and washed with dichloromethane (2X 15 mL). Then concentrated by distillation at atmospheric pressure, and the filtrate was replaced with hexane (about 350mL) to totalThe volume was 230 mL. The mixture was stirred at room temperature for 14 h, filtered and dried to yield 9.0872g (82%) of the title compound.

m.p.154.0-155.2℃

¹HNMR(400MHz，d₆-acetone): 1.00(t, 3, J ═ 7.5), 1.51-1.69(m, 3), 2.17-2.26(m, 1), 3.46-3.54(m, 1), 4.96(ddd, 1, J ═ 5.4, 9.5, 11.6), 5.14(d, 1, J ═ 12.9), 5.20(d, 1, J ═ 12.9), 5.66(br s, 1), 6.65(d, 1, J ═ 8.3), 6.71(br d, 1, J ═ 9.1), 7.20(dd, 1, J ═ 1.9, 8.9), 7.30-7.43(m, 6).

¹³CNMR(100MHz，CDCl₃)：9.89，29.24，35.34，48.16，52.44，67.27，113.70，118.85(q，J＝32.7)，121.37，124.12(q，J＝3.8)，125.14(q，J＝270.6)，125.72(q，J＝3.8)，128.38，128.51，128.86，136.57，147.71，156.74。

Example 9

(R) -3-Aminovaleronitrile methanesulfonate

Step 1: methanesulfonic acid 2-tert-butoxycarbonylamino-butyl ester

Batch #1: a solution of BOC anhydride (515.9g) in ethyl acetate (400mL) was added through an addition funnel to a solution of R- (-) -2-amino-1-butanol (200.66g) in ethyl acetate (1105 mL). The reaction mixture was stirred for about 30 minutes. Tetramethylethylenediamine (TMEDA) (360mL) was added and the reaction mixture was cooled to about 10 ℃. Methanesulfonyl chloride (184.7mL) was added to the reaction mixture over 30 minutes. After stirring for 1 hour, the reaction mixture was filtered and the filtrate was collected.

Batch # 2:a solution of BOC anhydride (514.5g) in ethyl acetate (400mL) was added via an addition funnel to a solution of R- (-) -2-amino-1-butanol (200.12g) in ethyl acetate (1101 mL). The reaction mixture is stirredFor 30 minutes. Tetramethylethylenediamine (TMEDA) (359.1mL) was added and the reaction mixture was cooled to about 10 ℃. Methanesulfonyl chloride (184.1mL) was added to the reaction mixture over 30 minutes. After stirring for 1 hour, the reaction mixture was combined with the filtrate of batch #1 and filtered. The solid was washed with 400mL ethyl acetate. Hexane (12L) was added to the filtrate. The mixture was cooled in an ice/water bath. After about 2.5 hours the solid was isolated by filtration, washed with hexane (2L) and dried under vacuum to give the title compound (971.57 g).

Step 2: (1-Cyanomethyl-propyl) -carbamic acid tert-butyl ester

Sodium cyanide (24.05g) was added to Dimethylformamide (DMF) (500L) and the mixture was stirred at 35 ℃ for 30 minutes. Tetrabutylammonium bromide was added and the reaction mixture was stirred at 35 ℃ for 2 hours. 2-tert-Butoxycarbonylamino-butyl methanesulfonate (101.23g) was added and the reaction mixture was stirred at 35 ℃ overnight. The mixture was then partitioned between 2 liters of water and 1 liter of isopropyl ether. All the organic and aqueous phases were separated and washed successively with water and with saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a solid (65.22 g). The solid (61.6g) was transferred to a flask equipped with a stirrer at the top. Hexane was added and the flask was heated to 65 ℃. After all solids were dissolved, the mixture was cooled to ambient temperature. The mixture was stirred overnight. The resulting solid was isolated by filtration to give the title compound (52.32 g).

And step 3: (R) -3-Aminovaleronitrile methanesulfonate

To a solution of (1-cyanomethyl-propyl) -carbamic acid tert-butyl ester in tetrahydrofuran (530mL) was added methanesulfonic acid (71 g). The reaction mixture was heated at 40 ℃ for about 30 minutes. The temperature was raised to 45 ℃ and stirred for about 1 hour. The temperature was then raised to 65 ℃ and the reaction mixture was stirred for about 5 hours. The mixture was allowed to cool to ambient temperature. The resulting solid was isolated by filtration to give the title compound (41.53 g).

Claims (8)

1. A compound of formula III

2. A compound of formula IV

3. A process for the preparation of a compound of formula III,

comprises coupling trifluoromethyl benzene with para-position substituted by halogen or O-trifluoromethyl sulfonate and a compound of a formula II in the presence of a metal catalyst,

to produce the compound shown in the formula III.

4. The process of claim 3, wherein the trifluoromethylbenzene compound is coupled with the compound of formula II in the presence of a phosphine ligand.

5. The process of claim 4 wherein the phosphine ligand is a dialkylphosphinobenzene ligand.

6. The process of claim 5, wherein the phosphine ligand is selected from the group consisting of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl and 2-dicyclohexylphosphino-2' -methylbiphenyl.

7. The method of claim 3, wherein said coupling comprises coupling said trifluoromethylbenzene compound with a compound of formula II in the presence of a base.

8. A process for the preparation of a compound of formula IV,

comprising hydrolyzing a compound of formula III with a hydrolyzing agent,

the hydrolyzing agent is selected from the group consisting of an acid and a base, thereby producing the compound of formula IV.