Intermediate compounds for cetp inhibitors and methods for their preparing

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds used as intermediates substances for inhibitors of transfer of cholesteryl ester protein (CETP) and methods for their preparing. Indicated compounds are represented by the following formulae:

, ,

wherein R is taken among methyl and benzyl and by the formula

wherein R represents methyl.

EFFECT: improved preparing method, valuable biochemical properties of inhibitors.

15 cl, 9 ex

 

The SCOPE of the INVENTION

The present invention relates to compounds that are used as intermediate compounds for inhibitors of protein transfer cholesterolemia ether (SETR), and methods for their preparation.

RATIONALE INVENTIONS

Atherosclerosis and associated coronary disease (coronary) artery (CAD) is the leading cause of death in the industrial society. Despite attempts to reduce secondary risk factors (Smoking, obesity, lack of exercise) and treatment of dyslipidemia by dietary modification and drug therapy, coronary (ischemic) heart disease (CHD) remains the most common cause of death in the United States.

It is shown that the risk of developing this disease clearly correlated with certain levels of lipids in plasma. Although elevated concentrations of low-density lipoproteins are the most recognized form of dyslipidemia, it is by no means the only significant associated with lipid factor of IHD. Low concentration of high density lipoprotein 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 levels of LDL-cholesterol and triglycerides are positively correlated, and high levels of HDL-cholesterol negatively correlated with the risk of developed what I cardiovascular disease. Thus, dyslipidemia does not define consistently the risk of developing CHD, and may include one or more abnormalities associated with lipids.

Among the many factors that regulate the levels of these dependent sources of this disease in the plasma, the activity of the protein transfer cholesterolemia ether (CETP) affects all three components. For a number of species of animals, including humans, it was found that the role of this glycoprotein in plasma 70000 daltons consists of transferring cholesterolemia ester and triglyceride between lipoprotein particles, including high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoproteins (VLDL) and chylomicrons. The end result of CETP activity is reduced HDL cholesterol and increased LDL-cholesterol. It is believed that this effect on the lipoprotein profile is proatherogenic, particularly in patients whose lipid profile is an increased risk of IHD.

There is not a fully satisfactory HDL-raising therapy. Niacin can significantly increase HDL, but is associated with serious problems of tolerance, leading to poor adherence and treatment. Fibrates and inhibitors of HMG-CoA-reductase only moderately increase HDL-C. as a result, there is a largely unmet needs of the medicine well in the portable medium, which can significantly increase the levels of HDL in the plasma, thereby reversing or slowing the progression of atherosclerosis.

Patent PCT application number WO 00/02887 describes the use of catalysts, including some new ligands of transition metals, in education linkages catalyzed by transition metal carbon-heteroatom and carbon-carbon.

Public U.S. patent No. 6140343, the disclosure of which is incorporated herein by reference, describes, among other things, a CETP inhibitor, namely complex isopropyl ether CIS-4-[acetyl - (3,5-bistrifluormethylbenzene)amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, and the means of obtaining it (for example, the method disclosed in example 46).

Public U.S. patent No. 6197786, the disclosure of which is incorporated herein by reference, describes, among other things, the CETP inhibitor is a complex ethyl ester of CIS-4-[(3,5-bistrifluormethylbenzene)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, and the means of obtaining it (for example, the method disclosed in example 7).

BRIEF description of the INVENTION

One aspect of the present invention is a compound of formula III,

A further aspect of the present invention is a compound of formula IV,

Another aspect of altoadige of the invention are the compounds of formula VI,

where R is selected from methyl, benzyl and substituted benzyl.

Another aspect of the present invention are the compounds of formula VII

where R is selected from methyl, benzyl and substituted benzyl.

In a preferred variant of developing type compounds of the present invention, R in the compounds of formula VI and compounds of formula VII are selected from the group comprising: methyl, benzyl and benzyl substituted by one or more substituents, each of which is independently selected from (C1-C3)-alkyl, (C1-C3)-alkyloxy and halogen.

In yet another embodiment, the specified compound of formula III is produced by the method comprising the combination of triptoreline, para-substituted with halogen or O-triflate, with a compound of formula II,

resulting in the formation of compounds of formula III.

In a preferred variant of the method of the present invention, for obtaining the compounds of formula III, the specified combination of the compounds of cryptomelane with the specified compound of formula II is carried out in the presence of a transition metal, preferably palladium.

In yet another preferred embodiment of the method of the present invention, kasagsagan is obtaining the compounds of formula III, the specified combination of the compounds of cryptomelane with the specified compound of formula II is carried out in the presence of a phosphine ligand, preferably dialkylphosphinate ligand, more preferably selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl and 2-dicyclohexylphosphino-2'-methylbiphenyl.

According to another preferred variant of the method of the present invention, for obtaining the compounds of formula III, the specified combination of the compounds of cryptomelane with the specified compound of formula II is carried out in the presence of a base, preferably cesium carbonate.

Another aspect of the present invention are methods of obtaining the above-mentioned compounds of formula IV, comprising the hydrolysis of the above compounds of formula III gidrolizuut agent selected from acids and bases, preferably of acid, more preferably sulfuric acid and water, which leads to the formation of compounds of formula IV.

Another aspect of the present invention are methods of obtaining the above-mentioned compounds of formula VI, including the accession of the above compounds of formula IV to the compound of formula V,

where R is selected from methyl, benzyl and substituted benzyl in the presence of bases of the tion, preferably tert-butyl lithium, to form compounds of formula VI.

An additional aspect of the present invention are methods of obtaining the above-mentioned compounds of the formula VII, which includes the restoration of the above mentioned compounds of formula VI, where R is chosen from methyl, benzyl and substituted benzyl, regenerating agent, preferably sodium borohydride, in the presence of a Lewis acid, preferably calcium ions or magnesium ions, which leads to a restored Union, and the cyclization of the recovered compounds in acidic conditions to form compounds of formula VII.

The term "substituted benzyl" as applied to the compounds of formulas V, VI and VII means benzyl, which is substituted on the benzene ring by one or more substituents so that such substitution does not prevent: (a) the interaction of the corresponding compounds of formula V with the compound of the formula IV, leading to the formation of the corresponding compounds of formula VI, (b) recovery and cyclization of the corresponding compounds of formula VI with the formation of the corresponding compounds of formula VIIB, (c) acetylation of compounds of formula VIIB, resulting in the formation of compounds of formula VIIIB, or (d) the stage of removing the protection to remove the corresponding substituted benzyloxycarbonyl group when the connection form is s IB of the compounds of formula VIIIB. Preferred substituents are (C1-C3)-alkyl and (C1-C3)-alkoxy and halogen-free.

Chemical structure presented here flat diagrams of chemical structures representing the views at the top of the plane structures. Present in such chemical structures of the V-linemeans of communication, the protruding upward above the plane of the structure.

DETAILED description of the INVENTION

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

SCHEME A

SCHEMA

According to scheme B, the compound of formula III is obtained by attaching chiral isomeric compounds of formula II ((R)-3-aminophthalonitrile) to triptoreline, which is para-substituted with halogen or O-triflate (-O-S(O)2CF3), in the presence of a metal catalyst, preferably Pd. For optimum joining of the reaction mix is carried out in the presence of ligand, preferably a phosphine ligand and base. Preferred phosphine ligand is dialkylphosphinate hand, preferably selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl and 2-dicyclohexylphosphino-2'-methylbiphenyl. The interaction is preferably carried out at a temperature of about 60-110°C. Chiral isomer of formula II can be obtained from (R)-2-amino-1-butanol (CAS# 005856-63-3) by methods known to the person skilled in the art, according to the scheme A and as described in example 9 experimental methods.

The compound of formula IV is obtained by hydrolysis of the nitrile compounds of formula III. The hydrolysis can be carried out in acidic or basic conditions. The preferred method of hydrolysis in acidic conditions, mainly with the use of sulfuric acid and water. For hydrolysis using a base preferred bases are hydroxychromone, preferably lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkoxysilane, preferably methylate and ethylate. Also for the hydrolysis with bases, it is preferable to use peroxide. The hydrolysis reaction is preferably carried out at a temperature of about 20-40°C.

The compound of formula VI is produced by interaction of the amide compounds of the formula IV with chloroformiate formula V in the presence of a base, preferably tert-butyl lithium. The interaction is preferably carried out at a temperature of about 0-35°C. If required, the button compound of formula VI contain as R is methyl, as the compounds of formula V using methylchloroform. If you want the compound of formula VI contain as R is benzyl, then use benzylchloride.

Compound of formula VII is obtained by interaction of imida the compounds of formula VI with a reducing agent, preferably sodium borohydride, in the presence of activator-Lewis acid, preferably calcium ions or magnesium, which gives the recovered intermediate connection. The interaction leading to the recovered intermediate compounds is preferably carried out at a temperature of about-20-20°C. In the acid conditions of the intermediate connection diastereoselective cichlisuite education tetrahydroquinoline cycle formula VII. Stage cyclization is preferably carried out at about 20-50°C.

The CETP inhibitor of formula IA is obtained by acylation of compounds of formula VII, where R is methyl, nitrogen tetrahydroquinoline using ethylchloride, in the presence of a base, preferably pyridine, which leads to the formation of compounds of formula VIIIA. The interaction is preferably carried out at a temperature of about 0-25°C.

The CETP inhibitor of formula IA is obtained by alkylation of compounds of formula VIII, where R is methyl, using 3,5-bis(trifluoromethyl)benzylchloride, preferably 3,5-bis(Tr is permitil)benzylbromide, in the presence of a base, preferably alkoxide or hydroxide, and more preferably of potassium tert-butylate. The preferred temperature range for communication is approximately 25-75°C.

The CETP inhibitor of formula IB is obtained by acylation of compounds VII, where R is benzyl or substituted benzyl in nitrogen tetrahydroquinoline using isopropylcarbamate in the presence of a base, preferably pyridine, which leads to the formation of compounds of formula VIIIB. The preferred temperature for the specified interaction is about 0-25°C.

The CETP inhibitor of formula IB can then be obtained from the compounds of formula VIIIB original by treating compound VIIIB excess hydrogen source (for example, cyclohexene, hydrogen gas or ammonium formate in the presence of a suitable catalyst in a polar solvent (e.g. ethanol) to remove benzyloxycarbonyloxy group. Can then be entered 3,5-bistrifluormethylbenzene group of compounds of formula IB by treatment of amine and acid, such as acetic acid, 3,5-bistrifluormethylbenzene with the subsequent processing of the source of hydrogen, such as triacetoxyborohydride. Then the amino group will acetimidoyl ways known to the person skilled in the art, receiving the compound of formula IB. The technique is perceived by the Oia, the compounds of formula IB of the compounds of formula VIIIB is additionally described in example 46 Public U.S. patent No. 6140343. Description of U.S. patent No. 6140343 mentioned here for details.

EXPERIMENTAL METHODS

The melting temperature is defined on the device Buchi to determine the melting temperature. An NMR spectrum is recorded by a Varian Unity 400 (Varian Co., Palo Alto, CA). Chemical shifts are expressed in ppm offset in the lower region of the solvent. Forms peaks have the following legend: s = singlet; d = doublet; t = triplet; q = Quartet; m = multiplet; USS = broadened singlet.

Example 1

(3R)-3-(4-triptoreline)pentenenitrile

In a glass tank 100 l, blow clean dry gaseous nitrogen load (R)-3-aminopentanedioic salt methanesulfonic acid (3000 g, 15,44 mol), sodium carbonate (2.8 kg of 26.4 mol) and methylene chloride (21 l). A heterogeneous mixture is well stirred for at least 2 hours. The mixture is filtered and the filter washed with methylene chloride (3.2 liters). The obtained filtrate is placed in a glass reaction tank 50 l, blow clean dry nitrogen gas. The methylene chloride is removed by distillation until then, until the internal temperature reaches 50-53°C, which gives the amine in the form of free base in the form of liquid oil. Then the tank is cooled to room temperature and load it with toluene (20 l), chloro-4-(trifluoromethyl)benzene (4200 g, 23,26 mol) and cesium carbonate (7500 g, 23,02 mo is b). Through the solution bubbled nitrogen gas for 1 hour. Closer to the time of completion of ozonation prepare a fresh solution of catalyst loading in a round bottom flask 2 l equipped with a stirrer in the form of a rod and filled with gaseous nitrogen, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl (68 g of 0.17 mol), phenylboronic acid (28 g, 0,23 g) and tetrahydrofuran (1.2 l), followed by the addition of palladium acetate (26 g, 0.12 mol). The catalyst solution was stirred at room temperature under nitrogen atmosphere for 15 minutes. The solution of catalyst added to the reaction tank 50 l, using a cannula (avoiding contact with air). The mixture is heated until the internal temperature 79°C in nitrogen atmosphere for 16 hours. The reaction solution is cooled to room temperature and filtered through Celite®. Solids washed with toluene (3×2 l) and collect the filtrate. All the filtrates are combined to give crude solution specified in the connection header.

1H-NMR (400 MHz, d6-DMSO): to 0.89 (t, 3, J=7,5), to 1.59 (m, 2), 2,64 (DD, 1, J=5,8, 17,0), is 2.74 (DD, 1, J=5,4, 17,0),3,66 (m, 1), 6,46, (d, 1, J=8,3), 6,72 (d, 2, J=8,7), 7,35 (d, 2, 0=8,7).

13C-NMR (100 MHz, d6-DHS): 10,96, 22,73, 27,32, 50,50, 112,34, 116,26 (kV, J=31,94), 119,51, 125,96 (kV, J=269,85), 127,03, 151,41.

Example 2

Amide (3R)-3-(4-triptoreline)pentanol acid

Aqueous sulfuric acid (8.2 liters of sulfuric acid and 1.1 l of water, pre-mixed and cooled to 35°or lower) is added to the crude toluene solution of (3R)-3-(4-triptoreline)pentenenitrile of example 1. The resulting double layer well mixed and heated to 35°C for 17 hours. The lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95 liters of water and 10.7 kg of sodium hydroxide) and diisopropyl ether (IPE) (40 l). After extraction and removal of the aqueous layer organic layer are combined and extracted with saturated aqueous NaHCO3(10 l). The organic phase obtained double layer concentrated by distillation to a volume of 19 liters Then the solution is cooled to room temperature, contribute diluted amide (3R)-3-(4-triptoreline)pentanol acid and left to granulomatosa for 3 hours under stirring. To a heterogeneous mixture cyclohexane (38 l) and the mixture granularit for 11 hours. Solids filtered, washed with cyclohexane (4 l), dried in vacuum at 40°C, getting 3021 g (75%) specified in the connection header.

1H-NMR (400 MHz, CDCl3): and 0.98 (t, 3, J=7,5), 1,60 to 1.76 (m, 2), a 2.45 (d, 2, J=5,8), to 3.73-of 3.80 (m, 1), of 5.53 (USS, 1), 5,63 (USS, 1), 6,65, (d, 2, J=8,7), 7,39 (d, 2, J=8,7).

13C-NMR (100 MHz, CDCl3): 10,74, 27,80, 40,02, 51,95, 112,63, 118,9 (kV, J=32,7), 125,18 (kV, J=271,0), 126,93 (kV, J=3,8), 150,17, 174,26.

Example 3

Methyl ester (3R)-[3-(4-triptoreline)pentano the l]carbamino acid

In a glass tank 100 l, blow clean dry gaseous nitrogen load amide (3R)-3-(4-triptoreline)pentanol acid (6094 g, 23,42 mol), isopropyl ether (30 l) and methylchloroform (2.7 kg, 29 mol). The resulting suspension is cooled to 2°C. In reaction tank and then download a solution of tert-butyl lithium (18-20% in THF, 24,6 kg, ˜58 mol) at such a rate to maintain the internal temperature below 10°C, and preferably at a temperature of about 5°C. ten minutes after complete addition of the base the reaction is quenched by addition of 1.5 M hydrochloric acid (36 l). The aqueous layer was removed and the organic phase is extracted with a saturated solution of NaCl/water (10 l). The aqueous layer was removed and the organic phase is concentrated by distillation in vacuum at a temperature of about 50°C up until volume is reduced to approximately 24 liter reaction vessel add cyclohexane (48 l) and repeat the distillation at an internal temperature of about 45-50°C, in vacuum until the volume of solution in the vessel is reduced to 24 liter reaction vessel add the second portion of the cyclohexane (48 l) and the distillation repeated again when the internal temperature of the order of 45-50°C under vacuum until the volume of solution in the vessel is reduced to 24 liters Maintaining the temperature at 50°C, in solution contribute as a seed methyl ester (3R)-[3-4-triptoreline)pentanoyl]carbamino acid and left to granulomatosa under stirring for 2 hours. Then the solution is cooled slowly (over 1.5 hours) to room temperature and left to granulomatosa under stirring for 15 hours. The mixture is filtered. The obtained solids washed with cyclohexane (10 l) and dried in vacuum at 40°C, receiving 7504 g specified in the connection header (94%).

TPL=142,3-142,4°C.

1H-NMR (400 MHz, d6-acetone)as 0.96 (t, 3, J=7,4), 1,55-1,75 (m, 2), of 2.86 (DD, 1, J=6,6, 16,2), 2,96 (DD, 1, J=6,2, 16,2), of 3.69 (s, 3), 3,92-to 3.99 (m, 1), 5,49 (USD, 1, J=8,7), 6,76 (d, 2, J=8,7), 7,37 (d, 2, J=8,7), 9,42 (USS, 1).

13C-NMR (100 MHz, CDCl3): 10,62, 28,10, 40,19, 51,45, 53,42, 112,54, 118,98 (kV, J=32,70), 125,16 (kV, J=270,2), 126,90 (kV, J=3,8), 150,10, 152,71, 173,40.

Example 4

Methyl ester (2R,4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamino acid

In a glass tank 100 l, blow clean dry gaseous nitrogen load methyl ester (3R)-[3-(4-triptoreline)pentanoyl]carbamino acid (7474 g) followed by the addition of ethanol 2B (46 l) and water (2,35 l). To the solution was added in one portion borohydride sodium (620 g). The nitrogen purge retain. The mixture is stirred at room temperature for 20 minutes and then cooled to -10°C. 3,3 M aqueous solution of magnesium chloride (4,68 kg MgCl2·6H2O 7 l of water) are added at such a rate that the internal temperature does not exceed -5°C. Immediately after the addition of reactio the hydrated solution was heated to 0° C for 45 minutes. The reaction is quenched by transferring the reaction mixture into the tank 200 l containing methylene chloride (70 l)and 1 M solution of hydrochloric acid/citric acid (5,8 l of concentrated hydrochloric acid, 64 l of water and 10.5 kg of citric acid). The space in the upper part of the tank purge nitrogen gas. Double layer stirred at room temperature for two hours. The phases are separated and removes bottom organic layer with the product. After removing the aqueous layer, the organic phase is returned to the reaction vessel and extracted with aqueous citric acid solution (6.3 kg citric acid, 34 liter of water). The mixture is stirred for 1 hour and left to stand over night. The layers are separated and the organic phase add activated carbon Darco® (marking G-60, 700 g) (Atlas Powder Co., Wilmington, DE) and the solution stirred for 30 minutes. The mixture is then filtered through Celite® and the coal is washed twice with methylene chloride (14 l and 8 l). The filtrate is distilled, periodically adding hexane to replace methylene chloride hexane to a total final volume of 70 l (only used 112 l hexane). During replacement, the product crystallizes. Immediately after reaching a stable temperature distillation, the solution is cooled and granularit under stirring at room temperature for 10 hours. Solids filtered, washing the Ute hexane (14 l) and dried at 40° C in vacuum, obtaining specified in the header connection (5291 g). (80%).

TPL=139,0-to 140.5°C.

1H-NMR (400 MHz, d6-acetone): 1,00 (t, 3, J=7,5)and 1.51-1,67 (m, 3), 2,19 (DDD, 1, J=2,9, 5,4, 12,4), 3,44-3,53 (m, 1), to 3.67 (s, 3), 4,89-4,96 (m, 1), 5,66 (USS, 1), 6,56 (USD, 1, J=8,7), of 6.65 (d, 1, J=8,7), 7,20 (d, 1, J=8,7), 7,30 (USS, 1).

13C-NMR (100 MHz, CDCl3): 9,88, 29,24, 35,47, 48,09, 52,42, 52,60, 113,66, 118,90 (kV, J=33,1), 121,40, 124,08 (kV, J=3,8), 125,08 (kV, J=270,6), 125,70 (kV, J=3,8), 147,68, 157,30.

Example 5

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

In a glass tank 100 l, blow clean dry gaseous nitrogen load methyl ester (2R,4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamino acid (5191 g, 17,17 mol), methylene chloride (21 l) and pyridine (4,16 l, 51,4 mol). The reaction vessel is cooled to -10°C. Slowly add ethylchloride (4,10 l, 42,9 mol) at such a rate that the internal temperature does not exceed -5°C. the Reaction solution is brought to a temperature 0°C and incubated for 20 hours. The reaction is quenched by adding to a mixture of diisopropyl ether (IPE) (36 l), methylene chloride (6.2 l) and 1.5 M hydrochloric acid (52 l). The resulting phases are separated and the organic layer extracted with 1 M sodium hydroxide solution (15 l). The resulting phases are separated and the organic layer was washed with saturated aqueous NaCl (1 l). The formed phases are separated and the organic layer is concentrated by distillation to a volume of 40 L. the smaller crystallization starts. Methylene chloride replaces IPE, turning the mixture and periodically adding IPE to maintain a constant volume of 40 l, while maintaining the temperature 68°C (only used 46 l IPE). The mixture is cooled and left to granulomatosa under stirring at room temperature for 19 hours. Solids filtered, washed with IPE (8 l) and dried in vacuum at 40°C, getting 5668 g specified in the connection header (88%).

TPL= 157,3-157,6°C.

1H-NMR (400 MHz, d6-acetone): 0,84 (t, 3, J=7,5), of 1.26 (t, 3, J=7,0), 1,44-of 1.73 (m, 3), at 2.59 (DDD, 1, J=4,6, 8,3, 12,9), 3,67 (C, 3), 4,14-to 4.28 (m, 2), 4,46-of 4.54 (m, 1), 4,66-4,74 (m, 1), 6,82 (USD, 1, J=9,1), 7,53 (s, 1), 7,58 (d, 1, J=8,3), of 7.69 (d, 1, J=8,3).

13C-NMR (100 MHz, CDCl3): 9,93, 14,55, 28,46, 38,08, 46,92, 52,64, 53,70, 62,42, 120,83 (kV, J=3,4), 124,32 (kV, J=271,7), 124,36 (kV, J=3,4), 126,38, 126,46 (kV, J=32,7), 134,68, 139,65, 154,66, 156,85.

Example 6

Complex ethyl ester (2R,4S)-4-[(3,5-bistrifluormethylbenzene)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid

In a glass tank 100 l, blow clean dry gaseous nitrogen load complex ethyl ester (2R,4S)-2-ethyl-4-methoxycarbonylamino-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (5175 g, 13,82 mol), CH2Cl2(20 l) and tert-butyl potassium (1551, 13,82 supposedly is) at room temperature. The mixture is stirred for five minutes. To the mixture in one portion of 3,5-bis(trifluoromethyl)benzylbromide (3,50 l, 19,1 mol). The internal temperature of the support between 20-25°C for 1.5 hours. After a reaction time of 2.3 hours add an additional portion of potassium tert-butylate (46,10 g, 0.41 mol). After a total reaction time of 4.5 hours the reaction is quenched. To the reaction solution was added 1,4-diazabicyclo[2.2.2]octane (DABCO) (918 g, 8,18 mol) and the mixture is stirred for 1 hour. To the reaction mixture are added IPE (40 l) and 0.5 M hydrochloric acid (30 l). The resulting organic and aqueous phases are separated and the organic layer extracted with 0.5 M hydrochloric acid (2,30 l). The resulting organic and aqueous phases are then separated and the organic layer extracted with saturated aqueous sodium chloride (15 l) and the resulting organic and aqueous phases are separated. To the organic layer added anhydrous magnesium sulfate (3.5 kg) and the mixture is stirred for 30 minutes. The mixture is then filtered (filter 0.5 micron) in a glass tank of 50 litres, using washing with two portions of IPE (8 l). The filtrate was concentrated in vacuo to a total volume of 12 l when the internal temperature of 35°C, receiving the oil. To the oil add ethanol 2B (25 l) and the solution was concentrated in vacuo to a volume of 12 liters of the solution add ethanol 2B (15 l) and the solution again concentrated in vacuo to about the of Yama 12 L. The solution is cooled to room temperature and bring in the diluted complex ethyl ester (2R,4S)-4-[(3,5-bistrifluormethylbenzene)-methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (3 g). The solution granularit about 38 hours, filtered and washed with ethanol 2B (4 l + 2 l). Solids are dried in vacuo (without heating), getting 4610 g (55%) specified in the connection header. The mother liquor from the above filtration was concentrated in vacuo (temperature of the solution = 62° (C) to a final volume of 6 l and cooled to 38°C. contribute To the solution diluted complex ethyl ester (2R,4S)-4-[(3,5-bistrifluormethylbenzene)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0.5 g) and left to cool and granulomatosa with stirring for 19 hours. The mixture is filtered and the solids washed with EtOH 2B (2.5 liters). The obtained dense precipitate on the filter is dried in vacuo (without heating), receiving the second portion, 1422 g (17%)specified in the connection header. The total yield is 6032 g (73%).

Example 7

Complex benzyl ester of (3R)-[3-(4-triptoreline)pentanoyl]carbamino acid

In the flask, purged clean dry gaseous nitrogen load amide (3R)-3-(4-triptoreline)pentanol acid (20,11 g, 77,27 mmol) and isopropyl ether (100 ml) and the mixture is cooled to -12&x000B0; C. Then add benzylchloride (13,25 ml of 92.8 mmol) followed by slow addition of 1.0 M solution of tert-butyl lithium in THF (185,5 ml). A solution of tert-butyl lithium add such a rate that the internal temperature remains below 0°C. fifteen minutes after the addition of base to the reaction quenched by adding a mixture of isopropyl ether (100 ml) and 1.5 M hydrochloric acid (130 ml). The phases are separated and the organic layer was washed with saturated aqueous sodium chloride (130 ml). The phases are separated and the organic layer is dried (MgSO4), filtered and concentrated under partial vacuum at 40° (C) to a total volume of 100 ml are Added isopropyl ether (200 ml) and the solution again concentrated under partial vacuum at 40° (C) to a total volume of 100 ml After cooling the solution contribute diluted complex benzyl ester of (3R)-[3-(4-triptoreline)pentanoyl]carbamino acid and allowed to mix at room temperature over night. The remaining solvent is substituted cyclohexane, using distilled under partial vacuum (bath 45°C, 200 ml and then 100 ml), the resulting suspension is cooled and stirred for 40 minutes, filtered and dried, obtaining 25,8714 g (85%) specified in the connection header.

TPL 100,6-101,4°C.

1H-NMR (400 MHz, d6/sub> -acetone)as 0.96 (t, 3, J=7,5), 1,57 is 1.75 (m, 2), 2,87 (DD, 1, J=6,6, 16,2), of 2.97 (DD, 1, J=6,2, 16,2), 3,94-4,00 (m, 1), 5,16 (s, 2), 5,50 (USS, 1), to 6.75 (d, 2, J=5,7), 7,33-the 7.43 (m, 7), 9,52 (USS, 1).

13C-NMR (100 MHz, CDCl3): 10,66, 28,13, 40,28, 51,47, 68,25, 112,52, 118,91 (kV, J=32,3), 125,21 (kV, J=269,9), 126,92 (kV, J=3,8), 128,64, 128,98, 129,04, 135,05, 150,12, 152,12, 173,52.

Example 8

Complex benzyl ether of (2R,4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamino acid

In the flask, purged clean dry gaseous nitrogen load complex benzyl ester of (3R)-[3-(4-triptoreline)pentanoyl]carbamino acid (11,51 g, 29,18 mmol) and 95% ethanol (80 ml) and the solution cooled in an ice bath/acetone (˜ -12°C). Then to the solution was added borohydride sodium (0,773 g of 20.4 mmol). The internal temperature of the reaction mixture equal -11,5°C. the reaction flask slowly add a solution of MgCl2·6H20 (6,23 g of 30.6 mmol, 13 ml of N2O). The internal temperature of the support below -5°C, by adjusting the speed of addition. Once the entire solution of magnesium was added, the temperature of the solution was raised to 0°C and the solution stirred for 30 minutes. Then the reaction quenched by the addition of methylene chloride (115 ml), 1 N. hydrochloric acid (115 ml) and citric acid (14,02 g, 72,97 mmol). The resulting double layer stirred at room temperature. After 3.75 hours, the cyclization reaction is completed according to GHUR analysis and f the s share. To the organic layer, add water (58 ml) and citric acid (to 8.41 g, 43,77 mmol) and the mixture is stirred at room temperature for 45 minutes. The phases are separated and the organic layer add activated charcoal g-60 Darco® (1.52 g) (Atlas Powder Co., Wilmington, DE). After stirring for 45 minutes the solution is filtered through Celite® and washed with methylene chloride (2,15 ml). Then the solvent in the filtrate replace hexane (approximately 350 ml) by distillation at atmospheric pressure and concentration of the mixture to a total volume of 230 ml, the Mixture is stirred at room temperature for 14 hours, filtered and dried, obtaining 9,0872 g (82%) specified in the connection header.

TPL 154,0-155, 2mm°C.

1H-NMR (400 MHz, d6-acetone): 1,00 (t, 3, J=7,5)and 1.51-1.69 in (m, 3), 2,17-of 2.26 (m, 1), of 3.46-of 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 (USS, 1), of 6.65 (d, 1, J=8,3), of 6.71 (USD, 1, J=9,1), 7,20 (DD, 1, J=1,9, 8,9), 7,30-7,43 (m, 6).

13C-NMR (100 MHz, CDCl3): 9,89, 29,24, 35,34, 48,16, 52,44, 67,27, 113,70, 118,85 (kV, J=32,7), 121,37, 124,12 (kV, J=3,8), 125,14 (kV, J=270,6), 125,72 (kV, J=3,8), 128,38, 128,51, 128,86, 136,57, 147,71, 156,74.

Example 9

(R)-3-aminopentanedioic salt methanesulfonic acid

Stage 1: a complex 2-tert-butoxycarbonylamino ether methanesulfonate acid.

Step #1: BOC anhydride (515,9 g) in ethyl acetate (400 ml) was added to a solution of R-(-)-2-amino-1-butanol (200,66 g) in ethyl acetate (1105 ml) using ka is part of the funnel. The reaction mixture is stirred for approximately 30 minutes. Add tetramethylethylenediamine (TMEDA) (360 ml) and the reaction mixture is cooled to approximately 10°C. To the reaction mixture over a 30 minute period methanesulfonanilide (184,7 ml). After stirring for 1 hour the reaction mixture is filtered and the filtrate is collected.

Step #2:BOC anhydride (514,5 g) in ethyl acetate (400 ml) was added to a solution of R-(-)-2-amino-1-butanol (200,12 g) in ethyl acetate (1101 ml) via a dropping funnel. The reaction mixture is stirred for approximately 30 minutes. Add tetramethylethylenediamine (TMEDA) (359,1 ml) and the reaction mixture is cooled to approximately 10°C. To the reaction mixture over a 30 minute period methanesulfonanilide (184,1 ml). After stirring for 1 hour the reaction mixture is combined with the filtrate in step # 1 and filtered. Solids washed with 400 ml of ethyl acetate. To the filtrate add hexane (12 l). The mixture is cooled in a bath of ice/water. After approximately 2.5 hours of solid products are separated by filtration, washed with hexane (2 l) and dried in vacuum, obtaining specified in the header connection (971,57 g).

Stage 2: complex tert-butyl methyl ether (1-cyanomethylene)carbamino acid.Sodium cyanide (24,05 g) are added to a dimethylformamide (DMF) (500 l) and the mixture was stirred at 35°C for 30 minutes. Add tet is butylammonium and the reaction mixture is stirred at 35° C for two hours. Add a complex 2-tert-butoxycarbonylamino ether methanesulfonate acid (101,23 g) and the reaction mixture is stirred at 35°C during the night. The mixture is then distributed between two liters of water and one liter of isopropyl ether. The resulting organic and aqueous phases are separated and washed successively with water and a saturated solution of sodium chloride in water. The organic layer is dried over magnesium sulfate, filtered and concentrated, obtaining solid product (65.22 per g). The solid product (61,6 g) is transferred into a flask equipped with overhead stirrer. Add hexane and the flask is heated to 65°C. After the transition of all solids in the solution, the mixture is cooled to ambient temperature. The mixture is stirred over night. The obtained solid products are separated by filtration, getting mentioned in the title compound (52,32 g).

Stage 3: (R)-3-aminopentanedioic salt methanesulfonic acid.Methansulfonate acid (71 g) is added to the complex solution of tert-butyl methyl ether (1-cyanomethylene)carbamino acid in tetrahydrofuran (530 ml). The reaction mixture is heated to 40°C for about 30 minutes. The temperature was raised to 45°C and stirred for approximately one hour. The temperature raises even up to 65°C and the reaction mixture stirred for toe the hours. The mixture is allowed to cool to ambient temperature. The obtained solids are filtered, getting mentioned in the title compound (41,53 g).

1. The compound of formula III

2. The compound of formula IV

3. The compound of formula VI

where R is selected from methyl and benzyl.

4. The compound according to claim 3, where R represents methyl.

5. Compound of formula VII

where R represents methyl.

6. The method of obtaining the compounds of formula III

with a combination of triptoreline, para-substituted with halogen or O-triflate, with a compound of formula II

with the formation of the compounds of formula III.

7. The method according to claim 6, where the specified connection triptoreline attached to the specified compound of formula II in the presence of a phosphine ligand.

8. The method according to claim 7, where the specified phosphine ligand means dialkylphosphinate ligand.

9. The method of claim 8, where the specified phosphine ligand selected from 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)diphenyl and 2-dicyclohexylphosphino-2'-methylbiphenyl.

10. The method according to claim 6, where the specified op is food involves attaching the specified connection triptoreline to the specified compound of formula II in the presence of a base.

11. The method of obtaining the compounds of formula IV

including the hydrolysis of compounds of formula III

gidrolizuut agent selected from acids or bases, with the formation of the compounds of formula IV

12. The method of obtaining the compounds of formula VI

including the accession of the compounds of formula IV

to the compound of formula V

where R is selected from methyl and benzyl, in the presence of a base to form compounds of formula VI.

13. The method according to item 12, where the specified radix is a tert-butyl lithium.

14. The method of obtaining the compounds of formula VII

including the restoration of the compounds of formula VI

where R represents a methyl, a reducing agent with obtaining the restored connection and the cyclization of the recovered compounds in acidic conditions to obtain the compounds of formula VII.

15. The method according to 14, where the specified reducing agent represents borohydride sodium in the presence of Lewis acid.



 

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