Method for producing butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate

Abstract

The present invention relates to a new and improved process for the preparation of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of formula (XII), to novel precursors for its preparation, and to its use in the preparation of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid. TIFF2023526402000096.tif66155

Description

Technical Field

[0001] The present invention relates to butyl (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of the following formula (XII):

Chemical formula

Background Art

[0002] The compound of formula (XII) is a precursor of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of the following formula (I).

Chemical formula

[0003] The compound of formula (XII) can be converted to the compound of formula (I) by ester hydrolysis.

[0004] The compound of formula (I) acts as an activator of soluble guanylate cyclase and can be used as a preventive and / or therapeutic agent for lung, cardiopulmonary and cardiovascular disorders, for example, as a therapeutic agent for pulmonary arterial hypertension (PAH), pulmonary hypertension (PH), pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD), pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP) or chronic thromboembolic pulmonary hypertension (CTEPH). Summary of the Invention Problems to be Solved by the Invention

[0005] The compound of formula (I) and the production method are described in WO2014 / 012934. The disadvantages of the synthesis described in WO2014 / 012934 are, in particular, that this synthesis is not suitable for an industrial-scale process because seven chromatographic purification steps and one chiral chromatographic step are required to separate the enantiomers of one racemate. These are generally very technically complex and costly and require a large amount of solvent consumption and should therefore be avoided if possible. Furthermore, the separation into enantiomers is carried out at an advanced stage of the synthesis by chromatography on a chiral phase. This results in a high proportion of products that cannot be used for further synthesis.

[0006] Some steps of the synthesis described in WO2014 / 012934 are also characterized by long reaction times over several days and low yields, which are quite disadvantageous for the efficiency of the synthesis on an industrial scale. For example, the reaction time is 4 days in the production of Example 6A and 3 days in the production of Example 92A. Furthermore, in the production of Example 92A, the use of an excess amount of methyl 4-(2-iodoethyl)benzoate can lead to polymerization. This forms polystyrene, which has to be removed in a complex manner.

[0007] Some steps cannot be carried out on an industrial scale due to safety and process-related difficulties. Some reaction steps proceed with very high dilutions and very large amounts of reagents, which means that only a small amount of product is produced relative to the batch volume. Furthermore, the synthesis disclosed in WO2014 / 012934 consists of 17 steps, which alone is extremely costly and time-consuming.

[0008] Therefore, there was a need for an industrial-scale, practical synthesis of the compound of formula (I) that could be reproducibly produced with high overall yield, low manufacturing cost, and high purity, while also meeting all regulatory requirements. [Means for solving the problem]

[0009] A key feature of the method according to the present invention is that the intermediate purification step is carried out by salt formation, and therefore the chromatographic purification step can be omitted. Enantioselective synthesis means that a chiral chromatography step is not required to separate the enantiomers of a racemic mixture. The number of synthesis steps in the method according to the present invention is reduced compared to the synthesis disclosed in WO2014 / 012934.

[0010] Therefore, the method according to the present invention is suitable for producing compounds of formula (I) with high overall yield and purity in a synthesis that can be carried out on an industrial scale.

[0011] Figure 1 [ka]

[0012] Diagram 2 [ka]

[0013] Diagram 3 [ka]

[0014] Diagram 4 [ka]

[0015] Figure 1 shows the preparation of compound (III) necessary for the preparation of compound (XII).

[0016] Figure 2 shows an overview of the synthetic steps for producing compound (XII) via an intermediate of compound (VIII).

[0017] Figure 3 shows an overview of the synthetic steps for producing compound (XII) via an intermediate of compound (XV).

[0018] Figure 4 shows an outline of the synthesis process for the compound of formula (XII), where the reaction is similar to that shown in Figure 3, except that various intermediate steps are not isolated. [Modes for carrying out the invention]

[0019] Description of each synthesis step Example 1 Process Stage 1 [ka]

[0020] Step 1 (Figures 2 and 3) describes the production of 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate of formula (V) from 4-(2-hydroxyethyl)benzonitrile of formula (IV). The compound of formula (IV), potassium hydroxide, and 4-toluenesulfonyl chloride (TsCl) are added to an inert solvent, such as 2-methyltetrahydrofuran (2-MTHF), tetrahydrofuran (THF), or dioxane, preferably a suitable ether such as THF, and stirred. To avoid elimination reactions that produce cyanostyrenes or their polymers, the temperature is maintained at -10°C to 0°C until all compounds are added. After this, stirring is carried out at a temperature of 0°C to 30°C, preferably 22°C, until the conversion is complete.

[0021] The compound of formula (V) can be isolated, for example, by aqueous post-treatment and subsequent crystallization. A preferred method of aqueous post-treatment is known to those skilled in the art and is an extraction capable of separating by-products and excess potassium hydroxide. The aqueous post-treatment can be carried out, for example, using dichloromethane (DCM) and water in the presence of ammonium chloride. Crystallization can be carried out, for example, in cyclohexane. This includes changing the solvent to cyclohexane, concentrating under reduced pressure at a temperature of 30°C to 50°C, preferably 41°C, cooling to a temperature of 20°C to 30°C, preferably 22°C, isolating the solid, and drying in a drying oven at a temperature of 30°C to 50°C, preferably 40°C in a drying cabinet.

[0022] The present invention relates to a compound of formula (V): [ka] A manufacturing method is provided. Compounds of the following formula (IV): [ka] This is characterized by reacting it with potassium hydroxide and 4-toluenesulfonyl chloride in an inert solvent.

[0023] The present invention further provides a method for producing the compound of formula (V) described above, wherein the inert solvent is an ether selected from the list consisting of 2-methyltetrahydrofuran, tetrahydrofuran, or dioxane, preferably tetrahydrofuran.

[0024] The present invention further provides a method for producing the compound of formula (V) described above, which maintains the temperature between -10°C and 0°C when adding the compound of formula (IV), potassium hydroxide, and 4-toluenesulfonyl chloride.

[0025] The present invention further provides a method for producing the compound of formula (V) described above, wherein the conversion is carried out at a temperature of 0°C to 30°C, preferably 22°C.

[0026] Example 2 Process Stage 2 [ka]

[0027] For the production of 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzonitrile of formula (VII) according to step 2 (Figures 2 and 3), 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate of formula (V) is suspended in a suitable ether, preferably THF, and 2-methoxyphenethylamine of formula (VI) and a tertiary amine base, for example, preferably triethylamine, are added, and the mixture is heated under reflux, preferably for 2 hours. Then, the solvent is changed to water, and a mineral acid, preferably hydrochloric acid, more preferably 25% hydrochloric acid, is added at a temperature of 0 to 30°C. The solids in the reaction mixture are isolated.

[0028] The compound of formula (VII) is preferably isolated as an oil after aqueous post-treatment. A preferred method of aqueous post-treatment is extraction, which is known to those skilled in the art and can separate by-products, such as excess toluenesulfonic acid. For example and preferably, the isolated solid is mixed with water, stirred, and the solid is removed by filtration. This operation can be repeated. The solid is mixed with ethyl acetate, preferably at a temperature of 30-60°C, more preferably at 50°C, and stirred, and the solid is isolated at a temperature of 10-30°C, more preferably at 20°C. This operation can be repeated, after which the solid is dried under reduced pressure, preferably at a temperature of 40°C. In a further step, the solid is mixed with a mixture of ethyl acetate and hydrochloric acid, preferably 15% hydrochloric acid, to obtain the hydrochloride salt of the compound of formula (VII), which is dried under atmospheric pressure, preferably at a temperature of 40°C. To obtain the free base of the compound of formula (VII), the obtained solid is dissolved in DCM and water, preferably in equal volume proportions, and the pH is adjusted to 13-14 with an alkali, preferably a sodium hydroxide solution, more preferably a 45% sodium hydroxide solution. The organic phase is isolated, washed with water, and concentrated under reduced pressure, preferably at a temperature of 40°C, to obtain an oily substance.

[0029] Alkylation reactions of primary amines generally yield a mixture of possible polyalkylation products. The advantage of this method is that, under optimized reaction and workup conditions, the desired monoalkylation product VII can be obtained in good purity and yield. The polyalkylation products formed here are also readily removed by optimized purification.

[0030] The present invention further comprises compounds of the following formula (VII): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0031] The present invention further provides oxalates of compounds of formula (VII).

[0032] The present invention further relates to a method for producing a compound of formula (VII), the first step being to suspend the compound of formula (V) below in a suitable ether in the presence of a tertiary amine base: [ka] The compound of the following formula (VI): [ka] The present invention provides a manufacturing method characterized by reacting with a substance, then in the second step changing the solvent to water, and adding a mineral acid.

[0033] The present invention further provides a method for producing the compound of formula (VII) described above, wherein the preferred ether is tetrahydrofuran.

[0034] The present invention further provides a method for producing the compound of formula (VII) described above, wherein the tertiary amine base is triethylamine.

[0035] The present invention further provides a method for producing the compound of formula (VII) described above, wherein the reaction is carried out at reflux temperature in the first step.

[0036] The present invention further provides a method for producing the compound of formula (VII) described above, wherein the second step is carried out at a temperature of 0°C to 30°C.

[0037] The present invention further provides a method for producing the compound of formula (VII) described above, wherein the mineral acid is hydrochloric acid, preferably 25% hydrochloric acid.

[0038] Example 3 Process Stage 3 [ka]

[0039] Prior art describes the reductive amination of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile(II) with an amine of formula XVII, followed by an alkylation reaction to produce the compound of formula (I), resulting in a racemic final product. Subsequently, it is necessary to separate the enantiomers in a chiral chromatography step, which is technically very complex, costly, and consumes a large amount of solvent. Surprisingly, the present invention has found an effective method for producing (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile (the compound of formula (III)). Using the compound of formula (III), it is possible to obtain an enantiomerically pure final product, thus avoiding the unfavorable chiral chromatography step.

[0040] For the production of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitride of formula (III) in step 3 (Figure 1), first, 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitride of formula (II) (produced as disclosed in WO2014 / 12934 as Example 4A) is placed in a suitable solvent. Suitable solvents are esters known to those skilled in the art, such as ethyl acetate, and ethers, such as diethyl ether, dioxane, and tetrahydrofuran, with ethyl acetate being preferred. A tertiary amine base, such as triethylamine and ruthenium-p-cymene-R,R-TsDPEN (CAS number: 192139-92-7), is added, preferably in a catalytic amount, at a temperature of preferably 0 to 40°C, more preferably 20°C. Formic acid is added, preferably at a temperature of -5 to 10°C, more preferably 0 to 5°C, to remove the formed gas. Stirring is continued at a temperature of preferably 20-50°C, more preferably 40°C, until the conversion is complete.

[0041] The compound of formula (III) is preferably isolated after post-treatment and subsequent crystallization. For post-treatment, the reaction mixture is preferably mixed with an equivolute of ethyl acetate and mineral acid, preferably hydrochloric acid, more preferably 1N hydrochloric acid, and stirred, and the upper layer is isolated. A C6-C8 alkane, preferably heptane, more preferably n-heptane, is added to the upper layer, and the mixture is concentrated under reduced pressure, preferably at a temperature of 20-50°C, more preferably 40°C. This step can be repeated. The compound of formula (III) is isolated from the mixture in solid form at a preferred temperature of 20°C and preferably vacuum-dried at a temperature of 40°C.

[0042] The present invention further comprises (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile of the following formula (III): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0043] The present invention further provides a method for producing a compound of formula (III), wherein the compound of formula (II): [ka] The present invention provides a method characterized by reacting with a tertiary amine base, ruthenium-p-cymene-R,R-TsDPEN, and formic acid to obtain a compound of formula (III).

[0044] The present invention further provides a method for producing the compound of formula (III) described above, wherein the amine base is triethylamine and ruthenium-p-cymene-R,R-TsDPEN is used in a catalytic amount.

[0045] The present invention further provides a method for producing the compound of formula (III) above, wherein, prior to the reaction, the compound of formula (II) is dissolved in a solvent selected from the list including ethyl acetate, diethyl ether, dioxane, and tetrahydrofuran, preferably ethyl acetate.

[0046] The present invention further provides a method for producing the compound of formula (III) described above, comprising mixing the compound of formula (II) with an amine base and ruthenium-p-cymene-R,R-TsDPEN in the first step, and then adding formic acid in the second step.

[0047] The present invention further provides a method for producing the compound of formula (III) described above, comprising: in the first step, mixing the compound of formula (II) with an amine base and ruthenium-p-cymene-R,R-TsDPEN at a temperature of 0°C to 40°C, preferably 20°C; and in the second step, adding formic acid at a temperature of -5°C to 10°C, preferably 0°C to 5°C.

[0048] The present invention further provides a method for producing the compound of formula (III) described above, wherein after adding formic acid, stirring is continued at a temperature of 20°C to 50°C, preferably 40°C, until the conversion is complete.

[0049] Example 4 Process Stage 4 [ka]

[0050] Step 4 (Figure 2) describes the production of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (VIII). For this purpose, a solution of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile (III) is dissolved in a suitable solvent, preferably by removing water, and more preferably under a protective gas atmosphere, for example, by blowing in argon. Suitable solvents are those that are liquid at the reaction temperature, such as THF or DCM, with DCM being preferred. A suitable base is added to the solution. Suitable bases are sterically hindered secondary amines or 2,6-disubstituted pyridines, such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable sterically hindered secondary amines include, for example, diisopropylamine, 2,5-dimethylpiperidine, or 2,2,5,5-tetramethylpiperidine. Surprisingly, using these compounds makes it possible to achieve better yields compared to sterically hindered amines or tertiary amines. It was not particularly surprising that the most advantageous yield was obtained by using diisopropylamine in molar excess based on the compound of formula (III). Diisopropylamine, being a secondary amine, is an unusual base for this type of reaction. The reaction mixture is cooled to a temperature of -90°C to -50°C, preferably -78°C to -65°C. While maintaining this temperature range, 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzonitrile of formula (VII) is added, preferably in a molar ratio of 1:1 based on the compound of formula (III), and stirred.

[0051] The compound of formula (VIII) is preferably isolated after aqueous post-treatment and subsequent crystallization. Such aqueous post-treatment methods are known to those skilled in the art and are extractions that allow for the separation and removal of by-products. For example, and preferably, after the conversion is complete, the reaction mixture is mixed with a suitable acid, preferably oxalic acid or phosphoric acid, more preferably oxalic acid, and the temperature is adjusted to -10 to 15°C, preferably 0 to 5°C. Diatomaceous earth is added to the mixture and it is stirred. The solid is filtered off and discarded, the liquid organic phase is washed with water, and the pH is adjusted to 7.5 to 9, preferably 8, with a base, preferably an ammonia solution, more preferably a 27% ammonia solution. The organic phase is isolated and concentrated under reduced pressure to obtain an oily substance.

[0052] The oily substance is dissolved in ethanol to crystallize the compound of formula (VIII). The compound of formula (VIII) is allowed to crystallize at a temperature of 50°C or lower, preferably 40°C or lower, more preferably 40°C, preferably after seed addition. The solid is isolated and dried under a nitrogen stream, preferably under reduced pressure, at a temperature of 25°C, by a method known to those skilled in the art.

[0053] The present invention further includes compounds of the following formula (VIII):

[0054] [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0055] The present invention further relates to a compound of the following formula (VIII-1): [ka] [In the formula, R 1 The material is a C1-C4 alkyl group, and also provides salts thereof, solvates, and solvates of salts thereof.

[0056] The present invention further relates to the compound of formula (VIII-1): [ka] [In the formula, R 1 is a C1-C4 alkyl compound. A method for producing [ ], in which, in the first step, at a temperature of -90°C to -50°C, the compound of formula (III): [ka] In the presence of a base selected from a list including sterically hindered secondary amines and 2,6-disubstituted pyridines, trifluoromethanesulfonic anhydride is added, and in the second step, the compound of the following formula (VII-1) is obtained: [ka] [In the formula, R 1 The present invention provides a method characterized by reacting with a C1-C4 alkyl group.

[0057] In the context of the present invention, "C1-C4-alkyl" refers to a monovalent alkyl group having 1 to 4 carbon atoms, either linear or branched. Preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0058] The present invention further includes R 1 The present invention provides a method for producing the compound of formula (VIII-1) above, wherein the compound is methyl.

[0059] The present invention further provides a method for producing the compound of formula (VIII-1) described above, wherein the reaction is carried out at a temperature of -78°C to -65°C.

[0060] The present invention further provides a method for producing the compound of formula (VIII-1) described above, wherein the sterically hindered secondary amine is selected from a list including diisopropylamine, 2,5-dimethylpiperidine, and 2,2,5,5-tetramethylpiperidine.

[0061] The present invention further provides a method for producing a compound of formula (VIII-1), wherein the base is diisopropylamine.

[0062] The present invention further provides a method for producing the compound of formula (VIII-1) at a temperature of -78°C to -65°C, preferably -76°C.

[0063] The present invention further provides a method for producing the compound of formula (VIII-1), wherein the compound of formula (III) is dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0064] The present invention further provides a method for producing the compound of formula (VIII-1) described above, wherein the base is added in a molar excess, preferably in a ratio of 3:1, based on the compound of formula (III).

[0065] The present invention further provides a method for producing the compound of formula (VIII-1) above, comprising adding trifluoromethanesulfonic anhydride in a molar excess based on the compound of formula (III), preferably in a ratio of 1.5:1.

[0066] The present invention further provides a method for producing the compound of formula (VIII-1) using the compound of formula (VII-1) in a molar ratio of 1:1 to 1.1:1 based on the compound of formula (III).

[0067] The present invention further provides a method for producing the compound of formula (VIII-1) described above, wherein the method is carried out by removing water, preferably under a protective gas atmosphere, and more preferably while blowing in argon.

[0068] The present invention further provides a method for producing the compound of formula (VIII-1) described above, wherein the method is carried out by removing water, preferably under a protective gas atmosphere, and more preferably while blowing in argon.

[0069] Example 5 Process Stage 5 [ka]

[0070] For the production of 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzonitrile of formula (XIII) in step 5 (Figure 3), first, aluminum chloride is stirred with a suitable alkylthiol, preferably n-dodecanethiol (dodecyl mercaptan), in a molar ratio of preferably 1:1 to 1:3, more preferably 1:1, until dissolved. At a temperature of 0 to 40°C, preferably 10 to 20°C, 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzonitrile of formula (VII) is added, and the mixture is stirred for several hours at a temperature of preferably 30 to 50°C, more preferably 40°C.

[0071] Surprisingly, the compound of formula (XIII) is insoluble as an aluminum complex (Al complex) in a suitable solvent, such as DCM or toluene, and precipitates, making its preparation using aluminum chloride advantageous. The solubility of the Al complex depends on the solvent; for example, it is soluble in THF. This unexpected situation can be advantageously used for the purification of the reaction mixture, as the formed reaction product can be isolated as an insoluble Al complex and washed with a suitable solvent, preferably DCM or toluene, more preferably DCM. The complex can then be dissolved in a suitable solvent, preferably THF, and the compound of formula (XIII) can be liberated from the complex by adding a tartrate, preferably potassium sodium tartrate solution, in a molar excess relative to the compound of formula (VII). The liberation from the complex by the addition of tartrate can be repeated.

[0072] The compound of formula (XIII) is preferably isolated after aqueous basic post-treatment. A preferred method of aqueous basic post-treatment is extraction, which is known to those skilled in the art and allows for the separation and removal of by-products. For example, the solvent is changed to DCM, an aqueous ammonia solution, preferably a 27% aqueous ammonia solution, the mixture is washed with water, and the organic phase is concentrated to obtain an oily substance.

[0073] The present invention further comprises compounds of the following formula (XIII): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0074] The present invention further relates to a method for producing a compound of formula (XIII), comprising: firstly, mixing aluminum chloride with a suitable alkylthiol; and secondly, producing a compound of the following formula (VII): [ka] The present invention provides a method characterized by reacting the material in a solvent such as dichloromethane or toluene.

[0075] The present invention further provides a method for producing the compound of formula (XIII) described above, wherein the preferred alkylthiol is n-dodecanethiol.

[0076] The present invention further provides a method for producing the compound of formula (XIII) described above, wherein the solvent is toluene and / or dichloromethane, preferably dichloromethane.

[0077] The present invention further provides a method for producing the compound of formula (XIII) above, wherein the preferred alkylthiol is added in a molar ratio of 1:1 to 1:3 based on the compound of formula (VII), more preferably in a molar ratio of 1:1.8 based on the compound of formula (VII).

[0078] The present invention further provides a method for producing the compound of formula (XIII) above, wherein the compound of formula (VII) is added at a temperature of 0°C to 40°C, preferably 10°C to 20°C.

[0079] The present invention further provides a method for producing the compound of formula (XIII) described above, wherein the conversion in the second step is carried out at a temperature of 30°C to 50°C, more preferably 40°C.

[0080] The present invention further provides a method for producing the compound of formula (XIII) described above, comprising isolating the formed insoluble compound of formula (XIII), dissolving it in tetrahydrofuran, and adding a tartrate solution.

[0081] Example 6 Steps 6A and 6B describe the production of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzonitrile of formula (XIV).

[0082] Process stage 6A: [ka]

[0083] For the production of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzonitrile of formula (XIV) according to step 6A (Figure 3), 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzonitrile of formula (XIII) is dissolved in a suitable solvent, such as ether or halohydrocarbon, preferably DCM. The hydroxyl group of the compound of formula (XIII) is protected with a silyl protecting group at a temperature of 0°C to 40°C, preferably 20°C to 35°C. The silyl protecting group used can be a silyl protecting group known to those skilled in the art, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), or tert-butyldimethylsilyl (TBDMS), preferably tert-butyldimethylsilyl (TBDMS). To this end, the compound of formula (XIII) is stirred with a suitable silyl chloride, preferably tert-butyldimethylsilyl chloride, in the presence of an amine base, preferably imidazole, at a temperature of 0°C to 40°C, preferably 20°C to 35°C, until the conversion is complete. The amine base is present in a molar ratio of 1:1 or in excess relative to the compound of formula (XIII), preferably in a 1.5-molar excess.

[0084] Before concentration, the reaction mixture can be purified by aqueous basic purification known to those skilled in the art. For example, an aqueous potassium carbonate solution is added to the reaction mixture, the organic phase is repeatedly washed with water, and the organic phase is dehydrated with sodium sulfate.

[0085] Another preferred purification can be achieved by precipitating the compound of formula (XIV) as an oxalate. To this end, the reaction mixture is washed with water, the solvent of the organic phase is changed to methanol, and the mixture is heated to a temperature of 40°C to 80°C, preferably 65°C. After adding an excess of oxalic acid relative to the compound of formula (XIV), the mixture is stirred at a temperature of 40°C to 65°C, preferably 50°C to 55°C, and then cooled to a temperature of 0°C to 20°C, preferably 5°C to 10°C. The precipitated solid is separated and suspended in water and a mixed solvent that exhibits phase separation with water, such as DCM, toluene, or ether, preferably DCM, and stirred. After adjusting the pH to 10.5 to 12.5 with a suitable base, such as and preferably a sodium hydroxide solution, the phases are separated and the organic phase is concentrated.

[0086] Concentration is carried out at a temperature of 25°C to 70°C, preferably 30°C to 50°C, more preferably 35°C, preferably under reduced pressure, to obtain the compound of formula (XIV) as an oily substance.

[0087] The present invention further comprises compounds of the following formula (XIV): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0088] The present invention further comprises compounds of the following formula (XIV-1): [ka] [In the formula, R 2 This is a silyl protecting group. The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0089] The present invention further comprises compounds of the following formula (XIV-1): [ka] [In the formula, R 2 is a silyl protecting group. A method for producing [ ] Compounds of the following formula (XIII): [ka] The present invention provides a method characterized by reacting with a suitable silyl chloride in the presence of an amine base.

[0090] In the context of the present invention, the “silyl protecting group” is a silyl protecting group known to those skilled in the art, which can convert a reactive functional group into a non-reactive form using an organosilicon compound. Preferably, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), or tert-butyldimethylsilyl (TBDMS) are used, and particularly preferably tert-butyldimethylsilyl (TBDMS).

[0091] In the context of the present invention, a suitable silyl chloride is a silyl chloride used in the production of each silyl protecting group.

[0092] The present invention further provides a method for producing a compound of formula (XIV-1), wherein the amine base is imidazole.

[0093] The present invention further includes R 2 The present invention provides a method for producing a compound of formula (XIV-1), selected from the group comprising trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, and tert-butyldimethylsilyl.

[0094] The present invention further includes R 2 The present invention provides a method for producing a compound of formula (XIV-1) in which is tert-butyldimethylsilyl.

[0095] The present invention further provides a method for producing a compound of formula (XIV-1), wherein the suitable silyl chloride is selected from the group comprising trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, tert-butyldiphenylsilyl chloride, and tert-butyldimethylsilyl chloride.

[0096] The present invention further provides a method for producing a compound of formula (XIV-1), wherein the suitable silyl chloride is tert-butyldimethylsilyl chloride.

[0097] The present invention further provides a method for producing the compound of formula (XIV-1), wherein the amine base is present in a molar ratio of 1.5:1 or in excess based on the compound of formula (XIII).

[0098] Process stage 6B: [ka]

[0099] Alternatively, the compound of formula (XIV) can be prepared in step 6B (Figure 4) from 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate of formula (V) and 2-(2-aminoethyl)phenol of formula (XVII). For this purpose, the compound of formula (V) is dissolved in a suitable solvent, such as ether, preferably DCM or THF, more preferably THF, and 2-(2-aminoethyl)phenol of formula (XVII) and triethylamine of formula (V) are added in a ratio of preferably 2:1 or higher based on the compound of formula (V). The reaction mixture is heated for several hours, preferably 20 to 60 hours, more preferably 46 hours, preferably at a temperature corresponding to the boiling point of the reaction mixture. If DCM is not used as the solvent, the solvent is preferably changed to DCM. This can be done, for example, by removing the original solvent under reduced pressure at a temperature of 60°C or lower, and then adding DCM. Next, this solution can be washed one or more times by a known method, preferably with sodium bicarbonate, and optionally further concentrated at a temperature of 45°C or lower.

[0100] To the resulting solution, add imidazole in a ratio of preferably 2:1 to 5:1, preferably 3:1, based on the compound of formula (V), and stir at 20 to 35°C, more preferably room temperature, until the conversion is complete.

[0101] This may then be subjected to aqueous basic purification known to those skilled in the art. For this purpose, the following steps are preferably envisaged: The reaction mixture is washed one or more times with water and the solvent is changed to methanol. Oxalic acid is added at a temperature of 40 to 70 °C, preferably 50 to 55 °C, and the mixture is stirred. After cooling to 0 to 20 °C, preferably 5 to 10 °C, the solid matter is isolated and washed with methanol. The residue is suspended in a mixture of DCM or toluene and water, preferably a mixture of DCM and water in a volume ratio of 1:1, and mixed at 15 to 40 °C, preferably 25 to 35 °C, with a concentrated base, preferably a sodium hydroxide solution, more preferably a 45% sodium hydroxide solution, to bring the pH to 10.5 to 12.5. After adding water, the organic phase is isolated and preferably concentrated under reduced pressure. The compound of formula (XIV) is obtained as an oil.

[0102] One advantage of this method is that the monoalkylation product of the desired primary amine can be obtained by alkylation of 2-(2-aminoethyl)phenol of formula (V) without prior protection of the hydroxyl functional group of phenol (which can participate in the alkylation reaction under basic conditions).

[0103] The present invention further provides a process for producing a compound of the following formula (XIV-1):

Chemical formula

Chemical formula

[0104] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the amine base in the first step is triethylamine.

[0105] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the first step is carried out in a suitable ether as a solvent.

[0106] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the preferred ether is dichloromethane or tetrahydrofuran.

[0107] The present invention further provides a method for producing the compound of formula (XIV-1) using the compound of formula (XVI) in a molar ratio of 2:1 or higher based on the compound of formula (V).

[0108] The present invention further provides a method for producing the compound of formula (XIV-1) described above, using triethylamine in a molar ratio of 3:1 or higher based on the compound of formula (V).

[0109] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the conversion in the first step is carried out at a boiling temperature for several hours, preferably 20 to 60 hours, more preferably 46 hours.

[0110] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the amine base in the second step is imidazole.

[0111] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the amine base in the second step is used in a molar ratio of 2:1 to 5:1, preferably 3:1, based on the compound of formula (V).

[0112] The present invention further provides a method for producing the compound of formula (XIV-1) described above, wherein the second step is carried out at a temperature of 20°C to 35°C.

[0113] Example 7 Process stage 7: [ka]

[0114] For the production of (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (XV) in step 7 (Figure 3), (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (III) is added to a suitable solvent. Suitable solvents are those that are liquid at the reaction temperature, such as THF or DCM; DCM is preferably used. Suitable bases are sterically hindered secondary amines or 2,6-disubstituted pyridines. Suitable sterically hindered secondary amines are, for example, diisopropylamine, 2,5-dimethylpiperidine, or 2,2,5,5-tetramethylpiperidine, preferably diisopropylamine. Particularly preferred is an excess amount of diisopropylamine, more preferably 3 equivalents of diisopropylamine on a basis of the compound of formula (X). Surprisingly, these compounds yielded better yields compared to sterically hindered amines or tertiary amines. Particularly surprising was that diisopropylamine yielded the most favorable results.

[0115] The reaction mixture is cooled to a temperature of -90°C to -50°C, preferably -78°C to -65°C, and trifluoromethanesulfonic anhydride is added, preferably in excess, more preferably 1.5 equivalents, based on the compound of formula (III), and the mixture is stirred. While maintaining the aforementioned temperature range, 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino}ethyl)benzonitrile of formula (XIV) is dissolved in DCM in an equimolar amount, preferably 1.0 to 1.2 equivalents, based on the compound of formula (III), and the mixture is stirred until the conversion is complete. The reaction mixture is then heated to a temperature of 10 to 30°C, preferably 20°C.

[0116] Before concentration, the reaction mixture can be purified by aqueous acidic purification known to those skilled in the art. For this purpose, the reaction mixture is acidified with a mineral acid, preferably phosphoric acid or hydrochloric acid, more preferably hydrochloric acid, and optionally washed with water to isolate the organic phase.

[0117] Concentration is carried out at a temperature of 30°C to 80°C, preferably 30°C to 60°C, more preferably 40°C, preferably under reduced pressure, to obtain the compound of formula (XV) as an oil.

[0118] Optionally, the resulting oily substance can be filtered through silica gel. To do this, the oily substance is dissolved in a suitable solvent, preferably DCM, filtered through silica gel, and then diluted with a suitable solvent, preferably a solvent mixture of ethyl acetate and n-hexane in a ratio of 1:2 (ethyl acetate:n-hexane). The product solution is then concentrated again under the conditions described above.

[0119] The present invention further comprises compounds of the following formula (XV): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0120] The present invention further comprises a compound of the following formula (XV-1): [ka] [In the formula, R 2 [ is a silyl protecting group.], as well as its salts, solvates, and solvates of salts are provided.

[0121] The present invention further comprises a compound of the following formula (XV-1): [ka] [In the formula, R 2is a silyl protecting group. A method for producing [ ], in which, in the first step, at a temperature of -90°C to -50°C, a compound of the following formula (III): [ka] In the presence of a base selected from a list consisting of a sterically hindered secondary amine and a 2,6-disubstituted pyridine, trifluoromethanesulfonic anhydride is added, and in the second step, a compound of the following formula (XVI-1) is obtained: [ka] [In the formula, R 2 The present invention provides a method characterized by reacting with a silyl protecting group.

[0122] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein the sterically hindered secondary amine is selected from a list including diisopropylamine, 2,5-dimethylpiperidine, and 2,2,5,5-tetramethylpiperidine.

[0123] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein the base is diisopropylamine.

[0124] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein the temperature is -78°C to -65°C, preferably -76°C.

[0125] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein the compound of formula (III) is dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0126] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein trifluoromethanesulfonic anhydride is added in a molar excess amount, preferably in a ratio of 1.5:1, based on the compound of formula (III).

[0127] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein the base is added in a molar excess, preferably in a ratio of 3:1, based on the compound of formula (III).

[0128] The present invention further provides a method for producing the compound of formula (XV-1) using the compound of formula (XIV-1) in a molar ratio of 1:1 to 1.1:1 based on the compound of formula (III).

[0129] The present invention further provides a method for producing the compound of formula (XV-1) described above, wherein the above step is carried out by removing water, preferably under a protective gas atmosphere, and more preferably while blowing in argon.

[0130] Example 8 Process stage 8: [ka]

[0131] For the production of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (XVI) in step 8 (Figure 3), (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (XV) in a suitable alcohol, preferably methanol, is miscible with highly concentrated hydrochloric acid, preferably 37% or 25% hydrochloric acid, at a temperature of 10°C to 40°C, preferably 25°C, until the conversion is complete.

[0132] After neutralization with an aqueous ammonia solution, preferably a 30% ammonia solution, the compound of formula (VI) can be extracted in solid form. These solids can be stirred in a mixture of water and dichloromethane, and the organic phase can be washed with water and concentrated.

[0133] The resulting solid can also be dissolved in a methanol-water mixture at reflux temperature and, upon cooling to room temperature, remarkably, with relatively high enantiomer purity without the addition of chiral reagents. This is particularly advantageous for the production of enantiomerically pure active ingredients.

[0134] The present invention further comprises compounds of the following formula (XVI): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0135] The present invention further provides a method for producing a compound of formula (XVI), wherein the compound of formula (XV-1) is as follows: [ka] [In the formula, R 2 The present invention provides a method characterized by reacting a silyl protecting group with a mineral acid.

[0136] The present invention further provides a method for producing the compound of formula (XVI) described above, wherein the mineral acid is hydrochloric acid, preferably 25% hydrochloric acid.

[0137] The present invention further provides a method for producing the compound of formula (XVI) described above, wherein the conversion is carried out at a temperature of 10°C to 40°C, preferably 25°C.

[0138] The present invention further provides a method for producing the compound of formula (XVI) described above, wherein the conversion is carried out in methanol.

[0139] The present invention further provides a method for producing the compound of formula (XVI) above, wherein, after the reaction, the mixture is mixed with an ammonia solution, preferably a 30% ammonia solution, and the compound of formula (VI) is extracted in solid form.

[0140] Example 9 Process stage 9A: [ka]

[0141] For the production of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (IX) in step 9A (Figure 3), (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (XVI) is suspended in highly concentrated hydrochloric acid, preferably 25% hydrochloric acid, at a temperature of 90°C to 110°C, preferably 103°C, until the conversion is complete. The reaction product can then be used directly in the next step.

[0142] Alternatively, the reaction product may be first cooled to a temperature of 15°C to 50°C, preferably 40°C, the suspension may be filtered, and the filtrate may be used in the next step.

[0143] The present invention further includes compounds of the following formula (IX): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0144] The present invention further provides a method for producing a compound of formula (IX), Compounds of the following formula (XVI): [ka] The present invention provides a method characterized by reacting with a mineral acid.

[0145] The present invention further provides a method for producing the compound of formula (IX) described above, wherein the mineral acid is hydrochloric acid, preferably 25% hydrochloric acid.

[0146] The present invention further provides a method for producing the compound of formula (IX) described above, wherein the conversion is carried out at a temperature of 90°C to 110°C, preferably 103°C.

[0147] Process stage 9B: [ka]

[0148] In a separate step 9B (Figure 2), the compound of formula (IX) can be produced from (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of formula (VIII). To do this, the compound of formula (VIII) is suspended in highly concentrated hydrobromic acid, preferably 48% hydrobromic acid, and stirred at a temperature of 90°C to 110°C, preferably 108°C, until the conversion is complete. Next, the reaction product is first cooled to 15°C to 40°C, preferably 25°C, washed with DCM, and the aqueous phase is used in the next step.

[0149] Since step 9B produces toxic methyl bromide, the resulting gas must be recovered using a gas scrubber. Furthermore, hydrobromic acid, used as a reactant, is highly corrosive.

[0150] The present invention further provides a method for producing a compound of formula (IX), Compounds of the following formula (VIII): [ka] The present invention provides a method characterized by reacting with hydrobromic acid at a temperature of 90°C to 110°C.

[0151] The present invention further provides a method for producing the compound of formula (IX) using 48% hydrobromic acid.

[0152] The present invention further provides a method for producing the compound of formula (IX) described above, wherein the conversion is carried out at a temperature of 108°C.

[0153] Example 10 [ka]

[0154] Process stage 10A: For the production of butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of formula (X) in step 10A (Figures 2 and 3), (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (IX) is heated to a boil in a mineral acid, preferably hydrochloric acid, and a suitable alcohol as a solvent, such as butanol, preferably n-butanol, and stirred until the conversion is complete. For example, aqueous solvent components present for the precursor and produced during the reaction are removed. This can be done, for example, by distillation with continuous addition of the organic solvent until the boiling point of the organic solvent is reached. The steps described are preferably carried out under reduced pressure. Subsequently, the mixture is cooled to a temperature of 10°C to 30°C, preferably 22°C, and then aqueous basic purification is performed. Optionally, filtration is performed after cooling, and then aqueous basic purification is performed using the filtrate.

[0155] The procedure of aqueous basic purification is known to those skilled in the art. For aqueous basic purification, ethyl acetate and an aqueous base solution, preferably an ammonia solution or potassium carbonate and water are added, stirred, and the aqueous phase is removed and discarded. In the second step, preferably, water and sodium chloride are added to the remaining organic phase, stirred, and the aqueous phase is removed and discarded. In the third step, preferably, water is added to the remaining organic phase, stirred, and the aqueous phase is removed and discarded. In the final step, the remaining organic phase is concentrated at a temperature of 30 °C to 80 °C, preferably 40 °C to 70 °C, more preferably 55 °C, preferably under reduced pressure, to obtain the compound of formula (X) as an oil.

[0156] Optionally, the obtained oil is dissolved in DCM and methanol, filtered through silica gel, and the obtained filtrate is concentrated again under the above conditions to obtain an oil.

[0157] One advantage of this process is that the water present or generated in the reaction can be very effectively removed from the reaction mixture by azeotropic distillation, thereby shortening the reaction time until complete conversion is achieved. Butanol, in this case, is notable compared to other solvents, such as acetonitrile, in that it removes a significantly greater amount of water from the reaction mixture based on the amount of solvent distilled off. This has an advantageous effect on the distillation time. On an industrial scale, shortening the distillation time leads to reduced operating costs, reduced equipment occupancy time, and reduced energy costs. Furthermore, the solvent used for azeotropic distillation is simultaneously a reagent for butyl ester formation, thereby eliminating the need to use an additional solvent. A further advantage of the process is that the reaction endpoint at which complete conversion is achieved is indicated by reaching the internal temperature at the boiling point of butanol under the selected distillation conditions (distillation pressure) without further analytical studies. This is particularly advantageous on an industrial scale.

[0158] The present invention further relates to a compound of the following formula (X):

Chemical formula

[0159] The present invention further provides a method for producing a compound of formula (X), comprising reacting a compound of the following formula (IX): [Chemical formula] with n-butanol in the presence of a mineral acid, characterized by the method.

[0160] The present invention further provides a method for producing the compound of formula (X) using n-butanol.

[0161] The present invention further provides a method for producing the compound of formula (X), wherein the mineral acid is hydrochloric acid.

[0162] The present invention further provides a method for producing the compound of formula (X), wherein the conversion is carried out at the boiling temperature.

[0163] Process step 10B; [Chemical formula]

[0164] Alternatively, butyl (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of formula (X) can be obtained from the compounds of formula (III) and formula (XIV) without isolation of the intermediate (Process step 10B - Scheme 4). For this purpose, process steps 7, 8, 9A and 10A are carried out well, and the individual products from those process steps are obtained as oils and used directly in the individual next steps.

[0165] The present invention further provides a compound of the following formula (X): [Chemical formula] A manufacturing method, comprising: in the first step, at a temperature of -90°C to -50°C, adding trifluoromethanesulfonic anhydride to the compound of the following formula (III):

Chemical formula

Chemical formula

[0166] The present invention further provides a manufacturing method of the compound of the above formula (X), wherein the sterically hindered secondary amine is selected from the list including diisopropylamine, 2,5-dimethylpiperidine and 2,2,5,5-tetramethylpiperidine.

[0167] The present invention further provides a manufacturing method of the compound of the above formula (X), wherein the base is diisopropylamine.

[0168] The present invention further provides a manufacturing method of the compound of the above formula (X), wherein the temperature in the first and second steps is -78°C to -65°C, preferably -76°C.

[0169] The present invention further provides a manufacturing method of the compound of the above formula (X), wherein the compound of the formula (III) is dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0170] The present invention further provides a method for producing the compound of formula (X) described above, wherein trifluoromethanesulfonic anhydride is added in a molar excess amount, preferably in a ratio of 1.5:1, based on the compound of formula (III).

[0171] The present invention further provides a method for producing the compound of formula (X) described above, wherein the base is added in a molar excess amount, preferably in a ratio of 3:1, based on the compound of formula (III).

[0172] The present invention further provides a method for producing the compound of formula (X) described above, using the compound of formula (XIV-1) in a molar ratio of 1:1 to 1.1:1 based on the compound of formula (III).

[0173] The present invention further provides a method for producing the compound of formula (X) described above, wherein the above step is carried out by removing water, preferably under a protective gas atmosphere, and more preferably while blowing in argon.

[0174] The present invention further provides a method for producing the compound of formula (X) described above, wherein the butanol used is n-butanol.

[0175] The present invention further provides a method for producing the compound of formula (X) described above, wherein the mineral acid is hydrochloric acid.

[0176] The present invention further provides a method for producing the compound of formula (X) described above, wherein the conversion in the third step is carried out at a temperature of 90°C to 110°C, preferably 103°C, and the conversion in the fourth step is carried out at the boiling temperature.

[0177] Example 11 Process stage 11 [ka]

[0178] To prepare the compound of formula (XII), butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of formula (X) (Step 11 - Figure 4) is dissolved in an inert polar solvent, such as a suitable ether, acetone, or acetonitrile, preferably acetonitrile, at a temperature of preferably 10°C to 40°C, preferably 25°C. Then, distillation is carried out, preferably at a temperature of preferably 40°C to 60°C, under reduced pressure, preferably at 80 mbar to 120 mbar, more preferably 120 mbar, and then acetonitrile is added. This step can be repeated.

[0179] Add 4-(bromomethyl)-3-chloro-4′-(trifluoromethyl)[biphenyl] of formula (XI) to the solution, preferably in an amount of 1 to 2 equivalents, more preferably 1.2 equivalents, based on the compound of formula (X). Add an additive selected from the list, preferably cesium carbonate, to the solution, such as an alkali metal carbonate, e.g., sodium carbonate, potassium carbonate, or cesium carbonate; or an alkali metal hydroxide, e.g., potassium hydroxide, or sodium hydroxide; or a tetraalkylammonium carbonate, e.g., tetramethyl-, tetraethyl-, tetrapropyl-, or tetrabutylammonium carbonate; benzyltrimethyl-, benzyltriethyl-, benzyltripropyl-, or benzyltributylammonium carbonate. The additive is added in a molar excess, preferably 2 to 4 equivalents, more preferably 2 equivalents, based on the compound of formula (X). Stir the mixture until the conversion to the compound of formula (XII) is complete. Additional amounts of additive, preferably cesium carbonate, can be added to the reaction mixture and stirred again. Filter the resulting suspension. Before discarding the filter residue, it should preferably be washed with acetonitrile.

[0180] Alternatively, the compound of formula (XII) can be isolated as an oil. To isolate the oil, the filtrate is concentrated at a temperature of 15°C to 60°C, preferably 30°C to 50°C, more preferably 40°C to obtain the oil. The concentration is preferably carried out under reduced pressure.

[0181] The present invention further comprises compounds of the following formula (XII): [ka] The present invention also provides salts thereof, solvates, and solvates of salts thereof.

[0182] The present invention further comprises compounds of the following formula (XII-1): [ka] [In the formula, R 3 and R 4 The is independently a C1-C4 alkyl group. Compound of the following formula (X-1): [ka] [In the formula, R 3 and R 4 The compounds of the following formula (XI) are independently C1-C4-alkyl. [The compounds are formed in the presence of an alkali metal carbonate, alkali metal hydroxide, or tetraalkylammonium carbonate:] [ka] The present invention provides a method characterized by reacting with [a specific substance].

[0183] The present invention further comprises compounds of the following formula (XII): [ka] A method for manufacturing, Compounds of the following formula (X): [ka] The compound of the following formula (XI) in the presence of an alkali metal carbonate, alkali metal hydroxide, or tetraalkylammonium carbonate: [ka] The present invention provides a method characterized by reacting with [a specific substance].

[0184] The present invention further provides a method for producing the compound of formula (XII-1) described above, using a suitable ether, acetone, or acetonitrile, preferably acetonitrile, as the solvent.

[0185] The present invention further provides a method for producing the compound of formula (XII-1) described above, using an alkali metal carbonate selected from a list including sodium carbonate, potassium carbonate, and cesium carbonate, preferably cesium carbonate.

[0186] The present invention further provides a method for producing the compound of formula (XII-1) described above, using an alkali metal hydroxide selected from a list including sodium hydroxide and potassium hydroxide.

[0187] The present invention further provides a method for producing the compound of formula (XII-1) using a tetraalkylammonium carbonate.

[0188] The present invention further provides a method for producing the compound of formula (XII-1) described above, using the alkali metal carbonate, alkali metal hydroxide, or tetraalkylammonium carbonate in a molar excess amount based on the compound of formula (X), preferably in a molar ratio of 2:1 to 4:1, and more preferably in a molar ratio of 2:1 based on the compound of formula (X).

[0189] The present invention further provides a method for producing the compound of formula (XII-1) described above, using the compound of formula (XI) preferably in a molar ratio of 1:1 to 2:1 based on the compound of formula (X), and more preferably in a molar ratio of 1.2:1 based on the compound of formula (X).

[0190] The compound of formula (I) can be prepared from the compound of formula (XII) or (XII-A) by ester hydrolysis methods known to those skilled in the art. For example, ester hydrolysis can be carried out in the same manner as described in Example 23 of WO2014 / 012934.

[0191] Experiment Section Abbreviations and acronyms [Table 1] TIFF0007835690000064.tif165134

[0192] Analysis method Method A High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength: 228 nm, range: 6 nm, oven temperature: 25 °C; column: Chiralpak AD-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: isopropanol + 0.1% diethylamine; gradient program: start 1 mL / min 80% eluent A, 20% eluent B; 16 mins 1 mL / min 40% eluent A, 60% eluent B. Sample solvent: ethanol + 0.1% diethylamine; analytical solution: substance approximately 1.0 mg / mL, dissolved in sample solvent, injection volume: 10 μL. R t Enantiomer 1: 7.6 minutes, Enantiomer 2: 8.5 minutes.

[0193] Method B High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength 206 nm, range 6 nm, oven temperature 30°C; column: Chiralpak AD-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: ethanol + 0.1% diethylamine; gradient program: start 1 mL / min 70% eluent A, 30% eluent B; 12 mins 1 mL / min 40% eluent A, 60% eluent B. Sample solvent: ethanol + 0.1% diethylamine; analytical solution: substance approximately 1.0 mg / mL, dissolved in sample solvent, injection volume: 5 μL. R t Enantiomer 1: 5.8 min (RRT 1.00), Enantiomer 2: 7.2 min RRT 1.25.

[0194] Method C High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength: 204 nm, range: 6 nm, oven temperature: 45 °C; column: Chiralpak AD-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: ethanol + 0.2% trifluoroacetic acid + 0.1% diethylamine; gradient program: 1.5 min 1 mL / min 60% eluent A, 40% eluent B; sample solvent: ethanol; analytical solution: approximately 1.0 mg / mL of substance, dissolved in sample solvent, injection volume: 10 μL. R t Enantiomer 1: 2.9 min RRT 1.00. Enantiomer 2: 3.7 min RRT 1.28.

[0195] Method D High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength 230 nm, range 6 nm; oven temperature 40°C; column: Chiralpak AD-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: ethanol + 0.1% diethylamine; gradient program: 1 min 1 mL / min 70% eluent A, 30% eluent B; sample solvent: ethanol + 0.1% diethylamine; analytical solution: substance approximately 2.0 mg / mL dissolved in sample solvent, injection volume: 10 μL. R t Enantiomer 1: 4.9 min (RRT 1.00), Enantiomer 2: 5.7 min (RRT 1.16).

[0196] Method E High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength: 226 nm, range: 6 nm, oven temperature: 35 °C; column: Chiralpak IB, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: isopropanol + 0.1% ethanolamine; gradient program: 1.5 min 1 mL / min 80% eluent A, 20% eluent B; sample solvent: n-heptane:isopropanol 1:1; analytical solution: approximately 2.0 mg / mL of substance dissolved in sample solvent, injection volume: 10 μL. R t Enantiomer 1: 4.1 minutes, Enantiomer 2: 4.5 minutes.

[0197] Method F Modification 1: High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength: 228 nm, range: 6 nm, oven temperature: 40 °C; column: Chiralpak OJ-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: ethanol + 0.1% diethylamine; gradient program: 1 min 1 mL / min 60% eluent A, 40% eluent B; sample solvent: ethanol; analytical solution: approximately 1.5 mg / mL of substance dissolved in sample solvent, injection volume: 10 μL. Rt Enantiomer 1: 10.68 minutes, Enantiomer 2: 12.13 minutes.

[0198] Modification 2: High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength: 228 nm, range: 6 nm, oven temperature: 40 °C; column: Lux 3 μ Cellulose-3 (Phenomenex), length: 150 mm, inner diameter: 4.6 mm, particle size: 3 μm; mobile phase: A: n-heptane, B: ethanol + 0.1% diethylamine; gradient program: 1 mL / min 75% eluent A, 25% eluent B; sample solvent: ethanol; analytical solution: approximately 1.0 mg / mL of substance dissolved in sample solvent, injection volume: 10 μL. R t Enantiomer 1: 7.6 minutes, Enantiomer 2: 8.6 minutes.

[0199] Method G High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system; measurement wavelength: 226 nm, range: 6 nm, oven temperature: 30 °C; column: Chiralpak AD-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm; mobile phase: A: n-heptane, B: isopropanol + 0.1% diethylamine; gradient program: 1 min 1 mL / min 96% eluent A, 4% eluent B; sample solvent: isopropanol + 0.1% diethylamine; analytical solution: approximately 2.0 mg / mL of substance dissolved in sample solvent, injection volume: 10 μL. R t Enantiomer 1: 8.6 minutes, Enantiomer 2: 10.7 minutes.

[0200] Method H Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x1mm; Eluent A: 1 liter water + 0.25 mL 99% formic acid, Eluent B: 1 liter acetonitrile + 0.25 mL 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50℃, Flow rate: 0.40 mL / min; UV detection: 210 nm.

[0201] Method I Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x1mm; Eluent A: 1 liter water + 0.25 mL 99% formic acid; Eluent B: 1 liter acetonitrile + 0.25 mL 99% formic acid; Gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A; Oven: 50℃; Flow rate: 0.35 mL / min; UV detection: 210 nm.

[0202] Method J Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9μ 50x1mm; Eluent A: 1 liter water + 0.5 mL 50% formic acid, Eluent B: 1 liter acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 97% A → 0.5 min 97% A → 3.2 min 5% A → 4.0 min 5% A; Oven: 50℃; Flow rate: 0.3 mL / min; UV detection: 210 nm.

[0203] Method K MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.0x50mm 3.5μ; Eluent A: 1 liter water + 0.01 mol ammonium carbonate, Eluent B: 1 liter acetonitrile; Gradient: 0.0 min 98% A → 0.2 min 98% A → 3.0 min 5% A → 4.5 min 5% A; Oven: 40℃; Flow rate: 1.75 mL / min; UV detection: 210 nm.

[0204] Method L MS instrument type: Waters Synapt G2S; UPLC instrument type: Waters Acquity I-CLASS; Column: Waters, HSST3, 2.1x50mm, C18 1.8μm; Eluent A: 1 liter water + 0.01% formic acid; Eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 2% B → 2.0 min 2% B → 13.0 min 90% B → 15.0 min 90% B; Oven: 50℃; Flow rate: 1.20 mL / min; UV detection: 210 nm.

[0205] Method M High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system, measurement wavelength 226 nm, range: 40 nm. Column: Zorbax Bonus-RP, length: 150 mm, inner diameter: 3.0 mm, particle size: 3.5 μm, mobile phase: A: water + 0.1% TFA, B: ACN + 0.1% TFA / methanol = 2 + 1, gradient program: 0.0 min 50% B → 12.0 min 70% B → 17.0 min 90% B → 25.0 min 90% B; flow rate: 0.60 mL / min; sample solvent: isopropanol + 0.1% diethylamine; analytical solution: dissolve approximately 35 mg of substance in 25 mL of ACN, and dilute to 50 mL with water + 0.1% TFA (0.7 mg / mL); injection volume: 3 μL.

[0206] Method N High-performance liquid chromatograph with constant temperature column oven, UV detector and data evaluation system, measurement wavelength 210 nm. Column: XBridge BEH Phenyl, length: 50 mm, inner diameter: 4.6 mm, particle size: 2.5 μm, mobile phase: A: 0.66 g of (NH4)2HPO4 and 0.58 g of (NH4)H2PO4 in 1 liter of Millipore water; B: ACN, gradient program: 0.0 min 95% B → 8.3 min 80% B → 11.0 min 80%; flow rate: 1.2 mL / min; sample solvent: ACN + water, injection volume: 3 μL.

[0207] Starting materials and intermediates Example 1 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate [ka]

[0208] In a 40-liter reaction vessel, 12.6 liters of tetrahydrofuran and 0.62 kg (11.05 mol) of potassium hydroxide (powder, 85%) were cooled to -10°C, and a solution of 813.3 g (5.53 mol) of 4-(2-hydroxyethyl)benzonitrile in 1.2 liters of tetrahydrofuran was added within 13 minutes. Next, 1.370 kg (7.18 mol) of 4-toluenesulfonyl chloride was added in several portions, and the mixture was stirred at -10°C for 20 minutes, then heated to 22°C, and stirred at 22°C for 1.5 hours. 12.2 liters of water and 12.2 liters of dichloromethane were added, and the mixture was stirred for 20 minutes, after which the organic phase was separated. The aqueous phase was washed with 12.2 liters of dichloromethane, and the combined organic phase was washed with 12.2 liters of saturated ammonium chloride aqueous solution.

[0209] The organic phases in the two batches were concentrated under reduced pressure at 45°C to 8.75 liters, and the residue was weighed into 40.7 liters of cyclohexane within 10 minutes. The container was washed with 1 liter of dichloromethane, and the washings were added to the cyclohexane. The mixture was concentrated under reduced pressure at 41°C to 24.4 liters, 24.4 liters of cyclohexane were added, and the mixture was concentrated again under reduced pressure at 41°C to 24.4 liters. The suspension was cooled to 22°C, stirred for 30 minutes, the solid was filtered, washed with 8.2 liters of cyclohexane, and dried in a vacuum drying cabinet at 40°C. Yield: 2.82 kg; 84.6% of the theoretical value. 1 H-NMR, DMSO: 2.41 (s, 3H), 2.99 (t, 2H), 4.29 (t, 2H), 7.21-7.42 (dd, 4H), 7.52-7.72 (dd, 4H) LC-MS (Method H);R t =1.03 minutes, 302.1[M+H] + .

[0210] Example 2 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzonitrile [ka]

[0211] In a reaction vessel, 1.507 kg (5.00 mol) of cyanophenethyl silate (Example 1) was suspended in 3.8 liters of tetrahydrofuran and heated under reflux (approximately 77°C) for 2 hours with 2.27 kg (15.0 mol) of 2-methoxyphenethylamine and 1.012 kg (10.0 mol) of triethylamine. The mixture was cooled to 50°C and 10.7 liters of water were added. The solvent was removed under reduced pressure until only water remained. The residue was cooled to 22°C and 6.78 liters of hydrochloric acid (25%) were added within 40 minutes. The mixture was stirred for 30 minutes, the solid was filtered by suction, and washed with 1 liter of water.

[0212] Two batches of solid were stirred with 15 liters of water for 30 minutes, the solids were filtered by suction, washed with 7.5 liters of water, and the procedure was repeated. The wet product was stirred with 7.5 liters of ethyl acetate at 50°C for 1.5 hours, cooled to 22°C, stirred at 22°C for 1 hour, filtered, washed with 5 liters of ethyl acetate, and dried in a vacuum drying cabinet at 40°C to obtain 2.13 kg. The dried product was stirred in 2.2 liters of ethyl acetate and 5.38 liters of hydrochloric acid (15%), filtered by suction, washed with 2.15 liters of water, and dried in a vacuum drying cabinet at 40°C to obtain 1.63 kg of hydrochloride salt.

[0213] The hydrochloride salt was dissolved in 8.25 liters of dichloromethane and 8.25 liters of water, the pH was adjusted to 13-14 using a 45% sodium hydroxide solution, the phases were separated, and the organic phase was washed with 2.75 liters of water. The organic phase was concentrated under reduced pressure at 40°C, 3 liters of dichloromethane were added, and the mixture was concentrated again to obtain 1.44 kg of oily substance. Yield: 1.44 kg; 51.5% of the theoretical value. 1 H-NMR, DMSO: 2.59-2.72 (m, 4H), 2.77 (s, 4H), 3.77 (s, 3H), 6.80-6.98 (m, 2H), 7.08-7.21 (m, 2H), 7.41 (d, 2H), 7.72 (d, 2H) LC-MS (Method H);R t =0.63 minutes, 281.2[M+H] + .

[0214] Example 3 (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile [ka]

[0215] In a 30-liter stainless steel reactor, 1.0 kg of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitride and 10.0 liters of ethyl acetate were initially added. 1.175 kg of triethylamine was weighed in at 20°C within 15 minutes. 18.5 g of ruthenium-p-cymene-R,R-TsDPEN (CAS number: 192139-92-7) was added to the solution at 20°C. 1.337 kg of formic acid was weighed into the solution at 0°C to 5°C within 1 hour (gas generation). The reaction mixture was stirred at an internal temperature of 40°C for 4 hours. Monitoring of the reaction showed that complete conversion occurred in just 2 hours at 40°C (laboratory HPLC). The reaction mixture was cooled to 20°C and stirred overnight at 20°C to release the gas. For post-treatment, the reaction mixture was mixed with 4.1 liters of ethyl acetate and 4.1 liters of 1N hydrochloric acid and stirred for a further 15 minutes. The phases were separated. Approximately 13.9 liters of a dark brown organic upper layer was obtained. The upper layer containing the product was mixed with 13.9 liters of n-heptane. The mixture was concentrated under reduced pressure for no more than 2.5 hours until approximately 17.6 liters of distillate were obtained (approximately 800 mbar, external temperature approximately 40°C). An additional 13.9 liters of n-heptane was added, and the mixture was concentrated again for no more than 2.5 hours until approximately 17.6 liters of distillate were obtained (final volume of mixture approximately 7 liters). The mixture was cooled to approximately 20°C and stirred overnight at 20°C. The product was isolated by filtration, and the crystals were washed twice with 3.7 liters each of n-heptane. The wet product was dried in a vacuum drying cabinet at an external temperature of approximately 40°C for approximately 17 hours until constant weight was achieved. Yield: 0.975 kg; 96% of the theoretical value. 1 H-NMR, DMSO (NBR 305-22-1): 1.60-1.85 (m, 2 H), 1.90-2.05 (m, 2 H), 2.75-2.93 (m, 2H), 4.65-4.70 (m, 1 H), 5.62 (d, 1 H), 7.85 (d, 1H), 8.0 (d, 1H) LC-MS (Method H):R t =0.52 minutes 175.1[M+H] + . Enantiomeric purity (HPLC method D): 98.03% ee.

[0216] Example 4 (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile [ka]

[0217] In a 6-liter flask, a solution of 121.2 g (0.696 mol) of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 3) in 220 mL of dichloromethane and 211.2 g (2.09 mol) of diisopropylamine was cooled under argon to -76°C. Within 85 minutes, 333.6 g (1.18 mol) of trifluoromethanesulfonic anhydride was weighed in at -76°C to -69°C, washed with 20 mL of dichloromethane, and the mixture was stirred for 20 minutes. Subsequently, within 35 minutes, 292.5 g (1.044 mol) of 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzonitrile (Example 3) in a solution in dichloromethane (720 mL) was weighed at -75°C to -67°C, washed with 80 mL of dichloromethane, and the mixture was stirred for 2 hours. 172.1 g (1.19 mol) of oxalic acid was added to the reaction mixture, the cooling bath was removed, and the mixture was stirred overnight. 216 g of diatomaceous earth was added, the reaction mixture was adjusted to a temperature of 0°C to 5°C, stirred for 30 minutes, and the solid was filtered by suction. The filter cake was washed with 1680 mL of cold dichloromethane, and the filtrate was washed with 2 liters of water. The organic phase was mixed with 2 liters of water, the pH was adjusted to 8 with 40 mL of aqueous ammonia solution (27%), and the aqueous phase was separated. The organic phase was concentrated under reduced pressure at 40°C using a rotary evaporator to obtain an oily substance (380.3 g). This oily substance was dissolved in 758 mL of ethanol under reflux, cooled to 40°C, seeded with the product, and further cooled to room temperature. The solid was filtered by suction, washed with 300 mL of ethanol, and dried in a vacuum drying cabinet at 25°C under a nitrogen stream. Yield: 167.8g (55.2% of the theoretical value). Enantiomer purity (HPLC method F): 87.9% ee. LC-MS (Method H);R t =1.31 minutes 437.2[M+H] + .

[0218] Example 5 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzonitrile [ka]

[0219] In a 2-liter flask, 155.6 g (1.167 mol) of aluminum chloride and 429.5 g (2.122 mol) of dodecyl mercaptan were stirred until dissolved (15 minutes). Within 30 minutes, 119.0 g (0.424 mol) of 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzonitrile (Example 2) in toluene (418 mL) was weighed in at 10°C to 20°C. It was washed with 42 mL of toluene, and the mixture was stirred overnight at 40°C. The resulting solid was filtered by suction, washed with 530 mL of dichloromethane, stirred with 800 mL of dichloromethane, and then filtered by suction. The wet product was dissolved in 835 mL of tetrahydrofuran, and 526 mL (2.33 mol) of saturated (360 g / L) potassium sodium tartrate solution was added while cooling. The two-layer mixture was filtered by suction, the solid was stirred with 1 liter of ethyl acetate, and then filtered by suction. The purified solid was suspended in 835 mL of tetrahydrofuran and stirred with 526 mL (2.33 mol) of saturated (360 g / L) potassium sodium tartrate solution for 30 minutes. The solid was filtered by suction from the product-containing filtrate and washed with 200 mL of tetrahydrofuran. The product-containing filtrates were combined, the organic phase was separated, and the mixture was concentrated. The residue was dissolved in 835 mL of dichloromethane, made alkaline with 31 mL of aqueous ammonia solution (27%), and washed three times with 309 mL of water each time. The combined organic phase was washed with 155 mL of dichloromethane, and the combined organic phase was concentrated to obtain an oily substance. Gross yield: 70.8g; 62.6% of the theoretical value. LC-MS (Method I);R t =1.20 minutes, 267.2[M+H] + .

[0220] Example 6 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]aminoethyl)benzonitrile [ka]

[0221] Method A: In a 2-liter flask, 68.99 g (0.26 mol) of 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzonitrile (Example 5) was dissolved in 690 mL of dichloromethane. While cooling, 68.43 g (0.44 mol) of tert-butyldimethylsilyl chloride and 26.5 g (0.39 mol) of imidazole were added at 23°C to 33°C, and the mixture was stirred at room temperature for 16 hours. Then, an aqueous solution of 60.85 g of potassium carbonate (420 mL of water) was added, and the organic phase was washed three times with 350 mL of water each time. The combined organic phase was then washed with 80 mL of dichloromethane, the combined organic phase was dehydrated with sodium sulfate, and the mixture was concentrated in a rotary evaporator at 35°C to obtain 116.5 g of crude product. Gross yield: 116.5g; 118% of the theoretical value. LC-MS (Method J);R t =2.21 minutes, 381.3[M+H] + ,382.2.

[0222] Method B; To a solution of cyanophenethyl silate (10 g, 33.2 mmol, 1.0 equivalent) in THF (130 mL), 2-(2-aminoethyl)phenol (9.1 g, 66.4 mmol, 2.0 equivalent) and triethylamine (13.8 mL, 99.5 mmol, 3.0 equivalent) were added at a temperature of 25-35°C. The reaction mixture was then heated under reflux for 46 hours. Subsequently, the THF was removed under reduced pressure at a temperature below 60°C, and the remaining crude product was mixed with DCM (50 mL). Next, the solution was washed with saturated sodium bicarbonate solution (twice with 50 mL), and the organic phase was concentrated at a temperature below 45°C.

[0223] To this DCM solution (40 mL), imidazole (6.8 g, 99.5 mmol, 3.0 equivalents) was added, followed by the addition of tert-butyl-dimethylsilyl chloride (14.0 g, 92.9 mmol, 2.8 equivalents) in small amounts. The reaction mixture was then stirred at 25-35°C for 2 hours. After the reaction was complete, the reaction mixture was washed with water (twice with 100 mL). The solvent was changed to methanol (100 mL) by distillation under reduced pressure, and the mixture was heated to 65°C. Then, oxalic acid (4.5 g, 49.7 mmol, 1.5 equivalents) was added, and the mixture was stirred at 50-55°C for 1-2 hours. The reaction mixture was gradually cooled to 5-10°C and stirred for another 1-2 hours. Next, the solid was filtered and washed with methanol (twice with 20 mL). Subsequently, the filter residue was suspended in DCM / water (137 mL each) and stirred at 25-35°C for several hours. Then, 45% NaOH (4.5 mL) was added to adjust the pH to 10.5-12.5. After 1 hour, an additional 70 mL of water was added and the phase was separated. The organic phase was concentrated under reduced pressure. The resulting residue corresponds to the target substance (6.78 g, 37%). Yield: 6.78g; 37% of the theoretical value. Purity (Area): 91.3% (Method N, R t 11 minutes).

[0224] Example 7 (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile [ka]

[0225] In a 1-liter flask, a solution of 15.0 g (86.1 mmol) of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 3) in 250 mL of dichloromethane and 36.2 mL (0.26 mol) of diisopropylamine was cooled under argon to -76°C. Within 30 minutes, 24.6 mL (0.15 mol) of trifluoromethanesulfonic anhydride was weighed in at -74°C to -68°C, and the mixture was stirred for 30 minutes. Then, within 46 minutes, a solution of 49.2 g (0.13 mol) of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzonitrile (Example 6) in 100 mL of dichloromethane was weighed in at -75°C to -72°C, washed with 20 mL of dichloromethane, and the mixture was stirred for 2 hours. 9.93 g (86.1 mmol) of 85% phosphoric acid was added to the reaction mixture, and the reaction mixture was washed twice with 500 mL of water each time at room temperature. The combined aqueous phase was washed with 300 mL of dichloromethane, and the combined organic phase was concentrated in a rotary evaporator under reduced pressure at 40°C to obtain an oily substance (96.6 g).

[0226] The oily substance was dissolved in 50 mL of dichloromethane, filtered through 150 g of silica gel, and the product was eluted with 800 mL of ethyl acetate / n-hexane in a 1:2 ratio. The resulting solution was concentrated under reduced pressure at 40°C using a rotary evaporator to obtain the oily substance (79.3 g).

[0227] The product was dissolved in 50 mL of dichloromethane, filtered through 150 g of silica gel, and eluted with 750 mL of ethyl acetate / n-hexane in a 1:2 ratio. The eluate was concentrated at 35°C using a rotary evaporator to obtain 48.2 g of crude product. Gross yield: 48.2g; 104% of the theoretical value. LC-MS (Method K);R t =3.70 minutes 537.2[M+H] + .

[0228] Example 8 (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile [ka]

[0229] In a 1-liter flask, 48.2 g (less than 86.1 mmol) of (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 7) was suspended in 550 mL of methanol, and 101.8 g of concentrated hydrochloric acid was added. The solution was stirred overnight at room temperature. 150.9 g of 30% ammonia solution was added while cooling, and the mixture was concentrated at 40°C using a rotary evaporator. The solid residue was stirred at room temperature for 30 minutes in 480 mL of demineralized water and 250 mL of dichloromethane, the organic lower layer was washed with 450 mL of water, and the mixture was concentrated at 35°C using a rotary evaporator to obtain 27.9 g. Yield: 27.9g; 76.8% of the theoretical value. Enantiomeric purity (HPLC method A): 91.4% ee.

[0230] The residue was heated under reflux in 100 mL of methanol / 10 mL of demineralized water, the suspension was cooled to room temperature, and stirred for 2 hours. The solid was filtered by suction, washed with 15 mL of methanol, and dried in a vacuum drying cabinet at 50°C. Yield: 12.96g; 35.6% of the theoretical value. Enantiomeric purity (HPLC method A): 98.6% ee.

[0231] Example 9 (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid [ka]

[0232] Method A: In a 25 mL flask, 1.0 g (2.4 mmol) of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 8) was suspended in 5.79 g of concentrated hydrochloric acid and stirred at 100°C for 24 hours. The reaction solution was used directly in the next reaction step (Example 10).

[0233] Method B: In a 6-liter flask equipped with a gas scrubber (contents: 600 g ethanolamine, 1200 g 5% sodium hydroxide solution, 1200 g isopropanol, and approximately 0.5 g bromothymol blue), 332.5 g (0.76 mol) of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 4) in 3210 g (2.15 mL) of 48% hydrobromic acid was heated to 108°C and stirred for 24 hours. The solution was cooled to 25°C and washed twice with 650 mL of dichloromethane each time. The aqueous product phase at the bottom was used in the next step (Example 10). The sample was purified for analytical purposes. LC-MS (Method H);R t =0.73 minutes, 461.2[M+H] + .

[0234] Example 10 Butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate [ka]

[0235] Method A; In a 6-liter flask, 1.5 liters of n-butanol were added to the aqueous product phase ((5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (Example 9). The solution was heated to a boiling point, and the butanol / water mixture was removed by distillation while continuously adding 6 liters of butanol until a top temperature of 117°C was obtained. The mixture was cooled to room temperature, the precipitated salt was filtered by suction, and the filter cake was washed with 600 mL of butanol. The combined filtrate was concentrated in a rotary evaporator under reduced pressure at 65°C to obtain 521.7 g. The residue was stirred with 2.2 liters of ethyl acetate and 1.1 liters of 14% aqueous ammonia for 30 minutes to separate the organic phase, washed twice with 1 liter of water each time, and concentrated in a rotary evaporator under reduced pressure at 40°C to obtain 409.6 g of oily substance.

[0236] The oily substance was dissolved in 500 mL of dichloromethane and filtered through a filter lined with 1 kg of silica gel, followed by 8 liters of additional dichloromethane and then 2 liters of methanol. The product solution was concentrated using a rotary evaporator to obtain 337.8 g of oily substance. Yield: 337.8g; 77.6% of the theoretical value. LC-MS (Method H);R t =1.34 minutes, 573.3[M+H] + .

[0237] The sample was purified for analytical purposes. 1H-NMR, (400 MHz, CDCl3): δ= 0.88 1.06 (m, 6H), 1.36 - 1.53 (m, 4H), 1.65 - 1.91 (m, 6H), 2.05 - 2.31 (m, 2H), 2.63 - 3.31 (m, 10H), 4.19 - 4.34 (m, 2H), 4.34 - 4.48 (m, 3H), 6.69 - 6.83 (m, 1H), 6.88 - 6.96 (m, 2H), 7.08 - 7.21 (m, 3H), 7.71 - 7.85 (m, 1H), 7.85 - 7.97 (m, 2H), 8.00 - 8.15 (m, 1H), 10.40 - 10.59 (br. s, 1H)ppm.

[0238] Method B In an inactivated 2-liter reactor, (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 3) (40 g, 1.0 equivalent) was first added to dichloromethane (850 mL). Diisopropylamine (3.0 equivalents, 69.6 g) was added, and the solution was cooled to T out = -90°C. int At -77 to -67°C, a solution of trifluoromethanesulfonic anhydride (1.5 equivalents, 60 mL) and dichloromethane (150 mL) was weighed in within approximately one hour. The mixture was then stirred for a further 45 minutes. Next, T int At -78 to -70°C, a solution of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzonitrile (Example 6) (1.05 equivalents, 70 g) and dichloromethane (200 mL) was weighed in within approximately 30 minutes. This was then stirred for a further 1.5 hours. Next, the mixture was heated and heated within 1 hour. int The temperature was set to 20°C. First, 3.6% hydrochloric acid (610 mL) was added to the second 2-liter reactor. The reaction mixture was added and the mixture was stirred for 5 minutes. The phase was stabilized, and the aqueous phase was separated (discarded). The organic phase was subjected to standard pressure and T out The mixture was concentrated to the limit of what could be stirred at 60°C. 25% hydrochloric acid was added, and the mixture was heated to standard pressure and T outIt was distilled until dry at 85°C. Then it was heated under reflux (T int =103℃, T out The mixture was stirred at 125°C for a further 5 hours. Next, the mixture was cooled to T int The temperature was raised to 40°C and stirred for another 14 hours. The resulting suspension was then filtered, and n-butanol (800 mL) was added to the filtrate. int The mixture was concentrated until an internal temperature of 88°C was achieved. 800 mL of n-butanol was added again, and the mixture was concentrated under the same conditions. int The temperature was set to 90°C. 800 mL of n-butanol was added again, and the mixture was concentrated under the same conditions. int The temperature was set to 102°C. Finally, n-butanol (800 mL) was added again, and the mixture was concentrated under the same conditions until it reached the limit of stirring. The solution was cooled to T int The temperature was set to 22°C. Ethyl acetate (800 mL), demineralized water (400 mL), and potassium carbonate (44 g) were added, and the mixture was stirred for a further 10 minutes. The phase was stabilized, and the aqueous phase was separated (discarded). Demineralized water (385 mL) and sodium chloride (43 kg) were added to the organic phase, and the mixture was stirred for 10 minutes. The phase was stabilized, and the aqueous phase was separated (discarded). Demineralized water (200 mL) was added to the organic phase, and the mixture was stirred for 10 minutes. The phase was stabilized, and the aqueous phase was separated (discarded). The organic phase was subjected to a pressure of 120 mbar and T out The solution was concentrated at 45-55°C until it reached the limit of agitation. The solution was then cooled to T int The temperature is set to 22°C and then distributed. Yield: 68.3 kg of solution with a content of 23.1% and 52%. Purity (area): 66.6% (method N, R t ;11 minutes).

[0239] Example 11 Butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate [ka]

[0240] 337 g (0.56 mol) of butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 10) was dissolved in acetonitrile (3765 g) in a 6 liter flask. 197.2 g (0.56 mol) of 4-(bromomethyl)-3-chloro-4′-(trifluoromethyl)[biphenyl] was added at room temperature. 551.3 g (1.70 mol) of cesium carbonate was added to the solution, and the mixture was stirred for 21 hours until the conversion was complete. The salt was then filtered by suction, washed with 600 mL of acetonitrile, and the combined filtrate was concentrated in a rotary evaporator at 40°C to obtain 484.4 g of oil. Gross yield: 484.4g; 103% of the theoretical value. Enantiomeric purity (HPLC method B): 100.0% ee. LC-MS (Method L);R t =14.63 minutes, 841.36[M+H] + .

Claims

1. Compound of the following formula (XII): 【Chemistry 1】 A method for manufacturing, Compound of the following formula (X): 【Chemistry 2】 The compound of the following formula (XI) is obtained in the presence of an alkali metal carbonate, alkali metal hydroxide, or tetraalkylammonium carbonate: 【Transformation 3】 A method characterized by reacting with [a certain substance].

2. A method for producing the compound of formula (XII) according to claim 1, wherein the alkali metal carbonate is cesium carbonate.

3. Butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of the following formula (XII): 【Chemistry 4】 Alternatively, a salt, solvate, or solvate of the salt of the compound.

4. Compound of formula (X) 【Transformation 5】 A method for producing the compound of the following formula (IX): 【Transformation 6】 A method characterized by reacting with butanol in the presence of a mineral acid.

5. Compound of formula (X) 【Transformation 7】 A method for producing the compound of the following formula (III), wherein in the first step, at a temperature of -90°C to -50°C, in the presence of a base selected from a list consisting of a sterically hindered secondary amine and a 2,6-disubstituted pyridine, the compound of the following formula (III): 【Transformation 8】 Then, trifluoromethanesulfonic anhydride is added, and in the second step, the compound of the following formula (XIV-1): 【Chemistry 9】 [In the formula, R ２ is a silyl protecting group. It is reacted with at a temperature of -90°C to -50°C. A method characterized by reacting the reaction product with hydrochloric acid in the third step, and reacting the reaction product with butanol in the presence of a mineral acid in the fourth step.

6. Butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of the following formula (X) 【Chemistry 10】 Alternatively, a salt, solvate, or solvate of the salt of the compound.

7. Compound of formula (IX) 【Chemistry 11】 A method for producing the compound of the following formula (XVI): 【Chemistry 12】 A method characterized by reacting with a mineral acid.

8. (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of the following formula (IX): 【Chemistry 13】 Alternatively, a salt, solvate, or solvate of the salt of the compound.

9. Compound of formula (XVI) 【Chemistry 14】 A method for producing the compound of the following formula (XV-1): 【Chemistry 15】 [In the formula, R ２ [is a silyl protecting group.] A method characterized by reacting with a mineral acid.

10. (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile of the following formula (XVI): 【Chemistry 16】 Alternatively, a salt, solvate, or solvate of the salt of the compound.

11. Compound of formula (XV-1) 【Chemistry 17】 [In the formula, R ２ This is a silyl protecting group. A method for producing the compound of the following formula (III), wherein in the first step, at a temperature of -90°C to -50°C, in the presence of a base selected from a list consisting of a sterically hindered secondary amine and a 2,6-disubstituted pyridine, the compound of the following formula (III): [Chemistry 18] Then, trifluoromethanesulfonic anhydride is added, and in the second step, the compound of the following formula (XVI-1): 【Chemistry 19】 [In the formula, R ２ A method characterized by reacting with a silyl protecting group.

12. Compound of formula (XIV-1) 【Chemistry 20】 [In the formula, R ２ This is a silyl protecting group. A method for producing the following, in the first step, compounds of the following formulas (XVII) and (V): 【Chemistry 21】 A method characterized by coupling in the presence of an amine base, and then, in a second step, reacting the reaction product with a suitable silyl chloride, similarly in the presence of an amine base.

13. A method for producing a compound of formula (III), wherein the compound of formula (II) is as follows: 【Chemistry 22】 This is reacted with a tertiary amine base, ruthenium-p-cymene-R,R-TsDPEN, and formic acid to form compound (III): 【Chemistry 23】 A method characterized by obtaining

14. (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile of the following formula (III): 【Chemistry 24】 Alternatively, a salt, solvate, or solvate of the salt of the compound.

15. Compound of formula (V) 【Chemistry 25】 A method for producing the compound of the following formula (IV): 【Chemistry 26】 A method characterized by reacting with potassium hydroxide and 4-toluenesulfonyl chloride in an inert solvent.

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